Whipple’s disease, a chronic multiorgan infection caused by Tropheryma whipplei, was first described in 1907. The long-held belief that Whipple’s disease is an infection was supported by observations on its responsiveness to antimicrobial therapy in the 1950s and the identification of bacilli via electron microscopy in small-bowel biopsy specimens in the 1960s. This hypothesis was finally confirmed by amplification and sequencing of a partial 16S rRNA polymerase chain reaction (PCR)–generated amplicon from duodenal tissue in 1991. The subsequent successful cultivation of T. whipplei enabled whole-genome sequencing and the development of additional diagnostic tests. The development of PCR-based diagnostics has broadened our understanding of both the epidemiology and the clinical syndromes attributable to T. whipplei. Exposure to T. whipplei, which appears to be much more common than has been appreciated, can be followed by asymptomatic carriage, acute disease, or chronic infection. Chronic infection (Whipple’s disease) is a rare development after exposure. “Classic” Whipple’s disease is manifested variably by a combination of arthralgias/arthritis, weight loss, chronic diarrhea, abdominal pain, and fever; less commonly, involvement at sites other than the gastrointestinal tract is documented. Acute infection and chronic organ disease in the absence of intestinal involvement (see “Isolated Infection,” below) are described with increasing frequency. Since untreated Whipple’s disease is often fatal and delayed diagnosis may lead to irreparable organ damage (e.g., in the CNS), knowledge of the clinical scenarios in which Whipple’s should be considered and of an appropriate diagnostic strategy is mandatory.
T. whipplei is a weakly staining gram-positive bacillus. Genomic sequence data have revealed that the organism has a small (<1-megabase) chromosome, with many biosynthetic pathways absent or incomplete. This finding is consistent with a host-dependent intracellular pathogen or a pathogen that requires a nutritionally rich extracellular environment. A genotyping scheme based on a variable region has disclosed more than 70 genotypes (GTs) to date. GTs 1 and 3 are most commonly reported, but all GTs appear to be capable of causing similar clinical syndromes.
Whipple’s disease is rare but has been increasingly recognized since the advent of PCR-based diagnostic tools. It occurs in all parts of the globe, with an incidence presently estimated at 1 case per 1 million patient-years. Seroprevalence studies indicate that ~50% of Western Europeans and ~75% of Africans from rural Senegal have been exposed to T. whipplei. A predilection for chronic disease has been observed in middle-aged Caucasian men. Males are infected five to eight times more frequently than females. To date, no clear animal or environmental reservoir has been demonstrated. However, the organism has been identified by PCR in sewage water and human feces. Workers with direct exposure to sewage are more likely to be asymptomatically colonized than controls, a pattern suggesting fecal-oral spread. Recent data support oral-oral or fecal-oral spread among family members. Further, the development of acute T. whipplei pneumonia in children raises the possibility of droplet or airborne transmission.
PATHOGENESIS AND PATHOLOGY
Since rates of exposure to T. whipplei appear to be much higher (e.g., ~50% in Western Europe, as stated above) than rates of chronic disease development (0.00001%), it has been hypothesized that chronically infected individuals possess a subtle host-defense abnormality that does not place them at risk for non–T. whipplei infection. The HLA alleles DRB1*13 and DQB1*06 may be associated with an increased risk of infection. Chronic infection results in a general state of immunosuppression characterized by low CD4+ T cell counts, high levels of interleukin 10 production, increased activity of regulatory T cells, alternative activation of macrophages with diminished antimicrobial activity (M2 polarization) and ensuing apoptosis, and blunted development of T. whipplei–specific T cells. Immunosuppressive glucocorticoid treatment or anti–tumor necrosis factor α therapy appears to accelerate progression of disease. Recently, asymptomatic HIV-infected individuals were found to have significantly higher levels of T. whipplei sequence in bronchoalveolar lavage fluid (BALF) than did non-HIV-infected individuals, and these levels decreased with antiretroviral therapy. A weak humoral response, perhaps due to bacterial glycosylation in patients with chronic disease, appears to differentiate persons who clear the bacillus from asymptomatic carriers. In the initiation of chronic infection, the relative importance of the host’s genetic background versus the modulation of the host response by T. whipplei is unknown.
T. whipplei has a tropism for myeloid cells, which it invades and in which it can avoid being killed. Infiltration of infected tissue by large numbers of foamy macrophages is a characteristic finding. In the intestine, villi are flat and wide with dilated lacteals. Involvement of lymphatic or hepatic tissue may manifest as noncaseating granulomas that can mimic sarcoid.
Studies using primarily PCR have detected T. whipplei sequence in stool, saliva, duodenal tissue, and (rarely) blood in the absence of symptoms. Although prevalence rates are still being defined, in Western European countries, detection in saliva (0.2%) is less common than that in stool (1–11%) and appears to occur only with concomitant fecal carriage. The prevalence of fecal carriage is elevated in individuals with exposure to waste water or sewage (12–26%). However, in rural Senegal, 44% of children age 2–10 had T. whipplei detected in fecal samples. The duration of carriage at these sites is still being examined but can be at least 1 year. It is not known how often the carrier state is associated with acute infection, but evolution into chronic disease is uncommon. Bacterial loads are lighter in asymptomatic carriage than in active disease.
T. whipplei has been implicated as a cause of acute gastroenteritis in children. It was also detected via PCR in the blood of 6.4% of febrile patients (primarily children) from two villages in Senegal, often with concomitant cough and rhinorrhea. Further, T. whipplei has been implicated as a cause of acute pneumonia in the United States and France. These data suggest that primary acquisition can result in symptomatic pulmonary or intestinal infection, which may be more common than has been thought, and only rarely results in chronic disease.
“CLASSIC” WHIPPLE’S DISEASE
So-called classic Whipple’s disease was the initial clinical syndrome recognized, with consequent identification of T. whipplei. This chronic infection is defined by involvement of the duodenum and/or jejunum that develops over years. In most individuals, the initial phase of disease manifests primarily as intermittent, occasionally chronic and destructive migratory oligo- or polyarthralgias/seronegative arthritis. Spondylitis, sacroiliitis, and prosthetic hip infection also have been described. This initial stage is often confused with a variety of rheumatologic disorders and, on average, lasts 6–8 years before gastrointestinal symptoms commence. Treatment of presumed inflammatory arthritis with immunosuppressive agents (e.g., glucocorticoids, tumor necrosis factor α antagonists) can accelerate progression of the disease process. Alternatively, antimicrobial therapy used for another indication may reduce symptoms. In fact, the modulation of symptoms in these settings should prompt consideration of Whipple’s disease. The intestinal symptoms that develop in the majority of cases are characterized by diarrhea with accompanying weight loss and may be associated with fever and abdominal pain. Diagnostic misdirection can be caused by co-infection with Giardia lamblia, which is occasionally identified. Occult gastrointestinal blood loss, hepatosplenomegaly, and ascites are less common. Anemia and hypereosinophilia may be detected. Rheumatoid factor and antinuclear antibody tests are usually negative. The most common finding on abdominal CT is mesenteric and/or retroperitoneal lymphadenopathy. The endoscopic or video capsule observation of pale, yellow, or shaggy mucosa with erythema or ulceration past the first portion of the duodenum suggests Whipple’s disease (Fig. 200-5). In addition to rheumatologic and proximal intestinal disease, neurologic (6–63%), cardiac (17–55%), pulmonary (10–40%), lymphatic (10%), ocular (5–10%), dermal (1–5%), and (in rare instances) other sites are variably involved in classic Whipple’s disease.
Endoscopic view of the jejunal mucosa demonstrating a thickened, granular mucosa and “white spots” due to dilated lacteals. (Reprinted with permission from J Bureš et al: Whipple’s disease: Our own experience and review of the literature. Gastroenterol Res Pract, 2013. http://dx.doi.org/10.1155/2013/478349.)
Asymptomatic neurologic involvement in Whipple’s disease has been documented by PCR-based detection in cerebrospinal fluid (CSF). A variety of neurologic manifestations have been reported, the most common of which are cognitive changes progressing to dementia; personality, mood, and sleep-cycle disorders; hypothalamic involvement; and supranuclear ophthalmoplegia. In addition to the latter, neuro-ophthalmologic manifestations of Whipple’s disease include supranuclear gaze palsy, oculomasticatory and oculofacial myorhythmia (highly suggestive of Whipple’s), nystagmus, and retrobulbar neuritis. Focal neurologic presentations (dependent on lesion location), seizures, ataxia, meningitis, encephalitis, hydrocephalus, myelopathy, and distal polyneuropathy also have been described. Neurologic sequelae occur with CNS disease, and the mortality risk is significant.
MRI results may be normal. Identified lesions (solitary or multifocal)are usually T2 and fluid-attenuated inversion recovery (FLAIR) hyperintense and may enhance with gadolinium. Findings are myriad and not diagnostic, but the limbic system is commonly involved. FDG-PET may reveal increased uptake. CSF analysis may be abnormal; leukocytosis (generally lymphocyte-predominant) and an elevated protein concentration are common. A low CSF glucose level has been reported.
Endocarditis, which is increasingly recognized in Whipple’s disease, presents as culture-negative infection and/or congestive heart failure; hypotension occurs rarely. Embolic events or various arrhythmias may also be noted. Fever is often absent, and Duke clinical criteria are rarely met. Vegetations are identified by echocardiography in 50–75% of cases. All valves, alone or in combination, can be affected; most commonly involved are the aortic and mitral valves. Preexisting valvular disease is found in only a minority of cases, although infection of bioprosthetic valves has been described. Mural, myocardial, or pericardial disease also occurs alone or in combination with valvular involvement. Constrictive pericarditis develops infrequently.
Some combination of interstitial disease, nodules, parenchymal infiltrate, and pleural effusion is observed. The clinical significance of T. whipplei dominating sequence reads in BALF from HIV-infected individuals is unresolved.
Mesenteric and retroperitoneal lymphadenopathy are common with intestinal disease, and mediastinal adenopathy may be associated with pulmonary infection. Peripheral adenopathy is less common.
Ocular disease (non-neuro-ophthalmologic)
Uveitis is the most common form of ocular disease, usually presenting as a change in vision or “floaters.” Anterior (anterior chamber), intermediate (vitreous), and posterior (retina/choroid) uveitis can occur alone or in combination. Postoperative acute or chronic ocular Whipple’s disease has been described in association with local or systemic glucocorticoid use; its detection in this setting raises the possibility that asymptomatic or subclinical disease has been unmasked. Keratitis and crystalline keratopathy also have been reported. Patients may be misdiagnosed with sarcoid or Behçet’s disease prior to the recognition of Whipple’s.
Skin hyperpigmentation, particularly in light-exposed areas in the absence of adrenal dysfunction, should be suggestive of Whipple’s disease. A variety of other cutaneous manifestations have been described, including erythematous macular lesions, nonthrombocytopenic purpura, subcutaneous nodules, and hyperkeratosis.
Thyroid, renal, testicular, epididymal, gallbladder, skeletal muscle, and bone marrow involvement have all been described. In fact, almost any organ can be involved in classic Whipple’s disease, with varying frequency, variable combinations, and myriad signs and symptoms. As a result, Whipple’s disease should be considered in the setting of a chronic multisystemic process. Despite its rarity, the combination of rheumatologic and intestinal disease with weight loss, with or without neurologic and cardiac involvement, warrants heightened suspicion.
This entity has been defined as infection in the absence of intestinal symptoms, although an occasional small-bowel biopsy may be PCR-positive in this setting. “Isolated infection” is something of a misnomer since multiple nonintestinal sites of T. whipplei infection are not uncommon. Infection at the same nonintestinal sites (single or multiple) that are variably involved in classic Whipple’s disease may also present as “isolated infection.” Endocarditis, neurologic disease, uveitis, rheumatologic manifestations, and pulmonary involvement are most commonly described. Signs and symptoms are similar to those described for T. whipplei infection of these sites in classic Whipple’s disease. With enhanced PCR-based diagnostic capabilities, T. whipplei infection without concomitant intestinal involvement (of which endocarditis is the best example) will probably be diagnosed increasingly often.
REINFECTION/RELAPSING DISEASE/IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME (IRIS)
It has been suggested that, if an underlying host immune defect places an individual at risk for chronic infection, then that person may be at risk for reinfection due to occupational exposure or contact with family members who are asymptomatically colonized. One case of apparent relapse that was due to a different genotype supports this contention.
Optimal treatment regimens and durations are still being defined. However, it is clear, especially in the setting of occult or overt CNS disease, that treatment with oral tetracycline or trimethoprim-sulfamethoxazole (TMP-SMX) alone may result in disease relapse.
As in patients treated for HIV or mycobacterial disease, IRIS has been described in patients treated for T. whipplei infection. Prior immunosuppressive therapy increases the likelihood of IRIS, in which inflammation recurs after an initial clinical response to treatment and loss of PCR detection of T. whipplei. Manifestations include fever, arthritis, skin lesions, pleuritis, uveitis, and orbital and periorbital inflammation.
Considering T. whipplei infection and ensuring that the appropriate tests are performed are the critical steps in making the diagnosis, which otherwise will likely be missed. The clinical presentation will in part dictate which clinical specimens are most likely to enable the diagnosis. In the presence (and perhaps the absence) of gastrointestinal symptoms, postbulbar duodenal biopsies should be performed. As a general rule, diagnostic yield is greater for tissue specimens than for body fluids. Biopsy of normal-appearing skin may detect T. whipplei in the setting of classic Whipple’s disease and serve as a minimally invasive means to establish the diagnosis. It is unclear whether CSF should be obtained in the absence of CNS symptoms, but its collection should be considered: the CNS is the most common site for relapse, and thus the information gained by CSF examination could influence the design of the treatment regimen.
The development and implementation of PCR-based diagnostics have significantly increased the sensitivity and specificity of T. whipplei identification. PCR can be applied to affected tissues (fixed and nonfixed) and various body fluids (e.g., CSF; aqueous or vitreous humor; joint, pericardial, or pleural fluid; BALF; blood; feces). In some clinical scenarios, a generic 16S rRNA bacterial assay combined with amplicon sequencing can be used to detect and identify T. whipplei sequence. Delineation of the T. whipplei genomic sequence has enabled the development and broad availability of more sensitive and specific PCR-based assays. The interpretation of a PCR-based diagnostic approach must take into account limitations such as false-positive results due to sample contamination and false-negative results due to organism load, sample quality, and inadequate DNA extraction.
The diagnosis of classic Whipple’s disease was originally based on histologic findings in intestinal biopsy specimens, and this diagnostic procedure remains important. Infiltration of the lamina propria with macrophages containing inclusions (representing ingested bacteria) that are positive on periodic acid–Schiff (PAS) staining and resistant to diastase is observed. However, PAS is nonspecific, also yielding positive results with mycobacteria (which can be differentiated with Ziehl-Neelsen stain), Rhodococcus equi, Bacillus cereus, Corynebacterium species, and Histoplasma species. T. whipplei can also be detected by silver stain, Brown-Brenn (weakly positive), or acridine orange and is not stained by calcofluor. Staining of other tissues or fluids (e.g., ocular aspirations) for PAS-positive inclusions in macrophages can be performed to support the diagnosis. Electron microscopy can be used to identify the trilaminar cell wall of T. whipplei.
When available, immunohistochemistry has greater specificity and sensitivity than PAS staining and can be performed on archived fixed tissue. T. whipplei has been successfully cultured from blood, CSF, synovial fluid, BALF, valve tissue, duodenal tissue, skeletal muscle, and lymph nodes, but culture is not practical since it takes months to obtain a positive result. Likewise, serology is of limited value for the diagnosis of Whipple’s disease because the prevalence of exposure is much higher than that of chronic disease development and the antibody response to T. whipplei appears to be blunted in the disease state.
Although histologic or cytologic detection of T. whipplei is less specific and sensitive than PCR, a positive result is strongly supportive within the appropriate clinical context and is definitive when combined with a more specific test (e.g., PCR, immunohistochemistry).
TREATMENT Whipple’s Disease
Data on treatment are emerging, but questions persist regarding the optimal regimen and duration, which may depend on the site of infection (e.g., CNS and heart valve). Appropriate treatment usually results in a rapid and at times remarkable clinical response (e.g., in CNS disease). Maintenance of a durable response has been more challenging.
Rates of relapse, particularly of CNS disease, were unacceptable with oral tetracycline or TMP-SMX monotherapy. Sequence data now indicate that TMP is not active against T. whipplei due to the absence of dihydrofolate reductase, but this drug was used extensively before this fact was known. This information prompted a randomized controlled trial in 40 patients, who received either ceftriaxone (2 g IV q24h) or meropenem (1 g IV q8h) for 2 weeks followed by oral TMP-SMX (160/800 mg) twice a day for 1 year. The efficacy of these regimens was outstanding. The only instance of therapy failure—in a case of asymptomatic CNS infection that was not eradicated by either regimen—was subsequently cured with oral minocycline and chloroquine (250 mg/d after a loading dose). A follow-up trial reported similar efficacy with a regimen of ceftriaxone (2 g IV q24h) for 2 weeks followed by oral TMP-SMX for 3 months. One issue in these trials was that the CNS doses—and perhaps the duration of ceftriaxone and meropenem treatment as well—were not optimal. Further, investigators have speculated that oral regimens with greater CNS penetrance, such as sulfadiazine (2–4 g/d in 3 or 4 divided doses) and/or doxycycline or minocycline (200 mg/d in 2 divided doses) plus hydroxychloroquine (200 mg three times a day, to raise phagosome pH and increase drug activity in vitro), might render the parenteral phase of treatment unnecessary, given that the one failure of therapy for CNS disease was cured with a similar regimen. Another issue is concern about the potential development of resistance to sulfa drugs. Lastly, it is unclear whether oral sulfa- or tetracycline-based regimens will suffice in endocarditis. Until more data become available, it seems prudent—at least in asymptomatic/symptomatic CNS disease or cardiac infection—to administer CNS-optimized doses of IV ceftriaxone (2 g q12h) or meropenem (2 g q8h) for at least 2 weeks followed by oral doxycycline or minocycline plus hydroxychloroquine or chloroquine for at least 1 year, if tolerated. Although data on the use of PCR to guide therapy do not exist, it seems reasonable that continued T. whipplei detection by PCR, especially in the CSF, should dictate at least continuation of therapy and perhaps consideration of an alternative regimen.
The occurrence of a Jarisch-Herxheimer reaction within 24 h of treatment initiation has been described, with rapid resolution. The addition of glucocorticoids may be beneficial in the management of clearly documented IRIS.
Data on certain site-specific treatment issues are even more limited. Anecdotal reports describe successful treatment of uveitis with oral TMP-SMX with or without rifampin, whereas treatment with tetracycline alone has resulted in relapse. Although a role for adjunctive intraocular therapy has been reported, the data are unclear on this point. Surgery may be needed in the setting of endocarditis with significant valve dysfunction; however, timely recognition can result in cure with medical management alone. Although data on the treatment of foreign body–associated infection are virtually nonexistent, medical treatment for a prosthetic hip infection was apparently successful; however, follow-up was limited.
Regardless of the therapeutic regimen chosen, an effort to ensure compliance and close follow-up for potential relapse (or perhaps reinfection), which can occur many years after an apparent cure, will maximize the chances for a good outcome.