The clinical presentation of Whipple disease includes classical signs of arthralgia, polyarthritis, fever and gastrointestinal complains. The gastrointestinal disturbances are manifested later and include abdominal pain, diarrhea, malabsorption, anorexia and weight loss. Steatorrhea and gastrointestinal bleeding follow, when the infection spreads to small intestine. In cases when the disease is left untreated or not treated completely, the central nervous system becomes affected in the later stage. The CNS signs are demonstrated as dementia, ataxia, meningoencephalitis, myoclonus and tinnitus [9] [10]. Other findings that may be present include lympadenopathy, increased skin pigmentation, splenomegaly, anemia, cough and hypotension. Rarely, the illness may affect the heart resulting in the development of congestive heart failure and pericarditis. 

• Weight Loss

  We report the case of a 38-year-old man who presented with severe diarrhea, weight loss of 10 kg, ankles paresthesia and severe motor weakness in the left fibular nerve territory after introduction of azathioprine and corticosteroid for proteinuria. [ncbi.nlm.nih.gov]

  The clinical manifestations typically involve abdominal pain, intestinal malabsorption, diarrhea, weight loss and arthralgia. [symptoma.com]

  The disorder is characterized clinically by arthralgia, abdominal pain, diarrhea, malabsorbtion and progressive weight loss. [doi.org]

  The four cardinal symptoms of Whipple disease are Arthralgia Diarrhea Abdominal pain Weight loss Usually, the first symptoms are arthritis and fever. [merckmanuals.com]

• Fever

  We report the case of a man with a history of intermittent fever and arthritis who presented with a dry cough and associated lung involvement, who was eventually given the diagnosis of Whipple disease. [ncbi.nlm.nih.gov]

  The clinical presentation of Whipple disease includes classical signs of arthralgia, polyarthritis, fever and gastrointestinal complains. [symptoma.com]

• Anemia

  He underwent esophagogastroduodenoscopy and jejunal biopsy for evaluation of anemia. The posterior uveitis was treated with a subtenon injection of triamcinolone. [ncbi.nlm.nih.gov]

  This will help determine if you have a low count of red blood cells and low amounts of albumin, which are both signs of anemia. Anemia is an indication that you might have Whipple’s disease. [healthline.com]

  It can affect any part of the body, leading to arthritis and then weight loss, cough, fever, diarrhea, hypotension ( low blood pressure ), abdominal swelling, increased skin pigmentation, and severe anemia. [medicinenet.com]

• Weakness

  A previously healthy male with subacute onset right leg weakness was suspected to have an astrocytoma as imaging showed a lesion. [ncbi.nlm.nih.gov]

  Gastrointestinal symptoms may include diarrhea, weight loss, fatigue, weakness, and abdominal bleeding and pain. Fever, cough, anemia, heart and lung damage, darkening of the skin, and joint soreness may also be present. [my.clevelandclinic.org]

• Lymphadenopathy

  However, peripheral lymphadenopathy as the sole clinical manifestation of Whipple disease is rare. We describe 2 patients with Whipple disease whose initial manifestation was lymphadenopathy. [ncbi.nlm.nih.gov]

  The following symptoms are frequent but not necessarily observed in each patient: weight loss, polyarthritis, diarrhea/malabsorption, fever, lymphadenopathy, cardiac valvular disease, culture-negative endocarditis, pleuritis, ocular inflammatory disease [orpha.net]

  There may also be: Generalised lymphadenopathy. Anaemia and, more rarely, clotting abnormalities. Cardiac involvement - pericarditis, myocarditis, valve lesions. [patient.info]

• Chronic Cough

  Chronic cough. Fat accumulation in the intestine, mesenteric lymph nodes and stool. [patient.info]

  Other findings include increased skin pigmentation, anemia, lymphadenopathy, chronic cough, serositis, peripheral edema, and CNS symptoms. [merckmanuals.com]

  cough chest pain pericarditis—inflammation of the membrane surrounding the heart heart failure Neurologic symptoms occur in some people diagnosed with Whipple’s disease and can mimic symptoms of almost any other neurologic condition. [gastronaples.com]

  Chronic cough. Problems affecting the eyes. Enlarged lymph nodes. Fatty stools. Gastrointestinal bleeding. Complications of Whipple’s disease If left untreated, Whipple’s disease can cause severe complications, including: Brain damage. [medic8.com]

• Pleural Effusion

  The association of mediastinal adenopathy or pleural effusion offers additional concern. Whipple disease may be fatal in the absence of treatment, but prolonged antibiotic treatment often leads to complete remission. [ncbi.nlm.nih.gov]

  Fluid may collect in the space between the pleural layers (a condition called pleural effusion ). The lymph nodes may become enlarged. In some people, the skin becomes darker. People with Whipple disease may develop heart murmurs. [merckmanuals.com]

  Pulmonary involvement - pleural effusion, mediastinal widening (due to lymphadenopathy). Protein-losing enteropathy with hypoalbuminaemia and oedema (due to protein loss). [patient.info]

  Thus the stool analysis showing increased fecal fat (i.e. malabsorption) is a pointer towards Whipple's disease; the hypoalbuminemia coupled with examination findings of peripheral edema and bilateral pleural effusions provide further supportive evidence [prognosisapp.com]

• Diarrhea

  In the presentation, the relevance of WD in the differential diagnosis of chronic diarrhea and the new findings of this enigmatic rare disorder will be discussed. [ncbi.nlm.nih.gov]

  Signs and symptoms [ edit ] The most common symptoms are diarrhea, abdominal pain, weight loss, and joint pains. [en.wikipedia.org]

  The clinical manifestations typically involve abdominal pain, intestinal malabsorption, diarrhea, weight loss and arthralgia. [symptoma.com]

  Evaluation of Chronic Diarrhea: AAFP, 2011 [prognosisapp.com]

  The disorder is characterized clinically by arthralgia, abdominal pain, diarrhea, malabsorbtion and progressive weight loss. [doi.org]

• Abdominal Pain

  The clinical manifestations typically involve abdominal pain, intestinal malabsorption, diarrhea, weight loss and arthralgia. [symptoma.com]

  The disorder is characterized clinically by arthralgia, abdominal pain, diarrhea, malabsorbtion and progressive weight loss. [doi.org]

  Migratory arthralgias and gastrointestinal problems, including malabsorption, abdominal pain, diarrhea, and weight loss, are common presenting symptoms. [ncbi.nlm.nih.gov]

  The four cardinal symptoms of Whipple disease are Arthralgia Diarrhea Abdominal pain Weight loss Usually, the first symptoms are arthritis and fever. [merckmanuals.com]

• Chronic Diarrhea

  In the presentation, the relevance of WD in the differential diagnosis of chronic diarrhea and the new findings of this enigmatic rare disorder will be discussed. [ncbi.nlm.nih.gov]

• Steatorrhea

  Chronic malabsorptive diarrhea may also develop and lead to steatorrhea. Symptoms of steatorrhea include fatty, offensive smelling stool; abdominal distention; and flatulence. [disability-benefits-help.org]

  SX: Most commonly diarrhea and malabsorption (steatorrhea) ; but other symptoms include fever, abdominal distention, weakness, fatigue, and weight loss. [enotes.tripod.com]

  Chronic malabsorptive diarrhea leads to the poor absorption of fat, causing steatorrhea (fatty, offensive-smelling stool), flatulence, and abdominal distension. [en.wikipedia.org]

  Cardinal Findings: Diarrhea, steatorrhea, weight loss, fever, arthritis, serositis, and lymphadenopathy are seen. Arthralgia or arthritis frequently precedes the intestinal features. [rheumaknowledgy.com]

• Loss of Appetite

  Symptoms include diarrhea, intestinal bleeding, abdominal pain, loss of appetite, weight loss, fatigue, and weakness. Arthritis and fever often occur several years before intestinal symptoms develop. [wakegastro.com]

  The four main symptoms of Whipple disease are Inflamed and painful joints Diarrhea Abdominal pain Weight loss Other common symptoms are fever, loss of appetite, fatigue and weakness caused by anemia, cough, and pain when breathing caused by inflammation [merckmanuals.com]

  Some of the side effects of this combination of medications are loss of appetite, nausea, vomiting and photosensitivity. [epainassist.com]

  Loss of appetite. Fatigue. Diarrhoea. Fever. Abdominal pain. Changes in the colour of the skin. Confusion and memory loss. Flatulence. Bloating. Chronic cough. Problems affecting the eyes. Enlarged lymph nodes. Fatty stools. [medic8.com]

  A wide range of symptoms may result, including: Weakness Darkened skin Fatty or bloody stools Loss of appetite Enlarged lymph nodes Vision problems Memory problems Facial numbness Muscle weakness and difficulty walking Joint stiffness Hearing problems [everydayhealth.com]

• Hyperpigmentation

  The first presented with melena and generalized hyperpigmentation. The second had depression for two years before the typical symptoms. Both hyperpigmentation and long-lasting depression without the typical manifestations of the disease are rare. [ncbi.nlm.nih.gov]

  However, this patient's examination reveals a valuable clue which helps short-circuit the diagnostic pathway: the presence of generalized hyperpigmentation. [prognosisapp.com]

  Symptoms of Whipple’s Disease Include: Diarrhea Abdominal cramping Pain in the abdomen, worsening after eating Weight loss Joint inflammation Fatigue Weakness Anemia Fever Cough Enlargement of lymph nodes Hyperpigmentation of the skin Chest pain Splenomegaly [epainassist.com]

  […] affects proximal intestine, mesenteric lymph nodes Also called intestinal lipodystrophy Usually white males ages 30 - 49 years Symptoms: Malabsorption with diarrhea, weight loss, abdominal pain Occasionally polyarthritis, CNS complaints, lymphadenopathy, hyperpigmentation [pathologyoutlines.com]

  The patient may also present with lymphadenopathy, hyperpigmentation and polyarthritis. Sites affected: Intestine, central nervous system, joints, lymphnodes, lungs and heart. [histopathology-india.net]

• Purpura

  Hyperpigmentation – due to pellagra or niacin (vitamin B3) deficiency, B12 deficiency or low cortisol levels Petechia or purpura – due to vitamin C or vitamin K deficiency Secondary palmoplantar keratoderma or ichthyosis – due to cholesterol deficiency [dermnetnz.org]

• Arthritis

  In the historical presentation, weight loss and diarrhoea are the most common symptoms and are preceded in three-quarters of cases by arthritis for a mean of six years. [ncbi.nlm.nih.gov]

  Whipple's arthritis: direct detection of Tropheryma whippelii in synovial fluid and tissue. Arthritis Rheum. 1999 Apr. 42(4):812-7. [Medline]. Celard M, de Gevigney G, Mosnier S, et al. [emedicine.com]

  The clinical presentation as inflammatory arthritis often leads to a misdiagnosis of spondyloarthritis, rheumatoid arthritis, or gouty arthritis [ 3 – 5 ]. [ojrd.biomedcentral.com]

  Cardinal Findings: Diarrhea, steatorrhea, weight loss, fever, arthritis, serositis, and lymphadenopathy are seen. Arthralgia or arthritis frequently precedes the intestinal features. [rheumaknowledgy.com]

• Arthralgia

  His recent symptoms included persistent fatigue, weight loss, fever, and arthralgias. [ncbi.nlm.nih.gov]

  The disorder is characterized clinically by arthralgia, abdominal pain, diarrhea, malabsorbtion and progressive weight loss. [doi.org]

• Back Pain

  pain there was no radiological evidence of spinal lesions. [pmj.bmj.com]

  Patient 5 was a 48-year-old white man with a history of diarrhea, back pain, arthralgias, uveitis, abdominal pain, and weight loss. [doi.org]

• Migratory Polyarthritis

  Introduction IN 1907, George Whipple reported a "hitherto undescribed disease" in a 36-year-old medical missionary with migratory polyarthritis, cough, diarrhea, malabsorption, weight loss, and mesenteric lymphadenopathy. 1 He named this disease "intestinal [doi.org]

• Joint Swelling

  Finally, because of inadequate treatment response and persistent joint swelling arthrocentesis was performed in six patients and analysis yielded a positive TW PCR in all. [ojrd.biomedcentral.com]

• Psychiatric Manifestation

  Patients with central nervous system (CNS) involvement may present in a variety of ways, including cognitive impairment, psychiatric manifestations, gaze palsies, upper motor neuron signs, and hypothalamic dysfunction. [link.springer.com]

  Patients may present in a variety of ways, including cognitive impairment, psychiatric manifestations, gaze palsies, upper motor neurone signs and hypothalamic dysfunction. [jmedicalcasereports.com]

• Headache

  We report a 54-year-old woman who presented subacutely with fever, headache, and seizures that led to a diagnosis of infectious meningoencephalitis. [ncbi.nlm.nih.gov]

  The most common symptoms of Whipple's disease are: diarrhea abdominal pain weight loss malabsorption edema Neurological symptoms may include: headaches, and vision problems memory problems and dementia muscle weakness or twitching Although not covered [ddc.musc.edu]

  Central nervous system (CNS) involvement in 10% - headache, confusion, dementia, ophthalmoplegia, myoclonus, oculomasticatory movements (convergent eye movements with simultaneous chewing movements), gait abnormalities, seizures, coma. [patient.info]

• Seizure

  The onset was characterized by a short-term amnesic syndrome for several months before the onset of generalized tonic-clonic seizures. Her amnesia was stable throughout her illness. [ncbi.nlm.nih.gov]

  Cognitive changes, supranuclear gaze palsy, altered consciousness, myoclonus, seizures, and ataxia occur. Oculomasticatory myorhythmia and oculofacioskeletal myorhythmia are pathognomonic signs. Isolated Whipple disease also mimics glioma. [medlink.com]

• Confusion

  Other important sites of infection include the heart (resulting in the clinical picture of endocarditis and heart failure) and the central nervous system (CNS) (manifestations include confusion, memory loss, focal cranial nerve signs, nystagmus and ophtalmoplegia [doi.org]

  We describe a patient with cerebral Whipple disease who presented with changes in mental status, confusion, inverse sleep-wake cycle, bilateral ptosis and vertical gaze palsy. [ncbi.nlm.nih.gov]

• Asthenia

  Half of patients are asymptomatic, and in the rest it can manifest as a malabsorption syndrome (diarrhea, abdominal pain, asthenia, and weight loss) (16,17). [scielo.isciii.es]

  We report the case of a 61-year-old male patient who presented to emergency room complaining of asthenia, arthralgia, anorexia, articular complaints intermittent diarrhea, and a 10-kg weight loss in one year. [scielo.br]

• Apathy

  System Manifestation Tropheryma Whipplei Recurrent Central Nervous System Introduction Whipple's disease (WD) is a rare condition caused by infection with Gram-positive bacilli ( Tropheryma whipplei ) characterised by fever, diarrhoea, arthropathy, apathy [jmedicalcasereports.com]

The most specific test for making an accurate diagnosis of Whipple disease is the determination of the presence of the bacterium Tropheryma whipplei DNA by polymerase chain reaction (PCR) [11]. Through this test, DNA of the bacteria is easily detected, but it is not available universally. In clinical settings, tissue biopsy of the affected organ along with identification of signs and symptoms specific to the disease, aid in making an appropriate diagnosis. Patients presenting with intestinal symptoms are diagnosed after tissue biopsy of the small instestine in which PAS positive macrophages with disrupted villi structure are observed under microscopic examination. Certain screening tests such as laboratory examination of stool, serum albumin, prothrombin time and serum carotene and imaging studies such as CT scan are helpful in determining the presence of malabsorption. A stereotactic brain biopsy is required in cases when the patients present with CNS signs. 

• Thrombocytosis

  Regarding laboratory findings, hypochromic anemia, limphocytopenia, thrombocytosis, increased C-reactive protein levels, vitamin deficiency, or indirect signs of malabsorption are all possible (7). [scielo.isciii.es]

• Tropheryma Whipplei

  tropheryma whipplei, immunology, pathogenesis, clinical features, therapy Abstract: Whipples disease (WD) is a rare chronic infectious disorder caused by the rod- shaped bacterium Tropheryma whipplei. [doi.org]

  Genotyping reveals a wide heterogeneity of Tropheryma whipplei. Microbiology. 2008; 154 :521–527. [ PubMed ] [ Google Scholar ] 21. [ncbi.nlm.nih.gov]

  Tropheryma whipplei infection (Whipple's disease) in a patient after liver transplantation. Transpl Infect Dis. 2016 Aug. 18(4):617-24. [Medline]. Tabuas-Pereira M, Vicente M, Coelho F, Santana I. [emedicine.com]

• Pleural Effusion

  The association of mediastinal adenopathy or pleural effusion offers additional concern. Whipple disease may be fatal in the absence of treatment, but prolonged antibiotic treatment often leads to complete remission. [ncbi.nlm.nih.gov]

  Fluid may collect in the space between the pleural layers (a condition called pleural effusion ). The lymph nodes may become enlarged. In some people, the skin becomes darker. People with Whipple disease may develop heart murmurs. [merckmanuals.com]

  Pulmonary involvement - pleural effusion, mediastinal widening (due to lymphadenopathy). Protein-losing enteropathy with hypoalbuminaemia and oedema (due to protein loss). [patient.info]

  Thus the stool analysis showing increased fecal fat (i.e. malabsorption) is a pointer towards Whipple's disease; the hypoalbuminemia coupled with examination findings of peripheral edema and bilateral pleural effusions provide further supportive evidence [prognosisapp.com]

Whipple disease, being a chronic infectious disease, requires prompt and aggressive antibiotic therapy and appropriate follow up tests to achieve complete remission and prevent relapse. The disease can be life threatening if not treated, but once treated correctly, the disease is cured completely. Treatment of Whipple disease requires long term antibiotic therapy up to 1 year because the disease tends to relapse on short courses.

Currently, the disease is initially treated with intravenous administration of ceftriaxone (2g once daily dosing) or intavenous administration of penicillin G (2-4 million units every 4 hours) for about 2-4 weeks. The regimen is followed by prolonged peroral administration of trimethoprim-sulfamethoxazole (160/800mg every 12 hours) for one year. In cases when the patient is allergic to sulfa drugs, penicillin G may be substituted with penicillin V or ampicillin. Trimethoprim-sulfamethoxazole may be alternatively replaced with oral administration of doxycyline (100mg every 12 hours) and hydroxychloroquine (200mg every 8 hours) if the patient is allergic to sulfamethoxalone or is resistant to the drug. Following treatment, most of the clinical signs of the disease are resolved within few days with eradication of intestinal symptoms in less than 4 weeks [12] [3].

In patients presenting with malabsorption, a supportive treatment with nutrition therapy is recommended to make up for the nutrient loss by the body. Typically, intravenous administration of fluids and electrolytes, supplementation with iron, folate, calcium and vitamin D and a diet rich in calories and protein are required. 

Whipple disease can proceed to life threatening situations in patients who are incorrectly diagnosed or receive a poor treatment and if left untreated, the mortality rate approaches to 100% within a year after development of the infection [6] [7] [8]. Although potentially fatal, the disease can be cured completely and long lasting remission can be achieved with a good prognosis if correctly diagnosed on time and treated adequately with long term antibiotic therapy. Treatment of Whipple disease typically lasts for a year with eradication of extraintestinal symptoms within few days following treatment whereas symptoms related to gastrointestinal tract disturbances and malnutrition are resolved within two to three months of treatment. Relapses during and after treatment are common in Whipple disease and 30-40% patient may relapse after treatment. In cases when the disease is spread to the CNS, prompt and vigorous treatment with antibiotics is required over a long period of time in order to achieve clinical remission and to prevent relapse in future. It is advisable to monitor patient's response to treatment during therapy and tissue biopsy is recommended after a year following treatment to assure good prognosis and prevent disease recurrence.

Tropheryma whipplei, a rod-shaped bacterium belonging to Actinomyecetes order, is the causative organism of Whipple disease. The bacterium is typically found in soil and enters the host body through oral route. 

The rod shaped structure of the bacterium was first identified in 1961, but it was not until 1991 when the bacterium was found to possess a unique structural appearance. It was recognized as the sole organism responsible for causing the infection. Once it enters the host cell, the infection develops when the bacterium causes the body to produce an abnormal host response to a frequently occuring microorganism [2] [3]. 

Since Whipple disease is an exceptionally rare systemic illness, not much is known about its epidemiology. To date, only small number of cases has been reported. The disease has mostly been diagnosed in middle-aged and elderly men belonging to North American and European countries with incidence estimation of less than 1 per 1,000,000 [4] [5]. Comparatively, the disease is more predominant in males with an approximate male to female ratio of 4:1. 

The rod-shaped bacilli, after entering the body, invade various body tissues and incorporate into tissue macrophages which results in the disordered immune response. Once the lamina propria of the small bowel is infiltrated by the bacteria, the normal function of villi becomes disrupted which is clinically manifested as intestinal malabsorption. Although intestinal tissues are found to be invaded most often, other organs may also present with similar findings including peripheral and mesenteric lymph nodes. 

When observed microscopically, the histopathological findings of tissue macrophages infiltered with T whipplei are to be positive on perdiodic acidSchiff (PAS) staining. The characteristic histopathological features with PAS-positive macrophages act a marker in establishing diagnosis of the disease following biopsy of the infected tissues [1].

Patients should be checked for response to antibiotic therapy during and after the treatment.  It is advisable to conduct tissue biopsy of the affected organ 1 year after treatment to assure that T whipplei are no longer present. The disease may take up to two years to heal completely [3].

Whipple disease, formerly known as intestinal lipodystrophy, is an extremely rare infectious disease caused by the bacterium Tropheryma whippelii, developing predominantly in middle-aged Caucasian men above 40 years of age. The disease is systemic in nature and can affect any organ system, although, it usually involves the gastrointestinal tract, heart and central nervous system. The clinical manifestations typically involve abdominal pain, intestinal malabsorption, diarrhea, weight loss and arthralgia. Diagnosis is based on assessment of patient's signs and symptoms based on clinical examination, tissue biopsy, certain screening tests and in some cases, imaging studies. Treatment of Whipple disease involves long term antibiotic therapy, measurement of patient's response to treatment and follow up tests to assure that the infection is being eradicated completely and to prevent relapse in future. [1] [3].

Whipple disease is a rare illness resulting from bacterial infection by the organism Tropheryma whipplei. It is found in soil and people working with soil and sewage are prone to suffer from this disease. The disease is common in middle-aged white men above 30 years of age belonging to North American or European ethnic background. The organism Tropheryma whipplei damages internal linings of different organs of body such as intestine, joints, brain, eyes and heart. Common symptoms of the disease are abdominal pain, diarrhea, painful joints, weight loss and fever. Whipple disease is diagnosed by tissue biopsy of affected organs in which the bacteria are observed under microscope. The disease is serious and progressively fatal if left untreated or not treated correctly. If treated promptly, it is completely cured. Treatment requires administration of antibiotic injections of ceftriaxone or penicillin initially and later the antibiotic trimethoprim-sulfamethoxazolne taken by mouth for 1 year. Most of the symptoms of the disease are subsided within few weeks of antibiotic treatment. The treatment also requires administration of vitamins, minerals, iron and fluids because of the presence of malabsorption. Patients are advised to schedule routine follow-ups with their doctor during and after treatment as the disease can relapse after treatment. Those patients who follow treatment regimen completely and go for regular follow-ups, tend to have good outcomes. 

1. Relman DA, Schmidt TM, MacDermott RP, et al. Identification of the uncultured bacillus of Whipple's disease. N Engl J Med. 1992;327(5):293-301.
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