This article reviews the microbiology, pathophysiology, epidemiology, clinical manifestations, diagnostic testing, and treatment of Whipple’s disease, an illness caused by Tropheryma whipplei and characterized by multivariate clinical manifestations including an inflammatory arthropathy. Diagnosis is confirmed by tissue sampling with periodic acid-Schiff staining and/or polymerase chain reaction. Clinical manifestations most frequently manifest in the gastrointestinal tract, musculoskeletal system, neurologic system, heart, and eyes, but can affect any site. Successful therapy with appropriate antibiotics is potentially curable, but recurrences may occur.
Key points
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Whipple’s disease is caused by the bacillus Tropheryma whipplei .
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The diagnosis is confirmed by tissue sampling with periodic acid-Schiff staining and/or polymerase chain reaction.
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The clinical manifestations most frequently manifest in the gastrointestinal, musculoskeletal, neurologic, cardiac, and ophthalmic organs, but can affect any site.
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Successful therapy with appropriate antibiotics is potentially curable, but recurrences may occur.
Although it is hypothesized that many rheumatic diseases may be initiated and perhaps maintained by an infectious agent, causative organisms have been rarely delineated as being causative in this group of illnesses. Whipple’s disease, an illness caused by Tropheryma whipplei and characterized by multivariate clinical manifestations including an inflammatory arthropathy, is one such disease. In the description of the first case of Whipple’s disease in a physician who had contracted this disease, by the pathologist George Whipple’s, the illness was characterized as an “intestinal lipodystrophy” and, although the focus was on the pathologic manifestations, an infectious cause was in fact considered, as Whipple’s noted “a bacillus belonging to the colonic group” in the submucosal layer of the intestine.
Over the last century the etiology of Whipple’s disease has been established, and the causative organism has been identified and characterized. However, many questions remain, as it is unknown as to why the clinical spectrum of the disease is so varied and why only a certain number of exposed patients develop the clinical illness. This article reviews the microbiology, pathophysiology, epidemiology, clinical manifestations, diagnostic testing, and treatment of Whipple’s disease.
Microbiology
George Hoyt Whipple’s was the first to consider an infectious cause based on the pathology, which demonstrated a bacillus. However, he was unsure as to whether this organism was in fact pathologic or part of the intestinal flora, and did not directly attribute the illness to an infectious cause. It was not until 1949, when the periodic acid-Schiff (PAS) stain revealed that foamy macrophages contained a glycoprotein material and not lipids, that an infectious cause was more concretely suspected. In 1961, Chears and Ashworth definitively identified macrophage-engulfed bacteria on electron microscopy. The PAS-positive bacilli with a classic trilamellar plasma membrane were hypothesized to be causative. The infectious nature of the disease has now been definitively confirmed using cell culture and polymerase chain reaction (PCR) assays.
Microbiology
George Hoyt Whipple’s was the first to consider an infectious cause based on the pathology, which demonstrated a bacillus. However, he was unsure as to whether this organism was in fact pathologic or part of the intestinal flora, and did not directly attribute the illness to an infectious cause. It was not until 1949, when the periodic acid-Schiff (PAS) stain revealed that foamy macrophages contained a glycoprotein material and not lipids, that an infectious cause was more concretely suspected. In 1961, Chears and Ashworth definitively identified macrophage-engulfed bacteria on electron microscopy. The PAS-positive bacilli with a classic trilamellar plasma membrane were hypothesized to be causative. The infectious nature of the disease has now been definitively confirmed using cell culture and polymerase chain reaction (PCR) assays.
Pathophysiology
Although there is clearly a direct infectious component to Whipple’s disease and, indeed, PCR can identify the characteristic unique bacterial 16S ribosomal RNA in affected tissues, there may be other potential etiologic factors that play a role in the phenotypic expression of this disease. Indeed there are 2 clinical stages of Whipple’s disease, separated by a prolonged period of time. The initial manifestations are undoubtedly infectious and are characterized by fever, fatigue, arthralgias, or arthritis, whereas the later manifestation, which includes diarrhea, weight loss, musculoskeletal symptoms, hepatic, cardiac, pulmonary, neurologic, and ophthalmic manifestations, may have an autoimmune component superimposed on an underlying infectious process.
Several autoimmune and genetic abnormalities have been hypothesized to be potentially present in patients with Whipple’s disease, with the predominant hypothesis being that immune abnormalities result in an increased risk of developing an infectious process such as Whipple’s disease. It is well known that the majority of people exposed to Tropheryma whipplei do not develop this illness. In a study of the prevalence of the organism in saliva and duodenal biopsies and/or gastric juice of asymptomatic healthy carriers, there was evidence of the organism. Between 1.5% and 7% of the general population may be asymptomatic carriers of the organism. T whipplei is a ubiquitous commensal bacterium.
Autoimmune abnormalities have been described in patients with Whipple’s disease. Circulating monocytes of patients with active Whipple’s disease are endogenously stimulated to express prothrombinase activity. A significantly reduced number of mononuclear cells express the complement receptor 3α chain (CD11b). T cells in acute Whipple’s disease are activated and exhibit a low CD4/CD8 ratio. Interleukin-16 is a critical cytokine in the pathogenesis of Whipple’s disease in that the expression of this cytokine is crucial for the replication of T whipplei in a monocyte/macrophage model, and blocking of this cytokine can result in bacterial clearance. An immune reconstitution syndrome characterized by fever and arthritis/arthralgias has also been described in a minority of patients after antibiotic therapy is instituted. A genetic association with human leukocyte antigen (HLA) B27 has also been hypothesized, though not universally accepted.
It is likely that the immunologic abnormalities in patients with Whipple’s disease predispose to the expression of an infectious illness. However, there may be a “reactive” autoimmune type response in the correct genetic host that is responsible for some of the clinical manifestations of this illness.
Epidemiology
Whipple’s disease is a rare condition, and little is known about its epidemiology. There is no universally accepted incidence rate, but there have been estimates of a worldwide annual incidence of 12 new cases per year. The incidence may be higher than previously thought owing to the establishment of PCR testing, which has definitively assisted in the diagnosis of this illness.
Whipple’s disease tends to present in middle age and is more common in males. As there is often a delay in the diagnosis attributable to nonspecific symptoms at presentation as well as antibiotic use before the expression of the most classic symptoms of the disease, the true age of onset is likely younger. Whipple’s disease has been reported in patients from 3 months to 83 years old, and a clinical review of 52 cases by Durand and colleagues found that in such a patient population, the mean age of diagnosis was between 48 and 54 years old.
Whipple’s disease affects males more often than females in an 8:1 ratio. However, recent studies have noted an increase in female patients from 13% to 20% compared with earlier data. The gender predisposition of Whipple’s disease is largely unexplained. It may be that similarly to ankylosing spondylitis, the disease may be less symptomatic in women. Although there is no evidence supporting a familial prevalence of the disease, genetic causes of disease expression have been proposed. In particular, an X-linked pattern of inheritance of regulatory genes integral in the expression of cytokines has been suggested. In addition, one review noted that 26% of patients with Whipple’s disease were positive for HLA B27.
Geographic and ethnic distributions also differ. In 696 cases studied, 55% were from Europe and 38% were from North America, with only a minority of cases in Hispanics, blacks, Indians, and Asians. Farmers and people working outdoors have been noted to be more likely to contract Whipple’s disease, suggesting that there may be a zoonotic component of transmission. This concept is particularly attractive, as T whipplei is gram-positive bacterium in the Actinomyces family, a group of bacteria active in decomposition of the soil and organic materials. Although many cases have been noted to occur in rural areas and the disease can occur in local clusters, no environmental factors or habitats have been definitively associated with the disease. The small intestines of a variety of domesticated animals have been tested for the presence of T whipplei . Although none of the samples were positive, the sample size was small and extraintestinal tissue was not sampled, so the presence of T whipplei in animals cannot be excluded. In a study that tested 38 samples of wastewater for DNA specific to T whipplei , 25 of the 38 samples tested positive, supporting the argument that T whipplei may be acquired through the environment.
Clinical manifestations
As in other infectious illnesses such as Lyme disease, which have a diverse clinical spectrum including rheumatic manifestations, Whipple’s disease tends to have 2 phases: an initial early phase with at times symptoms of infection but frequently including fever, arthritis, and/or arthralgias, followed by a late phase characterized by diarrhea, weight loss, and the potential involvement of almost every other organ system but predominantly affecting the eye, heart, and central nervous system (CNS).
Gastrointestinal
Whipple’s disease can affect almost any organ system in the human body. However, this condition, initially termed “intestinal lipodystrophy,” is frequently diagnosed on the basis of 1 of its cardinal symptoms, gastrointestinal involvement.
The mechanism of gastrointestinal manifestations of Whipple’s disease is probably from direct infection of macrophages in the small intestine by T whipplei and the consequences of a chronic intestinal infection. The infection appears histologically as foamy, PAS-positive macrophages found throughout the small intestine. The consequence of this contagion is the obliteration of the microvilli throughout the small intestine as well as lymphatic disruption. The particular localization and the subsequent effects on the surface of the gastrointestinal tract lead to many of the classic symptoms of Whipple’s disease. The duodenum, jejunum, and ileum are almost always affected, although liver, esophagus, stomach, and colon involvement have also been reported. Liver involvement can include granulomas that are negative for PAS staining, perhaps representing an autoimmune rather than a direct infectious origin in this organ.
The diagnosis of Whipple’s disease is generally made through endoscopy and a duodenal biopsy that demonstrates the presence of foamy, PAS-positive macrophages. Endoscopic evaluation reveals the destruction of the small intestinal mucosal architecture that results in pale, yellow lesions with shaggy, erythematous, and erosive mucosa. White-yellow plaques may also be present throughout the small intestine but not necessarily in a uniform pattern. For this reason, it is important to biopsy both the proximal and distal duodenum and jejunum to ensure that the diagnosis is not missed. Although antibiotic therapy may affect the pathologic findings, PAS-positive material in the macrophages can persist for years. An increase in PAS-positive material after prior resolution may be an indication of relapse.
The gastrointestinal symptoms of diarrhea, weight loss, and abdominal pain are the most common symptoms. However, manifestations of hepatosplenomegaly, anorexia, nutritional deficiencies, cachexia, hematochezia, and malabsorption are not uncommon findings of this disease. Diarrhea has been described as episodic or continuous, watery or fatty, and often occurs with colicky abdominal pain. In one study, occult blood was noted in the stools of up to 20% to 30% of patients with diarrhea. An abdominal mass caused by lymphadenopathy may also be noted. Unfortunately, not all patients with Whipple’s disease present with gastrointestinal symptoms. Early on in disease onset, articular symptoms are more common. In a study of 52 patients with Whipple’s disease, 35 (67%) showed early articular symptoms before diagnosis, whereas only 8 (15%) had gastrointestinal symptoms. In this same study, before diagnosis 8 of the 52 patients had gastrointestinal manifestations of the disease. By the time of confirmative diagnosis, diarrhea and weight loss were present in 44 (85%) of patients. There are, however, other studies in which gastrointestinal symptoms of diarrhea and weight loss were almost universally present by the time of diagnosis. A study by Mahnel and Marth of 27 patients with Whipple’s disease found that symptoms of arthropathy occurred on average 8 years before the diagnosis of Whipple’s disease in a majority of their patients. It is the later, gastrointestinal manifestations of the disease that most often lead to the diagnosis. This observation is particularly significant for rheumatologists, as it illustrates that although arthropathy may be a more common presenting symptoms of Whipple’s disease, it is the gastrointestinal symptoms that most often lead to definitive diagnosis.
Whipple’s disease has been described in association with Giardia . In one study, 53 fixed duodenal biopsy samples from 25 patients with Whipple’s disease were tested for the presence of Giardia and were compared with 150 duodenal biopsy samples from patients without Whipple’s disease. By histologic diagnosis, 3 of the 25 patients with Whipple’s disease had histologic evidence of giardiasis, whereas only 1 of the 150 control patients was affected. By PCR, 6 of the patients with Whipple’s disease were found to have evidence of Giardia , whereas this was found in only 2 of the control patients. A literature review identified 15 other cases of coinfection. There may be a common immune defect, a common source, or, perhaps, infection, with one organism predisposed to infection with the other.
In one study, the gastrointestinal manifestations of Whipple’s disease were noted to occur following initiation of immunosuppressive therapy for a presumed autoimmune arthropathy. This finding may lead to earlier identification of the disease, as the gastrointestinal symptoms occurred earlier than they otherwise would have.
Gastrointestinal manifestations of Whipple’s disease are varied and may at times be atypical. This organ system tends to be affected later in the disease process, and is a hallmark and, at times, dominant component of this disease. It is important to recognize that there are patients without gastrointestinal manifestations who may have this illness.
Musculoskeletal
Musculoskeletal manifestations of Whipple’s disease are very common, probably occurring in more than 80% of patients who have this illness. Involvement of the musculoskeletal system can occur both early and late in the disease. A spectrum of presentations exists. Arthralgias and arthritis both can occur, and these findings usually present 6 to 7 years before a definitive diagnosis of the illness is made. Although any pattern of arthritis can occur, an oligoarticular presentation, usually involving large joints, is most common, and the musculoskeletal symptoms may be migratory. Spondylitis has been described as occurring uncommonly. There may be an acute presentation followed by a more chronic polyarticular disease. As gastrointestinal manifestations present later in disease, frequently the musculoskeletal manifestations precede diarrhea and, as such, Whipple’s disease is not usually suspected, given its rarity and the absence of gastrointestinal manifestations. Therefore it is a diagnosis that should at least be considered particularly in male patients with an idiopathic oligoarticular or migratory arthropathy affecting large joints.
Patients are seronegative for other rheumatic illnesses, but radiographic studies may demonstrate joint-space narrowing and ankylosis. The organism has been cultured from synovial fluid and has been detected using PCR amplification in synovial fluid and tissue.
Nervous System
Neurologic manifestations can occur in 10% to 30% of patients with Whipple’s disease. These symptoms have been described in both the CNS and peripheral nervous system (PNS). Neurologic involvement in Whipple’s disease can present as either focal, isolated symptoms, or in an atypical nonuniform pattern dependent on lesion location. In one small study on postmortem examination of the brain and spinal cord, lesions were found in more than 90% patients. Although most patients who have this disease do not demonstrate clinical evidence of neurologic disease, it seems that T whipplei invades the nervous system frequently.
A report of 12 cases of patients with neurologic manifestations of Whipple’s disease found that neurologic symptoms in patients with this disease present either alone or with other manifestations of the disease. Clinical patterns and presentations vary depending on the site of infection. For example, if lesions are located in the hemispheres of the brain a patient may display dementia, personality changes, hemiparesis, or seizures. If the lesion is located in the mesencephalon, patients may present with ophthalmoplegia, nystagmus, or Wernicke’s encephalopathy. Hypothalamic lesions may lead to insomnia, hypersomnia, polyuria, and/or polydipsia, and hypothalamic-pituitary lesions can result in hypogonadism. Brainstem involvement can occur and is more common than spinal cord involvement. Peripheral nerve involvement has also been noted. Oculomasticatory myorhythmia and oculofacial skeletal myorhythmia do not occur in many other diseases, but have been described in Whipple’s disease. Other manifestations include personality changes, memory loss, psychosyndromes, ataxia, seizure, and hydrocephalus. CNS manifestations in patients with Whipple’s disease carry a worse prognosis than those with disease limited to the bowel, and these patients are more likely to relapse.
The diagnostic approach to neurologic Whipple’s disease includes testing of cerebrospinal fluid (CSF), tissue biopsy, and neuroimaging modalities. Brain magnetic resonance imaging can be used to localize lesions and guide a stereotactic cerebral biopsy with brain computed tomography (CT). On CT, hypodense lesions and edema are characteristic of the disease. PAS-positive perivascular macrophages, PCR-positive CSF or tissue biopsies confirm the diagnosis of neurologic Whipple’s disease.
Whipple’s disease can present in a myriad of ways in the nervous system. It is important to suspect this condition in any neurologic illnesses, particularly those associated with gastrointestinal symptomatology or other organ involvement. However, it is challenging that the neurologic manifestations of this condition are varied and can exist independently of any other clinical manifestations.
Ocular
Ophthalmic manifestations are uncommon, occurring in 4% to 27% of patients with Whipple’s disease. Although the most common ocular manifestation may be uveitis, other manifestations such as keratitis, retinitis, choroiditis, optic neuritis, and orbital inflammatory disease have been described. Indeed, recurrent flares of orbital pseudotumor have been found to indicate relapse of the disease. The diagnostic approach to patients with ophthalmic disease predominantly includes evaluation of vitreous fluid for PAS-positive macrophages and PCR.
Cardiac Manifestations
Although pericarditis has been frequently found in postmortem evaluations of patients with Whipple’s disease, this is rarely symptomatic. Endocarditis caused by this organism has been described in what was previously thought to be blood culture–negative endocarditis. Valve replacement has been required in several patients, and PCR analysis of the valve has confirmed evidence of T whipplei .
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