With the identification of the causative bacterium, Tropheryma whippelii, Whipples disease has grown out from its niche in textbooks and has colonized high ranked journals. Nevertheless, it is an uncommon multisystem disorder and not just an intestinal bacterial infection like many others. Thus, patient management is more complex. Based on lessons from history, and on new insights promoted by molecular biology in the past decade, a new concept of patient managment has emerged which is presented in this chapter.
The history of antibiotic therapy goes back to 1951, when a family physician, Dr. G. Ander in England, decided to try chloramphenicol, a new drug at the time, in a 56-year-old male with Whipples disease presenting with high fever and diarrhea. His patient’s symptoms vanished and remission continued.
As chroni called in Dobbins classic test, the patient was later reported (by Dr. Paulley) as an example of idiopathic steatorrhea, because the effect of chloramphenicol was considered as a control of secondary infection on the jejunal mucosa. The real implication was realized later when electron microscopy identified rod shaped bacteria in other patients’ tissues. Antibiotic therapy of Whipples disease started, in fact, in 1961. During the four decades since, several drugs have been used. In retrospect, three time periods may be recognized.
In the first period, various antibiotics were applied which were available in the 1960s; penicillin, streptomycin, and tetracyline (and some additional drugs) were all given with success. A sequential combination of these 3 drugs, lasting for at least 12 months, was recommended in 1963 (ie, “Duke regimen”). To avoid possible malabsorption of antibiotics, treatment was started with parenteral administration of penicillin and streptomycin. Follow-up observations were favorable, but perhaps due to the requirement of parenteral application, this regimen was less frequently applied in the 1970s.
A second period started in 1970, when knowledge accumulated that monotherapy with tetracycline was apparently also effective. This oral regimen was widely preferred until the late 1980s, and a low rate of relapses was observed.
However, Knox and colleagues (1976) reported severe central nervous system (central nervous system) relapses in their patients treated with tetracycline. Indeed, in 1985 a retrospective analysis on the long term outcome (ie, after a minimum of 2 years after diagnosis) in a cohort of 88 patients by Keinath and colleagues (1985) reported that signs or symptoms attributable to Whipples disease frequently recurred; among 49 patients treated with tetracycline alone, 21 (43%) had clinically defined relapses. Seven of the 49 patients (14%) developed neurologic features suggestive of central nervous system relapse, and two further patients developed their second relapse in the central nervous system. The outcome of patients with central nervous system relapse was generally poor, despite new antibiotic therapies.
A third period started in the mid 1980s. To overcome the crucial problem of central nervous system relapse, trimethoprim-sulphamethoxazole was preferred, because this drug can penetrate the blood-brain barrier, whereas tetracyline does not. The choice of this drug was later supported by a retrospective study by Feurle and colleagues in 1976. However, with increasing usage of trimethoprim-sulphamethoxazole, several patients were observed who developed late onset central nervous system Whipples disease. In parallel, we observed asymptomatic central nervous system infection with T. whippelii after long term therapy with trimethoprim-sulphamethoxazole. Thus, it was felt that a more active antimicrobial regimen is necessary to prevent central nervous system Whipples disease.
Cerebral Whipples disease
Some patients present initially with neurologic or psychiatric symptoms, but the majority of patients with cerebral Whipples disease develop symptoms later in the course of the disease. This may happen within arange of a few months to several years after the initial diagnosis of intestinal Whipples disease. At this time, a suboptimal examination may easily fail to detect residual PAS positive macrophages in intestinal mucosal biopsies. Treatment of this subset of patients is less effective and, even today, their prognosis is uncertain. One of the long term problems is differentiating persisting neurological deficits, which do not need antibiotic therapy, from persisting central nervous system infection.
Before the historical recognition of the bacterial association, patients with Whipples disease were sometimes treated with corticosteroids, and remission was observed. Even today, some patients apparently require additive corticosteroids to control their symptoms (eg, arthralgias, pleural effusion), although antibiotic drugs alone do not achieve this effect.
The background for these observations is still undefined. Assuming an immunological basis of Whipples disease, the idea of adjuvant immunotherapy is tempting. This hypothesis was tested in one rare patient with intestinal Whipples disease who was refractory to diverse antibiotic drugs. With combined therapy of chloramphenicol and interferon-gamma, remission was eventually achieved. However, in two further patients with refractory cerebral Whipples disease interferon-gamma was ineffective (unpublished). One of the latter patients later died.
Conclusions and Perspective
Treatment of Whipples disease is largely performed on a historical basis. It relies on observations from case reports, retrospective clinical series, and a meta-analysis. No evidence base is available. The recommendations and comments given in this chapter include our personal series of 162 patients studied during 1992 to 2002 at the University of Heidelberg, Germany and updated on our Web site.
The new concept of patient management was subjected to a prospective, randomized study, which started in September 1998 in Germany (Studie zur Initialtherapie bei Morbus Whipple [SIMW]). By December 31,2002,32 patients were enrolled. Preliminary data suggest that it works, but follow-up is still limited. Unfortunately, after some protocol violations, the study was disbanded before reaching its end point.
Meanwhile, cultivation of T. whippelii is possible (but still not available clinically), and this has allowed deciphering of the complete bacterial genome. This knowledge will facilitate the establishment of new diagnostic tests, including culture systems and tests of antibiotic sensitivity in individual isolates, and will help in designing new approaches to treatment. Progress in Whipple’s bacteriology has overshadowed the likely role of the immune system in the pathogenesis, which needs to be clarified.