Dear Label_Name,

Greetings! I hope you are well.

I am writing on behalf of an international publishing house, Science and Education Publishing, USA (http://www.sciepub.com).

Science and Education Publishing (SciEP) is a multidisciplinary open access publisher of Journals covering the fields of Science, Technology and Medicine. All SciEP publications are subject to high-quality peer review, editorial and production processes and are freely available online.

Welcome to the April, 2013 edition of SciEP newsletter, providing monthly summaries of articles on science & education related topics of interest to scientist and professionals. The mission of our journals is to provide an open access forum for publishing new findings on issues pertinent to scientific and academic field. We also invite you to submit original research papers, review articles, short reports, or case studies are considered for publication in our Multidisciplinary Journals.

American Journal of Public Health Research
DOI: 10.12691/ajphr-1-1-3

The Implementation of a Tele-Homecare System with Service Oriented Architecture and HL7 Message Transmission Standard
Ching-Sung Wang

American Journal of Medical and Biological Research
DOI: 10.12691/ajmbr-1-1-2

The Influence of Ethanol on Pyruvate Kinases Activity in Vivo, in Vitro, in Silico
Lelevich Sergey Vladimirovich, Khrustalev Vladislav Victorovich, Barkovsky Eugene Victorovich, Shedogubova Tatyana Aleksandrovna

American Journal of Medical Sciences and Medicine
DOI: 10.12691/ajmsm-1-1-1

Clinical and Histological Features in Wegener Granulomatosis
Li Cavoli Gioacchino, Passantino Rita, Bono Luisa, Tortorici Calogera, Ferrantelli Angelo, Giammarresi Carlo, Rotolo Ugo

American Journal of Infectious Diseases and Microbiology
DOI: 10.12691/ajidm-1-1-2

The Curse of Lymphatic Filariasis: Would the Continual Use of Diethylcarbamazine Eliminate this Scourge in Papua New Guinea?
Anne Lanham, Lillian Mwanri

We have released issues of some journals on February 2013.
American Journal of Public Health Research
American Journal of Medical Sciences and Medicine
American Journal of Medical and Biological Research
American Journal of Pharmacological Sciences
American Journal of Clinical Medicine Research
American Journal of Nursing Research
American Journal of Cancer Prevention
American Journal of Medicine Studies
American Journal of Infectious Diseases and Microbiology
American Journal of Cardiovascular Disease Research
American Journal of Biomedical Research
American Journal of Mechanical Engineering
American Journal of Microbiological Research
Journal of Preventive Medicine
American Journal of Food and Nutrition
American Journal of Hypertension Research
American Journal of Sports Science and Medicine
Journal of Cancer Research and Treatment
American Journal of Zoological Research
Journal of Biomedical Engineering and Technology
American Journal of Microbiological Research
Biomedical Science and Engineering

We are pleased to announce that submissions are now being accepted for peer review for all the journals across all our subject areas in SciEP.

Please submit your manuscript via our online submission system:
http://www.sciepub.com/author/signin

To unsubscribe from our mailing list, please click on the following link: unsubscribe

I am looking forward to hearing from you.

Kind regards,

David Rain
Email:join@sciepub.com
Science and Education Publishing (http://www.sciepub.com)

Label_Title

Dear Label_Name,

Greetings! I hope you are well.

I am writing on behalf of an international publishing house, Science and Education Publishing, USA (http://www.sciepub.com).

Science and Education Publishing (SciEP) is a multidisciplinary open access publisher of Journals covering the fields of Science, Technology and Medicine. All SciEP publications are subject to high-quality peer review, editorial and production processes and are freely available online.

Welcome to the April, 2013 edition of SciEP newsletter, providing monthly summaries of articles on science & education related topics of interest to scientist and professionals. The mission of our journals is to provide an open access forum for publishing new findings on issues pertinent to scientific and academic field. We also invite you to submit original research papers, review articles, short reports, or case studies are considered for publication in our Multidisciplinary Journals.

American Journal of Public Health Research
DOI: 10.12691/ajphr-1-1-3

The Implementation of a Tele-Homecare System with Service Oriented Architecture and HL7 Message Transmission Standard
Ching-Sung Wang

American Journal of Medical and Biological Research
DOI: 10.12691/ajmbr-1-1-2

The Influence of Ethanol on Pyruvate Kinases Activity in Vivo, in Vitro, in Silico
Lelevich Sergey Vladimirovich, Khrustalev Vladislav Victorovich, Barkovsky Eugene Victorovich, Shedogubova Tatyana Aleksandrovna

American Journal of Medical Sciences and Medicine
DOI: 10.12691/ajmsm-1-1-1

Clinical and Histological Features in Wegener Granulomatosis
Li Cavoli Gioacchino, Passantino Rita, Bono Luisa, Tortorici Calogera, Ferrantelli Angelo, Giammarresi Carlo, Rotolo Ugo

American Journal of Infectious Diseases and Microbiology
DOI: 10.12691/ajidm-1-1-2

The Curse of Lymphatic Filariasis: Would the Continual Use of Diethylcarbamazine Eliminate this Scourge in Papua New Guinea?
Anne Lanham, Lillian Mwanri

We have released issues of some journals on February 2013.
American Journal of Public Health Research
American Journal of Medical Sciences and Medicine
American Journal of Medical and Biological Research
American Journal of Pharmacological Sciences
American Journal of Clinical Medicine Research
American Journal of Nursing Research
American Journal of Cancer Prevention
American Journal of Medicine Studies
American Journal of Infectious Diseases and Microbiology
American Journal of Cardiovascular Disease Research
American Journal of Biomedical Research
American Journal of Mechanical Engineering
American Journal of Microbiological Research
Journal of Preventive Medicine
American Journal of Food and Nutrition
American Journal of Hypertension Research
American Journal of Sports Science and Medicine
Journal of Cancer Research and Treatment
American Journal of Zoological Research
Journal of Biomedical Engineering and Technology
American Journal of Microbiological Research
Biomedical Science and Engineering

We are pleased to announce that submissions are now being accepted for peer review for all the journals across all our subject areas in SciEP.

Please submit your manuscript via our online submission system:
http://www.sciepub.com/author/signin

To unsubscribe from our mailing list, please click on the following link: unsubscribe

I am looking forward to hearing from you.

Kind regards,

David Rain
Email:join@sciepub.com
Science and Education Publishing (http://www.sciepub.com)

Whipple’s Disease and Its Intestinal Mucosal Mimics

Hugh James Freeman*, James Gray

Department of Medicine (Gastroenterology), University of British Columbia, Vancouver, BC, Canada

Abstract: Recently, a male patient, presented to multiple medical specialties that eventually led to development of diarrhea and weight loss followed by eventual review by a gastroenterologist and a specific diagnosis of Whipple’s disease, a systemic disorder first described more than a century ago, but only recently recognized to be caused by Tropheryma whipplei. In this report, an updated review of this apparently very rare clinical disorder was done, including studies permitting a specific diagnosis of this disorder along with exclusion of other intestinal mucosal disorders that may potentially mimic Whipple’s disease.

Keywords: Whipple’s disease, Tropheryma whipplei, periodic acid Schiff positive macrophages, Mycobacterium avium-intracellulare. small intestinal malabsorption

Received July 27, 2023; Revised August 28, 2023; Accepted September 04, 2023

Citation: Hugh James Freeman, James Gray, Whipple’s Disease and Its Intestinal Mucosal Mimics. International Journal of Celiac Disease, 11 (1). 32-35. January 2023. doi:10.12691/ijcd-11-1-7

1. Case Review

A 59 year old Caucasian male developed intermittent, but increasingly severe and generalized joint pain without swelling or joint redness approximately 3 years earlier. In the past year, however, the joint pains increased in severity to the degree that he was virtually housebound. He was initially diagnosed with a “non-specific inflammatory arthritis” and was treated sequentially with a variety of agents. These included hydroxychloroquine, methotrexate, leflunomide, tocilizumab, and prednisone. There was no clinical response. During the past year, his appetite became limited accompanied by weight loss of 15 kg. An unexplained deep venous thrombosis developed. He also developed diarrhea with 5 to 6 loose watery and non-bloody stools daily. He reported poor memory and a generalized tremor. There was no family history of intestinal or joint symptoms. There was no travel history.

Over the 3 years since the onset of symptoms, he was seen in consultation by 2 rheumatologists, 2 hematologists, a neurologist, an ophthalmologist, and, most recently, a gastroenterologist.

Several studies were done revealing a mild anemia, normal white blood count, elevated C-reactive protein (i.e., 68), normal liver chemistry tests and protein electrophoresis. Serological studies for human immunodeficiency virus (HIV) were negative along with a bone marrow biopsy. Fecal studies were negative for routine bacteria, parasites and Clostridium difficile while imaging studies included normal chest radiographs, echocardiogram, computerized abdominal tomograms, except for splenomegaly. Upper GI endoscopy and colonoscopy were macroscopically normal, but biopsies from the duodenum and terminal ileum showed the presence of easily recognizable “foamy” macrophages were positive on Grocott silver and digested periodic acid Schiff (PAS) staining for Tropheryma whipplei. Acid fast staining for Mycobacterium were negative. Confirmatory PCR testing was positive.

He was subsequently treated with antibiotics and, within 2 weeks, his gasrointestinal and joint symptoms were markedly improved. A one-year course of antimicrobials is anticipated.

2. Introduction

Whipple’s disease, initially described in 1907, as a rare chronic intestinal disease with systemic features caused by Tropheryma whipplei. The causative organism, however, was only identified in 1992 [1] as a unique 1321-base bacterial 16S ribosomal RNA (rRNA) sequence using a frozen endoscopic duodenal biopsy from a patient with Whipple’s disease. This was later confirmed using the same polymerase chain reaction (PCR) method in other tissues from 5 other patients with Whipple’s disease [1]. Actual cultivation of the organism in vitro was only first reported in 2000 [2], almost an entire century after the first clinical description of the disease. Later, genome sequencing and antibiotic sensitivity testing were done [3] [4] [5] [6]. A PCR assay was first used for diagnosis in small intestinal biopsies in 1996 [7] with more precise disease monitoring [8].

Whipple’s disease is a systemic disease and, as in our case, may mimic a wide spectrum of disorders in multiple systems. In spite of this widespread involvement, only an estimated 1500 cases have been reported in the literature, and most expert clinicians have never seen even a single case in their entire professional careers, including gastroenterologists [9].

Whipple’s disease usually (but, not exclusively) affects mainly middle-aged Caucasian males leading to weight loss, arthralgia, diarrhea, steatorrhea and abdominal pain. Unusual presentations may occur with involvement of the heart (particularly valves), lungs and central nervous system (including cognitive decline and dementia). However, in a recent epidemiological evaluation from North America, men and women had similar rates [10]. In addition, children as young as 4 years have been described [11]. Interestingly, a German report showed an increasing proportion of women over the 30 year course of the study suggesting that the true prevalence has been increasing in females or, alternatively, the disease has been historically under-diagnosed in women [12]. In North America, older age over 65 years was associated with increased risk of Whipple’s disease [10]. A number of factors may play a role in this increased risk in the elderly including increased antibiotic exposure and increased immune dysfunction with aging. A more recent study of risk factors in hospitalized inpatients from the United States suggested a mean age over 60 years, disproportionately affecting elderly males with heterogeneous clinical presentations and a high mortality associated with central nervous system involvement [13].

The responsible agent is bacilliform or rod-shaped with different ultrastructural forms involving both cells and extra-cellular spaces [14] [15]. Lamina propria “foamy” macrophages in the small intestine (with PAS-positive particles, including duodenum, jejunum, ileum) and lymphatic drainage may be affected, often with obstruction and extensive deposits of extracellular lipids (leading to so-called “intestinal lipodystrophy”). As well, epithelial cells (with reduced microvilli) and immune cells may be involved. Occasionally, liver, esophagus, stomach and colon may be affected [16]. Intestinal symptoms (including diarrhea and weight loss) in Whipple’s disease due to Tropherma whipplei are not specific. These may occur in other diseases, including Crohn’s disease, celiac disease, amyloidosis and small intestinal lymphoma as well as other infections, particularly in AIDS patients. The clinical features associated with intestinal involvement in atypical mycobacterial infections are notorious for mimicry of clinical and pathological features of Whipple’s disease (so-called pseudo-Whipple’s disease), specifically, Mycobacterium avium-intracellulare [17] [18] [19] [20] or Mycobacterium genavense [21]. As noted elsewhere [16], no particular clinical differences from the infection in these immunosuppressed patients have been detailed to date.

In future, other infectious agents will likely be detected causing a clinical presentation mimicking Whipple’s disease. For example, another organism, Rhodococcus equi was also reported in an AIDS patient with a cavitating pneumonia, intestinal involvement and PAS-positive foamy macrophages containing variably shaped intra-cytoplasmic coccobacilli, histologically resembling the light and electron microscopic features of Whipple’s disease and Mycobacterium infections [22].

Some strains of Tropheryma whipplei are reported to be non-pathogenic while others have suggested that atypical strains of the organism may be responsible for some of the unusual presenting clinical features, including an isolated form of endocarditis [23]. Using PCR, Tropheryma whipplei has also been detected in the environment including sewage, water, fecal material and sewage plant workers without evidence of Whipple’s disease [24] [25]. It has been hypothesized that a selective immune defect in host T-cells or host macrophages may result in Whipple’s disease, or alternatively, such immune defects may be secondary to infection by the organism, itself. Environmental detection does raise the issue of contamination, potentially obviating any conclusion on an organism in a specific patient. Interestingly, even the first scientific report [1] of an uncultured bacillus in Whipple’s disease (using a formalin-fixed skin biopsy) in 1992 noted that the patient had underlying bacillary angiomatosis and Mycobacterium avium infection.

3. Clinical and Laboratory Changes

The percent frequencies of common clinical features in Whipple’s disease was analyzed by many authors [26] [27]. Some have suggested an apparent “prodrome” with fever and arthralgia followed by intestinal symptoms, such as diarrhea. Joint pain is often migratory and the rheumatoid factor test is negative. Large joint involvement predominates with resistance to initial anti-rheumatic drug treatment. In some of these, a duodenal biopsy may be negative but PCR testing, electron microscopy or immunohistochemistry of synovial fluid and biopsies may yield a diagnosis. Diarrhea and malabsorption leading to weight loss, a lowered serum carotene and nutrient deficiencies may develop. Anemia and protein-losing enteropathy with resultant hypoalbuminemia, peripheral edema and ascites may occur. Almost a third with Whipple’s disease develop neurological changes, including alterations in cognition with dementia. These may be the initial clinical feature and may occur without any other change. Despite treatment, changes may prove to be irreversible [28] [29] [30] [31]. Altered ocular muscle movement may develop, including progressive supranuclear type of ophthalmoplegia. Also frequent are headache, psychiatric changes, seizure disorders and ataxia. Cerebrospinal fluid infection may be defined by PCR [32]. In the eyes [33], uveitis, retinitis and optic neuritis with papilloedema may occur. The disorder may be recognized as a culture-negative form of endocarditis with diagnosis by valve explantation [23] [34].

Table 1.Frequency Of Clinical-Laboratory Changes

4. Intestinal Endoscopic and Histopathologic Features

Macroscopic features have been described in some, but not all, cases with endoscopic visualization. Duodenal folds may be thick, erythematous with several yellow to yellow-white plaques [35] [36]. These are not specific and may occur in forms of pseudo-Whipple’s disease [20] [22]. Duodenal biopsies are important in diagnosis of intestinal involvement [36]. Histological changes can be appreciated with routine hematoxylin-eosin stained sections showing massive infiltration of lamina propria foamy macrophages that contain the organism. Rarely, in some, the infiltrate may be limited to the submucosa. These macrophages are typically PAS stain-positive, but also diastase resistant. It is thought that this staining reaction is related to the inner membrane of the polysaccharide bacterial cell wall. A Ziehl-Nielsen stain (typically used for mycobacteria species) is negative in Whipple’s disease associated with Tropheryma whipplei, but positive with Mycobacterial infections. Plasma cells and lymphocytes in the lamina propria may appear to be decreased, especially with significant macrophage infiltration. Small fat collections may be present in the lamina propria (recall, intestinal lipodystrophy) and surface epithelial cells may appear to be vacuolated due to fat accumulation, possibly reflecting lacteal obstruction and regional lymph node involvement (also showing PAS-positive macrophages). Immunohistochemical staining with specific Tropheryma whipplei antibodies may reveal the organism, even in PAS-negative tissues. Post-treatment biopsies may show a reduction in numbers, even disappearance, of bacilli and macrophages, although these may persist for years.

5. Treatment Issues

Prior to antibiotic use, a fatal course was often recorded. Later, tetracycline was used as a form of monotherapy, but recurrence was common. More recently, recommendations were based on use of antibiotics that could cross the blood-brain barrier. Intravenous ceftriaxone for two weeks followed by oral cotrimoxazole for a year was recommended [37]. Resolution occurs, but neurological symptoms may persist. Others have recommended oral trimethoprim-sulfamethoxazole for up to 2 years [38].

Recurrent neurological symptoms in Whipple’s disease has a poor prognosis, and use of gamma-interferon has been suggested [39]. In some of these, persistence of an immune-based defect may be responsible. As in Mycobacterium infections in AIDS, resolution of the underlying immunological disorder may be critical to clearing the organism.

Along with increased susceptiblity to tuberculosis infections, a special high risk for Whipple’s disease may develop in patients treated with anti-tumor necrosis factor [40] [41]. Indeed, a number of Whipple’s disease cases have appeared in patients treated with an ongoing oral or parenteral form of the medication, often in those with rheumatological or gastrointestinal disorders [40] [41].

Statement of Competing Interests

The authors declare no conflicts of interest.

References

[1]   | Relman DA, Schmidt TM, MacDermott RP, Fallow S. Identification of the uncultured bacillus of Whipple’s disease. N Engl J Med 1992; 327: 293-301.
[2]   | Raoult D, Birg ML, La Scola B, Fournier PE, Enea M, Lepidi H, Roux V, Piette JC, Vandenesch F, Vital-Durand D, Marrie TJ. Cultivation of the bacillus of Whipple’s disease. N Engl J Med 2000; 342: 620-625.

[3]  
Bentley SD, Maiwald M, Murphy LD, Pallen MJ, Yeats CA, Dover LG, Norbertczak HT, Besra GS, Quail MA, Harris DE, von Herbay A, Goble A, Rutter S, Squares R, Squares S, Barrell BG, Parkhill J, Relman DA. Sequencing and analysis of the genome of the Whipple’s disease bacterium Tropheryma whipplei. Lancet 2003; 361: 637-644.

[4]   | Raoult D, Ogata H, Audic S, Robert C, Suhre K, Drancourt M, Claverie JM. Tropheryma whipplei twist: a human pathogenic Actinobacteria with a reduced genome. Genome Res 2003; 13: 1800-1809.
[5]   | Boulos A, Rolain JM, Raoult D. Antibiotic susceptibility of Tropheryma whipplei in MRC5 cells. Antimicrob Agents Chemother 2004; 48: 747-752.
[6]   | Boulos A, Rolain JM, Mallet MN, Raoult D. Molecular evaluation of antibiotic susceptiblity of Tropheryma whipplei in axenic medium. J Antimicrob Chemother 2005; 55: 178-181.
[7]   | Von Herbay A, Ditton HJ, Maiwald M. Diagnostic application of a polymerase chain reaction assay for Whipple’s disease bacterium to intestinal biopsies. Gastroenterology 1996; 110: 1735-1743.
[8]   | Ramzan NN, Loftus E, Burgart LJ. Diagnosis and monitoring of Whipple’s disease by polymerase chain reaction. Ann Intern Med 1997; 126: 520-527.
[9]   | Freeman HJ. Tropheryma whipplei infection. World J Gastroenterol 2009; 15: 2078-2080.
[10]   | Elchert JA, Mansoor E, Abou-Saleh M, Cooper GS. The epidemiology of Whipple’s disease in the United States between 2012 and 2017: a population based national study. Dig Dis Sci 2019; 64: 1305-1311.
[11]   | Duprez TP, Grandin CB, Bonnier C, Thauvoy CW, Gadisseux JF, Dutrieux JL, Evrard P. Whipple disease confined to the central nervous system in childhood. Am J Neuroradiol 1996; 17: 1589-1591.
[12]   | von Hebray A, Otto HF, Stolte M, Borchard F, Kirchner T, Ditton HJ. Epidemiology of Whipple’s disease in Germany: analysis of 110 patients diagnosed in 1965-95. Scandinavian J Gastroenterol 1997; 32: 52-57.
[13]   | Ahmad AI, Wikholm C, Pothoulakis I, Caplan C, Lee A, Buchanan F, Cho WK. Whipple’s disease review, prevalence, mortality and characteristics in the United States. Medicine 2022; 101: 49 (1-6).
[14]   | Yardley JH, Hendrix TR. Combined electron and light microscopy in Whipple’s disease. Demonstration of “bacillary bodies” in the intestine. Bull Johns Hopkins Hosp 1961; 109: 80-98.
[15]   | Trier JS, Phelps PC, Eidelman S, Rubin CE. Whipple’s disease: light and electron microscope correlation of jejunal mucosal histology with antibiotic treatment and clinical status. Gastroenterology 1965; 48: 684-707.
[16]   | Dutly F, Altwegg M. Whipple’s disease and “Tropheryma whippelii”. Clin Microbiol Rev 2001; 14: 561-583.
[17]   | Gillin JS, Urmacher C, West R, Shake M. Disseminated Mycobacterium avium-intracellulare infection in acquired immunodeficiency syndrome mimicking Whipple’s disease. Gastroenterology 1983; 85: 1187-1191.
[18]   | Kooijman CD, Poen H. Whipple-like disease in AIDS. Histopathology 1984; 8: 705-708.
[19]   | Poorman JC, Katon RM. Small bowel involvement by Mycobacterium avian complex in a patient with AIDS: endoscopic, histologic, and radiographic similarities to Whipple’s disease. Gastrointest Endosc 1994; 40: 753-759.
[20]   | Gray JR, Rabeneck L. Atypical mycobacterial infection of the gastrointestinal tract in AIDS patients. Am J Gastroenterol 1989; 84: 1521-1524.
[21]   | Albrecht HS, Rusch-Gerdes S, Stelbrink HJ, Greten H, Jackie S. Disseminated Mycobacterium genavense infection as a cause of pseudo-Whipple’s disease and sclerosis cholangitis. Clin Infect Dis 1997; 25: 742-743.
[22]   | Hamrock D, Azmi FH, O’Donnell E, Gunning WT, Philips ER, Zaher A. Infection by Rhodococcus equi in a patient with AIDS: histological appearance mimicking Whipple’s disease and Mycobacterium avium-intracellulare infection. J Clin Pathol 1999; 52: 68-71.

[23]  
Lepidi H, Fenollar F, Dumler JS, Gauduchon V, Chalabreysse L, Bammert A, Bonzi MF, Thivolet-Bejuui F, Vandenesch F, Raoult D. Cardiac valves in patients with Whipple’s endocarditis: microbiological, molecular, quantitative histologic, and immunohistochemical studies of 5 patients. J Infect Dis 2004; 190: 935-945.

[24]   | Maiwald M, Schuhmacher F, Ditton HJ, von Herbay A. Environmental occurrence of the Whipple’s disease bacterium (Tropheryma whipplei). Appl Environ Microbiol 1998; 64: 760-762.
[25]   | Schoniger-Hekele M, Petermann D, Weber B, Muller C. Tropheryma whipplei in the environment: survey of sewage plant influxes and sewage plant workers. Appl Environ Microbiol 2007; 73: 2033-2035.
[26]   | Fleming JL, Wiesner RH, Shorter RG. Whipple’s disease: clinical, biochemical, and histopathologic features and assessment of treatment in 29 patients. Mayo Clin Proc 1988; 63: 539-551.
[27]   | Maizel H, Ruffin JM, Dobbins WO 3rd. Whipple’s disease: a review of 19 patients from one hospital and a review of the literature since 1950. Medicine (Baltimore) 1993; 72: 343-355.
[28]   | Keinath RD, Merrell DE, Vlietstra R, Dobbins WO 3rd. Antibiotic treatment and relapse in Whipple’s disease. Long-term follow-up of 88 patients. Gastroenterology 1985; 88: 1867-1873.
[29]   | Gerard A, Sarrot-Reynauld F, Liozon E, Cathebras P, Besson G, Robin C, Vighetto A, Mosnier JF, Durieu I, Vital Durand D, Rousset H. Neurologic presentation of Whipple disease: report of 12 cases and review of the literature. Medicine (Baltimore) 2002; 81: 443-457.
[30]   | Mandel E, Khoo LT, Go JL, Hinton D, Zee CS, Apuzzo ML. Intracerebral Whipple’s disease diagnosed with stereotactic biopsy: a case report and review of the literature. Neurosurgery 1999; 44: 203-209.
[31]   | Panegyres PK, Edis R, Beaman M, Fallon M. Primary Whipple’s disease of the brain: characterization of the clinical syndrome and molecular diagnosis. QJM 2006; 99: 609-623.
[32]   | von Herbay A, Ditton HJ, Schuhmacher F, Maiwald M. Whipple’s disease: staging and monitoring by cytology and polymerase chain reaction analysis of cerebrospinal fluid. Gastroenterology 1997; 113: 434-441.
[33]   | Avila MP, Jaikh AE, Feldman E, Trempe CL, Schepens CL. Manifestations of Whipple’s disease in the posterior segment of the eye. Arch Ophthalmol 1984; 102: 384-390.
[34]   | Houpikian P, Raoult D. Blood culture-negative endocarditis in a reference centre: etiologic diagnosis of 348 cases. Medicine (Baltimore) 2005; 84: 162-173.
[35]   | Armelao F, Portolan F, Togni R. Mosaic-patterned and scalloped duodenal mucosa in Whipple’s disease. Clin Gastroenterol Hepatol 2008; 6: A32.
[36]   | Lewin KJ, Riddell RH, Weinstein WM. Gastrointestinal Pathology and Its Clinical Implications. New York: Igaku-Shoin, 1992: 779-782.
[37]   | Marth T, Schneider. Whipple disease. Curr Opin Gastroenterol 2008; 24: 141-148.
[38]   | Fenollar F, Puechal X, Raoult D. Whipple’s disease. N Engl J Med 2007; 356: 55-66.
[39]   | Schneider T, Stallmach A, von Herab A, Marth T, Strober W, Zeitz M. Treatment of refractory Whipple disease with interferon-gamma. Ann Intern Med 1998; 129: 875-877.
[40]   | Ramos JM, Pasquau F, Galipienso N, Valero B, Navarro A, Martinez A, Rosas J, Gutierrez A, Sanchez-Martinez R. Whipple’s disease diagnosed during anti-tutor necrosis factor alpha treatment: two case reports and review of the literature. J Med Case Reports 2015; 9: 165 (1-7).
[41]   | Kneitz C, Suerbaum S, Beer M, Miller J, Jahns R, Tony HP. Exacerbation of Whipple’s disease associated with infliximab treatment. Scand J Rheumatol 2005; 34: 148-151.