Kerckhoff Clinic and Foundation, Department of Rheumatology, Bad Nauheim and
1 III Medical Clinic, University of Giessen, Giessen, Germany
Abstract
Whipple's disease (WD) is an uncommon polysystem infectious disease. In the present report, we describe a patient who presented with a chronic illness consistent with WD and an avascular necrosis of the right hip joint. WD and its proposed causative bacillus, Tropheryma whippelii, was identified by molecular analysis (polymerase chain reaction) in bacterial DNA extracted from the synovial fluid. The diagnosis was additionally confirmed by upper gastrointestinal endoscopy and a small bowel biopsy with macrophages positive for periodic acidSchiff reagent demonstrated by light and electron microscopy.
This demonstrates that WD can be diagnosed without tissue biopsy. False diagnosis of the polymorphous signs and symptoms of WD can lead to invalidism and even death, whereas correct therapy leads to a cure in most cases. Thus, the current status of diagnosis and therapy is of key importance in the treatment of WD.
KEY WORDS: Whipple's disease, Infectious disease, Actinomycete.
Case report
A 60-yr-old male patient was admitted to hospital as a result of rapid decline and general malaise and increasing immobilization. No major health problems up to the age of 50 are registered. Since age 57 recurrent polyarthralgia at differing locations was first manifest bilaterally at the ankle joint for 6 weeks, along with recurrent febrile episodes of temperatures up to 40°C and night sweats. He lost 20 kg of weight over the last 8 months, 13 kg of which were lost in the last 4 months, accompanied by lack of appetite and diarrhoea (frequency: 13 times daily). Moreover, hip pain on the right side increased over the last 4 months, resulting in pain on walking and weight-bearing.
Upon admission, deteriorating general and nutritional condition as well as striking hyperpigmentation of the distal limbs (Fig. 1A and B) were found. Moreover, swelling and hyperthermia of both ankle joints, painful and limited flexion (up to 80°) of the right hip joint and closed internal and external rotation were observed. The length of the leg decreased by 4 cm on the right side.
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Standard values in routine laboratory tests, barring pathological findings, were as follows: sodium 130 mmol/l; calcium 1.9 mmol/l; chlorine 95 mmol/l; protein 53 g/l; albumin 23%; iron 16 µg/dl; and ferritin 635 ng/ml. An HIV test was negative.
The cell-surface markers showed CD3 cells 76%; CD4 cells 59%; CD8 cells 11%; B cells, total 5%; activated T cells 3%, the CD4/CD8 ratio was markedly increased with 5.3%. Tumour marker was normal, namely CEA/Ca19-9/Ca 72/Cyfra.
The immunological parameters were as follows: IgG 1120 mg/dl; IgA 642 mg/dl; IgM 40 mg/dl; C3 complement 102 mg/dl; and C4 complement 26 mg/dl.
Urinary status, urinary diagnosis including Bence-Jones proteins, coagulation parameters, tine test, haemoccult test 3-fold, serological microbiological examinations, pulmonary function and parasitological stool examination were all found to be normal.
The pelvic overview revealed a destruction/impression of the right head of the femor and bilateral sacroiliitis (Fig. 1C).
Polymerase chain reaction (PCR) detection of Tropheryma whippelii was performed by agarose gel electrophoresis of the synovial fluid from the right hip joint (see Fig. 1D).
Distal oesophagitis, normal stomach, fully developed deterioration of the villous relief starting at the bulbus duodeni and petechial, inhomogeneous, whitish staining of the mucous membrane with focal hyperaemia in the duodenum were found during proximal endoscopy.
Under light microscopy with periodic acidSchiff reagent (PAS), massive histiocytic storage of granular and rod-shaped PAS-positive material could be detected in the duodenal biopsies. Staining of acid-resisting rod cells was negative. Using electron microscopy, there was proof of intra- and extracellular bacteria showing the typical configuration of Tropheryma whippelii (Fig. 1EH).
Abnormalities and macroscopic indication of Whipple's disease could not be found during coloscopy. The abdominal CT showed lymph nodes of up to 1.5 cm in the root of the mesentery, but no further indication was observed. Selective representation of the small bowel according to Sellink revealed significant thickening of the plicae circulares, mainly in the jejunum.
Summary of the findings and diagnosis
In the presented case, polyarthralgias, arthritis of the right hip joint, loss of weight, febrile episodes, diarrhoea and hyperpigmentation in the hands and feet were the ambiguous, but characteristic, cardinal symptoms. Laboratory parameters were unspecific and did not indicate a precise diagnosis. The diagnosis was based on detection of T. whippelii after arthrocentesis by PCR, and additionally by proximal intestinoscopy with biopsy of macroscopically obvious duodenal mucous membrane with proof of PAS-positive macrophages in the mucous membrane and electron-microscopic proof of Whipple's bacteria, as well as radiological findings (CT: mesenterial lymph nodes; representation of the small bowel according to Sellink; deteriorating plicae circulares).
Therapy
Initially, co-trimoxazole (160 mg trimethoprim/800 g sulphamethoxazole three times/day) was administered as an intravenous antibiotic. After 10 days the diarrhoea ceased and the patient lost aversion to food and resumed eating.
This was followed by adaption to oral long-term therapy with co-trimoxazole (2x160 mg trimethoprim + 800 mg sulphamethoxazole) together with a prophylactic dose of folic acid (10 mg/week). After 5 months the patient was free of discomfort and in good general condition; even a decrease in the initial hyperpigmentation was observed. The laboratory tests showed normal values for the inflammatory parameters and body weight had stabilized.
Epidemiology
WD is a rare disease, and is probably often either misdiagnosed or missed owing to many non-typical symptoms. Thus, exact data regarding the incidence and prevalence are not available. In autopsy studies, prevalence was below 1 per million [1]. Worldwide, about 8001000 cases have been reported [2, 3].
The disease is far more common in middle-aged Caucasian men than in women (510-fold higher). However, in women the rate increases above the age of 70 [4]. WD has been diagnosed, although rarely, in early infancy and in the elderly [5, 6]. Rare cases in black patients and American Indians have been reported [7, 8].
Demographic data from 664 known cases up to 1985 were compiled by Dobbins [4]. Since 1960, 20 new cases worldwide have been reported yearly. Only about 3% of these were diagnosed before the age of 30. Interestingly, most patients are involved in the building trade or agriculture, having contact with soil and/or animals [9, 10]. A higher incidence was reported in rural environments in Italy, France and North Carolina [7, 11, 12]. The occurrence of the disease among siblings [4, 1315] as well as an association with the histocompatibility antigen B27 [16] were also observed, so that a genetic predisposition cannot be excluded.
Eighty-five years after the first description by George Hoyt Whipple (intestinal lipodystrophia [17], Relman et al. [18] related the bacterium to a new type of actinomycetes by means of PCR and phylogenetic comparison. In parallel, our group [19] as well as O'Duffy et al. [20] were the first to describe the identification of T. whippelii in synovial fluid by means of PCR. Up to this time, the diagnosis of WD was established by microscopic examination of small bowel biopsy specimens of involved tissue [5, 2124].
Pathology
The keystone to diagnosis is the documentation in biopsies of the presence of intracellular and extracellular Gram-labile, rod-shaped microbes in the affected tissue; Gram labile being those cases where Gram-negative results are observed but structures in the cell wall of characteristic Gram-positive and -negative bacteria are also present [9, 16, 25, 26].
For these bacteria, which could not be cultured up until then, the name Tropheryma whippelii was proposed [27, 28]. The bacteria or cell wall fragments of these correspond to the PAS-positive inclusions of macrophages [29, 30], the so-called SPC (sickle-form particle-containing) cells [31, 32], which are typical for WD.
Although WD must be regarded as an infectious disease after the identification of an associated bacterium, it is astonishing that the mode of transmission of the disease is not yet clarified. Worldwide, only a single publication exists on a supposed mode of transmission in an animal experiment [28]. Most probably, so-called cofactors/dispositions have to be considered in this case [9].
Interestingly, a publication in 1969 from de Grood-Lasseel et al. [33] suggests the possibility that the Whipple pathogen might belong to the actinomycetes.
Immunological studies
T-cell defects in WD patients have been observed in several studies [3436], but in these cases the question remains open as to whether this is a primary or secondary phenomenon, so that the significance of an immunodeficiency is currently controversial [4, 5, 3740]. Observation of a normalization in the course of the disease of immunological parameters that are initially pathological speaks for an epiphenomenon [41]. Nevertheless, the frequent detection of skin anergy and increased observations of opportunistic infections may be a symptom of immunodeficiency [42]. A cellular T-cell defect of the immune system is regarded as being predisposing. It is supposed that this defect is not acquired but rather inherited [43] as indicated by the detection of HLA-B27 in approximately 40% of the affected patients.
Systemic manifestation
Most organs can be involved in WD. The course of the disease is characterized by two stages: a prodromal stage, which is determined by unspecific findings, and a highly acute stage of the disease with the classic Whipple triad of diarrhoea, weight loss and malabsorption. The classic signs may be missing in about 20% of cases [21, 42, 44]. In such cases, extraintestinal manifestations play a pathognomonic role. Prodromal symptoms are observed over a period of 310 yr, but courses lasting over decades can also appear [45]. Peripheral arthritides appear in 6590% of cases, in which, as a rule, all joints can be affected [4650]. These represent the major primary and extraintestinal symptoms [51], in most cases knee and ankle joints are involved, followed by hip, finger and hand joints [45, 47]. Usually, the arthritis presents a transient course and character with an acute onset and a duration of hours to days with respect to the single attacks [45]. Chronic symptoms are exceptional.
An increased rate in the appearance of leucocytes, mainly granulocytes, and many macrophages can be identified in the synovia [48, 52, 53]. Interestingly, in one patient, electron microscopic analysis of the synovial fluid suggested a direct articular invasion by the Whipple bacillus [53].
Radiomorphologically, erosive or cystic changes in the joints are rarely observed, even after several years. In 25% of patients, the axial skeleton was affected in the form of sacroiliitis or spondylitis [42, 45, 47]. Joint involvement nearly always precedes the intestinal signs and symptoms by an average of about 510 yr [42, 45, 51, 54], although a time interval of 3539 yr has also been reported [42].
Within the scope of multisystemic manifestations in WD, hyperpigmentation, mainly around scars and the skin areas exposed to sunlight, is observed in 2050% of cases without signs of adrenal insufficiency [54, 55]. In 50% of cases, peripheral lymphoadenopathy and occasionally extended abdominal lymphoma are found [35, 5658]. However, pleural/pericardial effusions are only rarely observed, as are endocarditides, which can lead to heart failure, valvular defects and changes in the ECG [5961]. Central nervous symptoms such as ataxia, headaches, dementia, personality changes, meningitis, peripheral neuropathy and hypothalamic symptoms, as well as ophthalmological involvement (e.g. uveitis, vitritis, chorioretinitis and ophthalmoplegia) are present in 610% of patients [3, 37, 54, 59, 6164]. The neurological findings can be clinically subdued, but on the other hand may also determine the major clinical picture without intestinal symptoms. This is especially problematic in late recurrences after initially successful therapy, particularly in cases with antibiotics crossing ineffectively into the cerebrospinal fluid [16, 59]. Some 50% of the patients complain of chronic, non-productive coughing, suggesting pleural involvement, especially when in combination with fever attacks. A diffuse or granulomatous infection of the lung is rare [1, 54].
Laboratory findings
There are no pathognomonic laboratory findings in WD. Mostly an accelerated ESR and an increased CRP is found. Frequently a normocytic hypochromatic anaemia with or without detection of serum iron deficiency, normal or slightly increased leucocyte counts and, seldomly, folic acid or vitamin B12 deficiency are observed. Moreover, eosinophilia or leucopenia may also be present [21, 37, 59]. Levels of IgA are frequently increased, accompanied by normal IgG and IgM levels [65]. Other pathological changes include malabsorption and steatorrhoea [7, 21, 25, 51, 66]. The impaired protein balance causes hypoalbuminaemia due to exudative enteropathy, decreased hepatic synthesis and decreased mucosal assimilation of amino acids [51, 67, 68]. Immunological findings reveal a proportional shifting of T-cell subtypes, such as a decreased CD4/CD8 ratio [34, 35]. Rheumatoid factors and antinuclear factors are typically negative [46, 47].
Diagnosis
The keystone of the diagnosis is examination of biopsies of involved tissue with pathognomonic histological changes. Characteristic histological findings include dilated flattened villi, large extracellular vacuolated fat accumulation in macrophages and partial cuboid deformation and vacuolation of the surface epithelium [6971]. PAS-positive macrophages are found in the upper third of the lamina propria close to the lumen, but rarely below the lamina muscularis mucosae. Numerous polymorphonuclear leucocytes can be detected in the lamina propria, whereas lymphocytes and eosinophils, which are usually found here, are almost totally lacking. Masses of rod-shaped micro-organisms appear near the basal membrane of the surface epithelium as well as pericapillary and intracellularly. This is demonstrated by the typical changes in SPC cells and PAS-positive macrophages in the affected organs (Fig. 1EH). In exceptional cases, the duodenum as well as other clinically affected organs do not show typical histological changes [43, 63, 72].
Therapy
When WD is diagnosed an adequate antibiotic therapy can lead to a dramatic improvement, and the majority of patients can be cured [7376]. The first successful use of antibiotics was reported by Paulley in 1952, which led to the suggestion of a bacterial aetiology. Effective antibiotics include chloramphenicol, cephalosporin, tetracycline/doxycycline, penicillin/ampicillin, trimethoprimsulphamethoxazole, rifampicin and streptomycin [7377]. Owing to a lack of controlled studies the most important publications of the last few years are retrospective and as such suffer somewhat from selection effects [73, 74, 78, 79]. However, adequate administration of antibiotics must be as long-term therapy for a period of years, since recurrences are to be expected. In the largest study of medication involving 88 patients suffering from WD, the average duration of therapy with different antibiotics was approximately 1 yr [74], with a high recurrence rate being observed in the long-term course (31 patients after an average of 4 yr). Recent studies have shown that recurrences appear in up to 50% of cases under tetracycline therapy, especially when the CNS is involved [51, 80, 81]. In this respect it should be noted that, mainly in the case of cerebral invovement, some antibiotics are superior owing to a more advantageous liquor patency [44, 74, 75, 82, 83]. The efficacy of a shorter antibiotic treatment (lasting on average 8 weeks) was examined in another study involving 17 patients, which included clinical follow-up of several years [76]. Here, 21% of the patients treated with tetracycline had recurrences of disease, although the CNS was not involved.
In summary, it can be stated that several oral antibiotics and combinations are effective. Although an optimal antibiotic regimen has yet to be established, trimethoprimsulphamethoxazole appears to be superior at present, especially when the CNS is involved [79, 83, 84]. The administration of ampicillin/chloramphenicol represents an alternative [54], and successful treatment with rifampicin has also been reported [85].
Follow-up
In the case of extraintestinal manifestation, half-yearly small intestinal biopsies and corresponding organ biopsies serve as follow-up. Only the extracellular bacteria have been seen to disappear completely after antibiotic treatment [51, 59, 86], whereas remaining bacteria in the cytoplasm of macrophages can be detected after antibiotic treatment even after several years of therapy [59, 66]. Recurrence signals an extracellular reinfection in control biopsies [51, 59, 66, 70, 87]. When antibiotics are consequently given, a lethal course of this disease should be avoidable.
Outlook
Lowsky et al. [88] published two cases in which cultivatable erythrocyte-associated Gram-positive bacteria could be found in the peripheral blood, where the occurrence of T. whippelii was demonstrated by sequence analysis. Recently, Raoult et al. [89, 90] cultured and immunologically detected T. whippelii and identified it in the cytoplasm of blood monocytes. However, how far haematotropy of the bacterium can be suggested generally in every case needs further clarification.
Our work group [19] and O'Duffy et al. [20] described in parallel the first direct detection of T. whippelii in synovial fluid, and demonstrated that WD can be diagnosed without tissue biopsy. PCR of the synovial fluid is an important new tool in the diagnosis of WD. Whether the detection of T. whippelii by PCR in synovial fluid is always associated with WD, or whether the detection is associated with erosive changes and/or bone destruction needs to be evaluated in further studies. Molecular methods for early diagnosis may have a decided advantage over microscopic techniques owing to their high sensitivity and specificity, and because the method is less invasive than gastrointestinal biopsies.
The question of whether PCR may represent an advantageous step in the diagnosis of WD that could replace the classic mode of diagnosis (PAS staining of involved biopsy tissue) remains open. Nevertheless, we can look forward with great anticipation to further applications of PCR in the diagnosis of WD.
Differential diagnosis of WD
The differential diagnosis of WD includes diseases with primarily gastroenterological manifestations and the ability to show extraintestinal involvement such as skin lesions and arthritis; for example, chronic inflammatory intestinal infections [91, 92], sprue [75], infectious diseases such as tuberculosis [14, 93], yersiniosis [94], AIDS [9597] and non-Hodgkin's lymphoma [96].
Patients with HIV infection may have symptoms similar to those in WD that are caused intracellularly by Mycobacterium avium [50, 98100].
Sarcoidosis, malignant non-Hodgkin's lymphoma and abdominal tuberculosis show numerous pathogenetic and clinical similarities to WD [101, 102].
In monosymptomatic arthritis, all diseases accompanying arthritis should be taken into consideration [45, 103105]. Moreover, the seronegative spondylarthritides must be taken into consideration in case of additional spine symptoms and signs [45].
Acknowledgments
We thank H. Dotzlaw for critical reading of the manuscript.
Notes
Correspondence to: U. Lange, Kerckhoff Clinic and Foundation, Department of Rheumatology, Ludwig Str. 3739, 61231 Bad Nauheim, Germany. E-mail: uwe.lange{at}kerckhoff.med.uni-giessen.de
References
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