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Whipple Disease

Chapter 181 | Part 5: Infectious Diseases · Part 5 – Infectious Diseases: Bacterial

Detailed clinical reference synthesised from Harrison's Principles of Internal Medicine, 22nd Edition

🔑 Key Clinical Points

  1. Whipple disease (WD) is a chronic infection caused by Tropheryma whipplei, characterized by classic triad of arthralgias, weight loss, and chronic diarrhea.
  2. Histologic hallmark: Infiltration of lamina propria with macrophages containing PAS-positive inclusions resistant to diastase.
  3. Neurologic disease occurs in ~50% of patients and portends a poor prognosis; CNS is the most common site for relapse.
  4. Cardiac involvement (endocarditis) is increasingly recognized, often culture-negative, and fever is often absent.
  5. Saliva and fecal PCR are inappropriate as sole diagnostic tools due to low positive predictive values (identify colonization, not disease).
  6. A negative PCR result does not exclude WD; pretest probability is critical for interpretation.
  7. Optimal CNS treatment: IV ceftriaxone or meropenem for 2-4 weeks followed by oral doxycycline/minocycline plus hydroxychloroquine for at least 1 year.
  8. TMP-SMX monotherapy may result in relapse; TMP is not active against T. whipplei (absence of dihydrofolate reductase).
  9. IRF4 haploinsufficiency is a genetic factor associated with increased risk of WD.
  10. Lifelong suppressive therapy with doxycycline may be advocated to maximize chances for good outcome due to risk of relapse/reinfection.

📑 Table of Contents

📋 Figures in This Chapter

# Type Description
1 🖼 Figure Endoscopic view of the jejunal mucosa demonstrating a thickened, granular mucosa and...

1. DEFINITION & OVERVIEW

  • Whipple disease (WD), described by George Whipple in 1907, is a chronic infection caused by Tropheryma whipplei.
  • The long-held belief that WD is an infection was supported by observations on its responsiveness to antimicrobial therapy in the 1950s and 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 and tests.
  • 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—WD—is a rare development after exposure.
  • Classic WD is manifested by some combination of arthralgias/arthritis, weight loss, chronic diarrhea, and fever.

1.1 Classification

  • Classic WD: Chronic infection defined by involvement of the duodenum and/or jejunum that develops over years.
  • Isolated Infection: Infection in the absence of intestinal symptoms (e.g., endocarditis, neurologic disease, uveitis, rheumatologic manifestations, pulmonary involvement).

2. EPIDEMIOLOGY

  • WD is rare but has been increasingly recognized since the advent of PCR-based diagnostic tools.
  • Prevalence had been previously estimated at 1−3 cases per 1 million population, although a recent U.S. epidemiologic survey places the number closer to 10 cases per million.
  • Seroprevalence studies indicate that ~50% of Western Europeans and ~75% of Africans from rural Senegal have been exposed to T. whipplei.
  • Higher prevalence may be attributable to differences in sanitation.
  • Humans are the only known host.
  • In most studies, males more commonly develop WD; WD is more common in Caucasians and increases with age.
  • To date, no clear animal or environmental reservoir has been demonstrated.
  • 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.
  • Fecal PCR detection rates of 38% among family members of carriers or patients with infection support oral–oral or fecal–oral spread, although a common environmental exposure cannot be excluded.
  • Further, the development of acute T. whipplei pneumonia in children raises the possibility of droplet or airborne transmission.

2.1 Carriage Rates

  • Rates of asymptomatic carriage of T. whipplei are far higher than rates of chronic infection (<0.01% of those exposed).
  • 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 among individuals with exposure to waste water or sewage (12–26%) and among children living in tropical Africa and Asia (20–48%).
  • A duration of carriage of 7 years for the same strain has been described in a sewer worker.
  • Evolution of the carrier state into chronic disease is uncommon.
  • Bacterial loads are lighter in asymptomatic carriage than in active disease.

Table 1 — Table 181-1. Epidemiology and Carriage Rates

Population/Group Exposure/Context Detection Rate (PCR)
Western Europeans Seroprevalence ~50% exposed
Africans (Rural Senegal) Seroprevalence ~75% exposed
Saliva (General) Asymptomatic 0.2%
Stool (General) Asymptomatic 1–11%
Sewage Workers Exposure to waste water 12–26% fecal carriage
Children (Tropical Africa/Asia) Living in tropical regions 20–48% fecal carriage
Family Members Family of carriers/patients 38% fecal PCR detection

3. ETIOLOGY & PATHOPHYSIOLOGY

  • T. whipplei is a weakly staining gram-positive bacillus.
  • Genomic sequence data have revealed that the organism has a small (100 genotypes to date.
  • All genotypes appear to be capable of causing similar clinical syndromes.
  • Both decreased host pathogen-specific inflammatory response and pathogen-driven modulation of host inflammatory response likely play a role in establishing chronic infection.
  • The human leukocyte antigen (HLA) alleles DRB1()13 and DQB1()06, which stimulate humoral rather than cell-mediated immune responses, are associated with an increased risk of infection.
  • However, only a minority of infected patients possess these haplotypes, suggesting a role for other host factors.
  • IRF4, a transcription factor involved with the immune response, could be such a factor as evidenced by four related family members with WD who possessed IRF4 haploinsufficiency due to a loss-of-function mutation; the distribution of WD in this extended family was consistent with an autosomal dominant trait with incomplete penetrance.
  • Flow cytometry performed in WD patients demonstrates B-cell subset abnormalities when compared to matched controls.
  • Chronic infection is associated with an impaired T 1 response, enhanced production of anti-inflammatory cytokines, increased activity of regulatory T cells, M2 polarization of macrophages with diminished antimicrobial activity and impaired phagosome–lysosome fusion and ensuing apoptosis, and blunted development of T. whipplei–specific T cells.
  • Therapies that blunt cell-mediated host immune responses (e.g. systemic glucocorticoids or anti–tumor necrosis factor α [TNF-α] agents) may accelerate progression of chronic disease.
  • Impaired cell-mediated immunity may play a role in establishing chronic carriage of T. whipplei, as is evidenced by higher rates of detection in the secretions of HIV-infected persons.
  • T. whipplei has a tropism for myeloid cells, which it invades and in which it can avoid being killed.

3.1 Organism Characteristics

  • Gram-positive bacillus.
  • Small chromosome (100 genotypes identified.
  • Host-dependent intracellular pathogen.

3.2 Host Factors

  • HLA-DRB1()13 and DQB1()06 associated with increased risk.
  • IRF4 haploinsufficiency (autosomal dominant trait with incomplete penetrance).
  • B-cell subset abnormalities.
  • Impaired T1 response.
  • Enhanced anti-inflammatory cytokines.
  • Regulatory T cell activity increased.
  • M2 macrophage polarization.
  • Blunted T. whipplei-specific T cell development.

4. CLINICAL FEATURES

  • Asymptomatic Colonization/Carriage: Studies using primarily PCR have detected T. whipplei sequence in stool, saliva, duodenal tissue, and (rarely) blood in the absence of symptoms.
  • Acute Infection: T. whipplei has been implicated as a cause of acute gastroenteritis in children.
  • Acute Infection: It was also detected via PCR in the blood of 4.6% of febrile patients (75% of whom were <15 years of age) from two rural villages in Senegal as opposed to 0.25% of healthy controls.
  • Acute Infection: Further, T. whipplei has been implicated as a cause of acute pneumonia.
  • These data suggest that primary acquisition may result in symptomatic pulmonary or intestinal infection or a febrile syndrome, which perhaps co-infection with Giardia lamblia, which is occasionally identified.
  • The intestinal phase can also be confused with Crohn or celiac disease.
  • Chronic Infection: So-called classic WD 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, often symmetrical, occasionally chronic, and rarely destructive migratory oligo- or polyarthralgias/seronegative arthritis involving the knees, wrists, ankles, and metacarpal-interphalangeal joints most commonly.
  • Less frequently, spondylitis, sacroiliitis, discitis, tenosynovitis, bursitis, and prosthetic hip infection also have been described.
  • Intermittent fever, myalgias, and skin nodules may accompany joint symptoms.
  • Tests for rheumatoid factor and antinuclear antibody are usually negative.
  • 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, anti-TNF-α, anakinra) can accelerate progression of the disease process; thus, screening for WD prior to initiation of immunosuppressant therapy may be appropriate, depending on the clinical scenario.
  • Alternatively, antimicrobial therapy for another indication may reduce symptoms, and this situation should also prompt consideration of WD.
  • 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.
  • Occult gastrointestinal blood loss, vitamin deficiencies, hepatosplenomegaly (10–15%), and ascites (10%) are less common.
  • Anemia and hypereosinophilia may be detected.
  • The most common finding on abdominal computed tomography is mesenteric and/or retroperitoneal lymphadenopathy (usually raising concern about lymphoma).
  • The endoscopic or video-capsule observation of pale, yellow, or shaggy mucosa with erythema or ulceration past the first portion of the duodenum suggests WD (Fig. 181-1).
  • When endoscopy with duodenal biopsy is nondiagnostic, a video-capsule study may assist in identifying more distal lesions for subsequent biopsy.
  • 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) studies in patients with WD suggest the entire small bowel can be involved.
  • Diagnostic misdirection can be caused by variable involvement at neurologic (6–63%), cardiac (17–55%), pulmonary (10–50%), lymphatic (10–55%), ocular (5–10%), dermal (5–30%), and less commonly other sites are variably involved in classic WD.

4.1 Neurologic Disease

  • CNS disease, defined by PCR-based detection of T. whipplei in cerebrospinal fluid (CSF), develops in ~50% of patients, many of whom are asymptomatic.
  • A variety of neurologic manifestations have been reported and portend a poor prognosis.
  • The most common are cognitive changes including memory impairment progressing to dementia, personality and mood alterations, hypothalamic involvement (e.g., polyuria/polydipsia, sleep-cycle disorders), and supranuclear ophthalmoplegia.
  • In addition, neuro-ophthalmologic manifestations of WD include supranuclear gaze palsy (usually vertical), oculomasticatory and oculofacial myorhythmia (highly suggestive of WD), nystagmus, and retrobulbar neuritis.
  • Focal neurologic presentations (dependent on lesion location), seizures, ataxia, meningitis, encephalitis, rhombo- or limbic encephalitis, hydrocephalus, myelopathy, myoclonus, choreiform movements, and distal polyneuropathy also have been described.
  • Neurologic sequelae occur with CNS disease, and the mortality risk is significant.
  • Magnetic resonance imaging (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.
  • All sites can be involved, and the nature of lesions is variable (e.g., nodular, infiltrative, tumor-like).
  • Although imaging findings are myriad and are not diagnostic, the median temporal lobe, midbrain, hypothalamus, and thalamus are commonly affected.
  • FDG-PET may reveal increased uptake.
  • CSF analysis may be normal; when abnormal, leukocytosis (generally lymphocyte-predominant) and an elevated protein concentration are common.
  • A low CSF glucose level has been reported.

4.2 Cardiac Disease

  • Endocarditis is increasingly recognized in WD (85% of cases in males), causes 2.6−6.3% of culture-negative endocarditis cases, and may be complicated by congestive heart failure (40% of cases), embolic events, arrhythmias, mycotic aneurysm, or rarely hypotension.
  • Fever is often absent, and the 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, aortic (aortitis), or pericardial disease also occurs alone or in combination with valvular involvement.
  • Constrictive pericarditis develops infrequently.
  • The diagnosis of cardiac disease is rarely made prior to surgical intervention.

4.3 Pulmonary Disease

  • Some combination of interstitial disease, nodules, parenchymal infiltrate, and pleural effusion is observed.
  • An association with pulmonary hypertension has also been reported.
  • The clinical significance of T. whipplei sequence identified in bronchoalveolar lavage fluid (BALF) from asymptomatic HIV-infected individuals or in a case of interstitial lung disease is unresolved but suggests caution in diagnosing isolated pneumonia based on sequence alone.
  • Notably, while the bacterium seems to exist in the airways of HIV-infected persons at higher rates, its presence is not clearly associated with increased inflammation or a discernible decrease in lung function.

4.4 Lymphatic Disease

  • Mesenteric and retroperitoneal lymphadenopathy are common with intestinal disease, and mediastinal adenopathy may be associated with pulmonary infection.
  • Peripheral adenopathy is less common.

4.5 Ocular Disease

  • 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.
  • Treatment with glucocorticoids alone can worsen uveitis and unmask extraocular disease.
  • Likewise, use of local or systemic glucocorticoids after ocular surgery can precipitate ocular infection, likely as a result of asymptomatic or subclinical disease.
  • Keratitis, crystalline keratopathy, and optic neuritis also have been reported.
  • Patients may be misdiagnosed with sarcoid or Behçet’s disease prior to the recognition of WD.

4.6 Dermatologic Disease

  • Skin hyperpigmentation (melanoderma), particularly in light-exposed areas in the absence of adrenal dysfunction, is suggestive of WD.
  • A variety of other cutaneous manifestations have been described, including erythematous macular lesions, nonthrombocytopenic purpura, subcutaneous nodules, and hyperkeratosis.

4.7 Miscellaneous Sites

  • Thyroid, renal, testicular, epididymal, gallbladder, skeletal muscle, and bone marrow involvement and membranous nephropathy have all been described.
  • In fact, almost any organ can be involved in classic WD, with varying frequency, variable combinations, and myriad signs and symptoms.
  • As a result, WD 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.

5. DIFFERENTIAL DIAGNOSIS

  • Isolated Infection: This entity has been defined as infection in the absence of intestinal symptoms, although an occasional small-bowel biopsy may be PAS-positive or more commonly PCR-positive in this setting.
  • Isolated Infection: Is something of a misnomer since multiple nonintestinal sites of T. whipplei infection are not uncommon.
  • Isolated Infection: Infection at the same nonintestinal sites (single or multiple) that are variably involved in classic WD may also present as isolated infection.
  • Isolated Infection: Further, intestinal disease can subsequently develop.
  • Isolated Infection: Endocarditis, neurologic disease, uveitis, rheumatologic manifestations, and pulmonary involvement are most commonly described.
  • Isolated Infection: Signs and symptoms are similar to those described for T. whipplei infection of these sites in classic WD.
  • Isolated Infection: 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.
  • Mimics: The intestinal phase can also be confused with Crohn or celiac disease.
  • Mimics: Patients may be misdiagnosed with sarcoid or Behçet’s disease prior to the recognition of WD.

6. INVESTIGATIONS & DIAGNOSIS

  • 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.
  • Serology is of little value since patients with active infection usually mount a poor IgM/IgG response to T. whipplei and a positive result most likely reflects prior exposure and clearance.
  • 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, although a normal macroscopic appearance is common.
  • As a general rule, the 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 WD and serve as a minimally invasive means to establish the diagnosis.
  • It is prudent to collect CSF even in the absence of CNS symptoms; asymptomatic disease is common, the CNS is the most common site for relapse, and thus the information gained by CSF examination could influence the design and duration of the treatment regimen.
  • The diagnosis of classic WD was originally based on histologic findings in intestinal biopsy specimens.
  • Although this diagnostic procedure remains important, it is not optimally sensitive.
  • Infiltration of the lamina propria with macrophages containing PAS-positive inclusions that are resistant to diastase is observed.
  • However, PAS is nonspecific, also yielding positive results with mycobacteria as well as other microorganisms.
  • Staining of other tissues or fluids (e.g., ocular aspirations) for PAS-positive inclusions in macrophages can be performed to support the diagnosis.
  • The sensitivity of identification of PAS-positive inclusions in WD may be decreased by anti-TNF-α therapy.
  • 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.
  • Alternatively, the use of fluorescence in situ hybridization (FISH) has been reported as a complementary diagnostic tool with various tissue samples.
  • The development and implementation of specific PCR-based diagnostics have significantly increased the sensitivity and specificity of T. whipplei identification.
  • PCR can be applied to affected tissues (with greater sensitivity for non-formalin-fixed than for formalin-fixed tissue) in support of histologic findings and to various body fluids.
  • It is important to note that the interpretation of a PCR-based diagnostic approach must take into account limitations such as false-positive results due to sample contamination, false-negative results due to low organism load, poor sample quality, inadequate DNA extraction, and variability in performance of various PCR assays.
  • Quantitative comparisons from different sites can add specificity to PCR-based diagnostics of WD and distinguish between WD patients and asymptomatic carriers.
  • In patients suspected of having WD, PCR testing of duodenal biopsy specimens with a cycle threshold value of ≤30 can help confirm the diagnosis, even in cases with negative PAS staining.
  • As with all diagnostic tests, consideration of pretest probability is critical for interpretation, and a negative result does not exclude WD.
  • Urine PCR for T. whipplei infection may hold promise for the noninvasive diagnosis of classic and isolated WD.
  • In one study of 12 cases, urine PCR was positive in nine cases (75%) prior to treatment compared to zero (0%) of 110 controls, including 11 controls that were presumed carriers in whom feces PCR was positive, although there was no evidence of disease.
  • In addition, urine PCR is a potential tool to evaluate the success of WD therapy.
  • Saliva and fecal PCR are inappropriate as the sole diagnostic tools for WD due to low positive predictive values, which more commonly identify colonization, not disease; a positive result requires confirmation from an appropriate end-organ tissue or body fluid.
  • Next-generation sequencing techniques to evaluate for cell-free DNA (cfDNA) in plasma may lead to increased recognition of T. whipplei as a cause of endocarditis.
  • 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.
  • Affected anatomic sites in WD patients may demonstrate uptake on FDG-PET, which in turn could guide tissue sampling for use in specific tests.

Table 2 — Table 181-2. Diagnostic Criteria and Tests

Test/Method Specimen Sensitivity/Specificity Notes Clinical Utility
Histology (PAS) Duodenal biopsy Infiltration of lamina propria with macrophages containing PAS-positive inclusions resistant to diastase Originally based on this; not optimally sensitive
PCR Duodenal biopsy Cycle threshold value ≤30 Can confirm diagnosis even with negative PAS staining
PCR Body fluids (CSF, urine, synovial) Variable; Urine PCR positive in 75% of cases Support histologic findings
Immunohistochemistry Tissue Greater specificity and sensitivity than PAS Can be performed on archived fixed tissue
Electron Microscopy Tissue Identifies trilaminar cell wall Complementary
Serology Serum Poor IgM/IgG response in active infection Little value; reflects prior exposure
FDG-PET Whole body Entire small bowel involvement Guides tissue sampling
Saliva/Fecal PCR Saliva/Feces Low positive predictive values Inappropriate as sole diagnostic tools

6.1 Histology

  • Infiltration of the lamina propria with macrophages containing PAS-positive inclusions that are resistant to diastase is observed.
  • PAS is nonspecific, also yielding positive results with mycobacteria as well as other microorganisms.
  • Electron microscopy can be used to identify the trilaminar cell wall of T. whipplei.
  • Immunohistochemistry has greater specificity and sensitivity than PAS staining.
  • FISH has been reported as a complementary diagnostic tool.

6.2 PCR & Molecular

  • PCR applied to affected tissues (greater sensitivity for non-formalin-fixed than for formalin-fixed tissue).
  • PCR applied to various body fluids.
  • Cycle threshold value of ≤30 can help confirm the diagnosis.
  • Urine PCR positive in 75% of cases vs 0% of controls.
  • Next-generation sequencing for cfDNA in plasma.
  • Quantitative comparisons from different sites add specificity.

6.3 Imaging

  • FDG-PET studies suggest the entire small bowel can be involved.
  • Affected anatomic sites in WD patients may demonstrate uptake on FDG-PET, which in turn could guide tissue sampling for use in specific tests.

7. MANAGEMENT & TREATMENT

  • Data on treatment are emerging, but the optimal regimen and duration for chronic infection, which may depend on the sites involved (e.g., CNS and heart valve), are unclear.
  • Appropriate treatment usually results in a rapid—and at times remarkable—clinical response (e.g., in CNS disease), but eradication requires prolonged treatment.
  • Maintenance of a durable response has been more challenging because of both relapse and host predisposition to reinfection.
  • 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 (given the absence of dihydrofolate reductase in T. whipplei) and that resistance to SMX and sulfadiazine can occur.
  • However, 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, demonstrated outstanding efficacy.
  • The only case in which therapy failed—an 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 doses—and perhaps the duration of ceftriaxone and meropenem treatment as well—were not optimal for CNS infection.
  • By contrast, in a small retrospective series, outcome was better in patients treated with oral doxycycline (100 mg twice a day) plus hydroxychloroquine (200 mg three times a day to raise phagosome pH and increase drug activity in vitro) than in patients initially treated with TMP-SMX.
  • Until more data become available, it seems prudent—at least in asymptomatic/symptomatic CNS disease (which is present in many cases of WD)—first to administer CNS-optimized doses of IV ceftriaxone (2 g q12h) or meropenem (2 g q8h) for 2–4 weeks and then to treat with oral doxycycline, or minocycline plus hydroxychloroquine for at least 1 year, if tolerated.
  • Although TMP-SMX has been frequently used as the oral alternative with reported success, a number of relapses or reinfections with TMP-SMX treatment have been reported, thereby suggesting caution for its use in patients with infection in critical locations such as the CNS and the heart.
  • 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 and perhaps urine, should dictate at least continuation of therapy or perhaps consideration of an alternative regimen when in conjunction with a poor clinical response.
  • 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 IRIS, and thalidomide has been used in steroid-refractory cases.
  • Importantly, although data are lacking, due to the inherent risk of relapse or reinfection, lifelong suppressive therapy with doxycycline after completion of the initial treatment regimen has been advocated.
  • Regardless of the therapeutic approach chosen, an effort to ensure compliance and close follow-up for potential relapse or reinfection, which can occur many years after an apparent cure, will maximize the chances for a good outcome.
  • Current European guidelines for the treatment of endocarditis caused by T. whipplei recommend oral doxycycline plus hydroxychloroquine for ≥18 months or, alternatively, ceftriaxone (2 g q24h IV) or penicillin (2 million units q4h IV) plus streptomycin (1 g q24h IV) for 2–4 weeks followed by oral TMP-SMX (800 mg q12h); a small study from Spain reported that treatment durations of 12–13 months with these regimens or variations were efficacious.
  • Data on isolated infection and 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.
  • There is a single case report of clearance of infection in a chronically relapsing patient by the addition of interferon gamma to antimicrobials; supplementation to antimicrobials may be a consideration to address refractory disease or potential issues with antibiotic resistance.
  • 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.

Table 3 — Table 181-3. Treatment Regimens for Whipple Disease

Condition/Indication Regimen Duration Notes
Classic WD (General) Oral doxycycline (100 mg BID) + Hydroxychloroquine (200 mg TID) ≥1 year Better outcome than TMP-SMX monotherapy
CNS Disease IV Ceftriaxone (2 g q12h) or Meropenem (2 g q8h) 2–4 weeks Followed by oral doxycycline/minocycline + hydroxychloroquine
CNS Disease (Oral) Oral Doxycycline or Minocycline + Hydroxychloroquine ≥1 year If tolerated
Endocarditis Oral Doxycycline + Hydroxychloroquine ≥18 months European guidelines
Endocarditis (Alternative) Ceftriaxone (2 g q24h IV) or Penicillin (2M units q4h IV) + Streptomycin (1 g q24h IV) 2–4 weeks Followed by oral TMP-SMX (800 mg q12h)
Endocarditis (Spanish Study) Ceftriaxone/Penicillin + Streptomycin + TMP-SMX 12–13 months Variations efficacious
Refractory/Relapse Oral Minocycline + Chloroquine (250 mg/d after loading dose) Until clearance Case report success
IRIS Glucocorticoids As needed Beneficial in management
Steroid-Refractory IRIS Thalidomide As needed Used in refractory cases
Refractory Disease Antimicrobials + Interferon Gamma As needed Single case report

7.1 General Principles

  • Appropriate treatment usually results in a rapid—and at times remarkable—clinical response.
  • Eradication requires prolonged treatment.
  • Maintenance of a durable response has been more challenging because of both relapse and host predisposition to reinfection.
  • Rates of relapse, particularly of CNS disease, were unacceptable with oral tetracycline or TMP-SMX monotherapy.
  • Lifelong suppressive therapy with doxycycline after completion of the initial treatment regimen has been advocated.
  • Close follow-up for potential relapse or reinfection, which can occur many years after an apparent cure, will maximize the chances for a good outcome.

7.2 CNS Disease

  • 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.
  • Until more data become available, it seems prudent—at least in asymptomatic/symptomatic CNS disease (which is present in many cases of WD)—first to administer CNS-optimized doses of IV ceftriaxone (2 g q12h) or meropenem (2 g q8h) for 2–4 weeks and then to treat with oral doxycycline, or minocycline plus hydroxychloroquine for at least 1 year, if tolerated.
  • Although TMP-SMX has been frequently used as the oral alternative with reported success, a number of relapses or reinfections with TMP-SMX treatment have been reported, thereby suggesting caution for its use in patients with infection in critical locations such as the CNS and the heart.
  • The only case in which therapy failed—an 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).

7.3 Cardiac Disease

  • Current European guidelines for the treatment of endocarditis caused by T. whipplei recommend oral doxycycline plus hydroxychloroquine for ≥18 months.
  • Alternatively, ceftriaxone (2 g q24h IV) or penicillin (2 million units q4h IV) plus streptomycin (1 g q24h IV) for 2–4 weeks followed by oral TMP-SMX (800 mg q12h).
  • A small study from Spain reported that treatment durations of 12–13 months with these regimens or variations were efficacious.

7.4 IRIS Management

  • 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 IRIS.
  • Thalidomide has been used in steroid-refractory cases.
  • There is a single case report of clearance of infection in a chronically relapsing patient by the addition of interferon gamma to antimicrobials; supplementation to antimicrobials may be a consideration to address refractory disease or potential issues with antibiotic resistance.

8. PROGNOSIS & COMPLICATIONS

  • Rates of relapse, particularly of CNS disease, were unacceptable with oral tetracycline or TMP-SMX monotherapy.
  • Relapses or perhaps reinfections occurring years to decades after initial therapy have been described.
  • 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.
  • Neurologic sequelae occur with CNS disease, and the mortality risk is significant.
  • IRIS has been described in up to 17% of 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.
  • In patients with chronic WD, IRIS may be related to sustained disruption of the epithelial barrier, leading to increased translocation of gut-derived microbial products and dysbalanced T-cell restoration.
  • Manifestations include the development of fever, arthritis, skin lesions, subcutaneous nodules, pleuritis, uveitis, and orbital and periorbital inflammation; some cases have been fatal.

9. SPECIAL CONSIDERATIONS

  • HIV: As in patients treated for HIV or mycobacterial disease, IRF4 haploinsufficiency due to a loss-of-function mutation; the distribution of WD in this extended family was consistent with an autosomal dominant trait with incomplete penetrance.
  • HIV: Higher rates of detection in the secretions of HIV-infected persons.
  • Immunocompromised: Therapies that blunt cell-mediated host immune responses (e.g. systemic glucocorticoids or anti–tumor necrosis factor α [TNF-α] agents) may accelerate progression of chronic disease.
  • Immunocompromised: Impaired cell-mediated immunity may play a role in establishing chronic carriage of T. whipplei.
  • Foreign Body: 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.

9.1 HIV/Immunocompromised

  • Higher rates of detection in the secretions of HIV-infected persons.
  • Therapies that blunt cell-mediated host immune responses (e.g. systemic glucocorticoids or anti–tumor necrosis factor α [TNF-α] agents) may accelerate progression of chronic disease.
  • Impaired cell-mediated immunity may play a role in establishing chronic carriage of T. whipplei.

9.2 Foreign Body

  • 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.

10. KEY PEARLS & CLINICAL TRAPS

  • Saliva and fecal PCR are inappropriate as the sole diagnostic tools for WD due to low positive predictive values, which more commonly identify colonization, not disease; a positive result requires confirmation from an appropriate end-organ tissue or body fluid.
  • A negative result does not exclude WD.
  • Treatment of presumed inflammatory arthritis with immunosuppressive agents (e.g., glucocorticoids, anti-TNF-α, anakinra) can accelerate progression of the disease process; thus, screening for WD prior to initiation of immunosuppressant therapy may be appropriate, depending on the clinical scenario.
  • The combination of rheumatologic and intestinal disease with weight loss, with or without neurologic and cardiac involvement, warrants heightened suspicion.
  • Supranuclear gaze palsy (usually vertical), oculomasticatory and oculofacial myorhythmia (highly suggestive of WD).
  • Skin hyperpigmentation (melanoderma), particularly in light-exposed areas in the absence of adrenal dysfunction, is suggestive of WD.
  • Endoscopic or video-capsule observation of pale, yellow, or shaggy mucosa with erythema or ulceration past the first portion of the duodenum suggests WD.
  • Fever is often absent in cardiac disease (endocarditis), and the Duke clinical criteria are rarely met.
  • The most common finding on abdominal computed tomography is mesenteric and/or retroperitoneal lymphadenopathy (usually raising concern about lymphoma).

11. WHAT TO LOOK FOR — DIAGNOSTIC CLUES

  • Supranuclear gaze palsy (usually vertical).
  • Oculomasticatory and oculofacial myorhythmia (highly suggestive of WD).
  • Nystagmus.
  • Retrobulbar neuritis.
  • Skin hyperpigmentation (melanoderma), particularly in light-exposed areas in the absence of adrenal dysfunction.
  • Erythematous macular lesions.
  • Nonthrombocytopenic purpura.
  • Subcutaneous nodules.
  • Hyperkeratosis.
  • Endoscopic or video-capsule observation of pale, yellow, or shaggy mucosa with erythema or ulceration past the first portion of the duodenum.
  • Mesenteric and/or retroperitoneal lymphadenopathy.
  • Infiltration of the lamina propria with macrophages containing PAS-positive inclusions that are resistant to diastase.
  • Trilaminar cell wall of T. whipplei (electron microscopy).

12. WHAT EXCLUDES THE DIAGNOSIS

  • A negative result does not exclude WD.
  • Saliva and fecal PCR are inappropriate as the sole diagnostic tools for WD due to low positive predictive values, which more commonly identify colonization, not disease; a positive result requires confirmation from an appropriate end-organ tissue or body fluid.
  • Serology is of little value since patients with active infection usually mount a poor IgM/IgG response to T. whipplei and a positive result most likely reflects prior exposure and clearance.

Figures & Illustrations

Reproduced from Harrison's 22nd Edition.

Figure 1

Endoscopic view of the jejunal mucosa demonstrating a thickened, granular...

Caption: FIGURE 181-1 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.) — Endoscopic view of the jejunal mucosa demonstrating a thickened, granular mucosa and white spots due to dilated lacteals in Whipple disease.

Generated from Harrison's Principles of Internal Medicine, 22nd Edition.