Chapter 141: Pneumococcal Infections

In the late nineteenth century, pairs of micrococci were first recognized in the blood of rabbits injected with human saliva by both Louis Pasteur, working in France, and George Sternberg, an American army physician. The important role of these micrococci in human disease was not appreciated at that time. By 1886, when the organism was designated “pneumokokkus” and Diplococcus pneumoniae, it had been isolated by many independent investigators, and its role in the etiology of pneumonia was well known. In the 1930s, pneumonia was the third leading cause of death in the United States (after heart disease and cancer) and was responsible for ~7% of all deaths both in the United States and in Europe. While pneumonia was caused by a host of pathogens, lobar pneumonia—a pattern more likely to be caused by the pneumococcus—accounted for approximately one-half of all pneumonia deaths in the United States in 1929. In 1974, the organism was reclassified as Streptococcus pneumoniae.

Etiologic Agent

Pneumococci are spherical gram-positive bacteria of the genus Streptococcus. Within this genus, cell division occurs along a single axis, and bacteria grow in chains or pairs—hence the name Streptococcus, from the Greek streptos, meaning “twisted,” and kokkos, meaning “berry.” At least 22 streptococcal species are recognized and are divided further into groups based on their hemolytic properties. S. pneumoniae belongs to the α-hemolytic group that characteristically produces a greenish color on blood agar because of the reduction of iron in hemoglobin (Fig. 141-1). The bacteria are fastidious and grow best in 5% CO₂ but require a source of catalase (e.g., blood) for growth on agar plates, where they develop mucoid (smooth/shiny) colonies. Pneumococci without a capsule produce colonies with a rough surface. Unlike that of other α-hemolytic streptococci, their growth is inhibited in the presence of optochin (ethylhydrocupreine hydrochloride), and they are bile soluble.

In common with other gram-positive bacteria, pneumococci have a cell membrane beneath a cell wall, which in turn is covered by a polysaccharide capsule. Pneumococci are divided into serogroups or serotypes based on capsular polysaccharide structure, as distinguished with rabbit polyclonal antisera; capsules swell in the presence of specific antiserum (the Quellung reaction). The most recently discovered serotypes—6C, 6D, 6F, 6G, 6H, 11E, 20A, and 20B—have been identified with monoclonal antibodies and by serologic, genetic, and biochemical means. The currently recognized 98 serotypes fall into 21 serogroups, and each serogroup contains two to eight serotypes with closely related capsules. In the absence of type-specific antibody, the capsule protects the bacteria from phagocytosis by host cells and is arguably the most important determinant of pneumococcal virulence. Unencapsulated variants are occasionally identified in cases of invasive pneumococcal disease; however, when their genotype is assessed, they often contain capsular genes. Thus it is likely that they were encapsulated in vivo and have stopped producing capsule during the laboratory steps of pathogen isolation.

Virulence Factors

Within the cytoplasm, cell membrane, and cell wall, many molecules that may play a role in pneumococcal pathogenesis and virulence have been identified (Fig. 141-2). These proteins are often involved in direct interactions with host tissues or in concealment of the bacterial surface from host defense mechanisms. Pneumolysin is a secreted cytotoxin thought to result in cytolysis of cells and tissues, and LytA enhances pathogenesis. A number of cell wall proteins interfere with the complement pathway, thus inhibiting complement deposition and preventing lysis and/or opsonophagocytosis. The pneumococcal H inhibitor (Hic) impedes the formation of C3 convertase, while pneumococcal surface protein C (PspC), also known as choline-binding protein A (CbpA), binds factor H and is thought to accelerate the breakdown of C3. PspA and CbpA inhibit the deposition of or degrade C3b. The numerous pneumococcal proteins thought to be involved in adhesion include the ubiquitous surface-anchored sialidase (neuraminidase) NanA, which cleaves sialic acid on host cells and proteins, and pneumococcal surface adhesin A (PsaA). Pili recently recognized by electron microscopy also may play an important role in binding to cells. Some of the antigens mentioned above are potential vaccine candidates (see “Prevention,” below). Biofilm production by pneumococci is now well recognized and is likely to be an important mechanism aiding survival of pneumococci in the upper respiratory tract and contributing to local disease manifestations such as otitis media.

Although the capsule surrounding the cell wall of S. pneumoniae is the basis for categorization by serotype, the behavior and pathogenic potential of a serotype may also be related to the genetic origin of the strain. Molecular typing is therefore of considerable interest. Initially, techniques such as pulsed-field gel electrophoresis were used to determine genetic relatedness; such techniques have been superseded by sequencing of housekeeping genes to define a clone (multilocus sequence typing, MLST). For S. pneumoniae, alleles at each of the loci aroE, gdh, gki, recP, spi, xpt, and ddl are sequenced and compared with all of the known alleles at that locus. Sequences identical to a known allele are assigned the same allele number, whereas those differing from any known allele—even at a single nucleotide site—are assigned new numbers. Software for assignment of alleles at each locus is available on the pneumococcal MLST website (pubmlst.org/spneumoniae/), and the allelic profile of each isolate and its consequent sequence type are generated. With the advent of high-throughput and relatively inexpensive sequencing techniques, whole-genome sequencing will soon supersede MLST. The first pneumococcal genome was sequenced in 2001 (a serotype 4 strain known as TIGR4), and to date more than 10,000 pneumococcal strains have been sequenced. The pneumococcal genome has ~2.2 million base pairs containing 2236 predicted coding regions. Genome sequence analysis has made major contributions to the understanding of pneumococcal biology and diversity.

Pneumococcal infections remain a significant global cause of morbidity and death, particularly among children and the elderly (See also “Global Health,” below.). Rapid and dramatic changes in the epidemiology of this disease during the past 15 years in several developed countries followed the licensure and routine childhood administration of pneumococcal polysaccharide–protein conjugate vaccine (PCV). With PCV introduction in underdeveloped and middle-income countries, additional profound changes in pneumococcal ecology and disease epidemiology are occurring. The disease burden and serotype distribution in the PCV era are influenced not only by the reduction in disease caused by serotypes included in PCV but also by serotype replacement as a result of reductions in vaccine serotypes, concomitant secular trends in pneumococcal strains unrelated to vaccine use, the impact of antibiotic use on pneumococcal strain ecology, and surveillance system attributes that can themselves affect analysis of epidemiologic features of pneumococcal strains and disease.

Serotype Distribution

Not all pneumococcal serotypes are equally likely to cause disease; observed serotype distributions vary by age category, disease syndrome, and geography. Geographic differences may be driven by variations in the relative prevalence of syndromes causing disease rather than by true serotype distribution differences since certain serotypes are more common causes of some syndromes than others (e.g., pneumonia and meningitis). Most data on serotype distribution come from pediatric invasive pneumococcal disease (IPD, defined as infection of a normally sterile site); much less information on global or regional serotype distributions is available for disease in adults. In the era before PCV use, five to seven serotypes caused >60% of IPD cases among children <5 years of age in most parts of the world; seven serotypes (1, 5, 6A, 6B, 14, 19F, and 23F) accounted for ~60% of such cases in all areas of the world, but in any given region these seven serotypes may not all rank as the most common disease strains (Fig. 141-3). Some serotypes (e.g., types 1 and 5) not only tend to cause disease in areas with a high disease burden but also cause waves of disease in lower-burden areas (e.g., Europe) or outbreaks (e.g., in military barracks; meningitis in sub-Saharan Africa). The broader range of serotypes causing disease among adults than among children is apparent from a comparison of the coverage of existing multiserotype vaccines in different age groups. For example, data from the United States for 2013–2014 on the serotypes causing IPD indicated that a polysaccharide vaccine containing 23 serotypes (PPSV23) would include the serotypes causing 59% of cases among children <5 years of age, 70% of those among persons 18–64 years of age, and 57% of those among persons ≥65 years of age.

Nasopharyngeal Carriage

Pneumococci are intermittent inhabitants of the healthy human nasopharynx and are transmitted by respiratory droplets. In children, pneumococcal nasopharyngeal ecology varies by geographic region, socioeconomic status, climate, degree of crowding, and particularly intensity of exposure to other children, with children in day-care settings having higher rates of colonization. In developed-world settings, children serve as the major vectors of pneumococcal transmission. By 1 year of age, ~50% of children have had at least one episode of pneumococcal colonization. Cross-sectional prevalence data show rates of pneumococcal carriage ranging from 20% to 50% among children <5 years of age and from 5% to 15% among young and middle-aged adults; Fig. 141-4 shows relevant data from the United Kingdom. Data on colonization rates among healthy elderly individuals are limited. In developing-world settings, pneumococcal acquisition occurs much earlier, sometimes within the first few days after birth, and nearly all infants have had at least one episode of colonization by 2 months of age. Cross-sectional studies show that up to the age of 5 years, 70–90% of children carry S. pneumoniae in the nasopharynx, and a significant proportion of adults (sometimes >40%) also are colonized. Their high rates of colonization make adults an important source of transmission and may affect community transmission dynamics.

Invasive Disease and Pneumonia

IPD develops when S. pneumoniae invades the bloodstream and seeds other organs or directly reaches the cerebrospinal fluid (CSF) by local extension. Pneumonia may follow aspiration of pneumococci, although only 10–30% of pneumococcal pneumonia cases are associated with a positive blood culture (and thus contribute to the measured burden of IPD). The substantial variation of IPD rates with age is illustrated by data from the United States for 1998–1999, a period prior to PCV introduction. Rates of IPD were highest among children <2 years of age and among adults ≥65 years of age (188 and 60 cases/100,000, respectively; Fig. 141-5). Since the introduction of PCV, IPD rates among infants and children in the United States have fallen by >75%, a decrease driven by the near elimination of vaccine-serotype IPD. A similar impact of PCV on vaccine-serotype IPD rates has been consistently observed in countries where PCV has been introduced into the routine pediatric vaccination schedule. However, the magnitudes of change in the non-vaccine-serotype IPD rate in various countries have been heterogeneous; the interpretation of this heterogeneity is a complex issue. In the United States, Canada, and Australia, rates of non-vaccine-serotype IPD have increased but the magnitude of the increase is generally small relative to the substantial reductions in vaccine-serotype IPD. In contrast, in other settings (e.g., Alaska Native communities and the United Kingdom), the reduction in vaccine-serotype IPD has been offset by notable increases in rates of disease caused by non-vaccine serotypes. Explanations for the heterogeneity of findings include replacement disease resulting from vaccine pressure, changes in clinical case investigation, secular trends unrelated to PCV use, antibiotic pressure selecting for resistant organisms, changes in surveillance or reporting systems, rapidity of PCV introduction, and inclusion of a catch-up campaign. A recent systematic review concludes that serotype replacement in IPD follows the use of PCV7 but that the magnitude of this phenomenon is small relative to the reduction in disease from vaccine serotypes. Furthermore, much of the replacement disease has been caused by serotype 19A. In contrast to the changes seen following implementation of PCV7, the replacing serotypes are more diverse and a single serotype is not dominant with the use of expanded-valency PCV products (i.e., PCV10 and PCV13, the latter of which includes serotype 19A). In spite of some serotype replacement in disease, the net effect of PCV is to reduce the rate of pneumococcal disease both in the age group targeted for vaccination and in unvaccinated age groups.

Pneumonia is the most common of the serious pneumococcal disease syndromes and poses special challenges from a clinical and public health perspective. Most cases of pneumococcal pneumonia are not associated with bacteremia, and in these cases a definitive etiologic diagnosis is difficult or impossible. As a result, estimates of disease burden focus primarily on IPD rates and fail to include the major portion of the burden of serious pneumococcal disease. Among children, PCV trials designed to collect efficacy data on syndrome-based outcomes (e.g., radiographically confirmed pneumonia, clinically diagnosed pneumonia) have revealed the burden of culture-negative pneumococcal pneumonia. These trials have provided the means to infer that only ~5–20% of pneumococcal pneumonia cases result in bacteremia. An important randomized controlled trial of PCV among the elderly in the Netherlands (the Capita trial) has revealed the small fraction of adult pneumococcal pneumonia patients who also have bacteremia. Use of high-quality sputum specimens and, in the case of adults with a low likelihood of colonization absent disease, urine antigen detection both contribute to the diagnosis of nonbacteremic pneumococcal pneumonia. Furthermore, evidence continues to accrue that pneumococcal pneumonia events are often the result of co-infection with viral or other bacterial pathogens. Thus a pneumonia case resulting from a pulmonary infection with a single pathogen is probably an uncommon event; rather, most cases of pneumonia likely result from the sequential or contemporaneous co-infection of a host with multiple pathogens, often both viruses and bacteria.

The case–fatality ratios (CFRs) for pneumococcal pneumonia and IPD vary by age, underlying medical condition, and access to care. In addition, the CFR for pneumococcal pneumonia varies with the severity of disease at presentation (rather than according to whether the pneumonia episode is associated with bacteremia) and with the patient’s age (from <5% among hospitalized patients 18–44 years old to >12% among those >65 years old, even when appropriate and timely management is available). Notably, the likelihood of death in the first 24 h of hospitalization did not change substantially with the introduction of antibiotics; this surprising observation highlights the fact that the pathophysiology of severe pneumococcal pneumonia among adults reflects a rapidly progressive cascade of events that often unfolds irrespective of antibiotic administration. Management in an intensive care unit can provide critical support for the patient through the acute period, with lower CFRs, while antibiotics address the underlying infection.

Rates of pneumococcal disease vary by season, with higher rates in colder than in warmer months in temperate climates; by sex, with males more often affected than females; and by risk group, with risk factors including underlying medical conditions, behavioral issues (e.g., smoking), and ethnic group. In the United States, some Native American populations (including Alaska Natives) and African Americans have higher rates of disease than the general population; the increased risk is probably attributable to socioeconomic conditions and the prevalence of underlying risk factors for pneumococcal disease. Medical conditions that increase the risk of pneumococcal infection are listed in Table 141-1. Outbreaks of disease are well recognized in crowded settings with susceptible individuals, such as infant day-care facilities, military barracks, and nursing homes. Furthermore, there is a clear association between preceding viral respiratory disease (especially but not exclusively influenza) and risk of secondary pneumococcal infections. The significant role of pneumococcal pneumonia in the morbidity and mortality associated with seasonal and pandemic influenza is increasingly well recognized.

Antibiotic Resistance

Reduced pneumococcal susceptibility to penicillin was first noted in 1967, but not until the 1990s did reduced antibiotic susceptibility emerge as a significant clinical and public health issue, with an increasing prevalence of pneumococcal isolates resistant to single or multiple classes of antibiotics and a rising absolute magnitude of minimal inhibitory concentrations (MICs). Strains with reduced susceptibility to penicillin G, cefotaxime, ceftriaxone, macrolides, and other antibiotics are now found worldwide and account for a significant proportion of disease-causing strains in many locations, especially among children. Vancomycin resistance has not yet been observed in clinical pneumococcal strains. Lack of antimicrobial susceptibility is clearly related to a subset of serotypes, many of which disproportionately cause disease among children. Resistance phenotypes are based on a diverse array of mutational events and inter- and intraspecies gene-transfer phenomena carried out by several types of mobile genetic elements, with consequent dissemination of successful resistant clones. The vicious cycle of antibiotic exposure, selection of resistant organisms in the nasopharynx, and transmission of these organisms within the community, leading to difficult-to-treat infections and increased antibiotic exposure, has been interrupted to some extent by the introduction and routine use of PCV. The clinical implications of pneumococcal antimicrobial nonsusceptibility are addressed below in the section on treatment.

Pneumococci colonize the human nasopharynx from an early age; colonization acquisition events are generally described as asymptomatic, but evidence exists to associate acquisition with mild respiratory symptoms, especially in the very young. Bacteria survive in the nasopharynx protected by a variety of factors, including their bacterial capsule and the formation of a biofilm. From the nasopharynx, the bacteria spread either via the bloodstream to distant sites (e.g., brain, joint, bones, peritoneal cavity) or locally to mucosal surfaces where they can cause otitis media or pneumonia. Direct spread from the nasopharynx to the central nervous system (CNS) can occur in rare cases of skull-base fracture, although most cases of pneumococcal meningitis are secondary to hematogenous spread. The pneumococcus is not a static bacterium; rather, it modifies its expression of capsule in adaptation to the external environment. In the nasopharynx, the pneumococcus downregulates capsular expression, averting protective immunologic mechanisms that recognize capsule; the phenotype on culture are rough colonies. Upon invasion by traversal of the epithelium, the pneumococcus upregulates its capsular expression, transforming its appearance on culture to smooth colonies—a change illustrating the dynamic nature of the organism in response to the local environment. Pneumococci can cause disease in almost any organ or part of the body; however, otitis media, pneumonia, bacteremia, and meningitis are most common. Colonization is a relatively frequent event, yet disease is rare. In the nasopharynx, pneumococci survive in mucus secreted by epithelial cells and in a biofilm they create, where they can avoid local immune factors such as leukocytes and complement. The mucus itself is a component of local defense mechanisms, and the flow of mucus (driven in part by cilia in what is known as the mucociliary escalator) effects mechanical clearance of pneumococci. While many colonization episodes are of short duration, longitudinal studies in adults and children have revealed persistent colonization with a specific serotype over many months. Colonization eventually results in the development of capsule- and protein-specific serum IgG antibodies, which are thought to play a role in mediating clearance of bacteria from the nasopharynx. IgG antibodies to surface-exposed cell-wall or secreted proteins also appear in the circulation in an age-dependent fashion or after colonization; the biologic role of these antibodies is less clear. Recent acquisition of a new colonizing serotype is more likely to be associated with subsequent invasion, presumably as a result of the absence of type-specific immunity. Intercurrent viral infections make the host more susceptible to pneumococcal colonization, and pneumococcal disease in a colonized individual often follows perturbation of the nasopharyngeal mucosa by such infections. Local cytokine production after a viral infection is thought to upregulate adhesion factors in the respiratory epithelium, allowing pneumococci to adhere via a variety of surface adhesin molecules, including PsaA, PspA, CbpA, PspC, Hyl, pneumolysin, and the neuraminidases (Fig. 141-2). Adhesion coupled with inflammation induced by pneumococcal factors such as peptidoglycans and teichoic acids results in invasion. It is the inflammation induced by various bacterium-derived factors that is responsible for the pathology associated with pneumococcal infection. Pneumococcal cell wall–derived teichoic acids and peptidoglycans induce a variety of cytokines, including the proinflammatory cytokines interleukin (IL) 1, IL-6, and tumor necrosis factor, and activate complement via the alternative pathway. Polymorphonuclear leukocytes are thus attracted, and an intense inflammatory response is initiated. Pneumolysin also is important in local pathology, inducing proinflammatory cytokine production by local monocytes.

The pneumococcal capsule, consisting of polysaccharides with antiphagocytic properties (i.e., the capacity to resist complement deposition in the absence of type-specific antibody), plays an important role in pathogenesis. While most capsular types can cause human disease, certain capsular types are more commonly isolated from sites of infection. The reason for the dominance of some serotypes over others in IPD, as depicted in Fig. 141-3, is unclear.

Innate Immunity

As described above, intact respiratory epithelium and a host of nonspecific or innate immune factors (e.g., mucus, splenic function, complement, neutrophils, and macrophages) constitute the first line of defense against pneumococci. Physical factors such as the cough reflex and the mucociliary escalator are important in clearing bacteria from the lungs. Immunologic factors are critical as well: C-reactive protein (CRP) binds phosphorylcholine in the pneumococcal cell wall, inducing complement activation and leading to bacterial clearance; Toll-like receptor 2 (TLR2) recognizes both pneumococcal lipoteichoic acid and cell wall peptidoglycan; and in animal models, the absence of host TLR2 leads to more severe infection and impaired clearance of nasopharyngeal colonization. TLR4 appears to be necessary for the proinflammatory effect of pneumolysin on macrophages. The importance of TLR recognition is underlined by descriptions of an inherited deficiency of human IL-1 receptor–associated kinase 4 (IRAK-4) that manifests as an unusual susceptibility to infection with bacteria, including S. pneumoniae. IRAK-4 is essential for the normal functioning of several TLRs. Other factors that interfere with these nonspecific mechanisms (e.g., viral infections, cystic fibrosis, bronchiectasis, complement deficiency, and chronic obstructive pulmonary disease) all predispose to the development of pneumococcal pneumonia. Patients who lack a spleen or have abnormal splenic function (e.g., persons with sickle cell disease) are at high risk of developing overwhelming pneumococcal disease.

Acquired Immunity

Acquired immunity induced following colonization or through exposure to cross-reactive antigens rests largely on the development of serum IgG antibody specific for the pneumococcal capsular polysaccharide. Nearly all polysaccharides are T cell–independent antigens; B cells can make antibodies to such antigens without T cell help. However, in children <1–2 years old, such B cell responses are poorly developed. This delayed ontogeny of capsule-specific IgG in young children is associated with susceptibility to pneumococcal infection (Fig. 141-5). The extremely high risk of pneumococcal infection in the absence of serum immunoglobulin (i.e., in conditions such as agammaglobulinemia) highlights the important role of capsular antibody in protection against disease. Each serotype’s capsule is chemically distinct, even though for some serotypes the chemical distinction from another type may be a minor one; thus immunity tends to be serotype specific, although some cross-immunity exists. For example, conjugate vaccine–induced antibodies to serotype 6B prevent infection due to serotype 6A. However, cross-protection against serotypes within serogroups is not universal; for instance, antibodies to serotype 19F induced by some vaccines do not appear to confer protection against disease caused by serotype 19A. Antibodies to surface-exposed or secreted pneumococcal proteins (such as pneumolysin, PsaA, and PspA) also appear in the circulation with increasing age of the host, but their functional significance remains unclear. Data from murine models suggest that CD4+ T cells may play a role in preventing pneumococcal colonization and disease, and experimental data derived from humans suggest that IL-17-secreting CD4+ T cells may be relevant.

APPROACH TO THE PATIENT

The clinical manifestations of pneumococcal disease depend on the site of infection and the duration of illness. Clinical syndromes are classified as noninvasive (e.g., otitis media) or invasive (e.g., bacteremic pneumonia, meningitis) according to whether a normally sterile site is infected. The pathogenesis of noninvasive illness involves contiguous spread from the nasopharynx or skin; invasive disease involves infection of a normally sterile body fluid or follows bacteremia. Regardless of the mechanism, all pneumococcal infections result from nasopharyngeal acquisition of the organism.

Pneumonia

Pneumonia is the most common serious pneumococcal syndrome and is considered invasive when associated with a positive blood culture. Whether to categorize nonbacteremic pneumococcal pneumonia as invasive or noninvasive remains debatable.

Pneumococcal pneumonia can present as a mild community-acquired infection at one extreme and as a life-threatening disease requiring intubation and intensive support at the other.

Presenting Manifestations

The presentation of pneumococcal pneumonia does not reliably distinguish it from pneumonia of other etiologies. In a subset of cases, pneumococcal pneumonia is recognized at the outset as associated with a viral upper respiratory infection and is characterized by the abrupt onset of cough and dyspnea accompanied by fever, shaking chills, and myalgias. The cough evolves from nonpurulent to productive of sputum that is purulent and sometimes tinged with blood. Patients may describe stabbing pleuritic chest pain and significant dyspnea indicating involvement of the parietal pleura. Among the elderly, the presenting clinical symptoms may be less specific, with confusion or malaise but without fever or cough. In such cases, a high index of suspicion is required because failure to treat pneumococcal pneumonia promptly in an elderly patient is likely to result in rapid evolution of the infection, with increased severity, morbidity, and risk of death.

Findings on PHYSICAL Examination

The clinical signs associated with pneumococcal pneumonia among adults include tachypnea (defined as >30 breaths/min) and tachycardia, hypotension in severe cases, and fever in most cases (although not in all elderly patients). Respiratory signs are varied, including dullness to percussion in areas of the chest with significant consolidation, crackles on auscultation, reduced expansion of the chest in some cases as a result of splinting to reduce pain, bronchial breathing in a minority of cases, pleural rub in occasional cases, and cyanosis in cases with significant hypoxemia. Among infants with severe pneumonia, chest wall indrawing and nasal flaring are common. Nonrespiratory findings can include upper abdominal pain if the diaphragmatic pleura is involved as well as mental status changes, particularly confusion in elderly patients.

Differential Diagnosis

The differential diagnosis of pneumococcal pneumonia includes cardiac conditions such as myocardial infarction and heart failure with atypical pulmonary edema; pulmonary conditions such as atelectasis; and pneumonia caused by viral pathogens, mycoplasmas, Haemophilus influenzae, Klebsiella pneumoniae, Staphylococcus aureus, Legionella, or (in HIV-infected and otherwise immunocompromised hosts) Pneumocystis. In cases with abdominal symptoms, the differential diagnosis includes cholecystitis, appendicitis, perforated peptic ulcer disease, and subphrenic abscesses. The challenge in cases with abdominal symptoms is to remember to include pneumococcal pneumonia—a nonabdominal process—in the differential diagnosis.

Diagnosis

Some authorities advocate treating uncomplicated, nonsevere, community-acquired pneumonia without determining the microbiologic etiology, given that this information is unlikely to alter clinical management. However, efforts to identify the cause of pneumonia are important when the disease is more severe and when the diagnosis of pneumonia is not clearly established. The gold standard for etiologic diagnosis of pneumococcal pneumonia is pathologic examination of lung tissue. In lieu of that procedure, evidence of an infiltrate on chest radiography warrants a diagnosis of pneumonia. However, cases of pneumonia without radiographic evidence do occur. An infiltrate can be absent either early in the course of the illness or with dehydration; upon rehydration, an infiltrate usually appears. The radiographic appearance of pneumococcal pneumonia is varied; it classically consists of lobar or segmental consolidation (Fig. 141-6) but in some cases is patchy. More than one lobe is involved in ~30% of cases. Consolidation may be associated with a small pleural effusion or empyema in complicated cases. In children, “round pneumonia,” a distinctly spherical consolidation on chest radiography, is associated with a pneumococcal etiology. Round pneumonia is uncommon in adults. S. pneumoniae is not the only cause of such lesions; other causes, especially cancer, should be considered.

Blood drawn from patients with suspected pneumococcal pneumonia can be used for supportive or definitive diagnostic tests. Blood cultures are positive for pneumococci in a minority (<30%) of cases of pneumococcal pneumonia, as evidenced especially by vaccine clinical trials, which provide an independent method to reveal the contribution of the pneumococcus to pneumonia cases. Nonspecific findings include an elevated polymorphonuclear leukocyte count (>15,000/μL in most cases and upward of 40,000/μL in some), leukopenia in <10% of cases (a poor prognostic sign associated with a fatal outcome), and elevated values in liver function tests (e.g., both conjugated and unconjugated hyperbilirubinemia). Anemia, low serum albumin levels, hyponatremia, and elevated serum creatinine levels are all found in ~20–30% of patients.

Urinary pneumococcal antigen assays have facilitated etiologic diagnosis, but the application of the results is confounded by the fact that nasopharyngeal colonization with the pneumococcus, in the absence of disease, also results in a positive test. In adults, therefore, a positive pneumococcal urinary antigen test has a high predictive value for etiologic attribution of pneumonia because the prevalence of pneumococcal nasopharyngeal colonization is relatively low. In communities, particularly those in low-income countries, where colonization rates among adults are high, urine antigen assays may be less useful. The same issue holds for children, in whom a positive urinary antigen test is usually uninformative for etiologic attribution of their pneumonia illness because colonization rates are generally high. A recent advance is the development of quantitative serotype-specific urinary antigen detection assays; their application for adults and children holds promise, especially in detecting serotypes that are rarely identified in asymptomatic carriage (e.g., serotype 1), even among children.

Most cases of pneumococcal pneumonia in adults are diagnosed by Gram’s staining and culture of sputum. The utility of a sputum specimen is directly related to its quality and the patient’s antibiotic treatment status.

Complications

Empyema is the most common focal complication of pneumococcal pneumonia, occurring in <5% of cases. When fluid in the pleural space is accompanied by fever and leukocytosis (even low-grade) after 4–5 days of appropriate antibiotic treatment for pneumococcal pneumonia, empyema should be considered. Parapneumonic effusions are more common than empyema, representing a self-limited inflammatory response to pneumonia. Pleural fluid with frank pus, bacteria (detected by microscopic examination), or a pH of ≤7.1 indicates empyema and demands aggressive and complete drainage, usually through chest tube insertion.

Meningitis

Pneumococcal meningitis usually presents as a pyogenic condition that is clinically indistinguishable from meningitis of other bacterial etiologies. Meningitis can be the primary presenting pneumococcal syndrome or a complication of other conditions such as skull fracture, otitis media, bacteremia, or mastoiditis. Now that H. influenzae type b vaccine is routinely used in children, S. pneumoniae and Neisseria meningitidis are the most common bacterial causes of meningitis in both adults and children. Pyogenic meningitis, including that due to S. pneumoniae, is associated clinically with findings that include severe, generalized, gradual-onset headache, fever, and nausea as well as specific CNS manifestations such as stiff neck, photophobia, seizures, and confusion. Clinical signs include a toxic appearance, altered consciousness, bradycardia, and hypertension indicative of increased intracranial pressure. A small proportion of adult patients have Kernig’s or Brudzinski’s sign or cranial nerve palsies (particularly of the third and sixth cranial nerves).

A definitive diagnosis of pneumococcal meningitis rests on the examination of CSF for (1) evidence of turbidity (visual inspection); (2) elevated protein level, elevated white blood cell count, and reduced glucose concentration (quantitative measurement); and (3) specific identification of the etiologic agent (culture, Gram’s staining, antigen testing, or polymerase chain reaction [PCR]). A blood culture positive for S. pneumoniae in conjunction with clinical manifestations of meningitis also is considered confirmatory. As discussed in the section on pneumonia, among adults, detection of pneumococcal antigen in urine is considered highly specific because of the low prevalence of nasopharyngeal colonization in this age group.

The mortality rate for pneumococcal meningitis is ~20%. In addition, up to 50% of survivors experience acute or chronic complications, including deafness, hydrocephalus, and mental retardation in children and diffuse brain swelling, subarachnoid bleeding, hydrocephalus, cerebrovascular complications, and hearing loss in adults.

Other Invasive Syndromes

S. pneumoniae can cause other invasive syndromes involving virtually any body site. These syndromes include primary bacteremia without other sites of infection (bacteremia without a source; occult bacteremia), osteomyelitis, septic arthritis, endocarditis, pericarditis, and peritonitis. The essential diagnostic approach is collection of fluid from the site of infection by sterile technique and examination by Gram’s staining, culture, and—when relevant—capsular antigen assay or PCR. Hemolytic-uremic syndrome can complicate invasive pneumococcal disease.

Noninvasive Syndromes

The two major noninvasive syndromes caused by S. pneumoniae are sinusitis and otitis media; the latter is the most common pneumococcal syndrome and most often affects young children. The manifestations of otitis media include the acute onset of severe pain, fever, deafness, and tinnitus, most frequently in the setting of a recent upper respiratory tract infection. Clinical signs include a red, swollen, often bulging tympanic membrane with reduced movement on insufflation or tympanography. Redness of the tympanic membrane is not sufficient for the diagnosis of otitis media.

Pneumococcal sinusitis is also a complication of upper respiratory tract infections and presents with facial pain, congestion, fever, and—in many cases—persistent nighttime cough. A definitive diagnosis is made by aspiration and culture of sinus material; however, presumptive treatment is most commonly initiated after application of a strict set of clinical diagnostic criteria.

TREATMENT

Measures to prevent pneumococcal disease include vaccination against S. pneumoniae and influenza viruses, reduction of comorbidities that increase the risk of pneumococcal disease, and prevention of antibiotic overuse, which fuels pneumococcal resistance.

Capsular Polysaccharide Vaccines

The 23-valent pneumococcal polysaccharide vaccine (PPSV23), containing 25 μg of each capsular polysaccharide, has been licensed for use since 1983. Recommendations for its use vary by country. The U.S. Advisory Committee on Immunization Practices recommends PPSV23 for all persons ≥65 years of age and for those 2–64 years of age who have underlying medical conditions that put them at increased risk for pneumococcal disease or, if infected, disease of increased severity (Table 141-1; see also www.cdc.gov/vaccines/schedules). The committee updated their recommendations to include the combined use of PPSV23 and pneumococcal conjugate vaccine in at-risk individuals (see “Polysaccharide–Protein Conjugate Vaccines,” below). Revaccination 5 years after the first dose is recommended for persons >2 years of age who have underlying medical conditions but not routinely for those whose only indication is an age of ≥65 years. PPSV23 does not induce an anamnestic response, and antibody concentrations wane over time; thus revaccination is particularly important for individuals with conditions resulting in loss of antibody. Concerns about repeated revaccination have focused on safety (i.e., local reactions) and the induction of immune hyporesponsiveness. Neither the clinical relevance nor the biologic basis of hyporesponsiveness is clear, but, given the possibility of its occurrence, more than one revaccination has not been recommended.

The effectiveness of PPSV23 against IPD, pneumococcal pneumonia, all-cause pneumonia, and death is controversial, with wide variation in observations. The many published meta-analyses of PPSV efficacy have often reached opposing conclusions with regard to a given clinical entity. Generally, observational studies cite greater effectiveness than do controlled clinical trials. The consensus is that PPSV is effective against IPD but is less effective or ineffective against nonbacteremic pneumococcal pneumonia. However, the results of some published trials, observational studies, and meta-analyses contradict this view. Effectiveness is often lower in the elderly and in immunodeficient patients whose condition is associated with reduced antibody responses to vaccines than in younger, healthier populations. When PPSV is effective, the duration of protection following a single dose of vaccine is estimated to be ~5 years.

What is not disputed is that improved pneumococcal vaccines are needed for adults. Even in the setting of routine pneumococcal conjugate vaccination of infants (which indirectly protects adults from vaccine-serotype strains), disease caused by serotypes not represented in the conjugate vaccine continues to be a significant burden among adults.

Polysaccharide–Protein Conjugate Vaccines

Infants and young children respond poorly to PPSV, which contains T cell–independent antigens. Consequently, another class of pneumococcal vaccines, the PCVs, were developed specifically for infants and young children. The first product, a 7-valent PCV, was licensed in 2000 in the United States. Two PCV products—containing 10 and 13 serotypes, respectively—are currently (2017) commercially available. The serotypes included in these PCV formulations are important causes of IPD and antibiotic resistance among young children. Randomized controlled trials have demonstrated a high degree of efficacy of PCVs against vaccine-serotype IPD as well as efficacy against pneumonia, otitis media, nasopharyngeal colonization, and all-cause mortality. PCVs are recommended by the World Health Organization for inclusion in routine childhood immunization schedules worldwide, especially in countries with high infant mortality rates.

The United States was the first country to introduce PCV (in 2000) and therefore has the longest experience with its community-wide effects. The introduction of PCV in the United States has resulted in a >90% reduction in vaccine-serotype IPD among the whole population (Fig. 141-7). This decline has been noted not only in those age groups immunized but also in adults and is attributable to the near elimination of vaccine-serotype nasopharyngeal colonization in immunized infants, which reduces spread to adults. This protection of unimmunized community members through vaccination of a subset of the community is termed the indirect effect. Increases in colonization with—and concomitantly in disease due to—non-vaccine-serotype strains (i.e., replacement colonization and disease) have been seen; however, the absolute rate increases in IPD caused by non-vaccine serotypes are generally small, especially relative to decreases in vaccine-serotype IPD (see “Epidemiology,” above). Since vaccine-serotype strains are more commonly resistant to antibiotics than are non-vaccine serotypes, use of PCV has also resulted in substantial declines in the proportion and absolute rates of drug-resistant pneumococcal disease. The recommendations of the Advisory Committee on Immunization Practices for the use of conjugate vaccines can be found at www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/pneumo.html. PCV has been shown to prevent pneumococcal infection in HIV-infected adults. In the United States, PCV13 followed by a dose of PPSV23 is now recommended for all immunocompromised children and adults. PCV13 is also effective in preventing vaccine sero type pneumococcal pneumonia in healthy adults over 65 years of age and is recommended for routine use in that age group (followed by a dose of PPSV23) in the United States (www.cdc.gov/mmwr/preview/mmwrhtml/mm6337a4.htm). This recent policy change will be reviewed in 2018 in light of ongoing and rapid changes in pneumococcal epidemiology with widespread PCV13 use in infants.

Other Prevention Strategies

Pneumococcal disease can be averted through the prevention of illnesses that predispose individuals to pneumococcal infections. Relevant measures include influenza vaccination and improved management and control of diabetes, HIV infection, heart disease, and lung disease. Finally, the reduction of antibiotic misuse is a strategy for the prevention of pneumococcal disease in that antimicrobial resistance directly and indirectly perpetuates organism transmission and disease in the community.

Pneumococcal infections are estimated to cause ~330,000 annual deaths worldwide among children 1–59 months of age, accounting for 11% of the 3.2 million all-cause deaths in this age group in 2015. Reliable estimates of adult cases and deaths globally are more difficult to establish because of limited data from parts of the world where most disease occurs. Rates of pneumococcal disease and mortality vary substantially across geographic settings, with the highest rates in selected countries of sub-Saharan Africa and southern Asia, where risk factors for pneumococcal disease—including HIV infection, lack of breast feeding of infants and children, malnutrition, sickle cell disease, and limited access to medical care—are prevalent. Serotypes causing disease exhibit some heterogeneity across geographic settings, but a small number of serotypes universally account for the preponderance of disease in the absence of vaccination; accordingly, vaccine development and vaccination programs are globally relevant. Reductions in disease from pneumococcal infections are anchored in prevention through the inclusion of pneumococcal vaccines in infant immunization programs, timely assessment and appropriate treatment of persons with pneumococcal infections, and reduction of risk factors for pneumococcal disease. The availability of vaccines for the prevention of adult pneumococcal disease, particularly among the elderly, is currently restricted to high-income countries, with virtually no availability in low-income countries where most cases of disease exist.

Additional Online References