Whipple Disease

Article Author:
Catiele Antunes
Article Editor:
Mayank Singhal
Updated:
12/16/2018 9:47:18 AM
PubMed Link:
Whipple Disease

Introduction

Whipple's disease is caused by a gram-positive bacteria, Tropheryma Whipplei. This is a systemic disorder which not only involves malabsorption from gastrointestinal tract but also affect other systems like the cardiovascular, central nervous system, joints and the vascular system. Dr. George Hoyt Whipple initially described this condition in 1907. He was the first American Nobel Prize laureate in Physiology. Dr. Whipple described a case of a 36-year-old male who presented with malabsorption associated with mesenteric lymphadenopathy, arthralgias and skin pigmentation. The condition named by him "Intestinal Lipodystrophy" and his article was published in the Bulletin of Johns Hopkins Hospital. He hypothesized that an infectious agent has caused it but the bacteria was only fully identified in 1992.[1][2][3]

Etiology

Tropheryma whipplei was described in 1992. It was named Tropheryma whippelli until 2001 when its name was modified to conform with the proper spelling of Dr. George Hoyt Whipple's name. It is a gram-positive bacillus, periodic acid-Schiff-positive (PAS) and acid-fast negative. Electron microscopy showed that the bacillus core is enclosed within a plasma membrane, which is surrounded by a three layered cell wall. The inner layer contains polysaccharides that stain positive with PAS. The outer layer resembles a plasma membrane and may be of host origin, which possibly accounts for the failure of the host to mount a humoral antibody response to the infection.

Epidemiology

Globally, Whipple disease is a rare disorder with most reports published in North America and Europe. The disorder is associated with the HLA B27 haplotype. The overall incidence of Whipple disease is about one to three in every one million people. The mean age of onset of symptoms is age 55. It is much more frequent in males than in females, with a ratio of 4:1. The organism seems to be soil-dwelling which explains the increased prevalence in farmers.[4]

Pathophysiology

The detailed pathogenesis remains unclear but there is enough evidence to believe that host immunity plays an important role in it. Most individuals who contract T. whipplei are asymptomatic carriers or develop limited infection with subsequent development of protective humoral and cellular immunity. In diseased individuals, the inflammatory response to the organism is muted. It consists primarily of altered macrophage function and activation and an impaired type 1 T-cell response. Whipple bacillus shares antigenic similarity with Streptococcal groups B and G and with Shigella flexneri. Host factors play an important pathogenic role as suggested by the two to threefold increase in the frequency of HLA-B27 antigen among affected individuals.[5]

History and Physical

Whipple disease is characterized by myriad findings related to the infectious involvement of several organ systems. The typical presentation includes gastrointestinal symptoms that resemble other malabsorption syndromes. The prominent symptoms are weight loss, diarrhea, arthralgias, fever, and abdominal pain. Diarrhea has the usual features of steatorrhea but may be watery. Occult gastrointestinal bleeding is common (up to 80% of patients). Gross bleeding can also be present sometimes. Peripheral edema reflects hypoproteinemia from protein-losing enteropathy and poor nutrition. Arthralgias are migratory, nondestructive, and involve large joints. They often precede the intestinal manifestation. The articular attacks are usually acute in onset and last for hours to days. Sacroiliitis is common (20% to 30%), but ankylosing spondylitis is rare. Fever is also present in 30% to 50% of patients. At some point, at least one-third of patients will have involvement of the heart. Pericarditis and endocarditis are common (50% to 75%) but rarely produce significant symptoms. Apical systolic murmurs are detected in 25% of patients. Friction rubs and congestive heart failure develop in up to 10% of patients. Patients who develop central nervous system (CNS) involvement may have signs of frontal release, ataxia, or clonus. Supranuclear ophthalmoplegia has also been reported in medical literature. Other neurological features described in these patients include confusion, seizures, delirium, cognitive impairment, abnormal body movements, hypersomnia, and extrapyramidal symptoms. Post-mortem examination reveals that central nervous system is affected in 90% of patients, but clinical involvement becomes evident in only 10% to 40% of patients. Physical examination of patients will reveal peripheral lymphadenopathy in about 50% of the cases. Hyperpigmentation around the malar and orbital areas, Hyperkeratosis, Purpura, Abdominal distension, Glossitis, Cheilitis, Gingivitis, Chovstek or Trousseau sign can also be seen. [6]

Evaluation

The diagnosis of Whipple disease is made by a biopsy of the intestine and identification of the organism. Current diagnostic criteria require positive results for PAS positive foamy macrophages in the small bowel biopsy. If its negative, the diagnosis can also be made by showing positive results in the for two of the following:

  • PAS staining showing foamy macrophages in biopsy specimen of involved tissues
  • PCR Detection of T. whipplei or detection of the specific 16S rRNA of the bacterium
  • Immunohistochemical staining with T. whipplei antibodies

It is important to know that T. whipplei quickly becomes negative after the initiation of therapy, which may lead to false negatives since many patients receive antibiotics before undergoing extensive diagnostic testing for this condition. Other lab findings include anemia is present in 90% of cases and results from chronic disease, iron deficiency, and folate or vitamin B12 deficiency. Neutrophilia is present in one-third of patients. Mild lymphocytopenia is common. Eosinophilia and thrombocytopenia rarely occur. Hypoalbuminemia is prevalent whereas serum globulin levels are normal. The prothrombin time is prolonged. Steatorrhea occurs in 93% of cases.[3]

Treatment / Management

The mainstay of treatment for Whipple disease is antibiotics. Because of the possibility of CNS involvement, even in the absence of symptoms, use of antibiotics that penetrate the blood-brain barrier is desirable. One recommended regimen for initial phase is Ceftriaxone two grams daily or Penicillin G two million units every four hours. The usual duration for the initial phase is two weeks, followed by the maintenance phase with Trimethoprim 160 mg- Sulfamethoxazole 800 mg twice daily for twelve months. Meropenem can also be used for the initial phase in patients with Penicillin allergy. Long courses are usually necessary to prevent relapse. Unfortunately, relapse can occur even years after treatment. Often, CNS symptoms may be the first sign of relapse.[7][8]

Differential Diagnosis

The differential diagnoses of Whipple disease include:

  • HIV
  • Tuberculosis
  • Inflammatory Bowel disease with arthropathy
  • Connective tissue disorder
  • Hyperthyroidism.

Prognosis

Usually the prognosis is good with prompt diagnosis and treatment of Whipple disease. The patients feel a lot better within two to three weeks of initiation of the treatment.[9]

Complications

Whipple Disease is a progressive debilitating disease if it gets undiagnosed and untreated. Complications from untreated Whipple disease are mainly due to nutritional deficiencies as it interferes with the absorption process of the small intestine. Few disseminated cases of Whipple disease sepsis have also been reported. Irreversible brian damage and potential death can also occur. 

Consultations

Due to the need of small bowel biopsy and the treatment with long-term antibiotics, Gastroenterology and Infectious disease should be consulted.

Enhancing Healthcare Team Outcomes

The prompt diagnosis and successful treatment of Whipple disease requires a multidisciplinary approach involving Internal Medicine, Gastroenterology and Infectious Disease specialists to work in a coordinated manner with nursing and pharmacy staff. Regular clinic follow-ups are also critical due to the prolonged course of treatment.


References

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[2] Frickmann H,Hanke M,Hahn A,Schwarz NG,Landt O,Moter A,Kikhney J,Hinz R,Rojak S,Dekker D,Tannich E,Podbielski A, Detection of Tropheryma whipplei in stool samples by one commercial and two in-house real-time PCR assays. Tropical medicine     [PubMed PMID: 30347125]
[3] Crews NR,Cawcutt KA,Pritt BS,Patel R,Virk A, Diagnostic Approach for Classic Compared With Localized Whipple Disease. Open forum infectious diseases. 2018 Jul     [PubMed PMID: 29992176]
[4] Dolmans RA,Boel CH,Lacle MM,Kusters JG, Clinical Manifestations, Treatment, and Diagnosis of Tropheryma whipplei Infections. Clinical microbiology reviews. 2017 Apr     [PubMed PMID: 28298472]
[5] Hujoel IA,Johnson DH,Lebwohl B,Leffler D,Kupfer S,Wu TT,Murray JA,Rubio-Tapia A, Tropheryma whipplei Infection (Whipple Disease) in the USA. Digestive diseases and sciences. 2018 Mar 23     [PubMed PMID: 29572616]
[6] Bally JF,Méneret A,Roze E,Anderson M,Grabli D,Lang AE, Systematic review of movement disorders and oculomotor abnormalities in Whipple's disease. Movement disorders : official journal of the Movement Disorder Society. 2018 Nov     [PubMed PMID: 30338868]
[7] Moos V,Schneider T, [Whipple's disease]. Deutsche medizinische Wochenschrift (1946). 2014 Dec     [PubMed PMID: 25423457]
[8] Hagel S,Epple HJ,Feurle GE,Kern WV,Lynen Jansen P,Malfertheiner P,Marth T,Meyer E,Mielke M,Moos V,von Müller L,Nattermann J,Nothacker M,Pox C,Reisinger E,Salzberger B,Salzer HJ,Weber M,Weinke T,Suerbaum S,Lohse AW,Stallmach A, [S2k-guideline gastrointestinal infectious diseases and Whipple's disease]. Zeitschrift fur Gastroenterologie. 2015 May     [PubMed PMID: 25965989]
[9] Meunier M,Puechal X,Hoppé E,Soubrier M,Dieudé P,Berthelot JM,Caramaschi P,Gottenberg JE,Gossec L,Morel J,Maury E,Wipff J,Kahan A,Allanore Y, Rheumatic and musculoskeletal features of Whipple disease: a report of 29 cases. The Journal of rheumatology. 2013 Dec     [PubMed PMID: 24187107]