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Whipple disease is an infection caused by the bacterium Tropheryma whipplei. Due to its unspecific clinical symptoms, it is difficult to diagnose and often remains undetected for a long time. The case of a patient who presented with acute intestinal symptoms to the authors' department is reported. The diagnosis of classic Whipple disease was established. The symptoms subsided under antibiotic therapy. Complications in the form of immune reconstitution inflammatory syndrome (IRIS) occurred, requiring immunosuppressive treatment.Der Morbus Whipple ist eine durch das Bakterium Tropheryma whipplei verursachte Infektion, deren Diagnosestellung durch eine unspezifische Beschwerdesymptomatik erschwert wird und die häufig lange unerkannt bleibt. Wir berichten über einen Patienten, der sich mit neu aufgetretenen intestinalen Beschwerden in unserer Abteilung vorstellte. Es konnte die Diagnose eines klassischen Morbus Whipple gestellt werden. Unter antibiotischer Therapie wurde eine Remission der Symptomatik erreicht. Komplizierend traten Beschwerden im Sinne eines Immunrekonstitutionssyndroms (IRIS) auf, die eine immunsuppressive Behandlung erforderten.

Whipple's disease is a rare infectious disease, which can affect various organ systems. Arthritis is a common symptom and therefore the infection is often misdiagnosed as seronegative rheumatoid arthritis. In rare cases an infection with Tropheryma whipplei can also cause skin lesions, such as subcutaneous nodules, erythema nodosum or vasculitis. This article reports the case of a 77-year-old female patient with erosive joint changes, persistently elevated serological inflammation markers and recurrent ulcerative lesions of the lower extremities, which were initially misdiagnosed as rheumatoid vasculitis. In cases of a clinically suspected infection with Tropheryma whipplei an early biopsy of the affected organ system is essential for the diagnosis.

Whipple's disease (WD) is a rare, chronic multiorgan disease which can caused by Tropheryma whipplei, a ubiquitous gram positive bacterium. Detection of T. whipplei is mostly performed histologically using periodic acid-Schiff (PAS) staining in affected tissues to visualize characteristic PAS-positive macrophages and by the polymerase chain reaction (PCR). Clinically, WD is often characterized by gastrointestinal symptoms (diarrhea, colic-like abdominal pain and weight loss). Arthritis is a common presentation of WS, often leading to a misdiagnosis of seronegative rheumatoid arthritis and as a consequence to immunosuppressive therapy. The clinical presentation of WD is highly polymorphic affecting different organ systems (e. g. cardiac or neurological manifestation) and making an appropriate clinical diagnosis and even the diagnostic process itself difficult. This article reports on three cases presenting with completely different leading symptoms (initially misdiagnosed as seronegative rheumatoid arthritis, spondyloarthritis and adult onset of Still's disease, respectively) that illustrate the rich diversity of WD. The cases were chosen to draw attention to the fact that although WD is mainly associated with the field of gastroenterology and gastrointestinal (GI) involvement is common, it may appear without GI symptoms. In cases of a clinical suspicion of WD, diagnostic efforts should be made to detect the bacterium in the affected organ. The German S2k guidelines on GI infections and WD published in January 2015 summarized the current state of the art for WD. The currently recommended primary treatment is antibiotics that can infiltrate the cerebrospinal fluid, e. g. ceftriaxone, followed by cotrimoxazole, which should be maintained over several months.

Within the last years the understanding of infection with Tropheryma whipplei was significantly enhanced by improvement of molecular biology, microbiology and immunology. The following entities of infection or carriage, respectively, with T. whipplei must be differentiated: besides in the context of classical Whipple's disease (CWD), the rare chronic infection with T. whipplei (estimated incidence: 1 : 1,000,000), T. whipplei can be detected more frequently in stool specimens of children with acute gastroenteritis or asymptomatic carriers, or as a cause of isolated endocarditis. However, infection with T. whipplei only rarely results in CWD. T. whipplei was well characterized, raised in vitro and its genome completely sequenced within the last two decades. Very interesting is the resistance of the agent against glutaraldehyde.The histological detection within duodenal biopsies with "Periodic Acid Schiff" (PAS) staining still is first choice for the diagnosis of CWD. Today PCR or immunohistochemistry can identify the agent more specifically. In cases of isolated organ manifestations of e. g. joints or central nervous system the agent needs to be identified from specimen from the affected sites. Successful treatment can be achieved in most of the cases by antimicrobial therapy and first prospective treatment trials are published. However, neuronal CWD still can be progressive lethal and an immune reconstitution inflammatory syndrome (IRIS) might complicate the course of treatment and in worst case end fatal. Thus, because of the complexity of the disease a specialised reference centre should be consulted for diagnosis and treatment of CWD.

Whipple's disease is a rare infectious disease caused by the bacterium Tropheryma whipplei. Usually the course of the disease is characterized by fever, diarrhea, weight loss and polyarthritis. We report on a case with a 10-year course of the disease with endocarditis, myocarditis and involvement of the bone marrow but with negative histological results of the small intestine.

Isolated monarthritis caused by Tropheryma whipplei without involvement of the gastrointestinal tract is rare but is nowadays often described as an early manifestation of the disease. In a male patient with recurrent knee joint arthritis for several years, we could ultimately diagnose Whipple's disease based on PCR positive biopsies of synovial tissue and fluid. Furthermore, the patient was found to be an asymptomatic T. whipplei carrier. With adequate antibiotic therapy the patient has meanwhile fully recovered.

Inflammatory bowel diseases, such as Crohn's disease, ulcerative colitis, autoantibody driven celiac disease and infectious Whipple's disease can all be associated with neurological symptoms. The neurological manifestation may occur even before the gastrointestinal symptoms or the enteropathic symptoms can even be absent as in celiac disease. These diseases can be caused by malresorption and lack of vitamins due to enteral inflammation as well as (auto-)immunological mechanisms and drug-associated side effects. Thus, inflammatory bowel diseases have to be considered in the differential diagnosis. In this review the most common neurological manifestations of these diseases will be described as well as the diagnostic approach.

Five years ago a 52-year-old patient presented with arthritis of the small and large joints. Further symptoms were relapsing fever, unspecific gastrointestinal complaints with meteorism but no diarrhea, fatigue and impaired concentration. Subsequently increasing lower back pain developed. A lumbar-disc lesion was already known.Inflammatory markers were elevated including leucocytosis. Gastroscopy with intestinal biopsies and colonoscopy remained without pathologic findings. Whipple's disease was excluded, but unspecific lymphozyte infiltration of the duodenal mucosa was described. Magnetic resconance imaging of the lumbar spine showed spondylodiscitis in L3/4 which was punctured, and polymerase chain reaction revealed Tropheryma whipplei DNA. Retrospectively, this was also found in the intestinal biopsies of three years ago.After initial exclusion of Whipple's disease an unspecific systemic inflammatory disease had been presumed, and the patient had been treated with immunomodulatory therapies in alternating combinations. Steroids improved the symptoms but an increasing dosage of steroids was required. After the detection of Tropheryma whipplei and diagnosis of Whipple's disease the patient received ceftriaxon for a period of two weeks, subsequently cotrimoxazol for one year. Inflammatory activity decreased but unspecific symptoms remained almost unaffected.The differential diagnosis in patients with fever, elevated inflammatory markers and gastrointestinal symptoms must include Whipple's disease. A Tropheryma whipplei PCR from duodenal biopsies should be performed because of its higher sensitivity compared to histology alone.

Whipple's disease is a multisystemic infection caused by the ubiquitous bacterium Tropheryma whipplei. Immunological host factors enable classical Whipple's disease; however, T. whipplei can be found in three other clinical conditions: healthy colonization, self-limiting infections, and isolated endocarditis. The genetic predisposition of the host rather than the genotype of the bacterium influences the infection. Modern diagnostic methods elucidate the many facets of Whipple's disease. In particular, isolated T. whipplei-induced infective endocarditis can only be diagnosed after valve resection. The sole treatment of Whipple's disease evaluated prospectively comprises intravenous induction therapy with ceftriaxone or meropenem, followed by continuation therapy with oral TMP-SMX. In the case of Immune reconstitution inflammatory syndrome (IRIS) or inflammatory lesions of the CNS in the setting of Whipple's disease, additional treatment with corticosteroids should be considered to avoid severe tissue damage.

The diagnostic work-up in the case of a suspected cerebral involvement of Whipple's disease involves neuroimaging and analysis of cerebrospinal fluid (CSF) including polymerase chain reaction (PCR) assays for Tropheryma whipplei. As neurological findings may be complex and unspecific, extracerebral symptoms often lead to the suspicion of Whipple's disease. We report the cases of two patients in whom the suspected diagnosis of Whipple's disease could not be proved either by endoscopy or by the analysis of CSF. Only by means of a cerebral biopsy was the diagnosis assumed and specific therapy was initiated.

A 33-year-old woman with increasing back pain was referred to our hospital 8 years ago. As she had ankylosing sacroilitis and peripheral arthritis she was diagnosed as having ankolysing spondylitis with involvement of the peripheral joints. She recently developed persistent diarrhea, abdominal symptoms and weight loss.Laboratory findings revealed a chronic inflammatory disease. Infection of the gastrointestinal tract was excluded. Duodenal biopsy was normal on PAS staining, Tropheryma whipplei-DNA was detected by the polymerase chain reaction (PCR).Initially the patient was treated for 6 months with diclofenac and ibuprofen without improvement of her condition. As the spondylitis persisted, she was given anti-TNF-alpha treatment 7 years after the onset of symptoms. When Whipple's disease was diagnosed this treatment was stopped and antibiotics (ceftriaxone) was started and then continued with co-trimoxazole for one year with significantly improvement in her condition.In patients presenting with symptoms involving several organs, rare systemic diseases should be considered. If symptoms are typical of Whipple's disease, but duodenal biopsies are negative on PAS staining, a sensitive PCR assay may detect T. whipplei-DNA confirming this infection. Appropriate antibiotic treatment can then be initiated.

A 39-year-old man presented pronounced asthenia and diffuse myalgias 8 months after a vaccination against the tetanus toxoid. Muscle biopsy disclosed infiltration of the perimysium and endomysium by densely packed, PAS-positive macrophages. Tropheryma whippelii detection in blood and faeces allowed the initial assumption of atypical Whipple's disease with isolated muscle involvement. However, the histological detection of aluminium-containing macrophages by means of Morin stain immunofluorescence established the diagnosis of macrophagic myofascitis in an obviously asymptomatic T. whippelii carrier.

A 47-year-old dog breeder had suffered from unclassified polyarthritis for four years. During immunomodulatory therapy of an assumed seronegative chronic polyarthritis with Leflunomid and Adalimumab he developed severe systemic inflammatory disease with high fever, weight loss, and severe arthralgia. Fever and arthralgias temporarily improved under antibiotic therapy, although a causative organism had not been found. The clinical picture led to the differential diagnosis of Whipple's disease, but PAS-positive macrophages were not detected in duodenal biopsies. The diagnosis was finally based on a positive PCR result for Tropheryma whipplii, typical clinical symptoms and a complete response on adequate antibiotic long-term treatment with cotrimoxazol. The diagnosis of Whipple's disease was possibly masked by the initial antibiotic therapies. Therapies with immunomodulators, TNF-inhibitors, and corticosteroids may transform an infection with Tropheryma whipplii, normally in a subacute stage, into a septic, life-threatening disease.

A 67-year-old man with anemia was referred to our hospital. He had suffered from rheumatoid arthritis for ten years. Two months before admission he had been an inpatient at another hospital because of heart failure. He presented with edema, slightly elevated temperature and effusion in the right knee.Laboratory findings revealed a chronic inflammation and an anemia of iron malabsorption. Duodenal histology showed PAS-positive macrophages typical for Whipple's disease. Tropheryma whippelii-DNA was found by polymerase chain reaction (PCR) in synovial and cerebrospinal fluid and broncho-alveolar lavage.Antibiotic therapy was initiated, the antirheumatic medication terminated and iron was administered intravenously. The outcome was satisfactory.Rare systemic diseases should be considered in patients presenting with symptoms involving several organs. Whipple's disease can be cured only by adequate antibiotic therapy. The use of PCR facilitates the correct diagnosis.

Whipple's disease is a rare infectious disorder affecting mostly middle aged men. The causative organism, Tropheryma whipplei, recently has been cultivated and phylogenetically identified as an actinomycete. The rareness of the disease despite the ubiquitous occurence of T. whipplei presumably is related to a predisposing defect in cellular immunity. The diagnosis usually can be established by small bowel biopsy, but is frequently delayed due to protean clinical manifestations. The initiation of antibiotic treatment in most cases results in clinical remission, however, a significant number of patients is refractory to antimicrobial therapy or has a relapsing course.

Fever of unknown origin (FUO) is a rare but important disease. The definition of FUO has not changed in the last 50 years. Classical FUO is defined by an illness of at least 3 weeks duration with fever greater than 38 masculine C, and no established diagnosis after 1 week of hospital investigation. The causes of FUO can be divided in four categories: infectious diseases, noninfectious inflammatory diseases, neoplasms, and others (miscellaneous). Recent studies have surprisingly shown that despite improved diagnostic procedures the percentage of patients with FUO, in which no diagnosis after intensive investigations in specialized centres can be found, has increased. However, finding the correct diagnosis in FUO is essential for these patients for psychological and vital reasons. Therefore and because of economic reasons patients with FUO should be investigated in specialized centres with a department for rheumatology and infectious diseases.

The 68-year-old male patient complained of weight loss and -- since 15 years -- of arthralgias and had renal insufficiency and an aortic stenosis. Despite the lack of intestinal symptoms, M. Whipple could be diagnosed, being responsible for his symptoms and clinical signs. Under antibiotic and supportive treatment the patient recovered uneventfully.Whipple's disease, otherwise known as intestinal lipodystrophy, is a disease with various signs and symptoms. The principal signs are rheumatic complaints and weight loss. By contrast, there may be absolutely no gastrointestinal symptoms even at an advanced stage of the disease. The generally chronic clinical course of the disease may worsen acutely and may prove fatal. Symptoms frequently occur not simultaneously but successively. Diagnostically, it is crucial to consider the possibility of infection with Tropheryma whippelii primarily if the patient presents with multi-organ symptoms. The disease is easy to diagnose by taking bioptic samples endoscopically -- even in the absence of intestinal symptoms -- and antibiotic treatment is generally successful. However, permanent organic lesions must be anticipated.

A number of neurological symptoms have been described as complications of inflammatory bowel disorders such as coeliac disease, Whipple's disease, Crohn's disease and ulcerative colitis. The neurology of coeliac disease includes disorders of the central nervous system encompassing cerebellar ataxia, epilepsy, myoclonus, dementia and multifocal leukoencephalopathy. Peripheral neuropathies, of axonal and demyelinating types, and myopathies have also been reported. The pathomechanisms are more related to immunological-inflammatory processes than to a malresorptive vitamin deficiencies. While CNS symptoms of coeliac disease show a poor response to gluten restriction, peripheral symptoms may respond to elimination of gluten from the diet. There are few reports of a successful corticosteroid treatment in patients showing inflammatory findings in the CSF or bioptic material. Whipple's disease is caused by the gram-positive bacillus Tropheryma whipplei. Patients with a central nervous system manifestation of Whipple's disease may develop a variety of symptoms including dementia, supranuclear gaze palsy, movement disorders, hypothalamic dysfunction and myorhythmia. The CNS-infection is diagnosed by PCR of the CSF. Long-term antibiotic treatment is required, and relapses may occur after withdrawal of antimicrobial therapy. Crohn's disease and ulcerative colitis are complicated by various forms of polyneuropathies, and arterial and venous cerebrovascular diseases. In most cases with neurological complications of inflammatory gastrointestinal diseases an immune mediated inflammatory process is suspected to be the underlying pathomechanism.

Whipple's disease is a rare, without antibiotic treatment deadly systemic infectious disease caused by the ubiquitary Gram positive bacterium Tropheryma whipplei. The agent can be demonstrated by light and electron microscopy and by PCR in tissues and body fluids affected. Men are affected more often than women. Most patients lose weight, have diarrhea, abdominal pain and arthralgias. In 10-40% of cases involvement of the CNS, often asymptomatic, is observed. PAS-positive macrophages in the lamina propria of duodenal biopsies are typical but not pathognomonic of Whipple's disease. Nowadays, the infectious agent should also be demonstrated by PCR. Treatment, mostly as a sequential therapy, is with antibiotics that cross the blood-brain barrier and should last for at least 1 year in order to avoid relapses. Before ending therapy the absence of Tropheryma whipplei in duodenal tissue and cerebrospinal fluid must be confirmed.

6 years ago a 60-year-old man had been suffering from chronic diarrhea, weight loss and epigastric pain. Some years before he had developed joint pain, symmetric at both hands and feet. Duodenal biopsy and PCR reaction revealed Whipple's disease. Treatment with Co-trimoxazole for more than 21 months achieved remission. 6 years after diagnosis of Whipple's disease the patient presented with multilocal lymphadenopathy. Malignant Non-Hodgkin-Lymphoma (Centrocytom) stage PS IV b was diagnosed. COP-chemotherapy (Vincristine, Cyclophosphamide, Prednisone) achieved partial remission up to now. Whether the appearance of the malignant lymphoma is a consequence of Whipple's disease or a second neoplastic disease remains to be answered by further epidemiological studies.

Since the microbiological discovery of Tropheryma whippelii, Whipple's disease has attracted to new attention in clinical medicine. As small intestinal biopsy is the diagnostic procedure, the impact of knowledge about the histopathological features of Whipple's disease and its differential diagnosis has increased. PAS-positive macrophages in the intestinal mucosa are the diagnostic hallmark, but further subtyping of cells is important. In Whipple's disease macrophages with intensely PAS-positive granular particles in the cytoplasm (type 1) should be distinguished from cells with faintly PAS-positive cytoplasm without granular particles (type 3). The latter type of macrophages may persist even for many years but does not affect a diagnosis of intestinal remission. However, as systemic infection with T. whippelii is common, but intestinal biopsy specimens are not representative for other organs, additional investigations are performed. These include analysis of the cerebrospinal fluid by means of cytology and polymerase chain reaction, even in patients without neurological symptoms. For ascertaining eradication of T. whippelii in the cerebrospinal fluid, polymerase chain reaction is more reliable than cytology.

Whipple's disease has been diagnosed more frequently in recent years as a consequence of better awareness and of improved diagnostic tools. The number of case reports of Whipple's disease without gastrointestinal symptoms and without histological lesions of the intestinal mucosa is increasing. Therefore, the traditional perception of this disease as well as the methods for its diagnosis need to be revised. We report on 2 patients with Whipple's disease who had systemic inflammatory reactions but neither gastrointestinal symptoms nor an abnormal duodenal histology. Whipple's disease was diagnosed on the basis of extraintestinal tissue histology (lymph node, vertebral body) and by polymerase chain reaction, and was treated successfully with antibiotics. Recommendations for diagnostic procedure in Whipple's disease with both typical and atypical clinical presentation are discussed.

Whipple's disease is a rare systemic bacterial disease, affecting mostly middle-aged white men. Its clinical presentation is very variable. Arthralgias, fever of unknown origin or central nervous system symptoms may precede the more typical gastrointestinal manifestations with weight loss and chronic diarrhea. The diagnosis is based on the histopathologic demonstration of PAS-positive macrophages in duodenal or jejunal biopsies. In addition, it has become possible to detect the causative actinobacterium Tropheryma whippelii by amplification of a Whipple-specific PCR product. Therapeutic options are a sequential therapy with penicillin-streptomycin, followed by trimethoprim-sulfamethoxazole (TMP-SMX) or a monotherapy with TMP-SMX. These therapeutic modalities usually eradicate the infection and result in a rapid and sustained improvement of the Whipple-specific signs and symptoms. In view of the frequently uncharacteristic initial clinical presentation (arthralgias, fever, CNS symptoms), it is therefore of utmost importance to consider Whipple's disease in the differential diagnosis of the clinical signs and symptoms.

Whipple's disease is a rare infectious disease with systemic manifestation on different organs. In 1992 the typical rod-shaped bacillus was identified as a gram-negative actinomycete with distinctive morphologic characteristics and named as Tropheryma whippelii. The diagnosis is established by demonstrating the presence of PAS-positive macrophages in the mucosa, with large cytoplasmatic granules. We present two cases of Whipple's disease with different outcomes. Both were treated with the same antibiotics (penicillin/streptomycin). With this treatment one patient recovered completely. In a follow-up over 7 years no relapse occurred. The second patient died only 4 weeks after the diagnosis was established.

Whipple's disease is a systemic disease which may virtually affect any organ system, but in many cases it involves the small intestine causing gastrointestinal symptoms. The differential diagnosis is difficult since symptoms may be nonspecific. We report the case of a 44-year old white male patient with a history of migrating arthralgia and chronic fatigue. The patient newly developed an uveitis and underwent a vitrectomy; the further clinical work-up including gastroscopy with intestinal biopsy revealed no sufficient diagnosis. Subsequently, the patient's condition deteriorated with marked weight loss, fever and progressive weakness. An anaerobic sepsis with a corynebacterium was confirmed and with i.v.-antibiotics the patients's condition improved markedly. The further examinations disclosed enlarged mesenteric lymph nodes and the involvement of other organs (endocard, liver). CT-guided biopsy only showed fatty degeneration, but operative adenectomy confirmed Whipple's disease. The patient remained without relapse on long-term antibiotic treatment with doxycycline until today. Obviously, in our case the intestinal biopsies failed to detect Whipple's disease after the successful initiation of antibiotic treatment. In the absence of gastrointestinal findings and with concomitant secondary diseases the definitive diagnosis can be difficult. In addition, the previous uveitis and the endocardial involvement are most interesting.