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Whipple's disease is a multisystem disease caused by the actinomycete Tropheryma whipplei. Having been first described by George Whipple in 1907,1 it remains a rare disease with an incidence of less than 1 per 1 000 000 per annum. It appears to be a predominantly Caucasian disease with the highest incidence in middle-aged men.2 Agricultural and sewage workers are at the highest risk of infection, leading to suggestions that the source of infection in most cases is likely to be from soil or zoonosis.3
The most common symptoms that are reported in Whipple's disease are weight loss, diarrhoea and malabsorption. Arthralgia may precede these symptoms by many months or years,4 and skin involvement with hyperpigmentation or nodules occurs in around half of patients.5
The clinical course of Whipple's disease is often divided into three stages: prodromal, classical abdominal and generalised. The prodromal stage includes symptoms of migratory polyarthralgia, low-grade fever and anorexia. The abdominal stage includes chronic diarrhoea, abdominal pain and profound weight loss. The generalised phase includes lymphadenopathy, hyperpigmentation, uveitis and cardiovascular, pulmonary and neurological complications. Untreated patients showed an 80% 5-year survival rate after onset of arthralgia, but only 20% 5-year survival after the onset of diarrhoea or abdominal pain.
There has been an increase in the reported incidence of endocarditis in association with Whipple's disease. A number of these culture-negative vegetations have been found in patients not displaying classical Whipple's disease abdominal symptoms.6 Endocarditis predominantly affects the mitral and aortic valves. Two cases of tricuspid valve endocarditis without classical abdominal symptoms have been previously described in the literature.6 ,7
Central nervous system (CNS) involvement is usually preceded by gastrointestinal symptoms and at this stage represents a poorer prognosis. Fewer than 15% of patients develop CNS involvement, which may be neurological or psychiatric.8 The most common presentations of CNS Whipple's disease are with cognitive changes, movement disorders, hypothalamic problems and seizures.8 ,9
There has been one previous case of thrombocytopenia in Whipple's disease. This was in a 74-year-old Mumbai resident. In 2004, he presented with weight loss, abdominal symptoms, anaemia, thrombocytopenia and endocarditis.10 This patient's clinical course was complicated by heart failure due to the aortic valve vegetation. He refused cardiac intervention and was discharged on ceftriaxone and co-trimoxazole, but died 4 weeks after discharge.
A 62-year-old previously healthy female originally presented with behavioural changes of severe anxiety and withdrawal, weight loss and severe anaemia. Weight loss of 14 kg had been noticed in the previous 18 months, and she had become progressively more anxious and depressed. The haemoglobin level at presentation was 5 g/dL, with a mean cell volume of 67 fL. The platelet count at presentation was normal at 152×109/L. Her c-reactive protein was raised at 141 mg/L, but no infective focus was initially found.
An abdominal CT scan to investigate possible gastrointestinal malignancy revealed mesenteric and paraaortic lymphadenopathy, and she was therefore referred to the haematology services. An oesophagogastroduodenoscopy showed no gross abnormality, but duodenal biopsies were taken that showed numerous foamy macrophages within the lamina propria with dilated lacteals.
While investigations were ongoing, her anaemia persisted and she subsequently became profoundly thrombocytopenic. After 6 weeks, her platelet count fell from a normal level to fewer than 50×109/L. There was no clinically apparent sepsis or medication change during these weeks to account for the thrombocytopenia (figure 1).
A bone marrow biopsy and trephine showed abundant megakaryocytes in keeping with peripheral platelet sequestration. In addition, there was significant plasmacytosis, which on immune phenotyping proved to be polyclonal (figure 2).
Due to an occasional low-grade pyrexia and persistently raised inflammatory markers, an echocardiogram was performed that demonstrated a 1.6 cm tricuspid valve vegetation. There was no evidence of significant valve destruction, and multiple blood cultures were negative. A single splinter haemorrhage was present but no other cutaneous stigmata of endocarditis (figure 3).
The periodic acid-Schiff stain on the duodenal biopsy was intensely positive and strongly suggestive of Whipple's disease. Diagnosis was confirmed with electron microscopy, which demonstrated the unique trilaminar cell wall ultrastructure that is characteristic of these rod-shaped bacteria (figure 4).11
Further confirmation of the diagnosis was attempted through tissue PCR on duodenal tissue from a repeat biopsy 6 weeks after commencing treatment. Low levels of T whipplei's unique 16S rDNA sequence were detected. It must be noted, however, that the PCR levels detected were low and could not be classified as diagnostic. However, the electron microscopy appearance and the strong intensity of the PAS staining were very strong indicators of the diagnosis. This discrepancy will be further discussed below (figure 5).
The patient was treated with 2 weeks of intravenous ceftriaxone, to be followed by a year of oral co-trimoxazole therapy. The anaemia and thrombocytopenia rapidly resolved with antibiotic therapy and her anxiety and depression improved dramatically. Her weight has been steadily increasing, and a repeat echocardiography showed a gradual reduction in vegetation size.
The patient's thrombocytopenia, anaemia and associated bone marrow changes confirm the association of Whipple's disease with haematological consequences. The thrombocytopenia was likely due to immune-mediated peripheral platelet destruction. We did not look for platelet antibodies, but results of these investigations would have been interesting and should be sought in future cases. Whipple's disease, in our opinion, should now be included in the aetiological list for thrombocytopenia. The anaemia was most probably of a secondary nature due to the absence of haematinic deficiencies and its prompt resolution upon treating the infection.
The association of streptococcal and staphylococcal endocarditis with thrombocytopenia and anaemia is well documented, and the reported incidence of endocarditis in Whipple's disease is also increasing, likely due to improved diagnostic facilities.12 The endocarditis is predominantly left sided, but our patient suffered from a tricuspid valve lesion. The medical literature cites only two previous cases of tricuspid valve endocarditis in Whipple's disease. The tricuspid valve was not known to be abnormal prior to presentation.
Finally, a greater understanding of PCR results in mid-treatment Whipple's disease can be gained from this case. Due to the amount of tissue taken from the first duodenal biopsy, there was insufficient tissue to be sent for PCR analysis once a diagnosis of Whipple's was suggested. A repeat biopsy was performed having already received 6 weeks of intravenous antibiotics.
Despite PCR techniques not requiring viable bacteria to be present in the specimen, the magnitude of the signal decreases and often becomes negative with treatment. Due to a limited number of cases, this is not well described in Whipple's disease but has been well described for other bacteria, for example, Bordetella pertussis in Whooping Cough.13 In cases of Whooping Cough, it is generally not recommended to perform PCR if the patient is more than 5 days into treatment due to the risk of false-negative results.
The PCR result obtained in this case showed a trace of the 16S rDNA sequence. Following discussions with the PCR laboratory, it is assumed that this result represents a case of Whipple's disease mid-treatment. This is an important consideration considering that in many cases the diagnosis will not be originally evident. Many patients will therefore have commenced effective antibiotic therapy before specialist investigations are arranged. The diagnosis was further reinforced by the characteristic electron microscopy images of the bacterium T whipplei. This case demonstrates the value of electron microscopy images in PCR-negative cases.
This report confirms the association of thrombocytopenia with Whipple's disease. In patients with a long history of unintended weight loss, Whipple's disease is a rare but important differential diagnosis as it is ultimately fatal if left untreated. This differential should particularly be considered in the presence of extraintestinal manifestations, including arthralgia, haematological abnormalities, endocarditis and CNS involvement.
Confirmed association between Whipple's disease and thrombocytopenia.
Consider in cases of haematological abnormalities with gastroenterology, CNS or rheumatology symptoms.
Always consider endocarditis in Whipple’s cases.
Good outcome if commenced on appropriate antibiotic therapy.
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