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INTRODUCTION

Whipple’s disease, described by George Whipple in 1907, is a chronic infection caused by Tropheryma whipplei. Most commonly, years pass from the onset of symptoms to the recognition of the disease because of its rarity, its various manifestations mimicking other conditions, and the need to perform nonroutine diagnostic tests. The long-held belief that Whipple’s disease is an infection was supported by observations on its responsiveness to antimicrobial therapy in the 1950s and the identification of bacilli via electron microscopy in small-bowel biopsy specimens in the 1960s. This hypothesis was finally confirmed by amplification and sequencing of a partial 16S rRNA polymerase chain reaction (PCR)–generated amplicon from duodenal tissue in 1991. The subsequent successful cultivation of T. whipplei enabled whole-genome sequencing and the development of additional diagnostic tests. The development of PCR-based diagnostics has broadened our understanding of both the epidemiology of and the clinical syndromes attributable to T. whipplei. Exposure to T. whipplei, which appears to be much more common than has been appreciated, can be followed by asymptomatic carriage, acute disease, or chronic infection. Chronic infection—Whipple’s disease—is a rare development after exposure. “Classic” Whipple’s disease is manifested by some combination of arthralgias/arthritis, weight loss, chronic diarrhea, abdominal pain, and fever. Variable involvement at other sites also occurs; neurologic and cardiac disease are most common. Acute infection and chronic organ disease in the absence of intestinal involvement (see “Isolated Infection,” below) are described with increasing frequency. Since untreated Whipple’s disease is often fatal and delayed diagnosis may lead to irreparable organ damage (e.g., in the central nervous system [CNS]), knowledge of the clinical scenarios in which Whipple’s should be considered and of an appropriate diagnostic strategy is mandatory.

ETIOLOGIC AGENT

Image not available. T. whipplei is a weakly staining gram-positive bacillus. Genomic sequence data have revealed that the organism has a small (<1-megabase) chromosome, with many biosynthetic pathways absent or incomplete. This finding is consistent with a host-dependent intracellular pathogen or a pathogen that requires a nutritionally rich extracellular environment. It is one of the slowest growing human pathogens, with a doubling time of 18 days. A genotyping scheme based on a variable region has disclosed >100 genotypes to date. All genotypes appear to be capable of causing similar clinical syndromes.

EPIDEMIOLOGY

Image not available. Whipple’s disease is rare but has been increasingly recognized since the advent of PCR-based diagnostic tools. It occurs in all parts of the globe, with a prevalence estimated at 1–3 cases per 1 million population. Seroprevalence studies indicate that ~50% of Western Europeans and ~75% of Africans from rural Senegal have been exposed to T. whipplei. A predilection for chronic disease has been observed in middle-aged Caucasian men, who develop disease five to eight times more frequently than middle-aged women. Humans are the only known host. To date, no clear animal or environmental reservoir has been demonstrated. However, the organism has been identified by PCR in sewage water and human feces. Workers with direct exposure to sewage are more likely to be asymptomatically colonized than controls, a pattern suggesting fecal–oral spread. Fecal PCR detection rates of 38% among family members of carriers or patients with infection support oral–oral or fecal–oral spread, although a common environmental exposure ...

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