Section 1: Basic Considerations in Infectious Diseases

HISTORICAL PERSPECTIVE

The origins of the field of infectious diseases are humble. The notion that communicable diseases were due to a miasma (“bad air”) can be traced back to at least the mid-sixteenth century. Not until the work of Louis Pasteur and Robert Koch in the late nineteenth century was there credible evidence supporting the germ theory of disease—i.e., that microorganisms are the direct cause of infections. In contrast to this relatively slow start, the twentieth century saw remarkable advances in the field of infectious diseases, and the etiologic agents of numerous infectious diseases were soon identified. Furthermore, the discovery of antibiotics and the advent of vaccines against some of the most deadly and debilitating infections greatly altered the landscape of human health. Indeed, the twentieth century saw the elimination of smallpox, one of the great scourges in the history of humanity. These remarkable successes prompted Sir Frank MacFarlane Burnet, a noted immunologist and Nobel laureate, to write in a 1962 publication entitled Natural History of Infectious Diseases: “In many ways one can think of the middle of the twentieth century as the end of one of the most important social revolutions in history, the virtual elimination of infectious disease.” Professor Burnet was not alone in this view. Robert Petersdorf, a renowned infectious disease expert and former editor of this textbook, wrote in 1978 that “even with my great personal loyalties to infectious diseases, I cannot conceive a need for 309 more [graduating trainees in infectious diseases] unless they spend their time culturing each other.” Given the enormous growth of interest in the microbiome in the past 10 years, Dr. Petersdorf’s statement might have been ironically clairvoyant, although he could have had no idea what was in store for humanity, with an onslaught of new, emerging, and re-emerging infectious diseases.

Clearly, even with all the advances of the twentieth century, infectious diseases continue to represent a formidable challenge for patients and physicians alike. Furthermore, during the latter half of the century, several chronic diseases were demonstrated to be directly or indirectly caused by infectious microbes; perhaps the most notable examples are the associations of Helicobacter pylori with peptic ulcer disease and gastric carcinoma, human papillomavirus with cervical cancer, and hepatitis B and C viruses with liver cancer. In fact, ~16% of all malignancies are now known to be associated with an infectious cause. In addition, numerous emerging and re-emerging infectious diseases continue to have a dire impact on global health: HIV/AIDS, pandemic influenza, Ebola, and Zika are but a few examples. The fear of weaponizing pathogens for bioterrorism is ever present and poses a potentially enormous threat to public health. Moreover, escalating antimicrobial resistance in clinically relevant microbes (e.g., Mycobacterium tuberculosis, Staphylococcus aureus, Streptococcus pneumoniae, Plasmodium species, and HIV) signifies that the administration of antimicrobial agents—once thought to be a panacea—requires appropriate stewardship. For all these reasons, infectious diseases continue to exert grim effects on individual patients as well as on international public health. Even with all the successes of the past century, physicians must be as thoughtful about infectious diseases now as they were at the beginning of the twentieth century.

GLOBAL CONSIDERATIONS

Infectious diseases remain the second leading cause of death worldwide. Although the rate of infectious disease–related deaths has decreased dramatically over the past 25 years, there were still 10.9 million such deaths in 2013 (Fig. 115-1A). These deaths disproportionately affect children <1 year of age, adults older than 70 years, and persons living in low- and middle-income countries (Fig. 115-1B and 115-1C; Chap. 462); in 2013, 20% of all deaths worldwide were related to infectious diseases, with rates >50% in most sub-Saharan African countries.

Given that infectious diseases are still a major cause of global mortality, understanding the local epidemiology of disease is critically important in evaluating patients. Diseases such as HIV/AIDS have decimated sub-Saharan Africa, with HIV-infected adults representing 19–29% of the total population in countries like South Africa, Botswana, and Swaziland. Moreover, drug-resistant tuberculosis is rampant throughout the former Soviet-bloc countries, India, China, and South Africa. The ready availability of this type of information allows physicians to develop appropriate differential diagnoses and treatment plans for individual patients. Programs such as the Global Burden of Disease seek to quantify human losses (e.g., deaths, disability-adjusted life years) due to diseases by age, sex, and country over time; these data not only help inform local, national, and international health policy but can also help guide local medical decision-making.

Even though some diseases (e.g., pandemic influenza, Middle East respiratory syndrome) are seemingly geographically restricted, the increasing ease of rapid worldwide travel has raised concern about their swift spread around the globe. Indeed, human migration has historically been the source of epidemics: Yersinia pestis spread along trade routes in the fourteenth century, Native American populations were devastated by diseases such as smallpox and measles that were imported by European explorers in the fifteenth and sixteenth centuries, military maneuvers helped facilitate the spread of the 1918 influenza pandemic, and religious pilgrimages (e.g., the Hajj) provide the means for worldwide dissemination of diseases. The introduction of cholera into Haiti, the transmission of Ebola within the United States, and the emerging outbreak of Zika virus infection are recent examples that highlight the continued effects of global travel on the spread of infectious diseases. Not only can travelers carry person-to-person transmitted infections (e.g., influenza, HIV) anywhere in the world, but they can also introduce vector-borne infections to new geographic areas (e.g., chikungunya and Zika viruses) and contribute to the worldwide spread of multidrug-resistant organisms. The world’s increasing interconnectedness has profound implications not only for the global economy but also for medicine and the spread of infectious diseases.

UNDERSTANDING THE MICROBIOTA

Normal, healthy humans are colonized with ~50 trillion bacteria as well as countless viruses, fungi, and archaea; taken together, these microorganisms outnumber human cells by ~10 times in the human body (Chap. 459). The major reservoir of these microbes is the gastrointestinal tract, but substantial numbers of microbes live in the female genital tract, the oral cavity, and the nasopharynx. There is increasing interest in the skin and lungs as sites where microbial colonization might be highly relevant to the biology and disease susceptibility of the host. These commensal organisms provide the host with myriad benefits, from aiding in metabolism to shaping the immune system. With regard to infectious diseases, the vast majority of infections are caused by organisms that are part of the normal microbiota (e.g., S. aureus, S. pneumoniae, Pseudomonas aeruginosa), with relatively few infections due to organisms that are strictly pathogens (e.g., Neisseria gonorrhoeae, rabies virus). Perhaps it is not surprising that a general understanding of the microbiota is essential in the evaluation of infectious diseases. Individuals’ microbiotas likely have a major impact on their susceptibility to infectious diseases and even their responses to vaccines. Site-specific knowledge of the indigenous microbiota may facilitate appropriate interpretation of culture results, aid in selection of empirical antimicrobial therapy based on the likely causative agents, and provide additional impetus for rational antibiotic use to minimize the untoward effects of these drugs on the “beneficial” microbes that inhabit the body.

WHEN TO CONSIDER AN INFECTIOUS ETIOLOGY

The title of this chapter may appear to presuppose that the physician knows when a patient has an infectious disease. In reality, this chapter can serve only as a guide to the evaluation of a patient in whom an infectious disease is a possibility. Once a specific diagnosis is made, the reader should consult the subsequent chapters that deal with specific microorganisms in detail. The challenge for the physician is to recognize which patients may have an infectious disease as opposed to some other underlying disorder. This task is greatly complicated by the fact that infections have an infinite range of presentations, from acute life-threatening conditions (e.g., meningococcemia) to chronic diseases of varying severity (e.g., H. pylori–associated peptic ulcer disease) to no symptoms at all (e.g., latent M. tuberculosis infection). While it is impossible to generalize about a presentation that encompasses all infections, common findings in the history, physical examination, and basic laboratory testing often suggest that the patient either has an infectious disease or should be more closely evaluated for one. This chapter focuses on these common findings and how they may direct the ongoing evaluation of the patient.

APPROACH TO THE PATIENT

PERSPECTIVE

The study of infectious diseases is really a study of host–bacterial interactions and represents evolution by both the host and the bacteria—an endless struggle in which microbes have generally been more creative and adaptive. Given that one-fifth of deaths worldwide are still related to infectious diseases, it is clear that the war against infectious diseases has not been won. For example, a cure for HIV infection is still lacking, there have been only marginal improvements in the methods for detection and treatment of tuberculosis after more than a half century of research, new infectious disease outbreaks (e.g., pandemic influenza, viral hemorrhagic fevers, Zika) continue to emerge, and the threat of microbial bioterrorism remains high. The subsequent chapters in Part 5 detail—on both a syndrome and a microbe-by-microbe basis—the current state of medical knowledge about infectious diseases. At their core, all of these chapters carry a similar message: Despite numerous advances in the diagnosis, treatment, and prevention of infectious diseases, much work and research are required before anyone can confidently claim we have achieved “the virtual elimination of infectious disease.” In reality, this goal will never be attained, given the rapid adaptability of microbes.

FURTHER READING

INTRODUCTION

Over the past five decades, molecular studies of the pathogenesis of microorganisms have yielded a torrent of information about the various microbial and host molecules that contribute to the processes of infection and disease. These processes can be classified into several stages: microbial encounter with and entry into the host; microbial growth after entry; avoidance of innate host defenses; tissue invasion and tropism; tissue damage; and transmission to new hosts. Virulence is the measure of an organism’s capacity to cause disease and is a function of the pathogenic factors elaborated by microbes. These factors promote colonization (the simple presence of potentially pathogenic microbes in or on a host), infection (attachment and growth of pathogens and avoidance of host defenses), and disease (often, but not always, the result of activities of secreted toxins or toxic metabolites). In addition, the host’s inflammatory response to infection greatly contributes to disease and its attendant clinical signs and symptoms. A recent explosion of interest in the microbiome (the collection of microbial genomes present in or on mammalian organisms) and the microbiota (the collection of microbes residing in and on mammalian organisms) and their impact on physiology of, susceptibility to, and response to infection and on immune system development has greatly expanded our understanding of host–pathogen interactions. Furthermore, investigations in this field have documented effects of the microbiome on all aspects of animal—and even plant—physiology, greatly increasing our knowledge of the everyday influence of host–microbe interactions on life.

MICROBIAL ENTRY AND ADHERENCE

The Microbiome

We now know that the indigenous microbial organisms living in close association with almost all animals and plants are organized into complex communities that strongly modulate overall host physiology, including the ability of pathogenic microbes to establish themselves in or on host surfaces. The sheer numbers of these microbes and their genomic variability often exceed the numbers of host cells and the variability of host genes in a typical animal. Changes and differences in microbiomes within and between individuals, currently characterized by high-throughput DNA sequencing techniques and bioinformatic analysis, impact such diverse conditions as obesity; type 1 diabetes; cognition; neurologic states; autoimmune diseases; skin, gastrointestinal, respiratory, and vaginal infectious diseases; and development and control of the immune system. It has been difficult to directly associate specific types of microbiomes with pathophysiologic states, and our understanding of the degree to which microbial species are conserved or variable within human and other animal microbiotas is evolving. Experimental studies in laboratory animals, particularly in germ-free mammals, show the potent ability of changes in the microbiota to manipulate health status and outcomes. One of the clearest functions of the microbiota is to influence and mature the cells of the immune system, thereby exerting a major effect on susceptibility and resistance to microbial infection. The degree to which studies of the microbiome will translate into strategies for the management of human health and disease (e.g., the use of fecal transplants to treat and prevent recurrences of serious Clostridium difficile infection) is still an open question. For the moment, defining clusters of organisms associated with diseases may be more feasible than identifying single organisms or microbial molecules. Results from the Human Microbiome Project suggest a high level of variability among individuals in microbiome components, although many individuals appear to maintain a fairly conserved microbiome throughout their lives. In the context of infectious diseases, changes and disruptions of the indigenous microbiome—i.e., alterations of the normal flora due to antibiotic and immunosuppressive drug use, environmental changes, and the effects of microbial virulence factors used to displace the indigenous microbial flora and thus to facilitate pathogen colonization—have a strong and often fundamental impact on the progression of infection. While the technology for defining and understanding the microbiome is still quite young, there is little doubt that the resulting data will markedly affect our concepts of and approaches to microbial pathogenesis and infectious disease treatment.

Entry Sites

A microbial pathogen can potentially enter any part of a host organism. In general, the type of disease produced by a particular microbe is often a direct consequence of its route of entry into the body. The most common sites of entry are mucosal surfaces (the respiratory, alimentary, and urogenital tracts) and the skin. Ingestion, inhalation, and sexual contact are typical routes of microbial entry. Other portals of entry include sites of skin injury (cuts, bites, burns, trauma) along with injection via natural (e.g., vector-borne) or artificial (e.g., needlestick injury) routes. A few pathogens, such as Schistosoma species, can penetrate unbroken skin. The conjunctiva can serve as an entry point for pathogens of the eye, which occasionally spread systemically from that site.

Microbial entry usually relies on the presence of specific factors needed for persistence and growth in a tissue. Fecal–oral spread via the alimentary tract requires a biologic profile consistent with survival in the varied environments of the gastrointestinal tract (including the low pH of the stomach and the high bile content of the intestine) as well as in contaminated food or water outside the host. Organisms that gain entry via the respiratory tract survive well in small moist droplets produced during sneezing and coughing. Pathogens that enter by venereal routes often survive best in the warm moist environment of the urogenital mucosa and have restricted host ranges (e.g., Neisseria gonorrhoeae, Treponema pallidum, and HIV).

The biology of microbes entering through the skin is highly varied. Some of these organisms can survive under a broad range of environmental conditions, such as those in the salivary glands or alimentary tracts of arthropod vectors, the mouths of larger animals, soil, and water. A complex biology allows protozoan parasites such as Plasmodium, Leishmania, and Trypanosoma species to undergo morphogenic changes that permit transmission of the organism to mammalian hosts during insect feeding for blood meals. Plasmodia are injected as infective sporozoites from the salivary glands during mosquito feeding. Leishmania parasites are regurgitated as promastigotes from the alimentary tract of sandflies and injected by bite into a susceptible host. Trypanosomes are first ingested from infected hosts by reduviid bugs; the pathogens then multiply in the gastrointestinal tract of the insects and are released in feces onto the host’s skin during subsequent feedings. Most microbes that land directly on intact skin are destined to die, as survival on the skin or in hair follicles requires resistance to fatty acids, low pH, and other antimicrobial factors on the skin. Once it is damaged (and particularly if it becomes necrotic), the skin can be a major portal of entry and growth for pathogens and elaboration of their toxic products. Burn wound infections and tetanus are clear examples. After animal bites, pathogens resident in the animal’s saliva gain access to the victim’s tissues through the damaged skin. Rabies is the paradigm for this pathogenic process; rabies virus grows in striated muscle cells at the site of inoculation.

Microbial Adherence

Once in or on a host, many microbes must situate themselves favorably to avoid clearance mechanisms, in part by microbial anchoring to a tissue or tissue factor. (One possible exception is an organism that directly enters the bloodstream and multiplies there.) Because most host cells—responding to activation of innate immunity (see “Avoidance of Innate Host Defenses,” below)—express multiple surface and cytoplasmic molecules that detect pathogens and pathogen factors, a complex interplay ensues and determines whether the microbe will avoid host clearance and remain in a tissue. Viruses and intracellular pathogens like Mycobacterium tuberculosis must bind to cells and enter them, whereas common extracellular bacterial pathogens of the human respiratory tract survive better if they avoid binding to pulmonary epithelial cells.

Specific ligands or adhesins for host receptors constitute a major area of study in microbial pathogenesis. Adhesins comprise a wide range of surface structures, anchoring the microbe to a tissue and promoting cellular entry as well as eliciting host responses critical to innate immunity (Table 116-1). Most microbes produce multiple adhesins specific for multiple host receptors that often are redundant, are serologically variable, and act additively or synergistically with other microbial factors to promote sticking to host tissues. In addition, some microbes adsorb host proteins onto their surface and use the natural host protein receptor for binding and entry into cells. While it is clear that, for some pathogenic organisms, blocking adherence can be a means to prevent infection, for others it could have unintended consequences, decreasing the innate host response that facilitates elimination of the infecting microbe.

Viral Adhesins

All viral pathogens must bind to host cells, enter them, and replicate within them. Viral coat proteins serve as ligands for cellular entry, and more than one ligand–receptor interaction may be needed. In some types of viruses, such as lipid bilayer–encapsulated Retroviridae or Rhabdoviridae, a single protein mediates both viral binding and entry via fusion with the host cell membrane. In other cases, a second viral fusion protein is needed to complete viral entry. HIV uses its envelope glycoprotein (gp) 120 to enter host cells by binding to both CD4 and one of two receptors for chemokines (CCR5 or CXCR4). Measles virus requires two proteins for cellular entry: the hemagglutinin (H) glycoprotein of wild-type measles virus binds to the signaling lymphocytic activation molecule (SLAM or CD150) on macrophages and dendritic cells, where the virus initially replicates, and also to nectin-4 on respiratory epithelial cells, where later replication occurs. The vaccine strain of measles virus binds to both CD46 and SLAM. For full cellular entry, however, measles virus requires a second fusion (F) protein. The gB and gC proteins on herpes simplex virus bind to heparan sulfate, although this adherence is not essential for entry but rather serves to concentrate virions close to the cell surface; this step is followed by attachment to mammalian cells mediated by the viral gD protein, with subsequent formation of a homotrimer of viral gB protein or a heterodimer of viral gH and gL proteins that permits fusion of the viral envelope with the host cell membrane. Herpes simplex virus can use a number of eukaryotic cell-surface receptors for entry, including the herpesvirus entry mediator, members of the immunoglobulin superfamily, the proteins nectin-1 and nectin-2, and modified heparan sulfate.

Bacterial Adhesins

Among the adhesins studied in greatest detail are bacterial pili and flagella (Fig. 116-1). Pili or fimbriae are commonly used by gram-negative bacteria for attachment to host cells and tissues; similar factors are produced by gram-positive organisms such as group B streptococci. In electron micrographs, these hairlike projections (up to several hundred per cell) may be confined to one end of the organism (polar pili) or distributed more evenly over the surface. An individual cell may have pili with a variety of functions. Most pili are made up of a major pilin protein subunit (17,000–30,000 Da) that polymerizes to form the pilus. Many strains of Escherichia coli isolated from urinary tract infections express a mannose-binding type 1 pilus that attaches to the uroplakins coating the cells in the bladder epithelium. Other strains produce the Pap (pyelonephritis-associated) or P pilus adhesin that mediates binding to digalactose (gal-gal) residues on globosides of the human P blood groups. Both of these pili have proteins located at the tips of the main pilus unit that are critical to the binding specificity of the whole pilus unit. E. coli cells causing diarrheal disease express pilus-like receptors for enterocytes on the small bowel, along with other receptors termed colonization factors.

The type IV pili found in Neisseria species, Moraxella species, Vibrio cholerae, Legionella pneumophila, Salmonella enterica serovar Typhi, enteropathogenic E. coli, and Pseudomonas aeruginosa often mediate adherence of organisms to target surfaces. Type IV pili tend to have a relatively conserved amino-terminal region and a more variable carboxyl-terminal region. For some species (e.g., N. gonorrhoeae, Neisseria meningitidis, and enteropathogenic E. coli), the pili are critical for attachment to mucosal epithelial cells. For others, such as P. aeruginosa, the pili may inhibit colonization; recent studies of P. aeruginosa colonization showed that, in a bank of mutants in which all nonessential genes were interrupted, those unable to produce type IVa pili were actually better able to colonize the gastrointestinal and lung mucosa of mice. V. cholerae cells appear to use two different types of pili for intestinal colonization. Whereas interference with this stage of colonization would appear to be an effective antibacterial strategy, attempts to develop pilus-based vaccines against human diseases have not been highly successful to date.

Flagella are long appendages attached at one or both ends of the bacterial cell (polar flagella) or distributed over the entire cell surface (peritrichous flagella). Flagella, like pili, are composed of a polymerized or aggregated basic protein. In flagella, the protein subunits form a tight helical structure and vary serologically with the species. Spirochetes such as T. pallidum and Borrelia burgdorferi have axial filaments similar to flagella running down the long axis of the center of the cell, and they “swim” by rotation around these filaments. Some bacteria can glide over a surface in the absence of obvious motility structures.

Other bacterial structures involved in adherence to host tissues include staphylococcal and streptococcal proteins that bind to human extracellular matrix proteins such as fibrin, fibronectin, fibrinogen, laminin, and collagen. Fibronectin is a commonly used receptor for various pathogens; a particular amino acid sequence in fibronectin, Arg-Gly-Asp or RGD, is a conserved target used by bacteria to bind to host tissues. Binding of the Staphylococcus aureus surface protein clumping factor A (ClfA) to fibrinogen has been implicated in many aspects of pathogenesis. The conserved outer-core portion of the lipopolysaccharide (LPS) of P. aeruginosa mediates binding to the cystic fibrosis transmembrane conductance regulator (CFTR) on airway epithelial cells—an event that appears to be critical for normal host resistance to infection, initiating recruitment of polymorphonuclear neutrophils (PMNs) to the lung mucosa to kill the cells via opsonophagocytosis. A large number of microbial pathogens encompassing major gram-positive bacteria (staphylococci and streptococci), gram-negative bacteria (major enteric species and coccobacilli), fungi (Candida, Fusobacterium, Aspergillus), and even eukaryotic pathogens (Trichomonas vaginalis and Plasmodium falciparum) express a surface polysaccharide composed of β-1-6-linked-poly-N-acetyl-d-glucosamine (PNAG). One of its functions is to promote binding to synthetic materials used in catheters and other types of implanted devices. This polysaccharide may be a critical factor in the establishment of device-related infections by pathogens such as staphylococci and E. coli. High-powered imaging techniques (e.g., atomic force microscopy) have revealed that bacterial cells have a nonhomogeneous surface that is probably attributable to different concentrations of cell surface molecules, including microbial adhesins, at specific locations (Fig. 116-1, panels C and D).

Fungal Adhesins

Fungi produce adhesins that mediate colonization of epithelial surfaces, adhering particularly to structures like fibronectin, laminin, and collagen. The Candida albicans INT1 protein bears similarity to mammalian integrins that bind to extracellular matrix proteins. The agglutinin-like sequence (ALS) adhesins are large cell-surface glycoproteins mediating adherence of pathogenic Candida to host tissues. These adhesins possess a conserved three-domain structure composed of an N-terminus that mediates adherence to host tissue receptors, a central motif consisting of a number of repeats of a conserved sequence of 36 amino acids, and a C-terminal domain that varies in length and sequence and contains a glycosylphosphatidylinositol (GPI) anchor addition that allows the adhesins to bind to the fungal cell wall. Variability in the number of central domains characterizes different ALS proteins with specificity for different host receptors. The ALS adhesins are expressed under certain environmental conditions and are crucial for pathogenesis of fungal infections.

For several respiratory fungal pathogens, the inoculum is ingested by alveolar macrophages in which the fungal cells transform to pathogenic phenotypes. Like C. albicans, Blastomyces dermatitidis produces a 120-kDa surface protein, designated WI-1, that binds to CD11b/CD18 integrins as well as to CD14 on macrophages. An unidentified factor on Histoplasma capsulatum also mediates binding to the integrin surface proteins.

Eukaryotic Pathogen Adhesins

Eukaryotic parasites use complicated surface glycoproteins as adhesins, some of which are lectins (proteins that bind to specific carbohydrates on host cells). Plasmodium vivax, one of six Plasmodium species causing malaria, binds (via Duffy-binding protein) to the Duffy blood group carbohydrate antigen Fy on erythrocytes. Entamoeba histolytica, the third leading cause of death from parasitic diseases, expresses two proteins that bind to the disaccharide galactose/N-acetyl galactosamine. Children with mucosal IgA antibody to one of these lectins are resistant to reinfection with virulent E. histolytica. A major surface glycoprotein (gp63) of Leishmania promastigotes is needed for these parasites to enter human macrophages—the principal target cell of infection. This glycoprotein promotes complement binding but inhibits complement lytic activity, allowing the parasite to use complement receptors for entry into macrophages; gp63 also binds to fibronectin receptors on macrophages. As part of hepatic granuloma formation, Schistosoma mansoni expresses a carbohydrate epitope related to the Lewis X blood group antigen that promotes adherence of helminthic eggs to vascular endothelial cells under inflammatory conditions.

Host Receptors

Host receptors are found both on target cells (such as epithelial cells lining mucosal surfaces) and within the mucus layer covering these cells. Microbial pathogens bind to a wide range of host receptors to establish infection (Table 116-1). Selective loss of host receptors for a pathogen may confer natural resistance to an otherwise susceptible population. For example, 70% of individuals in western Africa lack Fy antigens and are resistant to P. vivax infection. S. enterica serovar Typhi, the etiologic agent of typhoid fever, produces a pilus protein that binds to CFTR to enter the gastrointestinal submucosa after being ingested by enterocytes. As homozygous mutations in CFTR are the cause of the life-shortening disease cystic fibrosis, heterozygote carriers (e.g., 4–5% of individuals of European ancestry) may have had a selective advantage due to decreased susceptibility to typhoid fever.

Numerous virus–target cell interactions have been described, and it is now clear that different viruses can use similar host cell receptors for entry. The list of certain and likely host receptors for viral pathogens is long. Among the host membrane components that can serve as receptors for viruses are sialic acids, gangliosides, glycosaminoglycans, integrins and other members of the immunoglobulin superfamily, histocompatibility antigens, and regulators and receptors for complement components. An example of the effect of host receptors on the pathogenesis of infection has emerged from studies comparing the binding of avian influenza A virus subtype H5N1 with that of influenza A strains expressing the H1 hemagglutinin subtype. These subtypes are highly pathogenic and transmissible from human to human, and they bind to a receptor composed of two sugar molecules: sialic acid linked α-2-6 to galactose. This receptor is expressed at high levels in the human airway epithelium; when virus is shed from this surface, its transmission via coughing and aerosol droplets is facilitated. In contrast, the H5N1 avian influenza virus binds to sialic acid linked α-2-3 to galactose, and this receptor is expressed at high levels on cells in the terminal bronchioles, including type II pneumocytes, alveolar macrophages, and nonciliated cuboidal epithelial cells. Infection at these sites is thought to underlie the high mortality rate associated with avian influenza but also the low interhuman transmissibility of this strain, which is not readily transported to the airways from which it can be expelled by coughing. Nonetheless, it has been shown that H5 hemagglutinins can acquire mutations leading to binding to α-2-6-linked sialic acids that increase their human transmissibility but retain their high level of lethality.

MICROBIAL GROWTH AFTER ENTRY

Once established on a mucosal or skin site, pathogenic microbes must replicate before causing full-blown infection and disease. Within cells, viral particles release their nucleic acids, which may be directly translated into viral proteins (positive-strand RNA viruses), transcribed from a negative strand of RNA into a complementary mRNA (negative-strand RNA viruses), or transcribed into a complementary strand of DNA (retroviruses). For DNA viruses, mRNA may be transcribed directly from viral DNA, either in the cell nucleus or in the cytoplasm. To grow, bacteria must acquire specific nutrients or synthesize them from precursors in host tissues. Many infectious processes are most often found in specific sites—e.g., H1 influenza in the respiratory mucosa, gonorrhea in the urogenital epithelium, and shigellosis in the gastrointestinal epithelium. While there are multiple reasons for this specificity, one important consideration is the ability of these pathogens to obtain the nutrients needed for growth and survival.

Temperature restrictions also play a role in limiting certain pathogens to specific tissues. Rhinoviruses, a cause of the common cold, grow best at 33°C and replicate in cooler nasal tissues but not in the lung. Leprosy lesions due to Mycobacterium leprae are found in and on relatively cool body sites. Fungal pathogens that infect the skin, hair follicles, and nails (dermatophyte infections) remain confined to the cooler, exterior, keratinous layer of the epithelium.

A topic of major interest is the ability of many bacterial, fungal, and protozoal species to grow in multicellular masses referred to as biofilms. These masses are biochemically and morphologically quite distinct from the free-living individual cells referred to as planktonic cells. Growth in biofilms leads to altered microbial metabolism, production of extracellular virulence factors, and decreased susceptibility to biocides, antimicrobial agents, and host defense molecules and cells. P. aeruginosa growing on the bronchial mucosa during chronic infection, staphylococci and other pathogens growing on implanted medical devices, and dental pathogens growing on tooth surfaces to form plaques represent several examples of microbial biofilm growth associated with human disease. Many other pathogens can form biofilms during in vitro growth. This mode of growth contributes to microbial virulence and induction of disease and can also be an important factor in microbial survival outside the host, promoting transmission to additional susceptible individuals.

AVOIDANCE OF INNATE HOST DEFENSES

Microbes have interacted with mucosal/epithelial surfaces since the emergence of multicellular organisms. Thus it is not surprising that multicellular hosts have a variety of innate surface defense mechanisms that can sense when pathogens are present and contribute to their elimination. The skin is acidic and bathed with fatty acids toxic to many microbes. Skin pathogens such as staphylococci must tolerate these adverse conditions. Mucosal surfaces are covered by a barrier composed of a thick mucus layer that entraps microbes and facilitates their transport out of the body by mucociliary clearance, coughing, and urination. Mucous secretions, saliva, and tears contain antibacterial factors such as lysozyme and antimicrobial peptides as well as antiviral factors such as interferons (IFNs). Gastric acidity and bile salts are inimical to the survival of many ingested organisms, and most mucosal surfaces—particularly the nasopharynx, vaginal tract, and gastrointestinal tract—contain a resident flora of commensal microbes that interfere with the ability of pathogens to colonize and infect a host. Major advances in the use of nucleic acid sequencing now allow extensive identification and characterization of the vast array of commensal organisms that have come to be referred to as the microbiota. In addition to its role in providing competition for mucosal colonization, acquisition of a normal microbiota is critical for proper development of the immune system, impacting maturation and differentiation of components of both the innate and acquired immune systems.

Pathogens that survive local antimicrobial factors must still contend with host endocytic, phagocytic, and inflammatory responses as well as with host genetic factors that determine the degree to which a pathogen can survive and grow. The growth of viral pathogens entering skin or mucosal epithelial cells can be limited by a variety of host genetic factors, including production of IFNs, modulation of receptors for viral entry, and age- and hormone-related susceptibility factors; by nutritional status; and even by personal habits such as smoking and exercise. The list of genes whose variants can affect host susceptibility and resistance to infection is rapidly expanding. A classic example is a 32-bp deletion in the gene for the HIV-1 co-receptor known as chemokine receptor 5 (CCR5), which, when present in the homozygous state, confers high-level resistance to HIV-1 infection. A now-famous case is that of the “Berlin Patient,” a man infected with HIV who received a hematopoietic stem-cell transplant from a donor homozygous for the 32-bp CCR5 deletion to treat acute myeloid leukemia. The apparent sterilizing cure of this patient’s HIV infection is likely due to his having only HIV-resistant T cells after the stem cell transplantation.

Encounters with Epithelial Cells

Over the past two decades, many pathogens have been shown to enter epithelial cells (Fig. 116-2) by using specialized surface structures that bind to receptors, with consequent internalization. However, the exact role and the importance of this process in infection and disease are not well defined for most of these pathogens. Microbial entry into host epithelial cells is seen as a path for translocation to adjacent or deeper tissues or as a route to a sanctuary site to avoid killing by professional phagocytes. Epithelial cell entry is a critical aspect of dysentery induction by Shigella.

Curiously, less virulent strains of many bacterial pathogens are more adept at entering epithelial cells than are more virulent strains; examples include pathogens that lack the surface polysaccharide capsule needed to cause serious disease. Thus, for Haemophilus influenzae, Streptococcus pneumoniae, Streptococcus agalactiae (group B Streptococcus), N. meningitidis, and S. pyogenes, isogenic mutants or variants lacking capsules enter epithelial cells more easily than the wild-type, encapsulated parental forms that cause disseminated disease. These observations have led to the proposal that epithelial cell entry may be primarily a manifestation of host defense, resulting in bacterial clearance by both shedding of epithelial cells containing internalized bacteria and initiation of a protective and nonpathogenic inflammatory response. However, a possible consequence of this process could be the opening of a hole in the epithelium, potentially allowing uningested organisms to enter the submucosa. This scenario has been documented in murine S. enterica serovar Typhimurium infections and in experimental bladder infections caused by uropathogenic E. coli. In the latter system, bacterial pilus-mediated attachment to uroplakins induces exfoliation of the cells with attached bacteria. Subsequently, infection is produced by residual bacterial cells that invade the superficial bladder epithelium, where they can grow intracellularly into biofilm-like masses encased in an extracellular polysaccharide-rich matrix and surrounded by uroplakin. It is likely that at low bacterial inocula epithelial cell ingestion and subclinical inflammation are efficient means to eliminate pathogens, whereas at higher inocula a proportion of surviving bacterial cells enter host tissue through the damaged mucosal surface and multiply, producing disease. Alternatively, failure of the appropriate epithelial cell response to a pathogen may allow the organism to survive on a mucosal surface where, if it avoids other host defenses, it can grow and cause a local infection. Along these lines, as noted above, P. aeruginosa is taken into epithelial cells by CFTR, a protein missing or nonfunctional in most patients with severe cases of cystic fibrosis. The major clinical consequence of this disease is chronic airway-surface infection with P. aeruginosa in 80–90% of patients. The failure of airway epithelial cells to ingest and promote the removal of P. aeruginosa via a properly regulated inflammatory response has been proposed as a key component of the hypersusceptibility of these patients to chronic airway infection with this organism.

Encounters with Phagocytes

Phagocytosis and Inflammation

Phagocytosis of microbes is a major innate host defense that limits the growth and spread of pathogens. Phagocytes appear rapidly at sites of infection in conjunction with the initiation of inflammation. Ingestion of microbes by both tissue-fixed macrophages and migrating phagocytes probably accounts for the limited ability of most microbial agents to cause disease. A family of related molecules called collectins, soluble defense collagens, or pattern-recognition molecules are found in blood (mannose-binding lectins), lung (surfactant proteins A and D), and most likely other tissues and bind to carbohydrates on microbial surfaces to promote phagocyte clearance. Bacterial pathogens are ingested principally by PMNs, while eosinophils are frequently found at sites of infection by protozoan or multicellular parasites. Successful pathogens, by definition, must avoid being cleared by professional phagocytes. One of several antiphagocytic strategies employed by bacteria and by the fungal pathogen Cryptococcus neoformans is to elaborate large-molecular-weight surface polysaccharide antigens, often in the form of a capsule that coats the cell surface. Most pathogenic bacteria produce such antiphagocytic capsules. On occasion, proteins or polypeptides form capsule-like coatings for organisms such as group A streptococci and Bacillus anthracis.

An area of both intense interest and controversy is the role of the release of neutrophil extracellular traps (NETs) in protection against infection. NETs are composed of DNA and other intracellular components with antimicrobial properties, such as histones, myeloperoxidase, and elastase. NET release has been described as both a “suicidal” event, wherein, in response to stimuli, PMNs lyse and release NET components, and a “vital” event, wherein intracellular NET components are released but neutrophils remain viable and functional. Microbial particle size might regulate release of NETs, as has been reported for larger microbial structures like C. albicans hyphae or cellular aggregates. NET formation can also be pathologic as these networks are associated with damage to cells, thrombosis, inhibition of wound healing, and autoimmunity.

As activation of local phagocytes in tissues is a key step in initiating inflammation and migration of additional phagocytes into infected sites, much attention has been paid to microbial factors that initiate inflammation. These are usually conserved factors critical to the microbes’ survival and are referred to as pathogen-associated molecular patterns (PAMPs). Cellular responses to microbial encounters with phagocytes are governed largely by the structure of the microbial PAMPs that elicit inflammation, and detailed knowledge of these structures of bacterial pathogens has contributed greatly to our understanding of molecular mechanisms of microbial pathogenesis mediated by activation of host cell molecules such as Toll-like receptors (TLRs; Fig. 116-3). One of the best-studied systems involves the interaction of LPS from gram-negative bacteria with the GPI-anchored membrane protein CD14 found on the surface of professional phagocytes, including migrating and tissue-fixed macrophages and PMNs. A soluble form of CD14 is also found in plasma and on mucosal surfaces. A plasma protein, LPS-binding protein, transfers LPS to membrane-bound CD14 on myeloid cells and promotes binding of LPS to soluble CD14. Soluble CD14/LPS/LPS-binding protein complexes bind to many cell types and may be internalized to initiate cellular responses to microbial pathogens. It has been shown that peptidoglycan and lipoteichoic acid from gram-positive bacteria and cell surface products of mycobacteria and spirochetes can interact with CD14 (Fig. 116-3). Additional molecules, such as MD-2, also participate in the recognition of bacterial activators of inflammation.

GPI-anchored receptors do not have intracellular signaling domains; therefore, it is the TLRs that transduce signals for cellular activation due to LPS binding. Binding of microbial factors to TLRs to activate signal transduction occurs in the phagosome—and not on the surface—of dendritic cells that have internalized the microbe. This binding is probably due to the release of the microbial surface factor from the cell in the environment of the phagosome, where the liberated factor can bind to its cognate TLRs. TLRs initiate cellular activation through a series of signal-transducing molecules (Fig. 116-3) that lead to nuclear translocation of the transcription factor nuclear factor κB (NF-κB), a master-switch for production of important inflammatory cytokines such as tumor necrosis factor α (TNF-α) and interleukin 1 (IL-1).

The initiation of inflammation can also occur with viral particles and other microbial products such as polysaccharides, enzymes, and toxins. Bacterial flagella activate inflammation by binding of a conserved sequence to TLR5. Some pathogens (e.g., Campylobacter jejuni, Helicobacter pylori, and Bartonella bacilliformis) make flagella that lack this sequence and do not bind to TLR5; thus efficient host responses to infection are prevented. Bacteria also produce a high proportion of DNA molecules with unmethylated CpG residues that activate inflammation through TLR9. TLR3 recognizes double-strand RNA, a pattern-recognition molecule produced by many viruses during their replicative cycle. TLR1 and TLR6 associate with TLR2 to promote recognition of acylated microbial proteins and peptides.

The myeloid differentiation factor 88 (MyD88) molecule and the Toll/IL-1R (TIR) domain–containing adapter protein (TIRAP) bind to the cytoplasmic domains of TLRs and also to receptors that are part of the IL-1 receptor families. Numerous studies have shown that MyD88/TIRAP-mediated transduction of signals from TLRs and other receptors is critical for innate resistance to infection, activating MAP kinases and NF-κB and thereby leading to production of cytokines/chemokines. Mice lacking MyD88 are more susceptible than normal mice to infections with a broad range of pathogens. In one study, nine children homozygous for defective MyD88 genes had recurrent infections with S. pneumoniae, S. aureus, and P. aeruginosa—three bacterial species showing increased virulence in MyD88-deficient mice. The MyD88-deficient children seemed to have no greater susceptibility to other bacteria, viruses, fungi, or parasites. Another component of the MyD88-dependent signaling pathway is a molecule known as IL-1 receptor–associated kinase 4 (IRAK4). Individuals with a homozygous deficiency in genes encoding this protein are at increased risk for S. pneumoniae and S. aureus infections and, to some degree, P. aeruginosa infections as well.

Some TLRs (e.g., TLR3 and TLR4) can also activate signal transduction via a MyD88-independent pathway involving TIR domain–containing, adapter-inducing IFN-β (TRIF) and the TRIF-related adapter molecule (TRAM). Signaling through TRIF and TRAM activates the production of both NF-κB-dependent cytokines/chemokines and type 1 IFNs. The type 1 IFNs bind to the IFN-α receptor composed of two protein chains, IFNAR1 and IFNAR2. Humans produce three type 1 IFNs: IFN-α, IFN-β, and IFN-γ. These molecules activate another class of proteins known as signal transducer and activator of transcription (STAT) complexes. The STAT factors are important in regulating immune system genes and thus play a critical role in responses to microbial infections.

Another intracellular complex of proteins found to be a major factor in the host cell response to infection is the inflammasome (Fig. 116-3), where inflammatory cytokines IL-1 and IL-18 are changed from their precursors to active forms by the cysteine protease caspase 1 and then secreted. The inflammasome is composed of proteins that are members of the nucleotide binding and oligomerization domain (NOD)–like receptor (NLR) family. Like the TLRs, NOD proteins within inflammasomes sense the presence of the conserved microbial factors either internalized from outside the cell to form canonical inflammasomes or released inside a cell (probably after microbial uptake) to directly activate pro-caspase-2. Recognition of these PAMPs by NLRs leads to caspase 1 or caspase 2 activation and to secretion of active IL-1 and IL-18. Studies of mice indicate that as many as four canonical inflammasomes with different components can be formed (Fig. 116-3). The components depend on the type of stimulus driving inflammasome formation and activation. A fifth, noncanonical inflammasome responding to intracellular LPS also has been described (Fig. 116-3).

Some recent additions to the identified intracellular components responding to microbial infection are autophagy (Fig. 116-4), initially described as an intracellular process for degradation and recycling of cellular components for reuse, and several pathways leading to cell death, including apoptosis, RIPK1-dependent apoptosis, and necroptosis (Fig. 116-4). The latter three pathways are means by which cells undergo a death program in response to infection (notably, viral infection) and inflammation. Autophagy is an early defense mechanism mediated by caspases in response to pathogens wherein, after ingestion, microbes in either vacuoles or the cytoplasm are delivered to lysosomal compartments for degradation. Avoidance of this process is critical if pathogens are to cause disease. Pathogens can avoid autophagy by multiple mechanisms; examples include the inhibition of proteins within the autophagic vacuole by Shigella, the recruitment of host proteins to prevent autophagy of Listeria monocytogenes, and the inhibition of vacuole formation by L. pneumophila. In the death pathways, cell death to inhibit viral replication (Fig. 116-4) is mediated by a series of reactions commencing with TNF-α production and binding of this molecule to its receptor, TNFR1. In the two apoptotic pathways, the final steps are activation of effector caspases 3 and 7 and apoptotic cell death. In necroptosis, oligomers of the mixed-lineage kinase domain–like protein (MLKL) form and insert into the cell’s plasma membrane; their insertion leads to lysis and release of damage-associated molecular patterns (DAMPs), resulting in protective innate immune responses. Finally, additional pathways of cell death are being described, including ferroptosis, oxytosis, parthanatos, pyronecrosis, and pyroptosis. The impact of these pathways on host–pathogen interactions is only beginning to be investigated.

Additional Interactions of Microbial Pathogens and Phagocytes

Other ways that microbial pathogens avoid destruction by phagocytes include production of factors that are toxic to these cells or that interfere with their chemotactic and ingestion function. Hemolysins, leukocidins, and the like are microbial proteins that can kill phagocytes. S. aureus elaborates a family of bi-component leukocidins that bind to host receptors such as the HIV co-receptor CCR5, which is also a receptor for the LukE/D toxin, and the receptor of the C5a component of activated complement used by LukF/S, also known as the Panton-Valentine leukocidin. The cytolytic staphylococcal α hemolysin binds to the disintegrin and metalloprotease 10 (ADAM-10) protein expressed on a variety of cells and also activates the NLRP3 inflammasome in monocytic cells, with consequent production of inflammatory cytokines as well as cell death. Streptolysin O made by S. pyogenes binds to cholesterol in phagocyte membranes and initiates a process of internal degranulation, with the release of normally granule-sequestered toxic components into the phagocyte’s cytoplasm. E. histolytica, an intestinal protozoan that causes amebic dysentery, can disrupt phagocyte membranes after direct contact via the release of protozoal phospholipase A and pore-forming peptides.

Microbial Survival Inside Phagocytes

Many important microbial pathogens use a variety of strategies to survive inside phagocytes (particularly macrophages) after ingestion. Inhibition of fusion of the phagocytic vacuole (the phagosome) containing the initially ingested microbe with the lysosomal granules containing antimicrobial substances (the lysosome) allows M. tuberculosis, S. enterica serovar Typhi, and Toxoplasma gondii to survive inside macrophages. Some organisms, such as L. monocytogenes, escape into the phagocyte’s cytoplasm to grow and eventually spread to other cells. Resistance to killing within the macrophage and subsequent growth are critical to successful infection by herpes-type viruses, measles virus, poxviruses, Salmonella, Yersinia, Legionella, Mycobacterium, Trypanosoma, Nocardia, Histoplasma, Toxoplasma, and Rickettsia. Salmonella species use a master regulatory system—in which the PhoP/PhoQ genes control other genes—to enter and survive within cells, with intracellular survival entailing structural changes in the cell envelope LPS.

TISSUE INVASION AND TISSUE TROPISM

Tissue Invasion

Most viral pathogens cause disease by growth at skin or mucosal entry sites, but some pathogens spread from the initial site to deeper tissues. Virus can spread via the nerves (rabies virus) or plasma (picornaviruses) or within migratory blood cells (poliovirus, Epstein-Barr virus, and many others). Specific viral genes determine where and how individual viral strains can spread.

Bacteria may invade deeper layers of mucosal tissue via intracellular uptake by epithelial cells, traversal of epithelial cell junctions, or penetration through denuded epithelial surfaces. Among virulent Shigella strains and invasive E. coli, outer-membrane proteins are critical to epithelial cell invasion and bacterial multiplication. Neisseria and Haemophilus species penetrate mucosal cells by poorly understood mechanisms before dissemination into the bloodstream. Staphylococci and streptococci elaborate a variety of extracellular enzymes, such as hyaluronidase, lipases, nucleases, and hemolysins, that are probably important in breaking down cellular and matrix structures and allowing the bacteria access to deeper tissues and blood. Staphylococcal α hemolysin binding to ADAM-10 leads to endothelial cell damage and disruption of vascular barrier function, events that are probably critical for systemic spread of S. aureus from an initial infectious site. Organisms that colonize the gastrointestinal tract can often translocate through the mucosa into the blood and, under circumstances in which host defenses are inadequate, cause bacteremia. Yersinia enterocolitica can invade the mucosa through the activity of the invasin protein. The complex milieu of basement membrane–containing structures such as laminin and collagen that anchor epithelial cells to mucosal surfaces must often be breached. A family of microbial surface components recognizing adhesive matrix molecules (MSCRAMMs) can attach bacteria to the extracellular matrix and, along with proteases that degrade the basement proteins as well as surface-bound plasminogen and matrix metalloproteinases recruited from the host, permit breaching of this structure. Some bacteria (e.g., Brucella) can be carried from a mucosal site to a distant site by phagocytic cells that ingest but fail to kill the bacteria.

Fungal pathogens almost always take advantage of host immunocompromise to spread hematogenously to deeper tissues. The AIDS epidemic has resoundingly illustrated this principle: the immunodeficiency of many HIV-infected patients permits the development of life-threatening fungal infections of the lung, blood, and brain. Other than the capsule of C. neoformans, specific fungal antigens involved in tissue invasion are not well characterized. Both fungal pathogens and protozoal pathogens (e.g., Plasmodium species and E. histolytica) undergo morphologic changes to spread within a host. C. albicans undertakes a yeast–hyphal transformation wherein the hyphal forms are found where the fungus is infiltrating the mucosal barrier of tissues, while the yeast form grows on epithelial cell surfaces as well as the tips of hyphae that have infiltrated tissues. Malarial parasites grow in liver cells as merozoites and are released into the blood to invade erythrocytes and become trophozoites. E. histolytica is found as both a cyst and a trophozoite in the intestinal lumen, through which this pathogen enters the host, but only the trophozoite form can spread systemically to cause amebic liver abscesses. Other protozoal pathogens, such as T. gondii, Giardia lamblia, and Cryptosporidium, also undergo extensive morphologic changes after initial infection to spread to other tissues.

Tissue Tropism

While it is well known that certain microbes cause disease by infecting specific tissues, the molecular basis for tissue tropism is understood somewhat better for viral pathogens than for other infectious agents. Specific receptor–ligand interactions clearly underlie the ability of certain viruses to enter cells within tissues and disrupt normal tissue function, but the mere presence of a receptor for a virus on a target tissue is not sufficient for tissue tropism. Factors in the cell, route of viral entry, viral capacity to penetrate into cells, viral genetic elements that regulate gene expression, and pathways of viral spread in a tissue all affect tissue tropism. Some viral genes are best transcribed in specific target cells, such as hepatitis B genes in liver cells and Epstein-Barr virus genes in B lymphocytes. The route of inoculation of poliovirus determines its neurotropism, although the molecular basis for this association is not understood.

Compared with viral tissue tropism, the tissue tropism of bacterial and parasitic infections has not been as clearly elucidated, but studies of Neisseria species have provided insights. Both N. gonorrhoeae, which colonizes and infects the human genital tract, and N. meningitidis, which principally colonizes the human oropharynx but can spread to the brain, produce type IV pili (Tfp) that mediate adherence to host tissues. In the case of N. gonorrhoeae, the Tfp bind to a glucosamine-galactose-containing adhesin on the surface of cervical and urethral cells; in the case of N. meningitidis, the Tfp bind to cells in the human meninges in order to cross the blood-brain barrier. N. gonorrhoeae can use cytidine monophosphate N-acetylneuraminic acid from host tissues to add N-acetylneuraminic acid (sialic acid) to its lipooligosaccharide O side chain, and this alteration makes the organism resistant to host defenses. Lactate, present at high levels on genital mucosal surfaces, stimulates sialylation of gonococcal lipooligosaccharide. Bacteria with sialic acid sugars in their capsules, such as N. meningitidis, E. coli K1, and group B streptococci, have a propensity to cause meningitis, but this generalization has many exceptions. For example, all recognized serotypes of group B streptococci contain sialic acid in their capsules, but only one serotype (III) is responsible for most cases of group B streptococcal meningitis. Moreover, both H. influenzae and S. pneumoniae can readily cause meningitis, but these organisms do not have sialic acid in their capsules.

TISSUE DAMAGE AND DISEASE

Disease is a complex phenomenon resulting from tissue invasion and destruction, toxin elaboration, and host response. Viruses cause much of their damage by exerting a cytopathic effect on host cells and inhibiting host defenses. The growth of bacterial, fungal, and protozoal parasites in tissue, which may or may not be accompanied by toxin elaboration, can also compromise tissue function and lead to disease. For some bacterial and possibly some fungal pathogens, toxin production is one of the best-characterized molecular mechanisms of pathogenesis, while host factors such as IL-1, TNF-α, kinins, inflammatory proteins, products of complement activation, and mediators derived from arachidonic acid metabolites (leukotrienes) and cellular degranulation (histamines) readily contribute to the severity of disease.

Viral Disease

Viral pathogens inhibit host immune responses by a variety of mechanisms—e.g., by decreasing production of major histocompatibility complex molecules (adenovirus E3 protein), diminishing cytotoxic T cell recognition of virus-infected cells (Epstein-Barr virus nuclear antigen 1 and cytomegalovirus intermediate–early protein), producing virus-encoded complement receptor proteins that protect infected cells from complement-mediated lysis (herpesvirus and vaccinia virus), making proteins that interfere with the action of IFN (influenza virus and poxvirus), and elaborating superantigen-like proteins (mouse mammary tumor virus and related retroviruses and the rabies nucleocapsid). Superantigens activate large populations of T cells that express particular subsets of the T cell receptor β protein, causing massive cytokine release and subsequent host reactions. Dengue virus is the most common insect-transmitted virus in the world, causing symptoms ranging from none to serious systemic illness or “break-bone” fever (severe fever and pain). Along with the recent epidemic of the related flavivirus Zika virus, disruptions to host innate immunity and inhibition of programmed cell death that allows continued viral replication underlie the ability of these viruses to cause infections. Infections of pregnant women with Zika virus can result in viral crossing of the placenta; viral entry into and growth in fetal brain tissues result in the birth of neonates with microcephaly. Viruses also produce peptide growth factors for host cells, which disrupt normal cellular growth, proliferation, and differentiation. In addition, viral factors can bind to and interfere with the function of host receptors for signaling molecules. Modulation of cytokine production during viral infection can stimulate viral growth inside cells with receptors for the cytokine, and virus-encoded cytokine homologues (e.g., the Epstein-Barr virus BCRF1 protein, which is highly homologous to the immunoinhibitory IL-10 molecule) can prevent immune-mediated clearance of viral particles. Viruses cause disease in neural cells by interfering with levels of neurotransmitters without necessarily destroying the cells, or they may induce either programmed cell death (apoptosis) to destroy tissues or inhibitors of apoptosis to allow prolonged viral infection of cells. For infection to spread, many viruses must be released from cells. The HIV protein U (Vpu) facilitates virus release, a process that is specific to certain cells. Mammalian cells produce a restriction factor that inhibits release of some viruses; for HIV, this factor is designated BST-2 (bone marrow stromal antigen 2)/HM1.24/CD317, or tetherin. Vpu of HIV interacts with tetherin, allowing release of infectious virus. Overall, virus-induced disruption of normal cellular and tissue function promotes clinical disease.

Bacterial Toxins

Among the first infectious diseases to be understood were those due to toxin-elaborating bacteria. Diphtheria, botulism, and tetanus toxins are responsible for the diseases associated with local infections due to Corynebacterium diphtheriae, Clostridium botulinum, and Clostridium tetani, respectively. C. difficile is an anaerobic gram-positive organism that elaborates two toxins, A and B, responsible for disruption of the intestinal mucosa when its numbers expand in the intestine, leading to antibiotic-associated diarrhea and potentially pseudomembranous colitis. A clinical trial evaluating prevention of recurrence of C. difficile infection by monoclonal antibodies to toxins A and B showed that antibody to toxin B, but not toxin A, had a significant impact. Enterotoxins produced by E. coli, Salmonella, Shigella, staphylococci, and V. cholerae contribute to diarrheal disease caused by these organisms. Staphylococci, streptococci, P. aeruginosa, and Bordetella elaborate various toxins that cause or contribute to disease, including toxic shock syndrome toxin 1; erythrogenic toxin; exotoxins A, S, T, and U; and pertussis toxin. A number of these toxins (e.g., cholera toxin, diphtheria toxin, pertussis toxin, E. coli heat-labile toxin, and P. aeruginosa exotoxin) have adenosine diphosphate ribosyl transferase activity; i.e., the toxins enzymatically catalyze the transfer of the adenosine diphosphate ribosyl portion of nicotinamide adenine diphosphate to target proteins and inactivate them. The staphylococcal enterotoxins, toxic shock syndrome toxin 1, and the streptococcal pyogenic exotoxins behave as superantigens, stimulating certain T cells to proliferate without processing of the protein toxin by antigen-presenting cells. Part of this process involves stimulation of the antigen-presenting cells to produce IL-1 and TNF-α, which have been implicated in many clinical features of diseases like toxic shock syndrome and scarlet fever. A number of gram-negative pathogens (Salmonella, Yersinia, and P. aeruginosa) can inject toxins directly into host target cells by means of a complex set of proteins referred to as the type III secretion system. Loss or inactivation of this virulence system usually greatly reduces the capacity of a bacterial pathogen to cause disease.

Endotoxin

The lipid A portion of LPS in some gram-negative bacteria has potent biologic activities that cause many of the clinical manifestations of gram-negative bacterial sepsis, including fever, muscle proteolysis, uncontrolled intravascular coagulation, and shock. The effects of lipid A appear to be mediated by the production of potent cytokines due to LPS binding to CD14 and signal transduction via TLRs, particularly TLR4. Cytokines exhibit potent hypothermic activity through effects on the hypothalamus; they also increase vascular permeability, alter the activity of endothelial cells, and induce endothelial-cell procoagulant activity. Numerous therapeutic strategies aimed at neutralizing the effects of endotoxin are under investigation, and while studies with laboratory animals have been promising, they have not yet translated into positive results for human septic shock.

Invasion

Many diseases are caused primarily by pathogens growing to high levels in tissues. Pneumococcal pneumonia is mostly attributable to the growth of S. pneumoniae in the lung and the attendant host inflammatory response, although specific factors that enhance this process (e.g., pneumolysin) may be responsible for some of the pathogenic properties of the pneumococcus. Disease that follows bacteremia and invasion of the meninges by meningitis-producing bacteria such as N. meningitidis, H. influenzae, E. coli K1, and group B streptococci appears to be due solely to the ability of these organisms to gain access to these tissues, multiply in them, and provoke cytokine production leading to tissue-damaging host inflammation.

Specific molecular mechanisms accounting for tissue invasion by fungal and protozoal pathogens are less well described. Except for studies pointing to factors like capsule and melanin production by C. neoformans, and possibly levels of cell wall glucans in some pathogenic fungi, the molecular basis for fungal invasiveness is not well defined. Melanism has been shown to protect the fungal cell against death caused by phagocyte factors such as nitric oxide, superoxide, and hypochlorite. Morphogenic variation and production of proteases (e.g., the Candida aspartyl proteinase) have been implicated in fungal invasion of host tissues.

If pathogens are to invade host tissues (particularly the blood), they must avoid the major host defenses represented by complement and phagocytic cells. Bacteria most often avoid these defenses through their surface polysaccharides—either capsular polysaccharides or long O-side-chain antigens characteristic of the smooth LPS of gram-negative bacteria. These molecules can prevent the activation and/or deposition of complement opsonins or can limit the access of phagocytic cells with receptors for complement opsonins to these molecules when they are deposited on the bacterial surface below the capsular layer. Another potential mechanism of microbial virulence is the ability of some organisms to present the capsule as an apparent self antigen through molecular mimicry. For example, the polysialic acid capsule of group B N. meningitidis is chemically identical to an oligosaccharide found on human brain cells.

Immunochemical studies of capsular polysaccharides have led to an appreciation of the tremendous chemical diversity that can result from the linking of a few monosaccharides. For example, three hexoses can link up in more than 300 different, potentially serologically distinct ways, while three amino acids have only six possible peptide combinations. Capsular polysaccharides have been used as effective vaccines against meningococcal meningitis as well as against pneumococcal and H. influenzae infections and may prove to be of value as vaccines against any organism that expresses a nontoxic, immunogenic capsular polysaccharide. In addition, most encapsulated pathogens become virtually avirulent when capsule production is interrupted by genetic manipulation; this observation emphasizes the importance of this structure in pathogenesis. A capsule-like surface polysaccharide, PNAG, has been found as a conserved structure shared by many microbes but generally is a poor target for antibody-mediated immunity because of the propensity of most humans and animals, all of which are colonized by PNAG-producing microbes, to produce a nonprotective type of antibody. Altering the structure of PNAG by removing the acetate substituents on the N-acetyl glucosamine monomers leads to an immunogenic form, deacetylated PNAG, that has been reported to induce antibodies that are protective in animals against diverse microbial pathogens.

Host Response

The inflammatory response of the host is critical for interruption and resolution of the infectious process but also is often responsible for the signs and symptoms of disease. Infection promotes a complex series of host responses involving the complement, kinin, and coagulation pathways. The production of cytokines such as IL-1, IL-17, IL-18, TNF-α, IFN-γ, and other factors regulated in part by the NF-κB transcription factor leads to fever, muscle proteolysis, and other effects. An inability to kill or contain the microbe usually results in further damage due to the progression of inflammation and infection. For example, in many chronic infections, degranulation of host inflammatory cells leads to release of host proteases, elastases, histamines, and other toxic substances that can degrade host tissues. Chronic inflammation in any tissue can lead to the destruction of that tissue and to clinical disease associated with loss of organ function, such as sterility from pelvic inflammatory disease caused by chronic infection with N. gonorrhoeae.

The nature of the host response elicited by the pathogen often determines the pathology of a particular infection. Local inflammation produces local tissue damage, while systemic inflammation, such as that seen during sepsis, can result in the signs and symptoms of septic shock. The severity of septic shock is associated with the degree of production of host effectors. Disease due to intracellular parasitism results from the formation of granulomas wherein the host attempts to wall off the parasite inside a fibrotic lesion surrounded by fused epithelial cells that make up so-called multinucleated giant cells. A number of pathogens, particularly anaerobic bacteria, staphylococci, and streptococci, provoke the formation of an abscess, probably because of the presence of zwitterionic surface polysaccharides such as the capsular polysaccharide of Bacteroides fragilis. The outcome of an infection depends on the balance between an effective host response that eliminates a pathogen and an excessive inflammatory response that is associated with an inability to eliminate a pathogen and with the resultant tissue damage that leads to disease.

TRANSMISSION TO NEW HOSTS

As part of the pathogenic process, most microbes are shed from the host, often in a form infectious for susceptible individuals. However, the rate of transmissibility may not necessarily be high, even if the disease is severe in the infected individual, as these traits are not linked. Most pathogens exit via the same route by which they entered: respiratory pathogens by aerosols from sneezing or coughing or through salivary spread, gastrointestinal pathogens by fecal–oral spread, sexually transmitted diseases by venereal spread, and vector-borne organisms by either direct contact with the vector through a blood meal or indirect contact with organisms shed into environmental sources such as water. Microbial factors that specifically promote transmission are not well characterized. Respiratory shedding is facilitated by overproduction of mucous secretions, with consequently enhanced sneezing and coughing. Diarrheal toxins such as cholera toxin, E. coli heat-labile toxins, and Shigella toxins probably facilitate fecal–oral spread of microbial cells in the high volumes of diarrheal fluid produced during infection. The ability to produce phenotypic variants that resist hostile environmental factors (e.g., the highly resistant cysts of E. histolytica shed in feces) represents another mechanism of pathogenesis relevant to transmission. Blood parasites such as Plasmodium species change phenotype after ingestion by a mosquito—a prerequisite for the continued transmission of this pathogen. Venereally transmitted pathogens may undergo phenotypic variation due to the production of specific factors to facilitate transmission, but shedding of these pathogens into the environment does not result in the formation of infectious foci.

SUMMARY

In summary, the molecular mechanisms used by pathogens to colonize, invade, infect, and disrupt the host are numerous and diverse. Each phase of the infectious process involves a variety of microbial and host factors interacting in a manner that can result in disease. Recognition of the coordinated genetic regulation of virulence factor elaboration when organisms move from their natural environment into the mammalian host emphasizes the complex nature of the host–parasite interaction. Fortunately, the need for diverse factors in successful infection and disease implies that a variety of therapeutic strategies may be developed to interrupt this process and thereby prevent and treat microbial infections.

FURTHER READING

INTRODUCTION

The physician treating the acutely ill febrile patient must be able to recognize infections that require emergent attention. If such infections are not adequately evaluated and treated at initial presentation, the opportunity to alter an adverse outcome may be lost. In this chapter, the clinical presentations of and approach to patients with relatively common infectious disease emergencies are discussed. These infectious processes and their treatments are discussed in detail in other chapters.

APPROACH TO THE PATIENT

TREATMENT

SPECIFIC PRESENTATIONS

The infections considered below according to common clinical presentation can have rapidly catastrophic outcomes, and their immediate recognition and treatment can be life-saving. Recommended empirical therapeutic regimens are presented in Table 117-1.

SEPSIS WITHOUT AN OBVIOUS FOCUS OF PRIMARY INFECTION

Patients initially have a brief prodrome of nonspecific symptoms and signs that progresses quickly to hemodynamic instability with hypotension, tachycardia, tachypnea, respiratory distress, and altered mental status. Disseminated intravascular coagulation (DIC) with clinical evidence of a hemorrhagic diathesis is a poor prognostic sign.

Septic Shock

Patients with bacteremia leading to septic shock may have a primary site of infection (e.g., pneumonia, pyelonephritis, or cholangitis) that is not evident initially (See also Chap. 297). Elderly patients with comorbid conditions, hosts compromised by malignancy and neutropenia, and patients who have recently undergone a surgical procedure or hospitalization are at increased risk for an adverse outcome. Gram-negative bacteremia with organisms such as Pseudomonas aeruginosa or Escherichia coli and gram-positive infection with organisms such as Staphylococcus aureus (including methicillin-resistant S. aureus [MRSA]) or group A streptococci can present as intractable hypotension and multiorgan failure. Treatment can usually be initiated empirically on the basis of the presentation, host factors (Chap. 297), and local patterns of bacterial resistance. Outcomes are worse when antimicrobial treatment is delayed or when the responsible pathogen ultimately proves not to be susceptible to the initial regimen. Active empirical antimicrobial coverage administered before admission to the intensive care unit is strongly associated with improved survival. Broad-spectrum antimicrobial agents are therefore recommended and should be instituted rapidly, preferably within the first hours after presentation. Risk factors for fungal infection should be assessed, as the incidence of fungal septic shock is increasing. Biomarkers such as C-reactive protein and procalcitonin have not proved reliable diagnostically but, when measured over time, can facilitate appropriate de-escalation of therapy and predict outcome. Glucocorticoids are often considered for patients with severe sepsis who do not respond to fluid resuscitation and vasopressor therapy. However, conclusive evidence for the efficacy of glucocorticoids in this setting is lacking.

Overwhelming Infection in Asplenic Patients

Patients without splenic function are at risk for overwhelming bacterial sepsis (See also Chap. 297). Asplenic adult patients succumb to sepsis at 58 times the rate of the general population. Most infections are thought to occur within the first l or 2 years, but the increased risk persists throughout life. The median interval between splenectomy and sepsis is 5.75 years, with a range of 1–19 years. In asplenia, encapsulated bacteria cause the majority of infections. Adults, who are more likely to have antibody to these organisms, are at lower risk than children. Streptococcus pneumoniae is the most common isolate, causing 40–70% of cases. The risk of infection with Haemophilus influenzae or Neisseria meningitidis is also greater in patients without splenic function, but reported cases are declining. Severe clinical manifestations of infections due to E. coli, S. aureus, group B streptococci, P. aeruginosa, Bordetella holmesii, and Capnocytophaga, Babesia, and Plasmodium species have been described.

Babesiosis

A history of recent travel to endemic areas raises the possibility of infection with Babesia (See also Chap. 220). Between 1 and 4 weeks after a tick bite, the patient experiences chills, fatigue, anorexia, myalgia, arthralgia, shortness of breath, nausea, and headache; ecchymosis and/or petechiae are occasionally seen. The tick that most commonly transmits Babesia, Ixodes scapularis, also transmits Borrelia burgdorferi (the agent of Lyme disease) and Anaplasma; co-infection can occur, resulting in more severe disease. Infection with the European species Babesia divergens is more frequently fulminant than that due to the U.S. species Babesia microti. B. divergens causes a febrile syndrome with hemolysis, jaundice, hemoglobinemia, and renal failure and is associated with a mortality rate of >40%. Severe babesiosis is especially common in asplenic hosts but does occur in hosts with normal splenic function, particularly those >60 years of age and those with underlying immunosuppressive conditions such as HIV infection or malignancy. Complications include renal failure, acute respiratory failure, and DIC.

Other Sepsis Syndromes

Tularemia (Chap. 165) is seen throughout the United States, but most cases recorded in 2015 occurred in South Dakota, Nebraska, Colorado, and Wyoming. This disease is associated with wild rabbit, tick, and tabanid fly contact. It can be transmitted by arthropod bite, handling of infected animal carcasses, consumption of contaminated food and water, or inhalation. The typhoidal form can be associated with gram-negative septic shock and a mortality rate of >30%, especially in patients with underlying comorbid or immunosuppressive conditions. Plague occurs infrequently in the United States (Chap. 166), primarily after contact with ground squirrels, prairie dogs, or chipmunks, but is endemic in other parts of the world, with >90% of all cases occurring in Africa. The septic form is particularly rare and is associated with shock, multiorgan failure, and a 30% mortality rate. These infections should be considered in the appropriate epidemiologic setting. The Centers for Disease Control and Prevention lists Francisella tularensis and Yersinia pestis (the agents of tularemia and plague, respectively) along with Bacillus anthracis (the agent of anthrax) as important organisms that might be used for bioterrorism (Chap. S2).

SEPSIS WITH SKIN MANIFESTATIONS

Maculopapular rashes may reflect early meningococcal or rickettsial disease but are usually associated with nonemergent infections (See also Chap. 16). Exanthems are usually viral. Primary HIV infection commonly presents with a rash that is typically maculopapular and involves the upper part of the body but can spread to the palms and soles. The patient is usually febrile and can have lymphadenopathy, severe headache, dysphagia, diarrhea, myalgias, and arthralgias. Recognition of this syndrome provides an opportunity to prevent transmission and to institute treatment and monitoring early on.

Petechial rashes caused by viruses are seldom associated with hypotension or a toxic appearance, although there can be exceptions (e.g., severe measles or arboviral infection). Petechial rashes limited to the distribution of the superior vena cava are rarely associated with severe disease. In other settings, petechial rashes require more urgent attention.

Meningococcemia

Almost three-quarters of patients with N. meningitidis bacteremia have a rash (See also Chap. 150). Meningococcemia most often affects young children (i.e., those 6 months to 5 years old). In sub-Saharan Africa, the high prevalence of serogroup A meningococcal disease has been a threat to public health for more than a century. Thousands of deaths occur annually in this area, which is known as the “meningitis belt,” and large epidemic waves occur approximately every 8–12 years. Serogroups W135 and X are also important emerging pathogens in Africa. In the United States, sporadic cases and outbreaks occur in day-care centers, schools (grade school through college, particularly among college freshmen living in residential halls), and army barracks. Household contacts of index cases are at 400–800 times greater risk of disease than the general population. Patients may have fever, headache, nausea, vomiting, myalgias, changes in mental status, and meningismus. However, the rapidly progressive form of disease is not usually associated with meningitis. The rash is initially pink, blanching, and maculopapular, appearing on the trunk and extremities, but then becomes hemorrhagic, forming petechiae. Petechiae are first seen at the ankles, wrists, axillae, mucosal surfaces, and palpebral and bulbar conjunctiva, with subsequent spread on the lower extremities and to the trunk. A cluster of petechiae may be seen at pressure points—e.g., where a blood pressure cuff has been inflated. In rapidly progressive meningococcemia (10–20% of cases), the petechial rash quickly becomes purpuric (see Fig. A1-41), and patients develop DIC, multiorgan failure, and shock; 50–60% of these patients die, and survivors often require extensive debridement or amputation of gangrenous extremities. Hypotension with petechiae for <12 h is associated with significant mortality. Cyanosis, coma, oliguria, metabolic acidosis, and elevated partial thromboplastin time also are associated with a fatal outcome. Antibiotics given in the office by the primary care provider before hospital evaluation and admission may improve prognosis; this observation suggests that early initiation of treatment may be life-saving. Meningococcal conjugate vaccines are protective against serogroups A, C, Y and W135 and are recommended for children 11–18 years of age and for other high-risk patients. Vaccines active against serogroup B are available and are recommended for high-risk individuals >10 years of age.

Rocky Mountain Spotted Fever and Other Rickettsial Diseases

RMSF is a tickborne disease caused by Rickettsia rickettsii that occurs throughout North and South America (See also Chap. 182). Other rickettsiae (e.g., R. parkeri, R. akari) can also cause spotted fever. Up to 40% of patients do not report a history of a tick bite, but a history of travel or outdoor activity (e.g., camping in tick-infested areas) can often be ascertained. For the first 3 days, headache, fever, malaise, myalgias, nausea, vomiting, and anorexia are documented. By day 3, half of patients have skin findings. Blanching macules develop initially on the wrists and ankles and then spread over the legs and trunk. The lesions become hemorrhagic and are frequently petechial. The rash spreads to palms and soles later in the course. The centripetal spread is a classic feature of RMSF but occurs in a minority of patients. Moreover, 10–15% of patients with RMSF never develop a rash. The patient can be hypotensive and develop noncardiogenic pulmonary edema, confusion, lethargy, and encephalitis progressing to coma. The CSF contains 10–100 cells/μL, usually with a predominance of mononuclear cells. The CSF glucose level is often normal; the protein concentration may be slightly elevated. Renal and hepatic injury as well as bleeding secondary to vascular damage are noted. For untreated infections, mortality rates are 20–30%. Delayed recognition and treatment are associated with a greater risk of death; Native Americans, children 5–9 years of age, adults >70 years old, and persons with underlying immunosuppression are at a 3- to 5-fold increased risk of death.

Other rickettsial diseases cause significant morbidity and mortality worldwide. Mediterranean spotted fever caused by Rickettsia conorii is found in Africa, southwestern and south-central Asia, and southern Europe. Patients have fever, flu-like symptoms, and an inoculation eschar at the site of the tick bite. A maculopapular rash develops within 1–7 days, involving the palms and soles but sparing the face. Elderly patients or those with diabetes, alcoholism, uremia, or congestive heart failure are at risk for severe disease characterized by neurologic involvement, respiratory distress, and gangrene of the digits or purpura fulminans. Mortality rates associated with this severe form of disease approach 50%. Epidemic typhus, caused by Rickettsia prowazekii, is transmitted in louse-infested environments and emerges in conditions of extreme poverty, war, and natural disaster. Patients experience a sudden onset of high fevers, severe headache, cough, myalgias, and abdominal pain. A maculopapular rash develops (primarily on the trunk) in more than half of patients and can progress to petechiae and purpura. Serious signs include delirium, coma, seizures, noncardiogenic pulmonary edema, skin necrosis, and peripheral gangrene. Mortality rates approached 60% in the preantibiotic era and continue to exceed 10–15% in contemporary outbreaks. Scrub typhus, caused by Orientia tsutsugamushi (a separate genus in the family Rickettsiaceae), is transmitted by larval mites or chiggers and is one of the most common infections in southeastern Asia and the western Pacific. The organism is found in areas of heavy scrub vegetation (e.g., along riverbanks). Patients may have an inoculation eschar and may develop a maculopapular rash, lymphadenopathy, and dyspnea. Severe cases progress to pneumonia, meningoencephalitis, myocarditis, DIC, and renal failure. Mortality rates range from 1% to 70% and vary by location, increasing age, myocarditis, delirium, pneumonitis, or signs of hemorrhage.

If recognized in a timely fashion, rickettsial disease is very responsive to treatment. Doxycycline (100 mg twice daily for 3–14 days) is the treatment of choice for both adults and children. The newer macrolides may be a suitable alternative, but mortality rates are higher when tetracycline-based treatment is not given.

Purpura Fulminans

Purpura fulminans is the cutaneous manifestation of DIC and presents as large ecchymotic areas and hemorrhagic bullae (See also Chaps. 150 and 297). Progression of petechiae to purpura, ecchymoses, and gangrene is associated with congestive heart failure, septic shock, acute renal failure, acidosis, hypoxia, hypotension, and death. Purpura fulminans has been associated primarily with N. meningitidis but, in splenectomized patients, may be associated with S. pneumoniae, H. influenzae, and S. aureus.

Ecthyma Gangrenosum

Septic shock caused by P. aeruginosa or Aeromonas hydrophila can be associated with ecthyma gangrenosum (see Figs. 159-1 and A1-34): hemorrhagic vesicles surrounded by a rim of erythema with central necrosis and ulceration. These gram-negative bacteremias are most common among patients with neutropenia, extensive burns, and hypogammaglobulinemia.

Other Infections Associated with Rash

Vibrio vulnificus and other noncholera Vibrio bacteremic infections (Chap. 163) can cause focal skin lesions and overwhelming sepsis in hosts with chronic liver disease, heavy alcohol consumption, iron storage disorders, diabetes, renal insufficiency, hematologic disease, or malignancy or other immunocompromising conditions. After ingestion of contaminated raw shellfish (typically oysters from the Gulf Coast in U.S. cases), there is a sudden onset of malaise, chills, fever, and hypotension. The patient develops bullous or hemorrhagic skin lesions, usually on the lower extremities, and 75% of patients have leg pain. The mortality rate can be as high as 50–60%, particularly when the patient presents with hypotension. Outcomes are improved when patients are treated with fluoroquinolones with or without cephalosporins or with tetracycline-containing regimens. Other infections, caused by agents such as Aeromonas, Klebsiella, and E. coli, can cause hemorrhagic bullae and death due to overwhelming sepsis in cirrhotic patients. Capnocytophaga canimorsus can cause septic shock in asplenic patients. Infection typically follows a dog bite. Patients present with fever, chills, myalgia, vomiting, diarrhea, dyspnea, confusion, and headache. Findings can include an exanthem or erythema multiforme (see Figs. 52-9 and A1-24), cyanotic mottling or peripheral cyanosis, petechiae, and ecchymosis. About 30% of patients with this fulminant form die of overwhelming sepsis and DIC, and survivors may require amputation because of gangrene.

Erythroderma

TSS (Chaps. 142 and 143) is usually associated with erythroderma. The patient presents with fever, malaise, myalgias, nausea, vomiting, diarrhea, and confusion. There is a sunburn-type rash that may be subtle and patchy but is usually diffuse and is found on the face, trunk, and extremities. Erythroderma, which desquamates after 1–2 weeks, is more common in Staphylococcus-associated than in Streptococcus-associated TSS. Hypotension develops rapidly—often within hours—after the onset of symptoms. Multiorgan failure occurs. Early renal failure may precede hypotension and distinguishes this syndrome from other septic shock syndromes. There may be no indication of a primary focal infection, although possible cutaneous or mucosal portals of entry for the organism can be ascertained when a careful history is taken. Colonization rather than overt infection of the vagina or a postoperative wound, for example, is typical with staphylococcal TSS, and the mucosal areas appear hyperemic but not infected. Streptococcal TSS is more often associated with skin or soft tissue infection (including necrotizing fasciitis), and patients are more likely to be bacteremic. TSS caused by Clostridium sordellii is associated with childbirth or with skin injection of black-tar heroin. The diagnosis of TSS is defined by the clinical criteria of fever, rash, hypotension, and multiorgan involvement. (Of note, fever is typically absent when TSS is caused by C. sordellii.) The mortality rate is 5% for menstruation-associated TSS, 10–15% for nonmenstrual TSS, 30–70% for streptococcal TSS, and up to 90% for obstetric C. sordellii TSS. Clindamycin improves outcomes when included in the treatment regimen. Some studies have shown that use of IV immunoglobulin is associated with improved survival as well.

Viral Hemorrhagic Fevers

Viral hemorrhagic fevers (Chaps. 204 and 205) are zoonotic illnesses caused by viruses that reside in either animal reservoirs or arthropod vectors. These diseases occur worldwide and are restricted to areas where the host species live. They are caused by four major groups of viruses: Arenaviridae (e.g., Lassa fever in Africa), Bunyaviridae (e.g., Rift Valley fever in Africa; hantavirus hemorrhagic fever with renal syndrome in Asia; and Crimean-Congo hemorrhagic fever, which has an extensive geographic distribution), Filoviridae (e.g., Ebola and Marburg virus infections in Africa), and Flaviviridae (e.g., yellow fever in Africa and South America and dengue in Asia, Africa, and the Americas). Lassa fever and Ebola and Marburg virus infections are also transmitted from person to person. The vectors for most viral fevers are found in rural areas; dengue and yellow fever are important exceptions. After a prodrome of fever, myalgias, and malaise, patients develop evidence of vascular damage, petechiae, and local hemorrhage. Shock, multifocal hemorrhaging, and neurologic signs (e.g., seizures or coma) predict a poor prognosis. Dengue (Chap. 204) is the most common arboviral disease worldwide. More than half a million cases of dengue hemorrhagic fever occur each year, with at least 12,000 deaths. Patients have a triad of symptoms: hemorrhagic manifestations, evidence of plasma leakage, and platelet counts of <100,000/μL. Mortality rates are 10–20%. If dengue shock syndrome develops, mortality rates can reach 40%. Ebola infection has been associated with outbreaks with high mortality rates. The 2014 outbreak in West Africa had a mortality rate of >50%. Symptoms can appear 2–21 days after exposure, but most patients become ill within 9 days. The patient first presents with fatigue, fever, headache, and muscle pains, and the illness can progress to multiorgan failure and hemorrhaging. Careful volume-replacement therapy to maintain blood pressure and intravascular volume is key to survival in these infections. Ribavirin also may be useful against Arenaviridae and Bunyaviridae.

Other viral illnesses with rash, such as measles, can be associated with significant mortality rates. Steroids may sometimes be useful in severe disease in malnourished populations, especially if neurologic complications are present.

SEPSIS WITH A SOFT TISSUE/MUSCLE PRIMARY FOCUS

See also Chap. 124.

Necrotizing Fasciitis

This infection is characterized by extensive necrosis of the subcutaneous tissue and fascia. It may arise at a site of minimal trauma or surgical incision and may also be associated with recent varicella, childbirth, or muscle strain. The most common causes of necrotizing fasciitis are group A streptococci alone (Chap. 143) and a mixed facultative and anaerobic flora (Chap. 124); the incidence of group A streptococcal necrotizing fasciitis has been increasing for the past quarter-century. Diabetes mellitus, IV drug use, chronic liver or renal disease, and malignancy are associated risk factors. Physical findings are initially minimal compared with the severity of pain and the degree of fever. The examination is often unremarkable except for soft tissue edema and erythema. The infected area is red, hot, shiny, swollen, and exquisitely tender. In untreated infection, the overlying skin develops blue-gray patches after 36 h, and cutaneous bullae and necrosis develop after 3–5 days. Necrotizing fasciitis due to a mixed flora, but not that due to group A streptococci, can be associated with gas production. Without treatment, pain decreases because of thrombosis of the small blood vessels and destruction of the peripheral nerves—an ominous sign. The mortality rate is 15–34% overall, >70% in association with TSS, and nearly 100% without surgical intervention. Necrotizing fasciitis may also be due to Clostridium perfringens (Chap. 149); in this condition, the patient is extremely toxic and the mortality rate is high. Within 48 h, rapid tissue invasion and systemic toxicity associated with hemolysis and death ensue. The distinction between this entity and clostridial myonecrosis is made by muscle biopsy. Necrotizing fasciitis caused by community-acquired MRSA also has been reported.

Clostridial Myonecrosis

Myonecrosis is often associated with trauma or surgery but can develop spontaneously (See also Chap. 149). The incubation period is usually 12–24 h long, and massive necrotizing gangrene develops within hours of onset. Systemic toxicity, shock, and death can occur within 12 h. The patient’s pain and toxic appearance are out of proportion to physical findings. On examination, the patient is febrile, apathetic, tachycardic, and tachypneic and may express a feeling of impending doom. Hypotension and renal failure develop later, and hyperalertness is evident preterminally. The skin over the affected area is bronze-brown, mottled, and edematous. Bullous lesions with serosanguineous drainage and a mousy or sweet odor can develop. Crepitus can occur secondary to gas production in muscle tissue. The mortality rate is >65% for spontaneous myonecrosis, which is often associated with Clostridium septicum or C. tertium and underlying malignancy. The mortality rates associated with trunk and limb infection are 63% and 12%, respectively, and any delay in surgical treatment increases the risk of death.

NEUROLOGIC INFECTIONS WITH OR WITHOUT SEPTIC SHOCK

Bacterial Meningitis

Bacterial meningitis is one of the most common infectious disease emergencies involving the central nervous system (See also Chap. 133). Although hosts with cell-mediated immune deficiency (including transplant recipients, diabetic patients, elderly patients, and cancer patients receiving certain chemotherapeutic agents) are at particular risk for Listeria monocytogenes meningitis, most cases in adults are due to S. pneumoniae (30–60%) and N. meningitidis (10–35%). The classic presentation of fever, meningismus, and altered mental status is seen in only one-half to two-thirds of patients. The elderly can present without fever or meningeal signs. Cerebral dysfunction is evidenced by confusion, delirium, and lethargy that can progress to coma. In some cases, the presentation is fulminant, with sepsis and brain edema; papilledema at presentation is unusual and suggests another diagnosis (e.g., an intracranial lesion). Focal signs, including cranial nerve palsies (IV, VI, VII), can be seen in 10–20% of cases; 50–70% of patients have bacteremia. A poor outcome is associated with coma, seizures, hypotension, a pneumococcal etiology, respiratory distress, a CSF glucose level of <0.6 mmol/L (<10 mg/dL), a CSF protein level of >2.5 g/L, a peripheral white blood cell count of <5000/μL, and a serum sodium level of <135 mmol/L. Rapid initiation of treatment is essential; the odds of an unfavorable outcome may increase by 30% for each hour that treatment is delayed. Dexamethasone is an adjunctive treatment for meningitis in adults, especially for infections caused by S. pneumoniae. It must be given before or with the first dose of antibiotics; otherwise, it is unlikely to improve outcomes.

Suppurative Intracranial Infections

In suppurative intracranial infections, rare intracranial lesions present along with sepsis and hemodynamic instability (See also Chap. 135). Rapid recognition of the toxic patient with central neurologic signs is crucial to improvement of the dismal prognosis of these entities. Patients with diabetes or hematologic disease may be at increased risk for these infections. Subdural empyema arises from the paranasal sinus in 60–70% of cases. Microaerophilic streptococci and staphylococci are the predominant etiologic organisms. The patient is toxic, with fever, headache, and nuchal rigidity. Of all patients, 75% have focal signs and 6–20% die. Despite improved survival rates, 15–44% of patients are left with permanent neurologic deficits. Septic cavernous sinus thrombosis follows a facial or sphenoid sinus infection; 70% of cases are due to staphylococci (including MRSA), and the remainder are due primarily to aerobic or anaerobic streptococci. Fungi have been common in some series. A unilateral or retro-orbital headache progresses to a toxic appearance and fever within days. Three-quarters of patients have unilateral periorbital edema that becomes bilateral and then progresses to ptosis, proptosis, ophthalmoplegia, and papilledema. The mortality rate is as high as 30%. Septic thrombosis of the superior sagittal sinus spreads from the ethmoid or maxillary sinuses and is caused by S. pneumoniae, other streptococci, and staphylococci. The fulminant course is characterized by headache, nausea, vomiting, rapid progression to confusion and coma, nuchal rigidity, and brainstem signs. If the sinus is totally thrombosed, the mortality rate exceeds 80%. Broad-spectrum antibiotics and early surgical intervention at the primary site of infection may improve outcomes. Anticoagulation or steroids are of uncertain benefit.

Brain Abscess

Brain abscess often occurs without systemic signs (See also Chap. 135). Almost half of patients are afebrile, and presentations are more consistent with a space-occupying lesion in the brain; 70% of patients have headache and/or altered mental status, 50% have focal neurologic signs, and 25% have papilledema. Abscesses can present as single or multiple lesions resulting from contiguous foci or hematogenous infection, such as endocarditis, or after surgery or trauma. The infection progresses over several days from cerebritis to an abscess with a mature capsule. More than half of infections are polymicrobial, with an etiology consisting of aerobic bacteria (primarily streptococcal species) and anaerobes. Abscesses arising hematogenously are especially apt to rupture into the ventricular space, causing a sudden and severe deterioration in clinical status and a high mortality rate. Otherwise, mortality is low (<20%) but morbidity is high (30–55%). Patients presenting with stroke and a parameningeal infectious focus, such as sinusitis or otitis, may have a brain abscess, and physicians must maintain a high level of suspicion. Prognosis worsens in patients with a fulminant course, delayed diagnosis, abscess rupture into the ventricles, multiple abscesses, or abnormal neurologic status at presentation. In one study, mortality at 1 year was 19%.

Cerebral Malaria

This entity should be urgently considered if patients who have recently traveled to areas endemic for malaria present with a febrile illness and lethargy or other neurologic signs (See also Chap. 219). Fulminant malaria is caused by Plasmodium falciparum and is associated with temperatures of >40°C (>104°F), hypotension, jaundice, acute respiratory distress syndrome, and bleeding. By definition, any patient with a change in mental status or repeated seizure in the setting of fulminant malaria has cerebral malaria. In adults, this nonspecific febrile illness progresses to coma over several days; occasionally, coma occurs within hours and death within 24 h. Nuchal rigidity and photophobia are rare. On physical examination, symmetric encephalopathy is typical, and upper motor neuron dysfunction with decorticate and decerebrate posturing can be seen in advanced disease. Unrecognized infection results in a 20–30% mortality rate.

Intracranial and Spinal Epidural Abscesses

Spinal and intracranial epidural abscesses (SEAs and ICEAs) can result in permanent neurologic deficits, sepsis, and death (See also Chap. 434). At-risk patients include those with diabetes mellitus; IV drug use; chronic alcohol abuse; recent spinal trauma, surgery, or epidural anesthesia; and other comorbid conditions, such as HIV infection. Fungal epidural abscess and meningitis can follow epidural or paraspinal glucocorticoid injections. In the United States and Canada, where early treatment of otitis and sinusitis is typical, ICEA is rare but the number of cases of SEA is on the rise. In Africa and areas with limited access to health care, SEAs and ICEAs cause significant morbidity and mortality. ICEAs typically present as fever, mental status changes, and neck pain, while SEAs often present as fever, localized spinal tenderness, and back pain. ICEAs are typically polymicrobial, whereas SEAs are most often due to hematogenous seeding, with staphylococci the most common etiologic agent. Early diagnosis and treatment, which may include surgical drainage, minimize rates of mortality and permanent neurologic sequelae. Outcomes are worse for SEA due to MRSA, for infection at a higher vertebral-body level, for impaired neurologic status on presentation, and for dorsal rather than ventral location of the abscess. Elderly patients and persons with renal failure, malignancy, and other comorbidities also have less favorable outcomes.

OTHER FOCAL SYNDROMES WITH A FULMINANT COURSE

Infection at virtually any primary focus (e.g., osteomyelitis, pneumonia, pyelonephritis, or cholangitis) can result in bacteremia and sepsis. Lemierre’s syndrome—jugular septic thrombophlebitis caused by Fusobacterium necrophorum—is associated with metastatic infectious emboli (primarily to the lung but sometimes to the liver or other organs) and sepsis, with mortality rates of >15%. TSS has been associated with focal infections such as septic arthritis, peritonitis, sinusitis, and wound infection. Rapid clinical deterioration and death can be associated with destruction of the primary site of infection, as is seen in endocarditis and in infections of the oropharynx (e.g., Ludwig’s angina or epiglottitis, in which edema suddenly compromises the airway).

Rhinocerebral Mucormycosis

Individuals with diabetes or immunocompromising conditions such as solid organ transplants or hematologic malignancies are at risk for invasive rhinocerebral mucormycosis (See also Chap. 213). Patients present with low-grade fever, dull sinus pain, diplopia, decreased mental status, decreased ocular motion, chemosis, proptosis, dusky or necrotic nasal turbinates, and necrotic hard-palate lesions that respect the midline. Without rapid recognition and intervention, the process continues on an inexorable invasive course, with mortality rates of 50–85% or greater. Uncontrolled diabetes and increasing age are negative prognostic factors.

Acute Bacterial Endocarditis

This entity presents with a much more aggressive course than subacute endocarditis (See also Chap. 123). Bacteria such as S. aureus, S. pneumoniae, L. monocytogenes, Haemophilus species, and streptococci of groups A, B, and G attack native valves. Native-valve endocarditis caused by S. aureus (including MRSA strains) is increasing, particularly in health care settings. Mortality rates range from 10% to 40%. The host may have comorbid conditions such as underlying malignancy, diabetes mellitus, IV drug use, or alcoholism. The patient presents with fever, fatigue, and malaise <2 weeks after onset of infection. On physical examination, a changing murmur and congestive heart failure may be noted. Hemorrhagic macules on palms or soles (Janeway lesions) sometimes develop. Petechiae, Roth’s spots, splinter hemorrhages, and splenomegaly are unusual. Rapid valvular destruction, particularly of the aortic valve, results in pulmonary edema and hypotension. Myocardial abscesses can form, eroding through the septum or into the conduction system and causing life-threatening arrhythmias or high-degree conduction block. Large friable vegetations can result in major arterial emboli, metastatic infection, or tissue infarction. Older patients with S. aureus endocarditis are especially likely to present with nonspecific symptoms—a circumstance that delays diagnosis and worsens prognosis. Rapid intervention is crucial for a successful outcome.

Inhalational Anthrax

Inhalational anthrax, the most severe form of disease caused by B. anthracis, had not been reported in the United States for more than 25 years until the use of this organism as an agent of bioterrorism in 2001 (See also Chap. S2). Patients presented with malaise, fever, cough, nausea, drenching sweats, shortness of breath, and headache. Rhinorrhea was unusual. All patients had abnormal chest roentgenograms at presentation. Pulmonary infiltrates, mediastinal widening, and pleural effusions were the most common findings. Hemorrhagic meningitis was documented in 38% of these patients. Survival was more likely when antibiotics were given during the prodromal period and when multidrug regimens were used. In the absence of urgent intervention with antimicrobial agents and supportive care, inhalational anthrax progresses rapidly to hypotension, cyanosis, and death.

Viral Respiratory Tract Illness

Viral respiratory tract illnesses can cause severe disease; several new syndromes have been described in the past decade. For patients who present with a respiratory illness and a relevant exposure and travel history, these viral illnesses must be considered and appropriate infection control measures instituted in addition to supportive care.

Avian and Swine Influenza

Human cases of avian influenza have occurred primarily in Southeast Asia, particularly Vietnam (H5N1) and China (H7N9) (See also Chap. 195). Avian influenza should be considered in patients with severe respiratory tract illness, particularly if they have been exposed to poultry. Patients present with high fever, an influenza-like illness, and lower respiratory tract symptoms; this illness can progress rapidly to bilateral pneumonia, acute respiratory distress syndrome, multiorgan failure, and death. Younger age appears to be associated with a lower risk of complications. Early antiviral treatment with neuraminidase inhibitors should be initiated along with aggressive supportive measures. Unlike avian influenza, whose human-to-human transmission has so far been rare and has not been sustained, influenza caused by a novel swine-associated A/H1N1 virus has spread rapidly throughout the world; by 2012, 214 countries had diagnosed cases of influenza A/H1N1, with 18,449 deaths. Patients most at risk of severe disease are children <5 years of age, elderly persons, patients with underlying chronic conditions, and pregnant women. Obesity also has been identified as a risk factor for severe illness. Immunosuppression and co-infection with S. aureus at presentation are independent risk factors for increased mortality.

SARS and MERS

Severe acute respiratory syndrome (SARS) was identified in 2002 in China but has been diagnosed in several countries, primarily in Asia. Possible animal reservoirs include bats and civets. SARS is caused by a coronavirus and is characterized by efficient human transmission but relatively low mortality. It spreads from person to person via droplets; “super-spreader” airborne events have occurred. The potential pandemic with SARS was controlled through identification and isolation of infected patients. A 3- to 7-day prodrome characterized by fever, malaise, headache, and myalgia can progress to nonproductive cough, dyspnea, and respiratory failure. The risk of contagion is low during the prodrome. Older patients and those with diabetes mellitus, chronic hepatitis B, and other comorbidities can have less favorable outcomes.

Middle East respiratory syndrome (MERS) is caused by a novel betacoronavirus and was first recognized in 2012 in Saudi Arabia. Human cases have been associated with direct and indirect contact with dromedary camels. Unlike SARS, MERS exhibits inefficient human transmission but carries a high mortality rate. As of 2015, 1180 cases had been confirmed, with 40% mortality. MERS ranges from asymptomatic infection to acute respiratory distress syndrome, multiorgan failure, and death. Elderly men with comorbidities appear to be at highest risk for poor outcomes. Despite little documented human-to-human transmission in the community, nosocomial infection must be prevented by adherence to strict infection control practices. MERS is currently a low-level public health threat and is likely to remain so unless the virus mutates and its transmissibility increases.

Hantavirus Pulmonary Syndrome

Hantavirus pulmonary syndrome has been documented in the United States since 1993 (primarily the southwestern states, west of the Mississippi River), Canada, and South America (See also Chap. 204). Most cases occur in rural areas and are associated with exposure to rodents. Patients present with a nonspecific viral prodrome of fever, malaise, myalgias, nausea, vomiting, and dizziness that may progress to pulmonary edema, respiratory failure, and death. Hantavirus pulmonary syndrome causes myocardial depression and increased pulmonary vascular permeability; therefore, careful fluid resuscitation and use of pressor agents are crucial. Aggressive cardiopulmonary support during the first few hours of illness can be life-saving in this high-mortality syndrome. The early onset of thrombocytopenia may help distinguish this syndrome from other febrile illnesses in an appropriate epidemiologic setting.

Clostridium difficile Infection

C. difficile infection (CDI) is a toxin-mediated diarrheal syndrome that is strongly associated with prior antibiotic use. Proton-pump inhibitors have also been identified as a potential risk factor for the disease. Although most cases of CDI have occurred in the health care setting, community-onset CDI is increasing. Overall, community-onset cases occur in younger patients than nosocomial cases. Patients with community-onset CDI are less likely to have a history of antibiotic or protein-pump inhibitor use. CDI is associated with significant morbidity and mortality, particularly among older patients. The Centers for Disease Control and Prevention has reported that C. difficile infection is one of the top three health threats associated with antibiotic use.

SUMMARY

Acutely ill febrile patients with the syndromes discussed in this chapter require close observation, aggressive supportive measures, and—in most cases—admission to intensive care units. The most important task of the physician is to distinguish these patients from other infected febrile patients whose illness will not progress to fulminant disease. The alert physician must recognize the acute infectious disease emergency and then proceed with appropriate urgency.

FURTHER READING

Additional Online References

INTRODUCTION

Few medical interventions of the past century can rival the effect that immunization has had on longevity, economic savings, and quality of life. Seventeen diseases are now preventable through vaccines routinely administered to children and adults in the United States (Table 118-1), and most vaccine-preventable diseases of childhood are at historically low levels (Table 118-2). Health care providers deliver the vast majority of vaccines in the United States in the course of providing routine health services and therefore play an integral role in the nation’s public health system.

VACCINE IMPACT

Direct and Indirect Effects

Immunizations against specific infectious diseases protect individuals against infection and thereby prevent symptomatic illnesses. Specific vaccines may blunt the severity of clinical illness (e.g., rotavirus vaccines and severe gastroenteritis) or reduce complications (e.g., zoster vaccines and postherpetic neuralgia). Some immunizations also reduce transmission of infectious disease agents from immunized people to others, thereby reducing the impact of infection spread. This indirect impact is known as herd immunity. The level of immunization in a population that is required to achieve indirect protection of unimmunized people varies substantially with the specific vaccine and disease.

Since childhood vaccines have become widely available in the United States, major declines in rates of vaccine-preventable diseases among both children and adults have become evident (Table 118-2). For example, vaccination of children <5 years of age against seven types of Streptococcus pneumoniae led to a >90% overall reduction in invasive disease caused by those types. Among children born during 1994–2013, a series of childhood vaccines targeting 13 vaccine-preventable diseases will prevent 322 million illnesses and 732,000 deaths over the course of their lifetimes and save $1.38 trillion (U.S.).

Control, Elimination, and Eradication of Vaccine-Preventable Diseases

Immunization programs are associated with the goals of controlling, eliminating, or eradicating a disease. Control of a vaccine-preventable disease reduces poor illness outcomes and often limits the disruptive impacts associated with outbreaks of disease in communities, schools, and institutions. Control programs can also reduce absences from work for ill persons and for parents caring for sick children, decrease absences from school, and limit health care utilization associated with treatment visits.

Elimination of a disease is a more demanding goal than control, usually requiring the reduction to zero of cases in a defined geographic area but sometimes defined as reduction in the indigenous sustained transmission of an infection in a geographic area. As of 2016, the United States had eliminated indigenous transmission of measles, rubella, poliomyelitis, and diphtheria. Importation of pathogens from other parts of the world continues to be important, and public health efforts are intended to respond promptly to such cases in order to limit forward spread of the infectious agent.

Eradication of a disease is achieved when its elimination can be sustained without the need to continue interventions. The only vaccine-preventable disease of humans that has been globally eradicated thus far is smallpox. Although smallpox vaccine is no longer given routinely, the disease has not reemerged naturally because all chains of human transmission were interrupted through earlier vaccination efforts and humans were the only natural reservoir of the virus. Currently, a major health initiative is targeting the global eradication of polio. Sustained transmission of polio has been eliminated from most nations but has not yet been interrupted in Afghanistan and Pakistan. In 2016, after Nigeria completed 2 years without a wild polio case detected, three cases were identified in a region where vaccinators have been unable to reach hundreds of thousands of children because of insurgency and the virus is likely to have been circulating undetected. Detection of a case of disease that has been targeted for eradication or elimination is considered a sentinel event that could permit the infectious agent to become reestablished in the community or region. Therefore, such episodes must be promptly reported to public health authorities.

Outbreak Detection and Control

Clusters of cases of a vaccine-preventable disease detected in an institution, a medical practice, or a community may signal important changes in the pathogen, vaccine, or environment. Several factors can give rise to increases in vaccine-preventable disease, including (1) low rates of immunization that result in an accumulation of susceptible people (e.g., measles resurgence among vaccination abstainers); (2) changes in the infectious agent that permit it to escape vaccine-induced protection (e.g., non-vaccine-type pneumococci); (3) waning of vaccine-induced immunity (e.g., pertussis among adolescents and adults vaccinated in early childhood); and (4) point-source introductions of large inocula (e.g., food-borne exposure to hepatitis A virus). Reporting episodes of outbreak-prone diseases to public health authorities can facilitate recognition of clusters that require further interventions.

Public Health Reporting

Recognition of suspected cases of diseases targeted for elimination or eradication—along with other diseases that require urgent public health interventions, such as contact tracing, administration of chemo- or immunoprophylaxis, or epidemiologic investigation for common-source exposure—is typically associated with special reporting requirements. Many diseases against which vaccines are routinely used, including measles, pertussis, Haemophilus influenzae type b invasive disease, and varicella, are nationally notifiable. Clinicians and laboratory staff have a responsibility to report some vaccine-preventable disease occurrences to local or state public health authorities according to specific case-definition criteria. All providers should be aware of state or city disease-reporting requirements and the best ways to contact public health authorities. A prompt response to vaccine-preventable disease outbreaks can greatly enhance the effectiveness of control measures.

Global Considerations

Several international health initiatives currently focus on reducing vaccine-preventable diseases in regions throughout the world. The American Red Cross, the World Health Organization (WHO), the United Nations Foundation, the United Nations Children’s Fund (UNICEF), and the Centers for Disease Control and Prevention (CDC) are partners in the Measles & Rubella Initiative, which targets reduction of worldwide measles deaths. During 2000–2014, global measles mortality rates declined by 78%—i.e., from an estimated 535,300 deaths in 2000 to 114,900 deaths in 2014. In 2015, the Americas became the first WHO region to be declared free of endemic transmission of rubella. Rotary International, UNICEF, the CDC, and the WHO are leading partners in the global eradication of polio, an endeavor that reduced the annual number of paralytic polio cases from 350,000 in 1988 to 74 in 2015. The GAVI Alliance and the Bill and Melinda Gates Foundation have brought substantial momentum to global efforts to reduce vaccine-preventable diseases, expanding on earlier efforts by the WHO, UNICEF, and governments in developed and developing countries.

Enhancing Immunization in Adults

Although immunization has become a centerpiece of routine pediatric medical visits, it has not been as well integrated into routine health care visits for adults. This chapter focuses on immunization principles and vaccine use in adults. Accumulating evidence suggests that immunization coverage can be increased through efforts directed at consumer-, provider-, institution-, and system-level factors. The literature suggests that the application of multiple strategies is more effective at raising coverage rates than is the use of any single strategy.

Recommendations for Adult Immunizations

The CDC’s Advisory Committee on Immunization Practices (ACIP) is the main source of recommendations for administration of vaccines approved by the U.S. Food and Drug Administration (FDA) for use in children and adults in the U.S. civilian population. The ACIP is a federal advisory committee that consists of 15 voting members (experts in fields associated with immunization) appointed by the Secretary of the U.S. Department of Health and Human Services; 8 ex officio members representing federal agencies; and 30 nonvoting representatives of various liaison organizations, including major medical societies and managed-care organizations. The ACIP recommendations, which are available at www.cdc.gov/vaccines/hcp/acip-recs/, are harmonized to the greatest extent possible with vaccine recommendations made by other organizations, including the American College of Obstetricians and Gynecologists, the American Academy of Family Physicians, and the American College of Physicians.

Adult Immunization Schedules

Immunization schedules for adults in the United States are updated annually and can be found online (www.cdc.gov/vaccines/schedules/hcp/adult.html). In February, the schedules are published in American Family Physician, Annals of Internal Medicine, and Morbidity and Mortality Weekly Report (www.cdc.gov/mmwr). The adult immunization schedules for 2016 are summarized in Fig. 118-1. Additional information and specifications are contained in the footnotes to these schedules. In the time between annual publications, additions and changes to schedules are published in Morbidity and Mortality Weekly Report.

IMMUNIZATION PRACTICE STANDARDS

Administering immunizations to adults involves a number of processes, such as deciding whom to vaccinate, assessing vaccine contraindications and precautions, providing vaccine information statements (VISs), ensuring appropriate storage and handling of vaccines, administering vaccines, and maintaining vaccine records. In addition, provider reporting of adverse events that follow vaccination is an essential component of the vaccine safety monitoring system. In 2014, the standards for adult immunization were revised to focus on vaccinating adults at every opportunity.

Deciding Whom to Vaccinate

Every effort should be made to ensure that adults receive all indicated vaccines as expeditiously as possible. When adults present for care, their immunization history should be assessed and recorded, and this information should be used to identify needed vaccinations according to the most current version of the adult immunization schedule. Decision-support tools incorporated into electronic health records can provide prompts for needed vaccinations. Standing orders, which are often used for routinely indicated vaccines (e.g., influenza and pneumococcal vaccines), permit a nurse or another approved licensed practitioner to administer vaccines without a specific physician order, thus lowering barriers to adult immunization.

Assessing Contraindications and Precautions

Before vaccination, all patients should be screened for contraindications and precautions. A contraindication is a condition that increases the risk of a serious adverse reaction to vaccination. A vaccine should not be administered when a contraindication is documented. For example, a history of an anaphylactic reaction to a dose of vaccine or to a vaccine component is a contraindication for further doses. A precaution is a condition that may increase the risk of an adverse event or that may compromise the ability of the vaccine to evoke immunity (e.g., administering measles vaccine to a person who has recently received a blood transfusion and may consequently have transient passive immunity to measles virus). Normally, a vaccine is not administered when a precaution is noted. However, situations may arise when the benefits of vaccination outweigh the estimated risk of an adverse event, and the provider may decide to vaccinate the patient despite the precaution.

In some cases, contraindications and precautions are temporary and may lead to mere deferral of vaccination until a later time. For example, moderate or severe acute illness with or without fever is generally considered a transient precaution to vaccination and results in postponement of vaccine administration until the acute phase has resolved; thus the superimposition of adverse effects of vaccination on the underlying illness and the mistaken attribution of a manifestation of the underlying illness to the vaccine are avoided. Contraindications and precautions to vaccines licensed in the United States for use in civilian adults are summarized in Table 118-3. It is important to recognize conditions that are not contraindications in order not to miss opportunities for vaccination. For example, in most cases, mild acute illness (with or without fever), a history of a mild to moderate local reaction to a previous dose of the vaccine, and breast-feeding are not contraindications to vaccination.

History of Immediate Hypersensitivity to a Vaccine Component

A severe allergic reaction (e.g., anaphylaxis) to a previous dose of a vaccine or to one of its components is a contraindication to vaccination. While most vaccines have many components, substances to which individuals are most likely to have had a severe allergic reaction include egg protein, gelatin, and yeast. In addition, although natural rubber (latex) is not a vaccine component, some vaccines are supplied in vials or syringes that contain natural rubber latex. These vaccines can be identified by the product insert and should not be administered to persons who report a severe (anaphylactic) allergy to latex unless the benefit of vaccination clearly outweighs the risk for a potential allergic reaction. The much more common local or contact hypersensitivity to latex, such as to medical gloves (which contain synthetic latex that is not linked to allergic reactions), is not a contraindication to administration of a vaccine supplied in a vial or syringe that contains natural rubber latex. Vaccines routinely indicated for adults that, as of February 2015, were sometimes supplied in a vial or syringe containing natural rubber include Havrix hepatitis A vaccine (syringe); Vaqta hepatitis A vaccine (vial and syringe); Engerix-B hepatitis B vaccine (syringe); Recombivax HB hepatitis B vaccine (vial); Cervarix HPV vaccine (syringe); Fluvirin, Agriflu (syringe), and Flucelvax (syringe) influenza vaccines; Adacel and Boostrix Tdap (tetanus and diphtheria toxoids and acellular pertussis) vaccines (syringe); Td (tetanus and diphtheria toxoids) vaccines (syringe); Twinrix hepatitis A and B vaccine (syringe); Menomune meningococcal polysaccharide vaccine (vial); and Bexsero meningococcal serogroup B vaccine (syringe).

Pregnancy

Live-virus vaccines are contraindicated during pregnancy because of the hypothetical risk that vaccine virus replication will cause congenital infection or have other adverse effects on the fetus. Most live-virus vaccines, including varicella vaccine, are not secreted in breast milk; therefore, breast-feeding is not a contraindication for live-virus or other vaccines. Pregnancy is not a contraindication to administration of inactivated vaccines, but most are avoided during pregnancy because relevant safety data are limited. Two inactivated vaccines, Tdap vaccine and inactivated influenza vaccine, are routinely recommended for pregnant women in the United States. Tdap vaccine is recommended during each pregnancy, regardless of prior vaccination status, in order to prevent pertussis in neonates. Annual influenza vaccination is recommended for all persons 6 months of age and older, regardless of pregnancy status. Some other inactivated vaccines, such as meningococcal vaccines, may be given to pregnant women in certain circumstances.

Immunosuppression

Live-virus vaccines elicit an immune response due to replication of the attenuated (weakened) vaccine virus that is contained by the recipient’s immune system. In persons with compromised immune function, enhanced replication of vaccine viruses is possible and could lead to disseminated infection with the vaccine virus. For this reason, live-virus vaccines are contraindicated for persons with severe immunosuppression, the definition of which may vary with the vaccine. Severe immunosuppression may be caused by many disease conditions, including HIV infection and hematologic or generalized malignancy. In some of these conditions, all affected persons are severely immunocompromised. In others (e.g., HIV infection), the degree to which the immune system is compromised depends on the severity of the condition, which in turn depends on the stage of disease or treatment. For example, measles-mumps-rubella (MMR) vaccine may be given to HIV-infected persons who are not severely immunocompromised. Severe immunosuppression may also be due to therapy with immunosuppressive agents, including high-dose glucocorticoids. In this situation, the dose, duration, and route of administration may influence the degree of immunosuppression.

VACCINE INFORMATION STATEMENTS

A VIS is a one-page (two-sided) information sheet produced by the CDC that informs vaccine recipients (or their parents or legal representatives) about the benefits and risks of a vaccine. VISs are mandated by the National Childhood Vaccine Injury Act (NCVIA) of 1986 and—whether the vaccine recipient is a child or an adult—must be provided for any vaccine covered by the Vaccine Injury Compensation Program. As of July 2016, vaccines that are covered by the NCVIA and that are licensed for use in adults include Td, Tdap, hepatitis A, hepatitis B, human papillomavirus, inactivated influenza, live intranasal influenza, MMR, pneumococcal conjugate, meningococcal conjugate, serogroup B meningococcal, polio, and varicella vaccines. When combination vaccines for which no separate VIS exists are given (e.g., hepatitis A and B combination vaccine), all relevant VISs should be provided. VISs also exist for some vaccines not covered by the NCVIA, such as pneumococcal polysaccharide, Japanese encephalitis, rabies, herpes zoster, typhoid, anthrax, and yellow fever vaccines. The use of these VISs is encouraged but is not mandated.

All current VISs are available on the Internet at two websites: the CDC’s Vaccines & Immunizations site (www.cdc.gov/vaccines/hcp/vis/) and the Immunization Action Coalition’s site (www.immunize.org/vis/). (The latter site also includes translations of the VISs.) VISs from these sites can be downloaded and printed.

STORAGE AND HANDLING

Injectable vaccines are packaged in multidose vials, single-dose vials, or manufacturer-filled single-dose syringes. The live attenuated nasal-spray influenza vaccine is packaged in single-dose sprayers. Oral typhoid vaccine is packaged in capsules. Some vaccines, such as MMR, varicella, zoster, and meningococcal polysaccharide vaccines, come as lyophilized (freeze-dried) powders that must be reconstituted (i.e., mixed with a liquid diluent) before use. The lyophilized powder and the diluent come in separate vials. Diluents are not interchangeable but rather are specifically formulated for each type of vaccine; only the specific diluent provided by the manufacturer for each type of vaccine should be used. Once lyophilized vaccines have been reconstituted, their shelf-life is limited and they must be stored under appropriate temperature and light conditions. For example, varicella and zoster vaccines must be protected from light and administered within 30 min of reconstitution; MMR vaccine likewise must be protected from light but can be used up to 8 h after reconstitution. Single-dose vials of meningococcal polysaccharide vaccine must be used within 30 min of reconstitution, while multidose vials must be used within 35 days.

Vaccines are stored either at refrigerator temperature (2–8°C) or at freezer temperature (–15°C or colder). In general, inactivated vaccines (e.g., inactivated influenza, pneumococcal polysaccharide, and meningococcal conjugate vaccines) are stored at refrigerator temperature, while vials of lyophilized-powder live-virus vaccines (e.g., varicella, zoster, and MMR vaccines) are stored at freezer temperature. Diluents for lyophilized vaccines may be stored at refrigerator or room temperature. Live attenuated influenza vaccine—a live-virus liquid formulation administered by nasal spray—is stored at refrigerator temperature.

Vaccine storage and handling errors can result in the loss of vaccines worth millions of dollars, and administration of improperly stored vaccines may elicit inadequate immune responses in patients. To improve the standard of vaccine storage and handling practices, the CDC has published detailed guidance (available at www.cdc.gov/vaccines/hcp/admin/storage/toolkit/storage-handling-toolkit.pdf). For vaccine storage, the CDC recommends stand-alone units—i.e., self-contained units that either refrigerate or freeze but do not do both—as these units maintain the required temperatures better than combination refrigerator/freezer units. Dormitory-style combined refrigerator/freezer units should never be used for vaccine storage.

The temperature of refrigerators and freezers used for vaccine storage must be monitored and recorded at least twice each workday. Ideally, continuous thermometers that measure and record temperature all day and all night are used, and minimal and maximal temperatures are read and documented each workday. The CDC recommends the use of calibrated digital thermometers with a probe in thermal-buffered material; more detailed information on specifications of storage units and temperature-monitoring devices is provided at the link given above.

ADMINISTRATION OF VACCINES

Most parenteral vaccines recommended for routine administration to adults in the United States are given by either the IM or the SC route; one influenza vaccine formulation approved for use in adults 18–64 years of age is given intradermally. Live-virus vaccines such as varicella, zoster, and MMR are given SC. Most inactivated vaccines are given IM. The 23-valent pneumococcal polysaccharide vaccine may be given either IM or SC, but IM administration is preferred because it is associated with a lower risk of injection-site reactions.

Vaccines given to adults by the SC route are administered with a 5/8-inch needle into the upper outer-triceps area. Vaccines administered to adults by the IM route are injected into the deltoid muscle (Fig. 118-2) with a needle whose length should be selected on the basis of the recipient’s sex and weight to ensure adequate penetration into the muscle. Current guidelines indicate that, for men and women weighing <152 lbs (<70 kg), a 1-inch needle is sufficient; for women weighing 152–200 lbs (70–90 kg) and men weighing 152–260 lbs (70–118 kg), a 1- to 1.5-inch needle is needed; and for women weighing >200 lbs (>90 kg) and men weighing >260 lbs (>118 kg), a 1.5-inch needle is required. Additional illustrations of vaccine injection locations and techniques may be found at www.immunize.org/catg.d/p2020a.pdf.

Aspiration, the process of pulling back on the plunger of the syringe after skin penetration but prior to injection, is not necessary because no large blood vessels are present at the recommended vaccine injection sites.

Multiple vaccines can be administered at the same visit; indeed, administration of all needed vaccines at one visit is encouraged. Studies have shown that vaccines are as effective when administered simultaneously as they are individually, and simultaneous administration of multiple vaccines is not associated with an increased risk of adverse effects. If more than one vaccine must be administered in the same limb, the injection sites should be separated by 1–2 inches so that any local reactions can be differentiated. If a vaccine and an immune globulin preparation are administered simultaneously (e.g., Td vaccine and tetanus immune globulin), a separate anatomic site should be used for each injection.

For certain vaccines (e.g., HPV vaccine and hepatitis B vaccine), multiple doses are required for an adequate and persistent antibody response. The recommended vaccination schedule specifies the interval between doses. Many adults who receive the first dose in a multiple-dose vaccine series do not complete the series or do not receive subsequent doses within the recommended interval; this lack of adherence to protocol compromises vaccine efficacy and/or the duration of protection. Providers should implement recall systems that will prompt patients to return for subsequent doses in a vaccination series at the appropriate intervals. With the exception of oral typhoid vaccination, an interruption in the schedule does not require restarting of the entire series or the addition of extra doses.

Syncope may follow vaccination, especially in adolescents and young adults. Serious injuries, including skull fracture and cerebral hemorrhage, have occurred. Adolescents and adults should be seated or lying down during vaccination. The majority of reported syncope episodes after vaccination occur within 15 min. The ACIP recommends that vaccine providers strongly consider observing patients, particularly adolescents, with patients seated or lying down for 15 min after vaccination. If syncope develops, patients should be observed until the symptoms resolve.

Anaphylaxis is a rare complication of vaccination. All facilities providing immunizations should have an emergency kit containing aqueous epinephrine for administration in the event of a systemic anaphylactic reaction.

MAINTENANCE OF VACCINE RECORDS

All vaccines administered should be fully documented in the patient’s permanent medical record. Documentation should include the date of administration, the name or common abbreviation of the vaccine, the vaccine lot number and manufacturer, the administration site, the VIS edition, the date the VIS was provided, and the name, address, and title of the person who administered the vaccine. Increasing use of two-dimensional bar codes on vaccine vials and syringes that can be scanned for data entry into compatible electronic medical records and immunization information systems may facilitate more complete and accurate recording of required information.

VACCINE SAFETY MONITORING AND ADVERSE EVENT REPORTING

Prelicensure Evaluations of Vaccine Safety

Before vaccines are licensed by the FDA, they are evaluated in clinical trials with volunteers. These trials are conducted in three progressive phases. Phase 1 trials are small, usually involving fewer than 100 volunteers. Their purposes are to provide a basic evaluation of safety and to identify common adverse events. Phase 2 trials, which are larger and may involve several hundred participants, collect additional information on safety and are usually designed to evaluate immunogenicity as well. Data gained from phase 2 trials can be used to determine the composition of the vaccine, the number of doses required, and a profile of common adverse events. Vaccines that appear promising are evaluated in phase 3 trials, which typically involve several hundred to several thousand volunteers and are generally designed to demonstrate vaccine efficacy and provide additional information on vaccine safety.

Postlicensure Monitoring of Vaccine Safety

After licensure, a vaccine’s safety is assessed by several mechanisms. The NCVIA of 1986 requires health care providers to report certain adverse events that follow vaccination. As a mechanism for that reporting, the Vaccine Adverse Event Reporting System (VAERS) was established in 1990 and is jointly managed by the CDC and the FDA. This safety surveillance system collects reports of adverse events associated with vaccines currently licensed in the United States. Adverse events are defined as untoward events that occur after immunization and that might be caused by the vaccine product or vaccination process. While the VAERS was established in response to the NCVIA, any adverse event following vaccination—whether in a child or an adult, and whether or not it is believed to have actually been caused by vaccination—may be reported through the VAERS. The adverse events that health care providers are required to report are listed in the reportable-events table on the VAERS website at vaers.hhs.gov/reportable.htm. During 2011–2014, approximately 30,000 VAERS reports were filed annually, with ~7% reporting serious events resulting in hospitalization, life-threatening illness, disability, or death.

Anyone can file a VAERS report, including health care providers, manufacturers, and vaccine recipients or their parents or guardians. VAERS reports may be submitted online (https://vaers.hhs.gov/reportevent.html) or by completing a paper form requested by email (info@vaers.org) or phone (800-822-7967). The VAERS form asks for the following information: the type of vaccine received; the timing of vaccination; the time of onset of the adverse event; and the recipient’s current illnesses or medications, history of adverse events following vaccination, and demographic characteristics (e.g., age and sex). This information is entered into a database. The individual who reported the adverse event then receives a confirmation letter by mail with a VAERS identification number that can be used if additional information is submitted later. In selected cases of serious adverse reaction, the patient’s recovery status may be followed up at 60 days and 1 year after vaccination. The FDA and the CDC have access to VAERS data and use this information to monitor vaccine safety and conduct research studies. VAERS data (minus personal information) are also available to the public.

While the VAERS provides useful information on vaccine safety, this passive reporting system has important limitations. One is that events following vaccination are merely reported; the system cannot assess whether a given type of event occurs more often than expected after vaccination. A second is that event reporting is incomplete and is biased toward events that are believed to be more likely to be due to vaccination and that occur relatively soon after vaccination. To obtain more systematic information on adverse events occurring in both vaccinated and unvaccinated persons, the Vaccine Safety Datalink project was initiated in 1991. Directed by the CDC, this project includes nine managed-care organizations in the United States; member databases include information on immunizations, medical conditions, demographics, laboratory results, and medication prescriptions. The Department of Defense oversees a similar system monitoring the safety of immunizations among active-duty military personnel. In addition, postlicensure evaluations of vaccine safety may be conducted by the vaccine manufacturer. In fact, such evaluations are often required by the FDA as a condition of vaccine licensure.

CONSUMER ACCESS TO AND DEMAND FOR IMMUNIZATION

By removing barriers to the consumer or patient, providers and health care institutions can improve vaccine use. Financial barriers have traditionally been important constraints, particularly among uninsured adults. Even for insured adults, out-of-pocket costs associated with newer, more expensive adult vaccines (e.g., zoster vaccine) are an obstacle to be overcome. After influenza vaccine was included by Medicare for all beneficiaries in 1993, coverage among persons ≥65 years of age doubled (from ~30% in 1989 to >60% in 1997). Other strategies that enhance patients’ access to vaccination include extended office hours (e.g., evening and weekend hours) and scheduled vaccination-only clinics where waiting times are reduced. Provision of vaccines outside the “medical home” (e.g., through occupational clinics, universities, pharmacies, and retail settings) can expand access for adults who do not make medical visits frequently. Increasing proportions of adults are being vaccinated in these settings.

Health promotion efforts aimed at increasing the demand for immunization are common. Direct-to-consumer advertising by pharmaceutical companies has been used for some newer adolescent and adult vaccines. Efforts to raise consumer demand for vaccines have not increased immunization rates unless implemented in conjunction with other strategies that target strengthening of provider practices or reduction of consumer barriers. Attitudes and beliefs related to vaccination can be considerable impediments to consumer demand. Many adults view vaccines as important for children but are less familiar with vaccinations targeting disease prevention in adults. Several vaccines are recommended for adults with certain medical risk factors, but self-identification as a high-risk individual is relatively rare. Communication research suggests that adults are motivated to get vaccines to protect their own health and many would get vaccinated to protect loved ones. Adults with chronic conditions are more likely to be aware that they need to protect their own health. Some vaccines are explicitly recommended for persons at relatively low risk of serious complications, with the goal of reducing the risk of transmission to higher-risk contacts. For example, for protection of newborns, vaccinations against influenza and pertussis are recommended for pregnant women.

STRATEGIES FOR PROVIDERS AND HEALTH CARE FACILITIES

Recommendation from the Provider

Health care providers can have great influence on patients with regard to immunization. A recommendation from a doctor or nurse carries more weight than do recommendations from professional societies or endorsements by celebrities. Providers should be well informed about vaccine risks and benefits so that they can address patients’ common concerns. The CDC, the American College of Physicians, and the American Academy of Family Physicians review and update the schedule for adult immunization on an annual basis and have developed educational materials to facilitate provider–patient discussions about vaccination (www.cdc.gov/vaccines/hcp.htm).

System Supports

Medical offices can incorporate a variety of methods to ensure that providers consistently offer specific immunizations to patients with indications for specific vaccines. Decision-support tools have been incorporated into some electronic health records to alert the provider when specific vaccines are indicated. Manual or automated reminders and standing orders have been discussed (see “Deciding Whom to Vaccinate,” above) and have consistently improved vaccination coverage in both office and hospital settings. Most clinicians’ estimates of their own performance diverge from objective measurements of their patients’ immunization coverage; quantitative assessment and feedback have been shown in pediatric and adolescent practices to increase immunization performance significantly. Some health plans have instituted incentives for providers with high rates of immunization coverage. Specialty providers, including obstetrician–gynecologists, may be the only providers serving some high-risk patients with indications for selected vaccines (e.g., Tdap, influenza, or pneumococcal polysaccharide vaccine).

Immunization Requirements

Vaccination against selected communicable diseases is required for attendance at many universities and colleges as well as for service in the U.S. military or in some occupational settings (e.g., child care, laboratory, veterinary, and health care). Immunizations are recommended and sometimes required for travel to certain countries (Chap. 119).

Vaccination of Health Care Staff

A particular area of focus for medical settings is vaccination of health care workers, including those with and without direct patient-care responsibilities. The Joint Commission (which accredits health care organizations), the CDC’s Healthcare Infection Control Practices Advisory Committee, and the ACIP all recommend influenza vaccination of all health care personnel; recommendations also focus on requiring documentation of declination for providers who do not accept annual influenza vaccination. As part of their participation in the Centers for Medicare and Medicaid Services’ Hospital Inpatient Quality Reporting program, acute-care hospitals are required to report the proportion of their health care personnel who have received seasonal influenza vaccine. Some institutions and jurisdictions have added mandates on influenza vaccination of health care workers and have expanded on earlier requirements related to vaccination or proof of immunity for hepatitis B, measles, mumps, rubella, and varicella.

VACCINATION IN NONMEDICAL SETTINGS

Receipt of vaccination in medical offices is most frequent among young children and adults ≥65 years of age. Patients in these age groups make more office visits and are more likely to receive care in a consistent “medical home” than are older children, adolescents, and nonelderly adults. Vaccination outside the medical home can expand access to those whose health care visits are limited and reduce the burden on busy clinical practices. In some locations, financial constraints related to inventory and storage requirements have led providers to stock few or no vaccines. Outside private office and hospital settings, vaccination may also occur at health department venues, workplaces, retail sites (including pharmacies and supermarkets), and schools or colleges.

When vaccines are given in nonmedical settings, it remains important for standards of immunization practice to be followed. Consumers should be provided with information on how to report adverse events (e.g., via provision of a VIS), and procedures should ensure that documentation of vaccine administration is forwarded to the primary care provider and the state or city public health immunization registry. Detailed documentation may be required for employment, school attendance, and travel. Personalized health records can help consumers keep track of their immunizations, and some occupational health clinics have incorporated automated immunization reports that help employees stay up-to-date with recommended vaccinations. Some pharmacy chain establishments are using automated systems to report immunization information to the state or local immunization information system.

PERFORMANCE MONITORING

Tracking of immunization coverage at national, state, institution, and practice levels can yield feedback to practitioners and programs and facilitate quality improvement. Healthcare Effectiveness Data and Information Set (HEDIS) measures related to adult immunization facilitate comparison of health plans. The CDC’s National Immunization Survey and National Health Interview Survey provide selected information on immunization coverage among adults and track progress toward achievement of Healthy People 2020 targets for immunization coverage. Influenza and pneumococcal vaccine coverage rates have been higher among persons ≥65 years of age (60–70%) than among high-risk 18- to 64-year-olds. Figures on state-specific immunization coverage with pneumococcal polysaccharide and influenza vaccines (as measured through the CDC’s Behavioral Risk Factor Surveillance System) reveal substantial geographic variation in coverage. There are persistent disparities in adult immunization coverage rates between whites and racial and ethnic minorities. In contrast, racial and economic disparities in immunization of young children have been dramatically reduced during the past 20 years. Much of this progress is attributed to the Vaccines for Children Program, which since 1994 has entitled uninsured children to receive free vaccines.

FUTURE TRENDS

Although most vaccines developed in the twentieth century targeted common acute infectious diseases of childhood, more recently developed vaccines prevent chronic conditions prevalent among adults. Hepatitis B vaccine prevents hepatitis B–related cirrhosis and hepatocellular carcinoma, and HPV vaccine prevents some types of cervical cancer, genital warts, and anogenital cancers and may also prevent some oropharyngeal cancers. A new herpes zoster subunit vaccine that was licensed in 2017 should substantially improve protection against zoster and postherpetic neuralgia. New targets of vaccine development and research may further broaden the definition of vaccine-preventable disease. Research is ongoing on vaccines to prevent insulin-dependent diabetes mellitus, nicotine addiction, and Alzheimer’s disease. Expanding strategies for vaccine development are incorporating molecular approaches such as DNA, vector, and peptide vaccines. New technologies, such as the use of transdermal and other needle-less routes of administration, are being applied to vaccine delivery.

FURTHER READING

INTRODUCTION

According to the United Nations World Tourism Organization, international tourist arrivals grew dramatically from 25 million in 1950 to >1 billion in 2016; limited data suggest that the only areas without the growth of tourism were in Africa. Not only are more people traveling; travelers are seeking more exotic and remote destinations. In addition to tourism travel, travel across borders has increased in other sectors as well—e.g., for visits with friends and relatives (VFRs) in travelers’ places of birth, for immigration, for business, and for missionary and volunteer work. Travel from industrialized to developing regions has been increasing, with Asia and the Pacific and the Middle East the emerging destinations. Figure 119-1 summarizes the monthly incidence of health problems during travel in developing countries. Studies continue to show that 50–75% of short-term travelers to the tropics or subtropics report some health impairment. Most of these health problems are minor: only 5% require medical attention, and <1% require hospitalization. Although infectious agents contribute substantially to morbidity among travelers, these pathogens account for only ~1% of deaths in this population. Cardiovascular disease and injuries are the most frequent causes of death among travelers from the United States, accounting for 49 and 22% of deaths, respectively. Age-specific rates of death due to cardiovascular disease are similar among travelers and non-travelers. In contrast, rates of death due to injury (the majority from motor vehicle, drowning, or aircraft accidents) are several times higher among travelers. Motor vehicle accidents account for >40% of travelers’ deaths that are not due to cardiovascular disease or preexisting illness.

GENERAL ADVICE

Health maintenance recommendations are based not only on the traveler’s destination but also on assessment of risk, which is determined by such variables as health status, specific itinerary, purpose of travel, season, and lifestyle during travel. Detailed information regarding country-specific risks and recommendations may be obtained from the Centers for Disease Control and Prevention (CDC) publication Health Information for International Travel (available at www.cdc.gov/travel).

Fitness for travel is an issue of growing concern in view of the increased numbers of elderly and chronically ill individuals journeying to exotic destinations (see “Travel and Special Hosts,” below). Since most commercial aircraft are pressurized to 2500 m (8000 ft) above sea level (corresponding to a Pao₂ of ~55 mmHg), individuals with serious cardiopulmonary problems or anemia should be evaluated before travel. In addition, those who have recently had surgery, a myocardial infarction, a cerebrovascular accident, or a deep-vein thrombosis may be at high risk for adverse events during flight. A summary of current recommendations regarding fitness to fly has been published by the Aerospace Medical Association Air Transport Medicine Committee (www.asma.org/publications/medical-publications-for-airline-travel). A pre-travel health assessment is advisable for individuals considering particularly adventurous recreational activities, such as mountain climbing and scuba diving.

IMMUNIZATIONS FOR TRAVEL

Immunizations for travel fall into three broad categories: routine (childhood/adult immunizations and boosters that are important regardless of travel), required (immunizations that are mandated by international regulations for entry into certain areas or for border crossings), and recommended (immunizations that are desirable because of travel-related risks). Required and recommended vaccines commonly given to travelers are listed in Table 119-1.

Routine Immunizations

DIPHTHERIA, TETANUS, AND POLIO

Diphtheria (Chap. 145) continues to be a problem worldwide. Large outbreaks have occurred in countries that do not have rigorous vaccination programs or that have reduced their public vaccination programs. Serologic surveys show that tetanus (Chap. 147) antibodies are lacking in many North Americans, especially in women aged >50. With the recent increase in pertussis among adults, the diphtheria–tetanus–acellular pertussis (Tdap) combination is now recommended for adults as a once-only replacement for the 10-year tetanus–diphtheria (Td) booster.

The risk of polio (Chap. 199) to the international traveler is extremely low despite challenges faced by eradication programs. Wild-type poliovirus has been eradicated from most areas of the world; Nigeria, Afghanistan, and Pakistan are the only countries where polio continues to be endemic. Some countries may actually require travelers who have been in country for >4 weeks to show proof on exiting that they have received polio vaccine within the previous year. (Because this list of countries changes, providers should check the CDC travelers’ health website at www.cdc.gov/travel.) Studies in the United States suggest that 12% of adult travelers are unprotected against at least one poliovirus serogroup. Foreign travel offers an ideal opportunity to have polio immunization updated.

MEASLES

Measles (rubeola) continues to be a major cause of morbidity and death in the developing world (Chap. 200). Several outbreaks of measles in the United States and Canada have been linked to imported cases, especially from Europe, where large outbreaks have occurred. The group at highest risk consists of persons born after 1956 and vaccinated before 1980, in many of whom primary vaccination failed. The measles–mumps–rubella (MMR) vaccine is typically used; its coverage of rubella also addresses a growing concern in some areas of Eastern Europe and Asia.

INFLUENZA

Influenza (Chap. 195)—possibly the most common vaccine-preventable infection in travelers—occurs year-round in the tropics and during the summer months in the Southern Hemisphere (coinciding with the winter months in the Northern Hemisphere). One prospective study showed that influenza developed in 1% of travelers to Southeast Asia per month of stay. Annual vaccination should be considered for all travelers who do not have a contraindication. The speed of global spread of the pandemic H1N1 virus in 2009 illustrated why influenza immunization is so important for travelers.

PNEUMOCOCCAL INFECTION

Regardless of travel, pneumococcal vaccine (Chap. 141) should be administered routinely to all persons aged >65 and to persons between the ages of 2 and 64 who are at high risk of serious infection, including those with diabetes mellitus; those with chronic heart, lung, or kidney disease; those who have been splenectomized or are immunocompromised; and those who have sickle cell disease.

Required Immunizations

YELLOW FEVER

Documentation of vaccination against yellow fever (Chap. 204) may be required or recommended as a condition for entry into or passage through countries of sub-Saharan Africa and equatorial South America, where the disease is endemic or epidemic, or (according to the International Health Regulations [IHR]) for entry into countries at risk of having the infection introduced. In 2014, the World Health Organization (WHO) adopted a recommendation to remove the 10-year booster-dose requirement from the IHR as of June 2016. Thus one dose of yellow fever vaccine and a completed International Certificate of Vaccination or Prophylaxis should be valid for the lifetime of the vaccinee. Some countries have already adopted this change, as noted on the CDC’s website under the yellow fever vaccine requirements on each country’s destination page. However, it is uncertain when and whether all countries with yellow fever vaccination requirements will adopt this change. Some countries may still require a booster after 10 years, and a booster may be recommended for other travelers as well. This vaccine is given only by state-authorized yellow fever centers, and its administration must be documented on an official International Certificate of Vaccination or Prophylaxis. A registry of U.S. clinics that provide the vaccine is available from the CDC (www.cdc.gov/travel). Data suggest that fewer than 50% of travelers entering areas endemic for yellow fever are immunized, and lack of coverage is a serious problem. Severe adverse events associated with this vaccine have increased in incidence. First-time vaccine recipients may present with a syndrome characterized as either neurotropic (1 case per 125,000 doses) or viscerotropic (overall, 1 case per 250,000 doses; among persons 60–69 years of age, 1 case per 100,000 doses; and among persons ≥70 years of age, 1 case per 40,000 doses). Immunosuppression and thymic disease increase the risk of these adverse events (https://www.cdc.gov/vaccines/hcp/vis/vis-statements/yf.pdf).

MENINGOCOCCAL MENINGITIS

Protection against meningitis is required for entry into Saudi Arabia during the Hajj (Chap. 150). Hajj visas cannot be issued without proof of meningococcal vaccination. All adults and children >2 years of age must have received a single dose of quadrivalent A/C/Y/W-135 vaccine and must show proof of vaccination on a valid International Certificate of Vaccination or Prophylaxis.

Recommended Immunizations

HEPATITIS A AND B

Hepatitis A (Chap. 332) is one of the most common vaccine-preventable infections of travelers. Older data demonstrated a risk six times greater for travelers who stray from the usual tourist routes. The mortality rate for hepatitis A increases with age, reaching almost 2% among individuals aged >50. Of the four hepatitis A vaccines currently available in North America (two in the United States), all are interchangeable and have an efficacy of >95%. Hepatitis A vaccine is currently given to all children in the United States. Since the most frequently identified risk factor for hepatitis A in the United States is international travel, and since morbidity and mortality risk increase with age, it seems appropriate that all adults be immune prior to travel.

Long-stay overseas workers appear to be at considerable risk for hepatitis B infection (Chap. 332), although even short-term travelers can acquire this infection if they indulge in behaviors that place them at risk. The recommendation that all travelers be immunized against hepatitis B before departure is supported by two studies showing that 17% of the assessed travelers who received health care abroad had some type of injection; according to the WHO, nonsterile equipment is used for up to 75% of all injections given in parts of the developing world. A 3-week accelerated schedule of the combined hepatitis A and B vaccine has been approved in the United States. Although no data are available on the specific risk of infection with hepatitis B virus among U.S. travelers, ~240 million people in the world have chronic infection. All children and adolescents in the United States are immunized against this illness. Hepatitis B vaccination should be considered for all travelers.

TYPHOID AND PARATYPHOID FEVER

Most cases of typhoid fever in North America are due to travel, with ~300 cases seen per year in the United States. The attack rate for typhoid fever (Chap. 160) is 1 case per 30,000 travelers per month of travel to the developing world. In the United States, >80% of reports of typhoid fever and >90% of reports of paratyphoid fever caused by Salmonella Paratyphi A are in travelers to southern Asia. One group at particular risk are immigrants and their families who have returned to their homelands for VFRs. Between 1999 and 2006 in the United States, 66% of imported cases of S. typhi infection involved the latter group. Unfortunately, data show that both S. typhi and S. paratyphi A have become increasingly resistant to fluoroquinolone antibiotics (especially strains acquired on the Indian subcontinent). Both of the available vaccines—one oral (live) and the other injectable (polysaccharide)—have efficacy rates of ~70% but are not protective against Paratyphi disease. In some countries, a combined hepatitis A/typhoid vaccine is available.

MENINGOCOCCAL MENINGITIS

Although the risk of meningococcal disease among travelers has not been quantified, it is likely to be higher among travelers who live with poor indigenous populations in overcrowded conditions (Chap. 150). Because of its enhanced ability to prevent nasal carriage (compared with the older polysaccharide vaccine), a quadrivalent conjugate vaccine is the product of choice (regardless of age) for immunization of persons traveling to sub-Saharan Africa during the dry season or to areas of the world where there are epidemics. The vaccine, which protects against serogroups A, C, Y, and W-135, has an efficacy rate of >90%. Except in rare outbreak situations, there is no role for meningococcal serogroup B immunization of travelers.

JAPANESE ENCEPHALITIS

The risk of Japanese encephalitis (Chap. 204), an infection transmitted by night-biting mosquitoes in rural Asia and Southeast Asia, can be as high as ~1 case per 5000 travelers per month of stay in an endemic area. Most infections are asymptomatic; however, among the very small proportion of infected persons who become ill, death and severe neurologic sequelae are common. Most symptomatic infections in recent years have occurred in tourists to Southeast Asia, of whom one-third had traveled for <1 month in an endemic area. The vaccine efficacy rate is >90%, and vaccination is recommended by the CDC for persons staying >1 month in rural endemic areas or for shorter periods if their activities in these areas (e.g., camping, bicycling, hiking) will increase exposure risk. Recent studies suggest that the vaccine schedule (off-label) may be accelerated to 2 doses within 1 week for last-minute travelers.

CHOLERA

The risk of cholera (Chap. 163) is extremely low, with ~1 case per 500,000 journeys to endemic areas. A live oral cholera vaccine was recently approved in the United States by the U.S. Food and Drug Administration (FDA). Its use should be considered for aid and health care workers in refugee camps or in disaster-stricken/war-torn areas.

RABIES

Domestic animals, primarily dogs, are the major transmitters of rabies in developing countries (Chap. 203). Several studies have shown that the risk of rabies posed by a dog bite in an endemic area translates into 1–3.6 cases per 1000 travelers per month of stay. Countries where canine rabies is highly endemic include Mexico, the Philippines, Sri Lanka, India, Thailand, China, and Vietnam. The two vaccines available in the United States provide >90% protection. Rabies vaccine is recommended for long-stay travelers, particularly children (who tend to play with animals and may not report bites), and for persons who may be occupationally exposed to rabies in endemic areas; however, in a large-scale study, almost 50% of potential exposures occurred within the first month of travel. Even after receipt of a preexposure rabies vaccine series, two postexposure doses are required; rabies immune globulin (which is often unavailable in developing countries) is not necessary.

PREVENTION OF MALARIA AND OTHER INSECT-BORNE DISEASES

It is estimated that >30,000 American and European travelers develop malaria each year (Chap. 219). The risk to travelers is highest in Oceania and sub-Saharan Africa (estimated at 1:5 and 1:50 per month of stay, respectively, among persons not using chemoprophylaxis); intermediate in malarious areas on the Indian subcontinent and in Southeast Asia (1:250–1:1000 per month); and low in South and Central America (1:2500–1:10,000 per month). Malaria surveillance in the United States from 2012 to 2013 showed a 2% increase in cases, and annual increases have been reported since the early 1970s. Of the more than 1700 cases reported in 2014, 66% were due to Plasmodium falciparum; of cases in which a purpose of travel was reported, 58% were associated with VFRs. Patients traveling for VFRs are at the highest risk of acquiring malaria and may die of the disease if their immunity has waned after living outside an endemic area. There were five deaths due to malaria in the United States in 2014. Only 8% of those infected had adhered to CDC guidelines for chemoprophylaxis. With the worldwide increase in chloroquine- and multidrug-resistant falciparum malaria, decisions about chemoprophylaxis have become more difficult. Table 119-2 lists the currently recommended drugs of choice for prophylaxis of malaria, by destination.

Several studies indicate that fewer than 50% of travelers adhere to basic recommendations for malaria prevention. Keys to the prevention of malaria include both personal protection measures against mosquito bites (especially between dusk and dawn) and malaria chemoprophylaxis. The former measures entail the use of DEET or picaridin-containing insect repellents, permethrin-impregnated bed nets and clothing, screened sleeping accommodations, and protective clothing. Thus, in regions where infections such as malaria are transmitted, protective products are recommended, even for children and infants. In general, higher concentrations of any active ingredient provide a longer duration of protection. However, studies suggest that concentrations of DEET above ~50% do not offer a marked increase in protection time against mosquitoes. The CDC also recommends oil of lemon eucalyptus (PMD, para-menthane-3,8-diol) and IR3535 (3-[N-butyl-N-acetyl]-aminopropionic acid, ethyl ester). Personal protection measures also help prevent other insect-transmitted illnesses, such as dengue, chikungunya, and Zika (Chap. 204).

Over the past decade, the incidence of dengue has increased considerably, particularly in the Caribbean region, Latin America, Southeast Asia, and Africa. Chikungunya, another mosquito-borne infection that clinically resembles dengue but primarily causes symptoms and signs of arthralgia and arthritis (at times chronic and destructive) has particularly affected the Caribbean in the last few years. Zika virus has also emerged in the past 2 years. Although only 20% of those who are infected have symptoms, Zika virus has been associated with severe complications (microcephaly and other neurologic and organ-system problems) in newborns of women who become infected during pregnancy. In addition, Guillain-Barré syndrome has been associated with Zika virus. Many questions linger with respect to this illness, its complications, and its transmission, especially its sexual transmission.

The CDC travelers’ health website must be checked prior to travel in order to assess the risk of all these mosquito-borne diseases at specific destinations. Pregnant women should not travel to Zika-affected areas. Dengue, chikungunya, and Zika viruses are transmitted by an urban-dwelling mosquito that may be found indoors and that bites during daylight, primarily at dawn and dusk. Mosquito avoidance measures are crucial for all travelers to regions where these vector-borne diseases are transmitted.

PREVENTION OF GASTROINTESTINAL ILLNESS

Diarrhea, the leading cause of illness in travelers (Chap. 128), is usually a short-lived, self-limited condition. However, 40% of affected individuals need to alter their scheduled activities, and another 20% are confined to bed. The most important determinant of risk is the destination. Incidence rates per 2-week stay have been reported to be 10–40%, with the highest rates in parts of Africa and southern Asia. Infants and young adults are at particularly high risk for gastrointestinal illness and for complications such as dehydration. Recent reviews suggest that there is little correlation between dietary indiscretions and the occurrence of travelers’ diarrhea (TD). Earlier studies of U.S. students in Mexico showed that eating meals in restaurants and cafeterias or consuming food from street vendors was associated with increased risk. For further discussion, see “Precautions,” below.

Etiology

The most frequently identified pathogens causing TD are enterotoxigenic Escherichia coli (ETEC) and enteroaggregative E. coli (EAEC) (Chap. 156), although in some parts of the world (notably northern Africa and Southeast Asia) Campylobacter infections (Chap. 162) appear to predominate (See also Table 128-3). Other common causative organisms include Salmonella (Chap. 160), Shigella (Chap. 161), rotavirus (Chap. 198), and norovirus (Chap. 198). The latter virus has caused numerous outbreaks on cruise ships and is an increasingly recognized cause of TD, causing up to 30% of such cases in some studies. Except for giardiasis (Chap. 224), parasitic infections are uncommon causes of TD in short-term travelers. A growing problem for travelers is the development of antibiotic resistance among many bacterial pathogens and the movement of such pathogens worldwide. In centers that have molecular diagnostics capacity, other organisms are being identified in stools of patients with acute and chronic TD, although difficulties are encountered in their significance. The greater availability of these new modes for detection of pathogens in stool samples will reveal more about other and perhaps new pathogens responsible for TD.

Precautions

Some experts think that it is not only what travelers eat but also where they eat that puts them at risk of illness. Food sold by street vendors can carry a high risk, and restaurant hygiene can be a major problem over which the traveler has no control. In addition to discretion in choosing the source of food and water, general precautions include eating foods piping hot; avoiding foods that are raw or poorly cooked; and drinking only boiled or commercially bottled beverages, particularly those that are carbonated. Heating kills diarrhea-causing organisms, whereas freezing does not; therefore, ice cubes made from unpurified water should be avoided. In spite of these recommendations, the literature has repeatedly documented dietary indiscretions by 98% of travelers within the first 72 h after arrival at their destination. The maxim “Boil it, cook it, peel it, or forget it!” is easy to remember but apparently difficult to follow. Using hand sanitizer regularly has been shown to reduce TD.

Self-Treatment

As TD often occurs despite rigorous food and water precautions, travelers may want to carry medications for self-treatment (See also Table 128-5). An antibiotic is useful in reducing the frequency of bowel movements and the duration of illness in moderate to severe diarrhea. The standard regimen is a 3-day course of a quinolone taken twice daily (or, in the case of some formulations, once daily) or, alternatively, a short regimen of azithromycin. However, studies have shown that one double dose of a quinolone or one dose of azithromycin may be equally effective. For diarrhea acquired in areas such as southern and Southeast Asia, where Campylobacter and other infections may be quinolone-resistant, azithromycin is the antibiotic of choice. Rifaximin, a poorly absorbed rifampin derivative, is highly effective against noninvasive bacterial pathogens such as ETEC and EAEC. The current approach to self-treatment of moderate to severe TD for the typical short-term traveler is to carry three once-daily doses of an antibiotic and to use as many doses as necessary to resolve the illness. If neither high fever nor blood in the stool accompanies diarrhea, loperamide may be taken alone or in combination with an antibiotic; studies have shown that the combination is better than the antibiotic alone and does not prolong illness.

Because of the growing problem of antimicrobial resistance worldwide, there is an effort to remind travelers that mild to moderate diarrhea may be managed with loperamide alone. For diarrhea that interferes with activity, adding an antibiotic is reasonable. However, the downside of antibiotic use is the change in the gut microbiota leading to carriage with extended-spectrum β-lactamase (ESBL)–producing Enterobacteriaceae that can persist for many months after return (50% for 1 month and 10% for 1 year). In one study, 28–80% of returned travelers carried these organisms after antibiotic self-treatment.

Prophylaxis

Bismuth subsalicylate remains a good option for the prophylaxis of TD but is only ~60% effective. For certain high-risk individuals (e.g., athletes, persons with a repeated history of TD, and persons with chronic diseases), a daily dose of a quinolone, azithromycin, or rifaximin during travel of <1 month’s duration is 75–90% efficacious in preventing TD. A recommendation for the use of probiotics or prebiotics is premature; not enough information is available about the efficacy of using agents containing different organisms, the ideal number of organisms per dose, and the lack of product standardization. Further research on the gut microbiome will further elucidate this area. In Europe and Canada, an oral subunit cholera vaccine (Dukoral) that cross-protects against ETEC has been shown to provide 30–50% protection against TD. However, given the epidemiology of ETEC-induced TD, it is expected that only ~10% of travelers will benefit from this vaccine.

Illness after Return

Although extremely common, acute TD is usually self-limited or amenable to antibiotic therapy. Persistent bowel problems after the traveler returns home have a less well-defined etiology and usually require medical attention from a specialist. Infectious agents (e.g., Giardia lamblia, Cyclospora cayetanensis, Entamoeba histolytica) appear to be responsible for only a small proportion of cases with persistent bowel symptoms. One of the most common diagnoses in persistent diarrhea after travel is postinfectious irritable bowel syndrome. In as many as 4–13% of cases, symptoms may last months or years. When no infectious etiology can be identified, a trial of metronidazole therapy for presumed giardiasis (or small-intestinal bowel overgrowth), a strict lactose-free diet for a short period, or a trial of high-dose hydrophilic mucilloid may relieve symptoms. Because management of postinfectious irritable bowel syndrome can be quite complicated, these patients should be referred to a specialist.

PREVENTION OF OTHER TRAVEL-RELATED PROBLEMS

Travelers are at high risk for sexually transmitted diseases (Chap. 131). Surveys have shown that large numbers of travelers engage in casual sex, and condoms are not used consistently. Increasing numbers of travelers are being diagnosed with illnesses such as schistosomiasis (Chap. 229), Zika (Chap. 204), dengue (Chap. 204), chikungunya (Chap. 204), and tick-borne rickettsial disease (Chap. 182). Travelers are cautioned to avoid bathing, swimming, or wading in freshwater lakes, streams, or rivers in parts of northeastern South America, parts of the Caribbean, Africa, and Southeast Asia. Travelers should avoid walking barefoot because of the risk of hookworm and Strongyloides infections (Chap. 227) and snakebites (Chap. 451). Insect repellents are important for prevention not only of malaria but also of other vector-borne diseases.

Prevention of travel-associated injury depends mostly on common-sense precautions. Riding on motorcycles (especially without helmets) and in overcrowded public vehicles is not recommended; in developing countries, individuals should never travel by road in rural areas after dark. Of persons who die during travel, fewer than 1% die of infection, whereas 40% die in motor vehicle accidents. Excessive alcohol use has been a significant factor in motor vehicle accidents, drownings, assaults, and injuries. During travel, situational awareness is important; wearing culturally appropriate clothing, avoiding flashy jewelry, and protecting one’s money and passport are safety essentials.

THE TRAVELER’S MEDICAL KIT

A traveler’s medical kit is strongly advisable. The contents may vary widely, depending on the itinerary, duration of stay, style of travel, and local medical facilities. While many medications are available abroad (often over the counter), directions for their use may be nonexistent or in a foreign language, or a product may be outdated or counterfeit. Recent studies of antimalarial products in sub-Saharan Africa and Southeast Asia showed that 30–50% were counterfeit or contained inadequate amounts of active drug. The sale and marketing of such medications are a growing industry that is expected to expand. In the medical kit, the short-term traveler should consider carrying an analgesic; an antidiarrheal agent and an antibiotic for self-treatment of TD; antihistamines; a laxative; oral rehydration salts; a sunscreen with broad-spectrum protection (UVA and UVB, with the latter at a level of at least 30 SPF); a DEET- or picaridin-containing insect repellent; an insecticide for clothing (permethrin); and, if necessary, an antimalarial drug. To these medications, the long-stay traveler might add a broad-spectrum general-purpose antibiotic (levofloxacin or azithromycin), an antibacterial eye and skin ointment, and a topical antifungal cream. The appropriate use of all antimicrobial agents should be reviewed prior to travel. Regardless of the duration of travel, a first-aid kit containing such items as scissors, tweezers, and bandages should be considered.

TRAVEL AND SPECIAL HOSTS

PREGNANCY AND TRAVEL

A woman’s medical history and itinerary, the quality of medical care at her destinations, and her degree of flexibility determine whether travel is wise during pregnancy (See also Chap. 466). According to the American College of Obstetrics and Gynecology, the safest part of pregnancy in which to travel is between 18 and 24 weeks, when there is the least danger of spontaneous abortion or premature labor. Some obstetricians prefer that women stay within a few hundred miles of home after the 28th week of pregnancy in case problems arise. In general, however, healthy women may be advised that it is acceptable to travel.

Relative contraindications to international travel during pregnancy include a history of miscarriage, premature labor, incompetent cervix, or toxemia. General medical problems such as diabetes, heart failure, severe anemia, or a history of thromboembolic disease also should prompt the pregnant woman to postpone her travels. Finally, destinations in which the pregnant woman and her fetus may be at excessive risk (e.g., those in Zika-affected areas, those at high altitudes, those where live-virus vaccines are required, and those where multidrug-resistant malaria is endemic) should be avoided.

Malaria

Malaria during pregnancy carries a significant risk of morbidity and mortality. Levels of parasitemia are highest and failure to clear the parasites after treatment is most frequent among primigravidae. Severe disease, with complications such as cerebral malaria, massive hemolysis, and renal failure, is especially likely in pregnancy. Fetal sequelae include spontaneous abortion, stillbirth, preterm delivery, and congenital infection. Chloroquine and mefloquine are considered to be safe in all trimesters.

Enteric Infections

Pregnant travelers must be extremely cautious regarding their food and beverage intake. Dehydration due to TD can lead to inadequate placental blood flow. Infections such as toxoplasmosis, hepatitis E, and listeriosis also can cause serious sequelae in pregnancy.

The mainstay of therapy for TD during pregnancy is rehydration. Loperamide may be used if necessary. For self-treatment, azithromycin may be the best option. Although quinolones are increasingly being used safely during pregnancy and rifaximin is poorly absorbed from the gastrointestinal tract, these drugs are not approved for this indication.

Because of the serious problems encountered when infants are given local foods and beverages, women are strongly encouraged to breast-feed when traveling with a neonate. A nursing mother with TD should not stop breast-feeding but should increase her fluid intake.

Air Travel and High-Altitude Destinations

Commercial air travel is not a risk to the healthy pregnant woman or to the fetus. The higher radiation levels reported at altitudes of >10,500 m (>35,000 ft) should pose no problem for the healthy pregnant traveler. Since each airline has a policy regarding pregnancy and flying, it is best to check with the specific carrier when booking reservations. Domestic air travel is usually permitted until the 36th week, whereas international air travel is generally curtailed after the 32nd week.

There are no known risks for pregnant women who travel to high-altitude destinations and stay for short periods. However, there are likewise no data on the safety of pregnant women at altitudes of >4500 m (15,000 ft). A prominent concern is that most of these destinations are remote.

THE HIV-INFECTED TRAVELER

The HIV-infected traveler is at special risk of serious infections due to a number of pathogens that may be more prevalent at travel destinations than at home (See also Chap. 197). However, the degree of risk depends primarily on the state of the immune system at the time of travel. For persons whose CD4+ T cell counts are normal or >500/μL, data suggest no greater risk during travel than for persons without HIV infection. Individuals with AIDS (CD4+ T cell counts of <200/μL) and others who are symptomatic need special counseling and should visit a travel medicine practitioner before departure, especially when traveling to developing countries.

Several countries deny entry to HIV-positive individuals for prolonged stay, even though these restrictions do not appear to decrease rates of transmission of the virus. In general, HIV testing is required for individuals who wish to stay abroad for >3 months or who intend to work or study abroad. Some countries will accept an HIV serologic test done within 6 months of departure, whereas others will not accept a blood test done at any time in the traveler’s home country. Border officials often have the authority to make inquiries of individuals entering a country and to check the medications they are carrying. If antiretroviral drugs are identified, the person may be barred from entering the country. Information on testing requirements for specific countries is available from consular offices but is subject to frequent change.

Immunizations

All of the HIV-infected traveler’s routine immunizations should be up to date (Chap. 118). The response to immunization may be impaired at CD4+ T cell counts of <200/μL and in some cases at even higher counts. Thus HIV-infected persons should be vaccinated as early as possible to ensure adequate immune responses. For patients receiving antiretroviral therapy, at least 3 months must elapse before regenerated CD4+ T cells can be considered fully functional; therefore, vaccination of these patients should be delayed. However, when the risk of illness is high or the sequelae of illness are serious, immunization is recommended. In certain circumstances, it may be prudent to check the adequacy of the serum antibody response before departure.

Because of the increased risk of infections due to Streptococcus pneumoniae and other bacterial pathogens that cause pneumonia after influenza, the conjugate pneumococcal vaccine (Prevnar 13) followed by the 23-valent polysaccharide vaccine (Pneumovax) as well as influenza vaccine should be administered. The estimated rates of response to influenza vaccine are >80% among persons with asymptomatic HIV infection and <50% among those with AIDS.

In general, live attenuated vaccines are contraindicated for persons with immune dysfunction. Because measles (rubeola) can be a severe or lethal infection in HIV-positive patients, these patients should receive the measles vaccine (or the combination MMR vaccine) unless the CD4+ T cell count is <200/μL. Between 18 and 58% of symptomatic HIV-infected vaccinees develop adequate measles antibody titers, and 50–100% of asymptomatic HIV-infected persons seroconvert.

In asymptomatic HIV-infected individuals, CD4+ T cell counts of 200–499/μL (moderate immune suppression) are considered a precaution for yellow fever vaccination; since there is no contraindication, yellow fever vaccine may be considered when these persons travel to endemic areas. Studies of these individuals, along with asymptomatic persons whose CD4+ T cell count is >500/μL, found no serious adverse events, although their immunologic response may be decreased. If the CD4+ T cell count is <200/μL, an alternative itinerary that poses no risk of exposure to yellow fever is recommended. If the traveler is passing through or traveling to an area where the vaccine is required but the disease risk is low, a physician’s waiver should be issued. Although the WHO indicates that a single dose of yellow fever vaccine provides lifetime protection, the CDC recommends boosters every 10 years for HIV-infected individuals.

A transient increase in HIV viremia (lasting days to weeks) has been demonstrated in HIV-infected individuals after immunization against influenza, pneumococcal infection, and tetanus (Chap. 197). At this point, however, no evidence indicates that this transient increase is detrimental.

Gastrointestinal Illness

Decreased levels of gastric acid, abnormal gastrointestinal mucosal immunity, other complications of HIV infection, and medications taken by HIV-infected patients make TD especially problematic in these individuals. TD is likely to occur more frequently, to be more severe, to be accompanied by bacteremia, and to be more difficult to treat. Cryptosporidium, Isospora belli, and Microsporidium infections, although uncommon, are associated with increased morbidity and mortality rates in patients with AIDS.

The HIV-infected traveler must be careful to consume only appropriately prepared foods and beverages, and some may benefit from antibiotic prophylaxis for TD. Sulfonamides (as used to prevent pneumocystosis) are ineffective because of widespread resistance.

Other Travel-Related Infections

Data are lacking on the severity of many vector-borne diseases in HIV-infected individuals. Malaria is especially severe in asplenic persons and in those with AIDS. The HIV load doubles during malaria, with subsidence in ~8–9 weeks; the significance of this increase in viral load is unknown.

Visceral leishmaniasis (Chap. 221) has been reported in numerous HIV-infected travelers. Diagnosis may be difficult, given that splenomegaly and hyperglobulinemia are often lacking and serologic results are frequently negative. Sandfly bites may be prevented by evening use of insect repellents.

Certain respiratory illnesses, such as histoplasmosis and coccidioidomycosis, cause greater morbidity and mortality among patients with AIDS. Although tuberculosis is common among HIV-infected persons (especially in developing countries), its acquisition by the short-term HIV-infected traveler has not been reported as a major problem. From a prospective study, it is estimated that, for travelers not engaged in health care, the risk of tuberculosis infection is ~3% per year of travel.

Medications

Adverse events due to medications and drug interactions are common and raise complex issues for HIV-infected persons. Rates of cutaneous reaction (e.g., increased cutaneous sensitivity to sulfonamides) are unusually high among patients with AIDS. Doxycycline appears to have no clinically significant interactions with either the protease inhibitors or the non-nucleoside reverse transcriptase inhibitors (NNRTIs). Zidovudine levels may be increased with atovaquone. The drug combination atovaquone/proguanil may interact with antiretroviral protease inhibitors such as ritonavir, darunavir, atazanavir, indinavir, and lopinavir as well as the NNRTIs nevirapine, etravirine, and efavirenz. In spite of potential interactions, atovaquone/proguanil is well tolerated and remains the choice for most HIV-infected travelers.

Concomitant administration of the antimalarial drug mefloquine and antiretroviral protease inhibitors such as ritonavir, lopinavir, darunavir, and atazanavir may result in increased levels of mefloquine, with an increased risk of QT prolongation. Similarly, ritonavir may increase chloroquine levels. On the other hand, serum levels of mefloquine may be lowered with the use of efavirenz, nevirapine, or etravirine. Because of the increase in antiretroviral agents and the lack of accumulated data on their interactions with antimalarial agents, decisions about malaria chemoprophylaxis continue to be difficult; with a short duration of travel, an interaction may be inconsequential. With regard to malaria treatment, a hypothetical concern is that the antimalarial drugs lumefantrine (combined with artemether in Coartem) and halofantrine (no longer recommended due to toxicity) may interact with HIV protease inhibitors and NNRTIs since drugs in the latter two categories are known to be potent inhibitors of cytochrome P450. In keeping current with antiretroviral drug interactions, a website from the University of Liverpool (www.hiv-druginteractions.org) is helpful.

CHRONIC ILLNESS, DISABILITY, AND TRAVEL

Chronic health problems need not prevent travel, but special measures can make the journey safer and more comfortable.

Heart Disease

Cardiovascular events are the main cause of deaths among travelers and of in-flight emergencies on commercial aircraft. Extra supplies of all medications should be kept in carry-on luggage, along with a copy of a recent electrocardiogram and the name and telephone number of the traveler’s physician at home. Pacemakers are not affected by airport security devices, although electronic telephone checks of pacemaker function cannot be transmitted by international satellites. Travelers with electronic defibrillators should carry a note to that effect and ask for hand screening. A traveler may benefit from supplemental oxygen; since oxygen delivery systems are not standard, supplementary oxygen should be ordered by the traveler’s physician well before flight time. Travelers may benefit from aisle seating and should walk, perform stretching and flexing exercises, consider wearing support hose, and remain hydrated during the flight to prevent venous thrombosis and pulmonary embolism.

Chronic Lung Disease

Chronic obstructive pulmonary disease is one of the most common diagnoses in patients who require emergency-department evaluation for symptoms occurring during airline flights. The best predictor of the development of in-flight problems is the sea-level PaO₂. A PaO₂ of at least 72 mmHg corresponds to an in-flight arterial PaO₂ of ~55 mmHg when the cabin is pressurized to 2500 m (8000 ft). If the traveler’s baseline PaO₂ is <72 mmHg, the provision of supplemental oxygen should be considered. Contraindications to flight include active bronchospasm, lower respiratory infection, lower-limb deep-vein phlebitis, pulmonary hypertension, and recent thoracic surgery (within the preceding 3 weeks) or pneumothorax. Decreased outdoor activity at the destination should be considered if air pollution is excessive.

Diabetes Mellitus

Alterations in glucose control and changes in insulin requirements are common problems among patients with diabetes who travel. Changes in time zones, in the amount and timing of food intake, and in physical activity demand vigilant assessment of metabolic control. Because of the risk of foot ulcers, travelers should wear closed footwear that has been proven to be comfortable. The traveler with diabetes should pack medication (including a bottle of regular insulin for emergencies), insulin syringes and needles, equipment and supplies for glucose monitoring, and snacks in carry-on luggage. Insulin is stable for ~3 months at room temperature but should be kept as cool as possible. The name and telephone number of the home physician and a card and bracelet listing the patient’s medical problems and the type and dose of insulin used should accompany the traveler. In order to facilitate international border crossings, travelers should carry a physician’s letter authorizing the carriage of needles and syringes. In traveling eastward (e.g., from the United States to Europe), the patient may need to decrease the morning insulin dose on arrival. The blood glucose can then be checked during the day to determine whether additional insulin is required. For flights westward, with lengthening of the day, an additional dose of regular insulin may be required.

Other Special Groups

Other groups for whom special travel measures are encouraged include patients undergoing dialysis, those with transplants, and those with other disabilities. Up to 13% of travelers have some disability, but few advocacy groups and tour companies dedicate themselves to this growing population. Medication interactions are a source of serious concern for these travelers, and appropriate medical information should be carried, along with the home physician’s name and telephone number. Some travelers taking glucocorticoids carry stress doses in case they become ill. Immunization of these immunocompromised travelers may result in less than adequate protection. Thus the traveler and the physician must carefully consider which destinations are appropriate.

TRAVEL HEALTH INSURANCE

Today, more elderly or chronically ill individuals travel, and more of these individuals journey to remote locations and enjoy adventurous activities. Illness or injury abroad is not uncommon and is best considered before the journey. Persons who develop health problems abroad may incur enormous out-of-pocket expenses. Thus prospective travelers should consider purchasing supplemental travel health insurance and should check with their health insurance company regarding whether they have coverage for illness or injury overseas. Unfortunately, many insurance companies will not cover preexisting illness if it is the reason for trip cancellation or illness abroad. Most countries do not accept routine health insurance from other countries unless there is a special traveler supplement. In most circumstances, travelers are asked to pay in cash for services rendered on an emergency basis, whether in a physician’s office, in an emergency or urgent care center, or even in a hospital. There are several types of travel insurance. It is wise to purchase trip cancellation insurance, especially, for example, if the traveler has an underlying chronic illness and may need to cancel a trip due to an exacerbation of disease. Travel health insurance will cover expenses in the event that medical care abroad is needed. Evacuation insurance will cover medical evacuation, usually to a medical center in another location where it is deemed that the care is similar to that available in the traveler’s home country. The cost of medical evacuation can easily exceed $100,000 U.S. There are a number of travel insurance providers, and it is very important to read the fine print carefully and to determine exactly what each company provides, thereby ensuring an appropriate fit for the individual’s particular circumstances. The U.S. Department of State website lists travel health insurance companies and provides information about whom to contact in an emergency through STEP (the Smart Traveler Enrollment Program: https://travel.state.gov/content/passports/en/go/health/doctors.html).

MEDICAL TOURISM

Travel for the purpose of obtaining health care abroad has received a great deal of attention in the medical literature and the media. Although the data are difficult to confirm, it has been estimated that at least 750,000 Americans travel each year for medical purposes. According to the Department of Commerce website, the numbers of such travelers have doubled recently, and some experts predict massive increases. Lower cost is usually cited as the motivation for this type of tourism, and an entire industry has flourished as a result of this phenomenon. However, the quality of facilities, assistance services, and care is neither uniform nor regulated; thus, in most instances, responsibility for assessing the suitability of an individual program or facility lies solely with the traveler. Persons considering this option must recognize that they are almost always at a disadvantage when being treated in a foreign country, particularly if there are complications. Concerns to be addressed include the quality of the health care facility and its staff; language and cultural differences that may impede accurate interpretation of both verbal and nonverbal communication; religious and ethical differences that may be encountered over issues such as efforts to preserve life and limb or the provision of care for the terminally ill; lack of familiarity with the local medical system; limited access of the care provider to the patient’s medical history; the use of unfamiliar drugs and medicines; the relative difficulty of arranging follow-up care back in the United States; and the possibility that such follow-up care may be fraught with problems should there be complications. If serious issues arise, legal recourse may be difficult or impossible. Patients planning to travel abroad to obtain health care, particularly when surgery is involved, should be immunized for hepatitis B and should consider having baseline hepatitis C and HIV tests preoperatively. Prevalence rates of hepatitis B and C and HIV infection vary considerably around the world and are generally higher in developing regions than in the United States and Western Europe. The latest information available on the safety of the blood supply outside the United States is the WHO’s Global Database on Blood Safety based on data from 2011 (www.who.int/topics/blood_safety/en). Persons researching the accreditation status of overseas facilities should note that, although these facilities may be part of a chain, they are surveyed and accredited individually. Accreditation resources include (1) the Joint Commission International (www.jointcommissioninternational.org), (2) the Australian Council for Healthcare Standards International (www.achs.org.au/achs-international/), and (3) Accreditation Canada International (www.internationalaccreditation.ca). The American Medical Association also offers guidelines for medical tourism (www.medretreat.com/templates/UserFiles/Documents/Whitepapers/AMAGuidelines.pdf).

PROBLEMS AFTER RETURN

The most common medical problems encountered by travelers after their return home are diarrhea, fever, respiratory illnesses, and skin diseases (Fig. 119-2). Frequently ignored problems are fatigue and emotional stress, especially in long-stay travelers. The approach to diagnosis requires some knowledge of geographic medicine, in particular the epidemiology and clinical presentation of infectious disorders. A geographic history should focus on the traveler’s exact itinerary, including dates of arrival and departure; exposure history (food indiscretions, drinking-water sources, freshwater contact, sexual activity, animal contact, insect bites); location and style of travel (urban vs rural, first-class hotel accommodation vs. camping); immunization history; and use of antimalarial chemosuppression. Recently, some travelers who have been hospitalized abroad have been shown on return to be colonized with multidrug-resistant bacteria such as Enterobacteriaceae producing ESBLs and bacteria producing NDM-1 (New Delhi metallo-β-lactamase 1); these bacteria may be transmitted to family members and other contacts, especially within the health care system.

DIARRHEA

See “Prevention of Gastrointestinal Illness,” above.

FEVER

Fever in a traveler who has returned from a malarious area should be considered a medical emergency because death from Plasmodium falciparum malaria can follow an illness of only several days’ duration. Although “fever from the tropics” does not always have a tropical cause, malaria should be the first diagnosis considered. The risk of P. falciparum malaria is highest among travelers returning from Africa or Oceania and among those who become symptomatic within the first 2 months after return. Other important causes of fever after travel include dengue, chikungunya, Zika, viral hepatitis (A and E), typhoid and paratyphoid fever, bacterial enteritis, rickettsial infections (including tick typhus, scrub typhus, and Q fever), and—in rare instances—leptospirosis, acute HIV infection, and amebic liver abscess. Studies published by GeoSentinel (an emerging infectious disease surveillance group established by the CDC and the International Society of Travel Medicine) have informed providers about specific illness and syndrome risks in ill returned travelers (Fig. 119-2). Outbreaks of dengue, previously considered to be very rare in Africa, have been documented recently across central Africa. However, in at least 25% of cases, no etiology of fever in a returning traveler can be found, and the fever resolves spontaneously. Clinicians should keep in mind that no present-day antimalarial agent guarantees protection from malaria and that some immunizations (notably, that against typhoid fever) are only partially protective.

When no specific diagnosis is forthcoming, the following investigations, where applicable, are suggested: complete blood count, liver function tests, thick/thin blood films or rapid diagnostic testing for malaria (repeated several times if necessary), urinalysis, urine and blood cultures (repeated once), rapid influenza diagnostic testing, chest x-ray, and collection of an acute-phase serum sample to be held for subsequent examination along with a paired convalescent-phase serum sample.

SKIN DISEASES

Pyodermas, sunburn, insect bites, skin ulcers, and cutaneous larva migrans are the most common skin conditions affecting travelers after their return home. In individuals with persistent skin ulcers, a diagnosis of cutaneous leishmaniasis, mycobacterial infection, or fungal infection should be considered. Careful, complete inspection of the skin is important in detecting the rickettsial eschar in a febrile patient or the central breathing hole in a “boil” due to myiasis.

EMERGING INFECTIOUS DISEASES

In recent years, travel and commerce have fostered the worldwide spread of chikungunya, Zika, influenza caused by novel serotypes, severe acute respiratory syndrome (SARS), and (earlier) HIV infection and the reemergence of cholera as a global health threat. For travelers, some of these issues, along with others, remain a concern. Dengue continues to pose serious health threats in Latin America and Southeast Asia; schistosomiasis is being described in previously unaffected lakes in Africa; and antibiotic-resistant strains of sexually transmitted and enteric pathogens are emerging at an alarming rate.

CONCLUSIONS

The growth of global travel and migration now demand that the clinician become as familiar as possible with travel medicine. Practitioners may choose either to refer their patients to a travel clinic before departure or to acquire knowledge that enables them to provide pre-travel counseling and to prescribe appropriate vaccinations and chemoprophylaxis. It is equally important for physicians seeing ill returned travelers to be familiar with common post-travel syndromes and diseases, particularly those that may have been acquired in the developing world, and to identify other physicians who can assist with complex post-travel illnesses. The CDC publishes a biennial text, Health Information for International Travel (accessed through their website at www.cdc.gov/travel), that provides pre-travel health recommendations. The International Society of Travel Medicine (www.istm.org) publishes a list of travel clinics, and the American Society of Tropical Medicine and Hygiene (www.astmh.org) publishes a list of clinical tropical medicine specialists.

As Nobel Laureate Dr. Joshua Lederberg pointed out, “The microbe that felled one child in a distant continent yesterday can reach yours today and seed a global pandemic tomorrow.” The vigilant clinician understands that the importance of a thorough travel history cannot be overemphasized.

FURTHER READING

INTRODUCTION

The release of greenhouse gases—principally carbon dioxide—into Earth’s atmosphere since the late nineteenth century has contributed to a climate unfamiliar to our species, Homo sapiens. This new climate has already altered the epidemiology of some infectious diseases. Continued accumulation of greenhouse gases in the atmosphere will further alter the planet’s climate. In some cases climate change may establish conditions favoring the emergence of infectious diseases, while in others it may render areas that are presently suitable for certain diseases unsuitable. This chapter presents the current state of knowledge regarding the known and prospective infectious-disease consequences of climate change.

OVERVIEW

The term climate change refers to long-term alterations in temperature, precipitation, wind, humidity, and other components of weather. Over the past 2.5 million years, the earth has warmed and cooled, cycling between glacial and interglacial periods during which average global temperatures moved up and down by 4–7°C. During the last glacial period, which ended roughly 12,000 years ago, global temperatures were, on average, 5°C cooler than in the mid-twentieth century (Fig. 120-1).

The present climate period, known as the Holocene, is remarkable for its stability: temperatures have largely remained within a range of 2–3°C. This stability has enabled the successful population and cultivation of much of the earth’s landmass by humanity. Current climate change differs from that in the past not only because its primary cause is human activities but also because its pace is faster. The current rate of warming on Earth is unprecedented in the last 50 million years. The 5°C of warming that occurred at the end of the last ice age about 12,000 years ago took roughly 5000 years, whereas such a temperature increment may occur within the next 150 years unless the release of greenhouse gases is substantially reduced in coming decades. Climate science, although still a relatively new discipline, has provided an ever-clearer picture of how the changing chemistry of the atmosphere has influenced, and will continue to influence, the global climate.

GREENHOUSE GASES

Greenhouse gases (Table 120-1 and Fig. 120-2) are a group of gases in Earth’s atmosphere that absorb infrared radiation and thus retain heat inside the atmosphere. In the absence of these gases, the earth’s average temperature would be about 33°C colder. Carbon dioxide, released into the atmosphere primarily from fossil fuel combustion and deforestation, has had the greatest effect on climate since the Industrial Revolution. Of note, the Swedish scientist Svante Arrhenius first suggested in the late nineteenth century that the addition of carbon dioxide to the Earth’s atmosphere would increase the planet’s surface temperature. Water vapor is the most abundant and a highly potent greenhouse gas but, given its short atmospheric life span and sensitivity to temperature, is not a major factor in recently observed climate change.

The atmosphere, some of the aerosols suspended in it, and clouds reflect a portion of incoming solar radiation back toward space. The remainder reaches Earth’s surface, where it is absorbed and some is then emitted back at the atmosphere. The earth emits energy absorbed from the sun at longer wavelengths, primarily infrared, that greenhouse gases are able to absorb. The change in wavelength that occurs as solar radiation is absorbed and re-emitted from the earth’s surface is fundamental to the greenhouse effect (Fig. 120-3).

TEMPERATURE

Climate change has become nearly synonymous with global warming, as a clear signal from rising greenhouse gas concentrations has been an increase in the mean global surface temperature of ~0.85°C since 1880. However, this mean warming belies warming that is occurring much faster in certain regions. The Arctic has warmed twice as fast overall, and winters are warming faster than summers. Nighttime minimum temperatures are also rising faster than daytime high temperatures. Each of these nuances bears upon the incidence of infectious diseases in general and vector-borne disease specifically.

A moderate projection based on the best available scientific evidence suggests that average global temperatures will warm an additional 1.4–3.1°C by 2100 as compared to the period 1986–2005. Because of climate change, extreme heat waves have already become more common and are expected to be even more frequent later in this century. Besides contributing directly to morbidity and mortality in human populations, heat waves wilt crops and are expected to contribute substantially to predicted agricultural losses. For example, the 2010 heat wave in Russia, which was unprecedented in its severity, contributed to hundreds of forest fires that generated enough air pollution to kill an estimated 56,000 people and that burned 300,000 acres of crops, including roughly 25% of the nation’s wheat fields. Nutritional deficiencies underlie a substantial portion of the global burden of many infectious diseases.

PRECIPITATION

In addition to changing temperature, the emission of greenhouse gases and the consequent increase in energy in Earth’s atmosphere have influenced the planet’s water cycle. Since 1950, substantial increases in the heaviest precipitation events (i.e., those above the 95th percentile) have been observed in Europe and North America. While trends over that same interval are less clear in other regions because of limited data, regions of Southeast Asia and southern South America have likely experienced increases in heavy precipitation as well. Other areas have seen greater drought, notably southern Australia and the southwestern United States.

A warmer atmosphere holds more water vapor; specifically, there is 6–7.5% more water vapor per degree (Celsius) of warming in the lower atmosphere. For areas that have traditionally had more precipitation on average, warming tends to promote heavier precipitation events. In contrast, in regions prone to drought, warming tends to result in greater periods between rainfalls and in the risk of drought.

HURRICANES

The world’s oceans have absorbed 90% of the excess heat that greenhouse gases have kept in Earth’s atmosphere since the 1960s. Ocean heat provides energy for hurricanes, and warmer years tend to have greater hurricane activity. Atlantic hurricanes are the best studied and have the most data available. An analysis of satellite observations from 1983 to 2005 has shown a trend toward increasing severity—albeit decreasing frequency—of Atlantic hurricanes. Modeling of future tropical cyclones suggests that their intensity may increase 2–11% by 2100 and that the average storm will bring 20% more rainfall.

SEA LEVEL RISE

Between 1901 and 2010, the global sea level rose ~200 mm, or ~1.7 mm per year on average. From 1993 to 2010, the rate of rise nearly doubled—i.e., to 3.2 mm annually. Most of this sea level rise has resulted from the thermal expansion of water. Glacial ice melt is the second greatest factor, and its contribution is accelerating. By 2100, global sea level may rise by 0.8–2 m, with an annual rate of rise of 8–16 mm at the century’s end. A large section of the West Antarctic ice sheet has begun to fall apart, and its melting alone may cause sea level to rise by ≥3 m in coming centuries.

Sea level rise is not uniform. The rate of rise on the eastern seaboard of North America has been roughly double the global rate. Compounding sea level rise is the subsidence of coastal areas due to human settlement. In the absence of levee upgrades, an estimated 170 million people living near coasts worldwide will be at risk of flooding in 2100 because of the combined effects of subsidence, erosion, and sea level rise.

Along with extreme storms and overuse of coastal aquifers, rising seas also contribute to salinization of coastal groundwater. About 1 billion people rely on coastal aquifers for potable water.

EL NIÑO SOUTHERN OSCILLATION

The El Niño Southern Oscillation (ENSO) refers to periodic changes in water temperature in the eastern Pacific Ocean that occur roughly every 5 years. ENSO cycles have dramatic effects on weather around the globe. Warmer-than-average water temperatures in the eastern Pacific define El Niño events (see below), whereas cooler-than-average water temperatures define La Niña periods. Evidence is accruing that climate change may be increasing the frequency and severity of El Niño events.

El Niño events drive alterations in weather worldwide (Fig. 120-4) and are associated with extreme events and consequently higher rates of morbidity and mortality. Hurricane Mitch, one of the most powerful hurricanes ever observed, with winds reaching 290 km/h, dropped 1–1.8 m (3–6 feet) of rain over 72 h on parts of Honduras and Nicaragua. As a result of this storm, 11,000 people died and 2.7 million were displaced. Outbreaks of cholera, leptospirosis, and dengue occurred in the storm’s aftermath.

POPULATION MIGRATION AND CONFLICT

The final common outcome of all climate-change effects is often population migration. Sea level rise, extreme heat and precipitation, droughts, and salinization of water supplies all conspire to make regions (including some inhabited by humans for millennia) uninhabitable. Among climate-change migrants in the near future may be the inhabitants of low-lying South Pacific islands that are vulnerable to sea level rise and residents of the Alaskan archipelago, where melting of permafrost has rendered traditional means of cold food storage difficult.

Climate change may also be contributing to humanitarian crises and conflicts. A severe 2011 drought in East Africa may have incited the Somali famine that resulted in 1 million refugees; mortality rates reached 7.4/10,000 in some refugee camps. Crop losses associated with the 2010 Russian heat wave led Russia to halt grain exports, causing higher grain prices on the world market and food riots in developing nations.

EFFECTS OF CLIMATE CHANGE ON INFECTIOUS DISEASE

The incidence of most, if not all, infectious diseases depends on climate. For any given infection, however, climate change is but one of many factors that determine disease epidemiology, and often it is not the most influential factor. Even in instances in which climate change creates conditions favorable to the spread of infections, diseases may be kept in check through interventions such as vector control or antibiotic treatment.

Detecting climate-change influence on an emerging human disease can be challenging. Research with animal pathogens, which in most instances are less well monitored and intervened upon than that with their human counterparts, has suggested how climate change may influence disease spread. For example, the life cycle of nematode parasites of caribou and musk oxen shortens as temperatures rise. As the Arctic has warmed, higher nematode burdens and consequently higher rates of morbidity and mortality have been observed. Other examples from animals, such as the spread of the protozoan parasite Perkinsus marinus in oysters, demonstrate how warming can enable range expansion of pathogens previously held in check by colder temperatures.

As these and other examples from studies of animals make clear, the influence of climate change on infectious diseases can be pronounced. The following sections deal with the infectious diseases for which research has explored the influence of climate change.

VECTOR-BORNE DISEASE

Because insects are cold-blooded, ambient temperature dictates their geographic distribution. With increases in temperatures (in particular, nighttime minimum temperatures), insects are freed to move poleward and up mountainsides. At the same time, as new areas become climatically suitable, current mosquito habitats may become unsuitable as a result of heat extremes.

In addition, insects tend to be sensitive to water availability. Mosquitoes that transmit malaria, dengue, and other infections may breed in pools of water created by heavy downpours. As has been observed in the Amazon, breeding pools can also appear during periods of drought when rivers recede and leave behind stagnant pools of water for Anopheles mosquitoes. These circumstances have raised interest in the potentially favorable impact of water-cycle intensification on the spread of mosquito-borne disease.

Malaria

TEMPERATURE

Higher temperatures promote higher mosquito-biting rates, shorter parasite reproductive cycles, and the potential for the survival of mosquito vectors of Plasmodium infection in locations previously too cold to sustain them. Modeling experiments have identified highland areas of East Africa and South America as perhaps most vulnerable to increased malarial incidence as a result of rising temperatures. In addition, an analysis of interannual malaria in Ecuador and Colombia has documented a greater incidence of malaria at higher altitudes in warmer years. Highland populations may be more vulnerable to malaria epidemics because they lack immunity.

Although rising temperature has the potential to expand the viable range of disease, malaria incidence is not associated with temperature in a strictly linear fashion. While mosquitoes and parasites may adapt to a warming climate, the present optimal temperature for malaria transmission is ~25°C, with a range of transmission temperatures between 16°C and 34°C. Rising temperatures also can have differential effects on parasite development during external incubation and on the mosquitoes’ gonotrophic cycle. Asynchrony between these two temperature-sensitive processes has been shown to decrease the vectorial capacity of mosquitoes.¹

PRECIPITATION

The abundance of Anopheles mosquitoes is strongly correlated with the availability of surface-water pools for mosquito breeding, and biting rates have been linked to soil moisture (a surrogate for breeding pools). Research in the East African highlands has documented that increased variance in rainfall over time has strengthened the association between precipitation and disease incidence. These disease-promoting effects of precipitation may be countered by the potential for extreme rainfall to flush mosquito larvae from breeding sites.

PROJECTIONS

Climate models have begun to deliver output on regional scales, permitting projections of climate-suitable regions to assist national and local health authorities. Climate models speak to the temperature and precipitation ranges necessary for malaria transmission but do not—and cannot—account for the capacity of malaria control programs to halt the spread of disease. The global reduction in malaria distribution over the past century makes it clear that, even with climate change, malaria occurs in far fewer places today because of public health interventions.

Despite intensive efforts, malaria remains the single greatest vector-borne disease cause of morbidity and death in the world. Particularly in regions that are most affected by malaria and where the public health infrastructure is inadequate to contain it, climate modeling may provide a useful tool in determining where the disease may spread. Modeling studies in sub-Saharan Africa have suggested that, although East African nations may encompass regions that will become more climatically suitable for malaria over this century, West African nations may not. By 2100, temperatures in West Africa may largely exceed those optimal for malaria transmission, and the climate may become drier; in contrast, higher temperatures and changes in precipitation may allow malaria to move up the mountainsides of East African countries. Climate change may create conditions favorable to malaria in subtropical and temperate regions of the Americas, Europe, and Asia as well.

Dengue

Like malaria epidemics, dengue fever epidemics depend on temperature (Fig. 120-5). Higher temperatures increase the rate of larval development and accelerate the emergence of adult Aedes mosquitoes. The daily temperature range may also influence dengue virus transmission, with a smaller range corresponding to a higher transmission potential. Temperatures <15°C or >36°C substantially reduce mosquito feeding. In a Rhesus model of dengue, viral replication can occur in as little as 7 days with temperatures of >32–35°C; at 30°C, replication takes ≥12 days; and replication does not reliably occur at 26°C. Research on dengue in New Caledonia has shown peak transmission at ~32°C, reflecting combined effects of a shorter extrinsic incubation period, a higher feeding frequency, and more rapid development of mosquitoes. Along with temperature, peak relative humidity is a strong predictor of dengue outbreaks.

The association between dengue epidemics and precipitation is less consistent in the peer-reviewed literature, possibly because of the mosquito vector’s greater reliance on domestic breeding sites than on natural pools of water. For instance, in some studies, increased access to a piped water supply has been linked to dengue epidemics, presumably because of associated increased domestic water storage. Nonetheless, several studies have established rainfall as a predictor of the seasonal timing of dengue epidemics.

The current global distribution of dengue largely overlaps the geographic spread of Aedes mosquitoes (Fig. 120-6). The presence of Aedes without dengue endemicity in large regions of North and South America and Africa illustrates the relevance of variables other than climate to disease incidence. Nevertheless, coupled climatic–epidemiologic modeling suggests dramatic shifts in the relative vectorial capacity for dengue by the end of this century should little or no mitigation of greenhouse gas emissions occur (Fig. 120-7). Given the joint effects of climate change and population growth, the number of people exposed to A. aegypti globally may nearly double by 2100 from roughly 4 billion to 8 billion or more.

Other Arbovirus Infections

Climate change may favor increased geographic spread of other arboviral diseases, including Zika virus disease, chikungunya virus disease, West Nile virus disease, and eastern equine encephalitis. Zika virus moved to the Western Hemisphere from French Polynesia around 2013 and rapidly spread in Brazil in 2016. Although air travel was essential for the delivery of the virus to the Americas, the available evidence suggests that the 2015 El Niño event provided an optimal climate for the infection to take root and spread. A. aegypti is the primary vector for Zika virus. Chikungunya virus disease emerged in Italy in 2007, having previously been mostly a disease of African nations. Climate models predict that, should competent vectors be present, conditions will be suitable for chikungunya virus to gain a foothold in Western Europe, especially France, in the first half of the twenty-first century. In North America, areas favorable to West Nile virus outbreaks are expected to shift northward in this century. Current hotspots in North America are the California Central Valley, southwestern Arizona, southern Texas, and Louisiana, which have both compatible climates and avian reservoirs for the disease. By mid-century, the upper Midwest and New England will be more climatically suited to West Nile virus; by the end of the century, the area of risk may shift even further north to southern Canada. Whether the disease will ultimately move northward will depend on reservoir availability and mosquito control programs, among other factors.

Lyme Disease

In the past few decades, Ixodes scapularis, the primary tick vector for Lyme disease as well as for anaplasmosis and babesiosis in New England, has become established in Canada because of warming temperatures. With climate change, the range of the tick is expected to expand further (Fig. 120-8).

Lyme disease, caused by the spirochete Borrelia burgdorferi, is the most commonly reported vector-borne disease in North America, with ~30,000 cases per year. The model used in Fig. 120-8 showed 95% accuracy in predicting current I. scapularis distribution and suggests substantial expansion of tick habitat and consequently of populations at risk for the diseases this tick transmits, particularly in Quebec, Iowa, and Arkansas, by 2080. Of note, some areas on the Gulf Coast may become less suitable for ticks by the end of the century.

WATERBORNE DISEASE

Outbreaks of waterborne disease are associated with heavy rainfall events. A review of 548 waterborne disease outbreaks in the United States found that 51% were preceded by precipitation levels above the 90th percentile. Since 1900, most regions of the United States except the Southwest and Hawaii have experienced an increase in heavy downpours (Fig. 120-9), with the greatest intensification of the water cycle in New England and Alaska. Climate models suggest that by 2100 daily heavy-precipitation events, which are defined as a cumulative daily amount that now occurs once every 20 years, will increase nationwide (Fig. 120-10). This scenario may be from two to as much as five times more likely, depending on the extent of greenhouse gas emission reductions achieved early in the twenty-first century.

Most disease outbreaks after heavy precipitation occur through contamination of drinking-water supplies. While outbreaks related to surface-water contamination generally occur within a month of the precipitation event, disease outbreaks from groundwater contamination tend to occur ≥2 months later. According to a review of published reports of waterborne disease outbreaks, Vibrio and Leptospira species are the pathogens most commonly involved in the wake of heavy precipitation.

Combined Sewer Systems

Roughly 40 million people in the United States and millions more around the world rely on combined sewer systems in which storm water and sanitary wastewater are conveyed in the same pipe to treatment facilities. These systems were designed on the basis of the nineteenth-century climate, in which heavy downpours were less frequent than they are today. The frequency of combined sewer overflows resulting in untreated sewage discharge, usually into freshwater bodies, has been increasing in cities worldwide. Overflows are associated with discharges of heavy metals and other chemical pollutants as well as a variety of pathogens. Outbreaks of hepatitis A, Escherichia coli O157:H7 infection, and cryptosporidial disease have been associated with sewer overflows in the United States.

Rising Temperatures and Vibrio Species

Warmer temperatures favor proliferation of Vibrio species and disease outbreaks, as has been demonstrated in countries surrounding the Baltic Sea, Chile, Israel, northwestern Spain, and the U.S. Pacific Northwest. Around the Baltic Sea, outbreaks of Vibrio infection may be particularly likely because of faster warming near the poles and the sea’s relatively low salt content. In 2004, a Vibrio parahaemolyticus outbreak arising from consumption of Alaskan oysters occurred. This pathogen was unknown in Alaskan oysters prior to this event and extended the known geographic range of the disease 1000 km northward.

ENSO-Related Outbreaks

In the past, El Niño events were used as a model to investigate the potential for extreme weather–related infectious disease epidemics occurring in association with climate change. Recent evidence indicates that climate change itself may be strengthening El Niño events. These events tend to promote epidemic infections in certain regions (Fig. 120-11).

Associations of El Niño with outbreaks of Rift Valley fever in eastern and southern Africa have been known since the 1950s. El Niño favors wet conditions suitable for the insect vectors of the disease in these regions. Given the strong association between El Niño conditions and disease incidence, models have successfully predicted Rift Valley fever epidemics in humans and animals. In the 2006–2007 El Niño season, for example, outbreaks of Rift Valley fever were accurately predicted 2–6 weeks prior to epidemics in Somalia, Kenya, and Tanzania.

El Niño has had inconsistent associations with malaria incidence in African countries. Some of the strongest associations between El Niño and malaria have been identified in South Africa and Swaziland, where available data on incidence are relatively robust; however, even in these instances, the observed increased risk did not reach statistical significance. A stronger link to El Niño has been found in several studies done in South America. Research on malaria incidence in Colombia between 1960 and 2006 found that a 1°C temperature rise contributed to a 20% increase in incidence.

El Niño years are often associated with an increased incidence of dengue. Research on dengue outbreaks in Thailand from 1996 to 2005 revealed that 15–22% of the variance in monthly dengue disease incidence was attributable to El Niño. In South America, data on dengue outbreaks between 1995 and 2010 showed an increased incidence during the El Niño events of 1997–1998 and 2006–2007.

CLIMATE CHANGE, POPULATION DISPLACEMENT, AND INFECTIOUS DISEASE EPIDEMICS

For many reasons, including freshwater shortages, flooding, food shortages, and climate change–driven conflicts, climate change has and will continue to put pressure on human populations to move. Human migrations have long been associated with epidemic disease in the migrating populations themselves and in the communities in which they settle. The specific pathogens and patterns of disease that may appear after population migration relate to endemic diseases present in the migrant populations.

Large-scale migrations are common after extreme precipitation events. Hurricane Katrina, for instance, displaced about 1 million people from the U.S. Gulf Coast. Among Katrina refugees, outbreaks of respiratory, diarrheal, and skin diseases were most common. While attribution of a single weather event to increased greenhouse-gas emissions is difficult, research can provide information on the likelihood of such events. It is expected, for example, that warming by 1°C increases the odds of a storm as strong as or stronger than Katrina two- to sevenfold.

In the developing world, infectious disease outbreaks associated with population displacement due to extreme weather events may be especially hard to detect and respond to. Mitigation of disease risk requires overlaying of climate-related migration risk with foci of disease epidemics.

A BROADER VIEW OF CLIMATE CHANGE AND HEALTH

Climate change has far-reaching implications for the distribution and spread of infectious diseases worldwide. However, the greatest disease burdens related to climate change may not be due to infections. Because climate change disrupts the foundations of health, such as access to safe drinking water and food, it has the potential to undermine progress against major existing health problems such as malnutrition. In addition, resource scarcity and climate instability are increasingly associated with conflicts. Scholars have argued that events related to climate change were a factor in the revolutions of the Arab Spring and the Syrian civil war.

The public health response to climate change entails both mitigation and adaptation measures. Mitigation represents primary prevention and involves the reduction of greenhouse gas emissions into the atmosphere. Although no clear safety threshold of greenhouse gas emissions has been agreed upon, national governments from the major industrialized countries have agreed to set a warming target of <2°C above preindustrial levels by 2050; the attainment of this goal will require reducing greenhouse gas emissions by 40–70% below 2010 levels. The 2016 Paris Agreement on climate change provides a framework for the establishment of a global carbon market that may speed reductions in greenhouse gas emissions, along with several other seminal provisions. Mitigation also confers co-benefits, including better air quality that results when fewer bio- or fossil fuels are burned. Biofuel-burning cookstoves, for instance, used by some 3 billion people around the world, release air pollution that constitutes about one-fourth of the global black-carbon emissions that warm the planet and kill roughly 4 million people a year. Clean cookstoves simultaneously mitigate climate change and indoor air pollution–related mortality.

Adaptation represents secondary prevention and is aimed at reducing the harms associated with sea level rise, heat waves, floods, droughts, wildfires, and other greenhouse gas–driven events. The efficacy of adaptation is constrained by the challenges inherent in predicting the precise location, duration, and severity of extreme weather events and flooding related to sea level rise, among other considerations.

FURTHER READING

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