on 21-Sep-2022 (Wed)

In Europe the prevalence of the bacterium in fecal samples from healthy adults ranges from 1% to 11%

In addition, the bacterium has been detected in sewage and is more prevalent in the fecal samples of healthy sewage workers (12%–26%) compared with the general population.12,13

These conditions, including isolated Whipple endocarditis, should be separated from the classic form of WD, which was described initially and is characterized by certain immune dysfunctions.

Classic Whipple disease (CWD) is rare, and no valid estimation on the incidence is available. The prevalence recently has been estimated at approximately 10 per 1 million people.16a

The disorder has been described most frequently in whites. Only rare occurrences have been reported in Hispanics, African Americans, Native Americans, and Asians.2

It has been presumed that the disease may occur in local clusters, that many patients reside in rural areas, and that farming often is found among the documented occupations.2,8

WD occurs primarily in middle-aged individuals, with a mean age at diagnosis of about 50 years.

In the published literature the disease is approximately eight times more common in men than in women2,8; newer series find a relatively higher incidence in women (male-to-female ratio 3 : 1).17

Recently, a gene defect of a transcription factor involved in immunity has been detected in some patients with familial WD.18a The interferon regulating factor 4 (IRF4) haploinsufficiency may be a rare but important factor to predispose for T. whipplei infection in certain individuals and in an age-dependent manner.

An immunologic defect in the pathogenesis of WD is probably based on the specific features of the T. whipp lei genome, suggesting an immune evasion and host-adapted lifestyle, and the very low disease incidence despite the ubiquitously present bacteria.

patients with the disease usually are not predisposed to infections with other organisms.

Newer data point to the possibility that intestinal manifestations (i.e., diarrhea) in WD are triggered by medical immunosuppression, which is given for the treatment of unclear arthropathy.19

Recent studies on a greater number of WD patients confirmed the alternative activated phenotype of the macrophages in the lamina propria, which correlated with a lack of excessive local inflammation and may explain in part the hallmark of WD—invasion of the intestinal mucosa with macrophages incompetent to degrade T. whipplei.20

Together, the local immune response on the mucosal level is apparently insufficient to kill ingested bacteria in patients with WD. Despite the more recent findings describing the subtle and persistent immune disturbance causing a disturbed phagocytosis and intracellular degrada- tion of T. whipplei, it remains unclear whether the immune defect is primarily macrophage or T-cell related

Studies on the B-cell level have found reduced numbers of immu- noglobulin A (IgA)-positive cells but increased numbers of surface IgM-positive B cells in the lamina propria.26

It has been shown that lamina propria and circulating populations on the T-cell level in active WD are characterized by a reduced CD4+/CD8+ T-cell ratio, a shift toward mature T-cell subpopulations (e.g., CD45RO expression increased, CD45RA expression decreased), and increased cell activation markers.21

Transient and acute infection with T. whipplei/transient and acute Whipple disease (TWD). This has been shown so far most impressively in French and African children. In the course of short-term and self-limiting diarrheal disease, up to 75% of patients may excrete T. whipplei in their stools, have T. whipplei bacteremia, or cough.14,15,30

Asymptomatic carriers of T. whipplei/asymptomatic Whipple disease (AWD). In these cases most of the individuals pass the agent into their stool. T. whipplei is present in saliva, or individuals may carry serum antibodies. Presumably, most have acquired T. whipplei via a subclinical or short-term acute infection.14,15,30 Very few will develop systemic WD later in their lives.

An increased proportion (≈12%–26%) of asymptomatic carriers were found in workers who have close contact with sewage.12,13 The bacterial load in the stool of these patients is lower than in untreated patients with CWD

Localized T. whipplei infection/localized Whipple disease (LWD) without systemic or CWD. This manifestation occurs most frequently as culture-negative bacterial endocarditis, for instance, on degenerative valve lesions, leading to a slowly progressive valve damage.32 In addition, LWD can be found in the eye, CNS, lymph nodes, and bone

Classic and systemic Whipple disease (CWD), with the leading symptoms of weight loss, diarrhea, and arthropathies. In 75% of cases these symptoms are found together by the time of diagnosis.8,33 The clinical presentation of patients may vary to a great extent, however, because of the differential organ involvement and the stage of the disease. In cases of CWD a reduced CD4+ T-cell response against T. whipplei is present.22

Immunosuppressive treatment may favor the occurrence of diarrheal disease, leading to the diagnosis of systemic WD.19 Alternatively, medical immunosuppression therapy may lead to isolated endocarditis, spon- dylitis, or CNS manifestations.32,35,37,38

In addition, after the use of immunosuppressive therapy, WD has a more complicated course after the initiation of therapy (see discussion of IRIS later) (see Table 210.1).

The clinical features of CWD are described in more detail, in many instances (63% in our large series)33 with CWD beginning insidiously with arthropathy. This symptom may precede the diagnosis by a considerable length of time (mean, 8 years in one series, up to 30 years),33 and consists usually of chronic migratory, nondestructive, and seronegative joint disease involving predominantly the peripheral joints; in addition, it often is accompanied by myalgias.2,8

Weight loss is found nearly invariably in all patients with CWD at the time of diagnosis. We found that weight loss was present in two-thirds of patients more than 4 years before diagnosis and was clinically relevant (often loss of ≥20% of initial weight).17,33

Gastrointestinal (GI) symptoms, which usually begin later and ultimately often lead to diagnosis, consist of episodic and watery diarrhea or steatorrhea, in many cases accompanied by colicky abdominal pain and occult blood in the stool.41,42 These symptoms and concomitant anorexia may lead to the full picture of a malabsorption syndrome with severe weight loss, weakness, and general cachexia, and it may be associated with ascites.

Systemic symptoms occur frequently (i.e., in about half of patients with WD). These symptoms consist of intermittent, mostly low-grade fever and night sweats.

Other frequent features of WD are peripheral and abdominal lymphadenopathy; mesenteric lymphadenopathy is found often in radiologic investigations but also may manifest as an abdominal mass.

Skin hyperpigmentation, particularly affecting light-exposed skin, has been observed.

Chronic, nonproductive cough, chest pain, and reversible pulmonary hypertension have been described.43 In 3% of bronchioalveolar lavages of intensive care unit patients and in 13% of HIV patients, T. whipplei has been found by PCR assay.16,44

Pleuritis, polyserositis, ascites, hypotension, and edema are among other frequently found signs and symptoms.

Hepatomegaly or splenomegaly may be present in some patients with this disorder. Less frequently, involvement of the genitourinary system and the endocrine system have been reported (see Table 210.2).2,8

Cardiac involvement in CWD may occur. In recent years endocarditis with T. whipplei (LWD) is reported more frequently without CWD (no other evidence of clinical WD and duodenal biopsy may be negative).32 These cases seem to be of increasing clinical relevance. Clinical symptoms depend on the stage of the disease and may include cardiac murmur and valve (often aortic or mitral) insufficiency, leading finally to valve replacement. Patients are typically diagnosed by histology and PCR assay on the explanted valve.32,40 Patients often do not fulfill Duke criteria for infective endocarditis and progress more slowly than patients with typical streptococcal or staphylococcal endocarditis.

In one large ret- rospective series, greater than 6% of all infective endocarditis cases were due to T. whipplei infection. Thus it was the most frequent cause of culture-negative endocarditis.32

A major and frequently overlooked area of involvement in CWD is the CNS. This involvement manifests most often as memory disorder, personality change, and dementia. Other frequent clinical signs include ophthalmoplegia, nystagmus, or myoclonia. These often may be found in combination with a disturbed sleep pattern, ataxia, seizure, or symptoms of cerebral compression (because of hydrocephalus). Various cranial nerve symptoms, such as hearing loss and blurred vision, have been reported.

In some patients a specific, if not pathognomonic, oculomasticatory myorhythmia or myoclonus with ophthalmoplegia has been described.38,45

There seem to exist some characteristic radiologic signs of CNS WD by using specific sequences (“flair” and “T1” sequences) of magnetic resonance imaging.46

CNS symptoms have a frequency of about 15%. CNS and ocular symptoms, such as blurred vision or ophthalmoplegia, may occur with minimal or absent GI involvement (i.e., localized WD).45

The diagnosis of CWD usually is made by upper endoscopy.

The diagnosis usually can be established if the characteristic PAS-positive material is present in the lesions (see Fig. 210.1B).

Involvement of the GI tract or lymphatic tissue may be accompanied by noncaseating, epithelioid cell (sarcoid-like) granulomas. Sarcoid-like granulomas have been found in patients with CWD in other organ systems and the skin. Infections with Rhodococcus equi and Mycobac- terium tuberculosis complex in patients with AIDS and infections with fungi, Histoplasma spp., and others, may be histologically similar to WD, some of which may be ruled out by a Ziehl-Neelsen stain.

Although the clinical picture, together with a pathognomonic PAS- positive histology from the duodenum, usually may be sufficient to establish the diagnosis, a specific diagnostic test, such as PCR and/or immunohistochemistry, is recommended in every newly identified patient; it is mandatory in cases of doubt or if the diagnosis is based on extraduodenal tissue (see Fig. 210.2). This recommendation reflects the fact that PAS staining is of limited value in extraintestinal tissue and for monitoring the effect of therapy.

PCR and quantitative PCR of T. whipplei in stool or saliva in individuals with TWD, AWD, LWD, or CWD differ to a great extent (e.g., in stool approximately 1%–75%).12–15,30,48a Quantita- tive PCR of saliva and stool are not helpful in establishing diagnosis of WD requiring therapy but could be used for noninvasive screening or follow-up purposes in the future.

Newer studies show that PCR-based T. whipplei diagnosis by urine samples in untreated patients is interesting.48b

The diagnosis of CWD is highly probable if the bacterial load is high in these specimens. In these cases the diagnosis should be confirmed by upper endoscopy and PAS staining of small intestinal biopsy specimens

Before definitive diagnosis, and particularly when atypical cases are reported, the use of at least two PCR tests, based on primers obtained from two different genes to avoid a false-positive result caused by contamination, or the use of immunohistochemistry is recommended

Sample specimens usable for PCR-based diagnosis of WD are duodenal biopsy, synovial fluid, lymph node, cardiac valve, vitreous humor, and CSF.8,13,40

Laboratory testing can reveal evidence of malabsorption and protein-losing enteropathy: reduced serum levels of β-carotene, various vitamins (B12, D, K, and folic acid), albumin, cholesterol, and electrolytes; lymphocytopenia; elevated stool fat excretion; and reduced d-xylose absorption.2,19,33 Some patients with WD have eosinophilia and abnormali- ties of serum immunoglobulins, such as low IgM, IgG2, or high IgA.2,27,28,38

Diarrhea and fever may disappear within 1 week of therapy, whereas arthropathy and other symptoms often are improved after 2 to 4 weeks. The laboratory findings normalize often over several weeks.

Current treatment recommendations are based not only on retrospec- tive analysis of small patient cohorts but, since 2010, also on a prospective randomized controlled trial.17

Because new study data argue for a short treatment duration of, for instance, 3 months,49 an issue that is currently still controversial, and others argue for a lifelong treatment, further treatment trials are awaited. So far, short-term treatment should be reserved for clinical studies

Although most patients recover completely and long-lastingly after antibiotic therapy, on occasion, inflammation reappears (mostly as high and recurrent fevers) after initial improvement; this is often interpreted as refractory or recurrent disease. However, PCR assay for T. whipplei in tissue of these patients is frequently negative, indicating absence of vital bacteria, and this reinflammation does not respond to antimicrobials but does respond to corticosteroids.

In a recent study IRIS was found in approximately 10% of patients with WD, with an outcome that varied from mild to fatal. The great majority of WD patients who developed IRIS had previous immunosuppressive therapy, which has been given under the suspected diagnosis of rheumatic disease.

In patients with CNS symptoms, neurologic defects are difficult to reverse.

A possible alternative to long-term oral cotrimoxazole may be doxycycline (2 × 100 mg/day; in some cases minocycline has been used) in combination with hydroxy- chloroquine (600 mg/day), which enhances the in vitro activity of doxycycline by increasing the pH in the phagolysosomes of the mac- rophages.51,52

Additional supportive therapy with Th1 cytokines (IFN-γ) has been described as beneficial.25

As mentioned, the immunologic defect seems to be specific for T. whipplei because a correlation with other infectious diseases was not found

All patients should be followed with duodenal biopsies and, in cases of cerebral involvement, with CSF analysis at 6 months and 1 year after diagnosis. If PAS-positive material is absent after 1 year and no bacteria are detected by PCR assay, antibiotic therapy can be stopped.

Therapy probably can be stopped safely if the histology has been stationary for more than 2 years. Monitoring of therapy in the future may be improved with the use of PCR assay (e.g., from the stool), immunohistology, or serology