Whipple Disease Research Accelerates Kenneth

The face of Whipple disease is changing rapidly. The disease was originally described in 1907 by the pathologist George Hoyt Whipple [1], but it was not until 1961 that electron microscopic studies showed it definitively to be caused by bacteria [2, 3]. The causative organism could not be cultivated, and the cell wall ultrastructure was considered ambiguous, so there was even uncertainty as to whether the pathogen was Gram positive or Gram negative. In the early 1990s, ribosomal DNA sequence analysis showed it to be a Gram-positive actinomycete, and the organism was named on the basis of this sequence [4, 5]. The technology used to clarify the phylogeny of Tropheryma whipplei could also then be used to detect the organism directly by molecular means. Over the ensuing 2 decades, there has been an explosion of publications describing the detection of T. whipplei in many tissues. This work has both confirmed what had previously been reported in Whipple disease [6] and described new findings [7, 8]. What has emerged is the picture of a disease with many manifestations. It most often presents as originally described by Whipple: with infection of the small bowel submucosa leading to a malabsorption syndrome, often with mesenteric lymphadenopathy. The ensuing diarrhea and weight loss may be preceded by a more subtle systemic illness, often associated with arthralgia or arthritis. T. whipplei may also be present in a variety of other tissues, including skin, brain, spinal cord, vertebra, lung, heart valve, myocardium, pericardium, bone marrow, prosthetic materials, lymph nodes, synovium, and other sites. The disease may present with extraintestinal involvement, or involvement of these sites may become apparent upon treatment, resulting from an immune reconstitution inflammatory syndrome–like illness [9]. Treatment is still probably less than optimal; the organism can acquire resistance to trimethoprim-sulfamethoxazole, which is the antibiotic most commonly used to treat it [10]. As a result of such resistance, and possibly because of other factors, the disease is subject to relapse, and it is common for the presentation at relapse to reflect extraintestinal infection, particularly in the central nervous system. Despite its various presentations, the disease has been considered a progressive process with a final common pathway if untreated—dissemination and death. An understanding of the ecology of T. whipplei is emerging. If it were widely distributed in the environment, one would expect this fact to have become apparent by now. This apparent lack of dispersion is not surprising in light of the organism’s genome, which is small in comparison to those of most other bacteria [11, 12]. This reduced genome is deficient in genes coding for amino acid metabolism and in pathways for energy metabolism, probably reflecting obligate association with a host. The organism also appears to be capable of altering its surface proteins, presumably as a way of evading the immune system. It appears that at least one of its hosts is human. Its DNA has been found in the stool, saliva, and gingival crevice of healthy humans but not, thus far, in monkeys or apes [13]. T. whipplei DNA has also been found in sewage influxes, and its presence in humans is associated with work exposing the carrier to sewage water. The picture is emerging of an organism that is more often a parasite or commensal of the alimentary tract than a pathogen. We do not often think of intracellular bacteria as being parasites or commensals, but there are precedents in nature, such as Bartonella henselae in cats, Wolbachia species in insects or, for that matter, mitochondria. Because there is no evidence that T. whipplei benefits the host, we can call it a parasitic bacterium for now. It is often the case that the most severe end of the spectrum for an infectious disease is the first to be described. Thus, it may not simply be the case that the parasitic organism, T. whipplei, occasionally kills its host. It may also cause less severe disease. Recently Raoult et al [14] Received and accepted 8 March 2011. Potential conflicts of interest: none reported. Correspondence: Kenneth H. Wilson, MD, Infectious Diseases Section, VA Medical Center (111H), 508 Fulton St., Durham, NC 27705 ([email protected]). The Journal of Infectious Diseases 2011;204:4–5 The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected] 0022-1899 (print)/1537-6613 (online)/2011/2041-0002$14.00 DOI: 10.1093/infdis/jir213