CHAPTER 72: ACTINOMYCOSIS AND WHIPPLE’S DISEASE

Actinomycosis and Whipple’s disease share characteristics that confound even the skilled diagnostician. Because both diseases are uncommon, the physician’s personal experience with their clinical presentations is limited. The laboratory identification of the etiologic agents from the order Actinomycetales is not routine. Thus they remain a diagnostic challenge. However, both of these chronic infections are curable, usually with medical therapy alone. Therefore, an awareness of the full spectrum of these diseases, prompting clinical suspicion, can expedite their diagnosis and treatment and minimize unnecessary surgical interventions (especially with actinomycosis), morbidity, and mortality risk.

Actinomycosis is an indolent, slowly progressive infection caused by anaerobic or microaerophilic bacteria, primarily of the genus Actinomyces, that colonize the mouth, colon, and vagina. Mucosal disruption may lead to infection at virtually any site in the body. In vivo growth of actinomycetes usually results in the formation of characteristic clumps called grains or sulfur granules. The clinical presentations of actinomycosis are myriad. Common in the preantibiotic era, actinomycosis has diminished in incidence, as has its timely recognition. Actinomycosis has been called the most misdiagnosed disease, and it has been said that no disease is so often missed by experienced clinicians.

Three “classic” clinical presentations that should prompt consideration of this unique infection are (1) the combination of chronicity, progression across tissue boundaries, and mass-like features (mimicking malignancy, with which it is often confused); (2) the development of a sinus tract, which may spontaneously resolve and recur; and (3) a refractory or relapsing infection after a short course of therapy, since cure of established actinomycosis requires prolonged treatment.

ETIOLOGIC AGENTS

Actinomycosis is most commonly caused by A. israelii, A. naeslundii, A. odontolyticus, A. viscosus, A. meyeri, and A. gerencseriae. Most if not all actinomycotic infections are polymicrobial. Aggregatibacter (Actinobacillus) actinomycetemcomitans, Eikenella corrodens, Enterobacteriaceae, and species of Fusobacterium, Bacteroides, Capnocytophaga, Staphylococcus, and Streptococcus are commonly isolated with actinomycetes in various combinations, depending on the site of infection. Their contribution to the pathogenesis of actinomycosis is uncertain.

Comparative 16S rRNA gene sequencing has led to the identification of an ever-expanding list of Actinomyces species and a reclassification of some species to other genera. At present, 46 species and 2 subspecies have been recognized (www.bacterio.cict.fr/a/actinomyces.html). A. europaeus, A. neuii, A. radingae, A. graevenitzii, A. turicensis, A. cardiffensis, A. houstonensis, A. hongkongensis, A. lingnae, A. massiliensis, A. timonensis, and A. funkei as well as two former Actinomyces species—Arcanobacterium pyogenes and Arcanobacterium bernardiae—are additional causes of human actinomycosis, albeit not always with a “classic” presentation.

EPIDEMIOLOGY

Actinomycosis has no geographic boundaries and occurs throughout life, with a peak incidence in the middle decades. Males have a threefold higher incidence than females, possibly because of poorer dental hygiene and/or more frequent trauma. Improved dental hygiene and the initiation of antimicrobial treatment before actinomycosis fully develops have probably contributed to a decrease in incidence since the advent of antibiotics. Individuals who do not seek or have access to health care, those who have an intrauterine contraceptive device (IUCD) in place for a prolonged period (see “Pelvic Disease,” below), and those who receive bisphosphonate treatment (see “Oral-Cervicofacial Disease,” below) are probably at higher risk.

PATHOGENESIS AND PATHOLOGY

The etiologic agents of actinomycosis are members of the normal oral flora and are often cultured from the bronchi, the gastrointestinal tract, and the female genital tract. The critical step in the development of actinomycosis is disruption of the mucosal barrier. Local infection may ensue. Once established, actinomycosis spreads contiguously in a slow, progressive manner, ignoring tissue planes. Although acute inflammation may initially develop at the infection site, the hallmark of actinomycosis is the characteristic chronic, indolent phase manifested by lesions that usually appear as single or multiple indurations. Central necrosis consisting of neutrophils and sulfur granules develops and is virtually diagnostic. The fibrotic walls of the mass are typically described as “wooden.” The responsible bacterial and/or host factors have not been identified. Over time, sinus tracts to the skin, adjacent organs, or bone may develop. In rare instances, distant hematogenous seeding may occur. As mentioned above, these unique features of actinomycosis mimic malignancy, with which it is often confused.

Foreign bodies appear to facilitate infection. This association most frequently involves IUCDs. Reports have described an association of actinomycosis with HIV infection; transplantation; common variable immunodeficiency; chronic granulomatous disease; treatment with infliximab, glucocorticoids, or bisphosphonates; and radio- or chemotherapy. Ulcerative mucosal infections (e.g., by herpes simplex virus or cytomegalovirus) may facilitate disease development.

CLINICAL MANIFESTATIONS

Oral-cervicofacial disease

Actinomycosis occurs most frequently at an oral, cervical, or facial site, usually as a soft tissue swelling, abscess, or mass lesion that is often mistaken for a neoplasm. The angle of the jaw is generally involved, but a diagnosis of actinomycosis should be considered with any mass lesion or relapsing infection in the head and neck (Chap. 20). Radiation therapy and especially bisphosphonate treatment have been recognized as contributing to an increasing incidence of actinomycotic infection of the mandible and maxilla (Fig. 72-1). Canaliculitis (also commonly due to Propionibacterium propionicum), otitis, and sinusitis also can develop. Pain, fever, and leukocytosis are variably reported. Contiguous extension to the cranium, cervical spine, or thorax is a potential sequela.

Thoracic disease

Thoracic actinomycosis, which may be facilitated by foreign material, usually follows an indolent progressive course, with involvement of the pulmonary parenchyma and/or the pleural space. Chest pain, fever, and weight loss are common. A cough, when present, is variably productive. The usual radiographic finding is either a mass lesion or pneumonia. On CT, central areas of low attenuation and ringlike rim enhancement may be seen. Cavitary disease or mediastinal or hilar adenopathy may develop. More than 50% of cases include pleural thickening, effusion, or empyema (Fig. 72-2). Rarely, pulmonary nodules or endobronchial lesions occur. Lesions ­suggestive of actinomycosis include those that cross fissures or pleura; extend into the mediastinum, contiguous bone, or chest wall; or are associated with a sinus tract. In the absence of these findings, thoracic actinomycosis is usually mistaken for a neoplasm or pneumonia due to more usual causes.

Mediastinal infection is uncommon, usually arising from thoracic extension but rarely from perforation of the esophagus, trauma, or extension of head and neck or abdominal disease. The structures within the mediastinum and the heart can be involved in various combinations; consequently, the possible presentations are diverse. Primary endocarditis (in which A. neuii has been increasingly described) and isolated disease of the breast occur.

Abdominal disease

Abdominal actinomycosis poses a great diagnostic challenge. Months or years usually pass from the inciting event (e.g., appendicitis, diverticulitis, peptic ulcer disease, spillage of gall stones or bile during laparoscopic cholecystectomy, foreign-body perforation, bowel surgery, or ascension from IUCD-associated pelvic disease) to clinical recognition. Because of the flow of peritoneal fluid and/or the direct extension of primary disease, virtually any abdominal organ, region, or space can be involved. The disease usually presents as an abscess, a mass, or a mixed lesion that is often fixed to underlying tissue and mistaken for a tumor. On CT, enhancement is most often heterogeneous and adjacent bowel is thickened. Sinus tracts to the abdominal wall, to the perianal region, or between the bowel and other organs may develop and mimic inflammatory bowel disease. Recurrent disease or a wound or fistula that fails to heal suggests actinomycosis.

Hepatic infection usually presents as one or more abscesses or masses (Fig. 72-3). Isolated disease presumably develops via hematogenous seeding from cryptic foci. Imaging and percutaneous techniques have resulted in improved diagnosis and treatment.

All levels of the urogenital tract can be infected. Renal disease usually presents as pyelonephritis and/or renal and perinephric abscess. Bladder involvement, usually due to extension of pelvic disease, may result in ureteral obstruction or fistulas to bowel, skin, or uterus. Actinomyces can be detected in urine with appropriate stains and cultures.

Pelvic disease

Actinomycotic involvement of the pelvis occurs most commonly in association with an IUCD. When an IUCD is in place or has recently been removed, pelvic symptoms should prompt consideration of actinomycosis. The risk, although not quantified, appears small. The disease rarely develops when the IUCD has been in place for <1 year, but the risk increases with time. Actinomycosis can also present months after IUCD removal. Symptoms are typically indolent; fever, weight loss, abdominal pain, and abnormal vaginal bleeding or discharge are the most common. The earliest stage of disease—often endometritis—commonly progresses to pelvic masses or a tuboovarian abscess (Fig. 72-4). Unfortunately, because the diagnosis is often delayed, a “frozen pelvis” mimicking malignancy or endometriosis can develop by the time of recognition. Ca125 levels may be elevated, further contributing to misdiagnosis.

Actinomyces-like organisms (ALOs), which are identified in Papanicolaou-stained specimens in (on average) 7% of women using an IUCD, have a low positive predictive value for diagnosis. Nonetheless, although the risk appears small, the consequences of infection are significant. Therefore, until more quantitative data become available, it seems prudent to remove the IUCD in the presence of symptoms that cannot be accounted for, regardless of whether ALOs are detected, and—if advanced disease is excluded—to initiate a 14-day course of empirical treatment for possible early endometritis. The detection of ALOs in the asymptomatic patient warrants education and close follow-up but not removal of the IUCD unless a suitable contraceptive alternative is agreed on.

Central nervous system disease

Actinomycosis of the central nervous system (CNS) is rare. Single or multiple brain abscesses are most common. An abscess usually appears on CT as a ring-enhancing lesion with a thick wall that may be irregular or nodular. Magnetic resonance perfusion and spectroscopy findings have also been described, as have primary meningitis, epidural or subdural space infection, and cavernous sinus syndrome.

Musculoskeletal and soft tissue infection

Actinomycotic infection of bone and joints is usually due to adjacent soft-tissue infection but may be associated with trauma (e.g., fracture of the mandible), injections, surgery, osteoradionecrosis and bisphosphonate osteonecrosis (limited to mandibular and maxillary bones), or hematogenous spread. Because of slow disease progression, new bone formation and bone destruction are seen concomitantly. Infection of an extremity is uncommon and is usually a result of trauma. Skin, subcutaneous tissue, muscle, and bone (with periostitis or acute or chronic osteomyelitis) are involved alone or in various combinations. Cutaneous sinus tracts frequently develop.

Disseminated disease

Hematogenous dissemination of disease from any location rarely results in multiple-organ involvement. A. meyeri is most commonly involved. The lungs and liver are most commonly affected, with the presentation of multiple nodules mimicking disseminated malignancy. The clinical presentation may be surprisingly indolent given the extent of disease.

DIAGNOSIS

The diagnosis of actinomycosis is rarely considered. All too often, actinomycosis is first mentioned by the pathologist after extensive surgery. Since medical therapy alone is frequently sufficient for cure, the challenge for the clinician is to consider the possibility of actinomycosis, to diagnose it in the least invasive fashion, and to avoid unnecessary surgery. The clinical and radiographic presentations that suggest actinomycosis are discussed above. Of note, hypermetabolism has been demonstrated by ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET) in actinomycotic disease. Aspirations and biopsies (with or without CT or ultrasound guidance) are being used successfully to obtain clinical material for diagnosis, although surgery may be required. The diagnosis is most commonly made by microscopic identification of sulfur granules (an in vivo matrix of bacteria, calcium phosphate, and host material) in pus or tissues. Occasionally, these granules are identified grossly from draining sinus tracts or pus. Although sulfur granules are a defining characteristic of actinomycosis, granules also are found in mycetoma (Chaps. 71 and 118) and botryomycosis (a chronic suppurative bacterial infection of soft tissue or, in rare cases, visceral tissue that produces clumps of bacteria resembling granules). These entities can easily be differentiated from actinomycosis with appropriate histopathologic and microbiologic studies. Microbiologic identification of actinomycetes is often precluded by prior antimicrobial therapy or failure to perform appropriate microbiologic cultures. For optimal yield, the avoidance of even a single dose of antibiotics is mandatory. Primary isolation usually requires 5–7 days under anaerobic conditions but may take as long as 2–4 weeks. Although not routinely used, 16S rRNA gene amplification and sequencing have been successfully applied to increase diagnostic sensitivity and specificity. Because actinomycetes are components of the normal oral and genital-tract flora, their identification in the absence of sulfur granules in sputum, bronchial washings, and cervicovaginal secretions is of little significance.

TREATMENT

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.

ETIOLOGIC AGENT

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.

EPIDEMIOLOGY

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.

CLINICAL MANIFESTATIONS

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. 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.

Acute infection

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.

Chronic infection

“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. 72-5). 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.

Neurologic disease

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.

Cardiac disease

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.

Pulmonary disease

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.

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.

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.

Dermatologic disease

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.

Miscellaneous sites

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.

Isolated infection

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.

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. 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