Over the past 20 years there has been an explosion of knowledge about Whipple disease. It is now known that Whipple bacillus causes not only classic Whipple disease, a rare, systemic bacterial infection that can be fatal without therapy but also acute infection such as gastroenteritis, pneumonia, and bacteremia. In its most common form, Whipple disease affects white, middle-aged men, causing diarrhea, weight loss, abdominal pain, arthralgias, and fever. Although it is extraordinarily rare in children, its recognition may be crucial because simple treatment with appropriate antibiotics may be curative and lifesaving.
History
Whipple disease was described in 1907 by George Hoyt Whipple, at that time an instructor in pathology at the Johns Hopkins University. Whipple’s description probably was not the first; Allchin and Webb apparently described a patient with “Whipple disease” in 1895.
In Whipple’s account, a 37-year-old medical missionary was admitted to the Johns Hopkins Hospital with low-grade fever, steatorrhea, and an abdominal mass. The patient had a 5-year history of sporadic migratory polyarthritis. These attacks of arthritis were associated with a gradual loss of weight and strength. His skin was pigmented with a brownish hue. Laboratory evaluation found severe anemia and an enormous number of fatty acid crystals in the stool. Explorative laparotomy revealed large, firm mesenteric lymph nodes, and a diagnosis of either Hodgkin disease or tuberculosis was made. The patient died 1 week later, and autopsy revealed marked fatty deposition within intestinal mucosa and the mesenteric and retroperitoneal lymph nodes. Other findings included polyserositis (peritonitis, pleuritis, and pericarditis) and endocarditis. Histologic examination revealed infiltration of the lamina propria of the small intestine by large, foamy mononuclear cells that did not stain for fat. Fatty acids and triglycerides were found in dilated lymph channels. Silver stains of the mesenteric lymph nodes showed “great numbers of rod-shaped organisms” that resembled the tubercle bacillus. Whipple suggested that these bacillus-like organisms in the nodes could be the cause.
Whipple reported “a hitherto undescribed disease characterized anatomically by deposits of fat and fatty acids in the intestinal and mesenteric lymphatic tissues.” He concluded that the patient had “an obscure disease of fat metabolism” and proposed the term intestinal lipodystrophy . Whipple recognized the most important features of this disease except for the involvement of the central nervous system (CNS). In 1949, Black-Schaffer showed that macrophages within the intestinal mucosa of patients with Whipple disease are stained intensely by the periodic acid–Schiff (PAS) method, proving that the macrophages contained glycoprotein or mucopolysaccharide, not fat, as Whipple had suggested.
In 1992, Relman and colleagues identified a gram-positive bacillus in association with Whipple disease by use of polymerase chain reaction (PCR). They reported a unique 1321-base-pair, 16S ribosomal RNA sequence amplified by PCR on intestinal and lymph node tissue from five unrelated patients with Whipple disease. They suggested that the responsible bacillus is a member of actinomycetes. Relman and colleagues concluded that the phylogenetic relationships of the Whipple disease bacillus, the features of the illness, and its distinct morphologic characteristics provided sufficient grounds to propose a new genus and species name: Tropheryma whippelii from the Greek trophe , or “nourishment”; eryma , or “barrier,” because of the malabsorption it causes; and whippelii (now whipplei ), in honor of Whipple.
Epidemiology
Classic Whipple disease characteristically occurs in white middle-aged men. Its true incidence and prevalence are unknown because fewer than 1000 cases have been reported worldwide. It is an extremely rare disease in children, with fewer than 10 cases reported. The youngest patient was a neonate, and the oldest was 83 years old. The peak age at presentation is 40 to 49 years. In a literature review of 114 patients, 88% were men and 12% were women. Most of these patients were white. Most patients reported as having Whipple disease are from continental Europe or the United States. In an extensive review of 741 cases, Dobbins found that most academic centers in the United States had records of three or four unreported cases. He estimated that for every published report at least two or three unpublished cases exist and that 1500 to 2000 individuals probably have had Whipple disease.
Although classic Whipple disease is quite rare, the incidence of T. whipplei –related infection may be higher than previously thought. Raoult and associates found stool PCR evidence of T. whipplei in 36 of 241 (15%) children with acute gastroenteritis but in none of 47 control subjects. Thirty-three percent of children with a positive stool PCR also had another identified diarrheal pathogen. The bacterial load in the children’s stool was higher than in asymptomatic controls and more in line with numbers found in classic Whipple disease. These children showed seropositivity with IgM during the acute infection and recovered without treatment within 2 weeks. T. whipplei has also been identified in patients with pneumonia and bacteremia.
The prevalence of asymptomatic carriage of T. whipplei varies by country and exposure. For example, in stools, prevalence estimates range from 2% to 4% of the general population, 12% in sewer workers, and 44% in healthy children in Senegal. T. whipplei has been identified in 0.5% to 30% of healthy adults in saliva and gingival plaque. Such studies confirm the existence of asymptomatic carriage.
Etiology and Pathogenesis
Although humans are the only species to display clinical signs of T. whipplei infection, they are likely not the only reservoir. In a study of sewage water in Austria, T. whipplei was found by PCR in 17 of 46 (37%) of samples. Transmission of T. whipplei is most likely fecal-oral. Among asymptomatic workers in those plants, 16 of 64 (25%) were PCR positive for T. whipplei in their stool. This compared to a baseline rate of 7% of PCR-positive stools in controls. A study in France identified an asymptomatic control population with PCR-positive T. whipplei in 4% in their stool. Similar to the Austrian study, sewage workers had a higher carrier rate of 12%. The same study did not identify T. whipplei in the stool of monkeys or apes.
Classic Whipple disease is caused by an organism known as Whipple bacillus or T. whipplei. Despite Whipple’s account of “great numbers of rod-shaped organisms,” culture of the organism was unsuccessful until more recently. In 2000, Raoult and associates reported that the bacterium T. whipplei had been cultured successfully from an aortic valve vegetation in a patient with prolonged endocarditis. The bacteria were isolated after inoculation in a human fibroblast cell line (HEL). Analysis by PCR confirmed that the 16S ribosomal RNA gene of the cultured bacterium was identical to the T. whipplei sequence. Subcultures of the bacterium also were obtained, and high-titer polyclonal antibodies against T. whipplei were produced. Such antibodies potentially may allow serologic diagnosis to become a reality.
T. whipplei may be a member of the actinomycetales, which are gram-positive bacteria with DNA rich in guanine and cytosine. The genus consists of actinomycetes, streptomycetes, and the nocardioforms. T. whipplei seems to be related most closely to the four actinobacteria Dermatophilus congolensis, Arthrobacter globiformis, Terrabacter tumescens, and Micrococcus luteus. Using so-called bootstrap analysis, some researchers have argued that the Whipple bacillus is only 67% associated with actinobacteria, far from the level needed for scientific conclusion. The Whipple bacillus may represent another, separate, fourth line of descent with the actinomycetes. Amplification, cloning, and sequencing of a 620-base-pair fragment of T. whipplei heat shock protein led to the conclusion that T. whipplei is a member of the actinomycetales.
Scant support exists for a primary humoral immunodeficiency in Whipple disease, but stronger evidence exists for a distinct defect in the cell-mediated immune function. Dobbins reviewed data of 30 patients with HLA-A and HLA-B locus typing and 47 patients with HLA-B27 typing. He found an increased incidence of patients who were positive for HLA-B27 (28%), even with absence of concomitant sacroiliitis. Other reports have failed to confirm the increased association with the HLA-B27 antigen. Marth and associates studied 27 patients with Whipple disease. They found a significantly reduced number of cells expressing the complement receptor 3 L-chain (CD11B), a reduced proliferation to phytohemagglutinin and to sheep red blood cells, and a hypoergic skin reaction. These findings indicated a defect of cell-mediated immunity.
In patients with active disease, the number of CD8 + cells is increased, which results in a reduced CD4/CD8 ratio. Such defects of cellular immunity seem to persist in patients for several years, despite complete remission of the disease. Schoeden and associates were able to culture T. whipplei in mononuclear phagocytes deactivated with interleukin-4 (IL-4), IL-10, and dexamethasone. IL-4 was found to be the crucial deactivating signal that rendered monocytes permissive for intracellular multiplication of T. whipplei. IL-4 is an immunoregulatory cytokine. Schoeden and associates suggested that host factors, such as an imbalance in the T-helper 1 and T-helper 2 immune response, may contribute to the pathogenesis of Whipple disease.
Desnues and colleagues reported a specific gene expression pattern associated with replication of T. whipplei in macrophages. T. whipplei organisms are killed by monocytes. The addition of exogenous IL-16 enabled T. whipplei to replicate in monocytes and increased bacterial replication in macrophages. T. whipplei replication in macrophages was completely prevented after blocking IL-16 activity with the use of anti–IL-16 antibodies. Untreated patients with Whipple disease were noted to have significantly higher circulating IL-16 than did control subjects and patients treated for Whipple disease. They concluded that response of monocytes and macrophages to IL-16 likely is crucial for replication of T. whipplei to occur in patients with Whipple disease.
Oral acquisition of the Whipple bacillus seems most likely, emphasizing greater involvement of the duodenum and proximal jejunum than the more distal small intestine. Only three reports of siblings with this disease exist; contagious spread of Whipple disease seems unlikely. T. whipplei has been identified free in the small intestine next to the glycocalyx of the enterocyte’s microvilli, in epithelial cells, and in the lamina propria. Even in patients with extraintestinal Whipple disease, the organism usually is identified in the small bowel. The bacillus seems to spread through the lymphatics and through the systemic circulation and then can involve several extraintestinal organs. T. whipplei can be seen faintly by light microscopy. The bacilli are seen best by transmission electron microscopy, which reveals a rod-shaped organism 0.2 µm wide and 1.5 to 2.5 µm long ( Fig. 46.1 ). The ultrastructure of the wall of T. whipplei is similar to that of other gram-positive bacteria, with the exception of an additional surface membrane. This membrane is different from the outer membrane of gram-negative bacteria because it is thinner, has a symmetric profile, and has no PAS-positive components. After the bacillus has been ingested by the macrophage, the degenerative process that occurs leads to the accumulation of bacterial remnants that are resistant to degradation. The polysaccharide-containing portion of the bacillus wall correlates with these remnants, and its progressive accumulation leads to the typical intramacrophagic inclusions. These inclusions are PAS positive and one of the key features in the histologic diagnosis of Whipple disease. Biopsy specimens from the small intestine in patients with Whipple disease usually show characteristic changes. The intestinal villi are preserved, but distortion of the architecture occurs. A clubbed appearance of the intestinal villi usually is present caused by the accumulation of foamy macrophages in the lamina propria. The enterocytes may appear normal, or they may show flattening and vacuolization and occasionally appear cuboidal ( Fig. 46.2 ). Lipid accumulation, with large fat droplets within the lamina propria and smaller droplets within and between the absorptive cells, occurs commonly. In some instances, prominent, dilated lacteals are present. Ectors and associates reported reduced and absent lactase and major histocompatibility complex class II (HLA-DR) expression that normalized within 3 to 6 months of starting antibiotic therapy.
The characteristic feature of Whipple disease is the presence of PAS-positive, diastase-resistant macrophages. These findings are not pathognomonic, however, because intestinal PAS-positive macrophages can be found in other conditions, such as histiocytosis, melanosis coli, and Mycobacterium avium-intracellulare infection, and even within macrophages in healthy individuals. The macrophages in Whipple disease do not stain with Ziehl-Neelsen. A sickle-shaped appearance of the PAS-positive granules often is present in the macrophages of patients with Whipple disease.
Sieracki and Fine observed systemic involvement in the autopsies of five patients with Whipple disease. The sickle-shaped, PAS-positive macrophages were thought to be specific for Whipple disease, showing involvement of the entire gastrointestinal tract and the pancreas; diffuse involvement of the retroperitoneum and lymph nodes, the adrenals, the liver with sickle-form particles in Kupffer cells and in histiocytes, the brain, the heart, and the visceral pleura of the lungs; and minimal involvement of the genitourinary tract, skeletal muscles, and bone marrow. James and associates examined the vessels of the gastrointestinal system and found abundant bacilli in the arteries of the small intestinal serosa and liver. They noted focal degeneration and fibrosis in the tunica media with arteritis and intimal proliferation. Rickman and coworkers reported a case that confirmed the presence of T. whipplei in the vitreous of the eye.
T. whipplei produces a predominantly histiocytic inflammatory reaction, with infiltration by macrophages. Noncaseating, epithelioid cell, sarcoid-like granulomas are located preferentially in peripheral lymph nodes and the liver. These granulomas occasionally can be seen in different tissues, including three reports of granulomas in the intestinal tract. Mesenteric lymph nodes often are strikingly enlarged.
Electron microscopy can be useful, often revealing the presence of the rod-shaped bacterium (see Fig. 46.1 ). Electron microscopy also shows intestinal macrophages containing bacteria with signs of lysis. Silva and associates described steps of a degradative process of the bacillus that starts with disorganization of the surface membrane and the thick outer wall. With the loss of intracellular material, bacterial “ghosts” composed of the three inner layers of the envelope are present. The two electron-dense layers of the cytoplasmic membrane become disorganized and solubilized, leaving the inner dense layer of the cell wall as the final bacterial remnant ( Fig. 46.3 ).
Clinical Manifestations
The manifestations of T. whipplei infections now include at least three forms, “classic” Whipple disease; acute infection, such as gastroenteritis and bacteremia; and asymptomatic carriage ( Box 46.1 ).
Acute infection:
Gastroenteritis
Bacteremia
Pneumonia
Asymptomatic carriage
“Classic” Whipple disease
Acute Infection
Gastroenteritis
T. whipplei is associated with a mild acute gastroenteritis in young children. Diarrhea typically lasts from 4 to 5 days and is associated with weight loss and 1 to 2 days of fever. Additional side effects include vomiting (55%), abdominal pain (25%), and bloody diarrhea (8%). The infection has no seasonality.
Bacteremia
In rural West Africa, T. whipplei was found by PCR in the blood of adults and children with unexplained fever. Patients with T. whipplei bacteremia also have associated cough and sleep disorders. The bacteremia has seasonality, occurring primarily during the months of December and January. Fevers are not commonly associated with gastrointestinal symptoms, and patients rarely have PCR-positive stool or saliva.
Pneumonia
Severe cases of pneumonia in adults and children are associated with T. whipplei . PCR has detected T. whipplei in the bronchoalveolar lavage of mechanically ventilated patients in intensive care units. Initial presentations include aspiration pneumonia, community-acquired pneumonia, and ventilator-associated pneumonia. Duration of mechanical ventilation ranges from 3 to 81 days, and the mortality rate is high (33%).
“Classic” Whipple Disease
Whipple disease is viewed best as a multisystem illness. It usually manifests as arthralgias and then progresses to involve the gastrointestinal tract. Malabsorption is the key feature of clinical disease, but no specific signs or symptoms for Whipple disease are known. The major symptoms and signs of Whipple disease are listed in Table 46.1 . In children, failure to thrive, malnutrition, and chronic diarrhea appear most frequently. Abdominal distention, abdominal pain, and generalized lymphadenopathy may be found. Response to antibiotic treatment may be dramatic, with rapid weight gain and resolution of symptoms.
| Cases (%) | |
|---|---|
| Symptoms | |
| Weight loss | 65–100 |
| Chronic diarrhea | 60–85 |
| Arthralgia | 65–80 |
| Abdominal pain | 60 |
| Fever | 10–55 |
| CNS-related complaints | 10–40 |
| Signs | |
| Malnutrition | 90–95 |
| Hypotension | 70 |
| Lymphadenopathy | 55 |
| Hyperpigmentation | 45–55 |
| Abdominal tenderness | 50 |
| Edema | 30 |
| Abdominal mass | 20 |
| Hepatomegaly | 1–14 |
| Splenomegaly | 5–10 |
| Ascites | 8 |
Gastrointestinal Tract
One of the most common symptoms is weight loss, which is found in 65% to 100% of patients. Weight loss may be the only symptom. Diarrhea is reported in 60% to 85% of patients. The diarrhea usually is watery or fatty. Several mechanisms have been proposed to explain the malabsorption and steatorrhea in Whipple disease. Direct infection and secondary enterocyte dysfunction may prevent the esterification of fatty acids to triglycerides and inhibit the uptake of carbohydrates and amino acids. Blockage of transport of triglyceride-rich chylomicrons into lacteals may result from the deposition of foamy macrophages in the lamina propria. Lymphatic obstruction may occur by involvement of the mesenteric lymph nodes. Malabsorption and diarrhea tend to resolve within a few days after initiation of antibiotic treatment, whereas the lacteal dilation and PAS-positive macrophages can remain for months to years. Occult gastrointestinal bleeding frequently is found, but melena and gross gastrointestinal bleeding are rare. Hematemesis has been reported. Endoscopy revealed diffuse hemorrhagic duodenitis with bleeding on contact.
Abdominal pain is experienced by 60% of patients. The pain is nonspecific, is generally epigastric, and may be worse after meals. Abdominal pain and anorexia may lead to reduced calorie intake and further weight loss. Abdominal distention occurs commonly and may be secondary to intraabdominal lymphadenopathy or to thickening of loops of diseased intestine. Ascites occasionally is seen and may be chylous, secondary to lymphatic obstruction.
Joints
Arthralgia, the most frequent nongastrointestinal symptom in Whipple disease, is present in 65% of adult cases. Arthralgia may precede manifestation of gastrointestinal symptoms by many years or decades and occurs less frequently in children. Generally joint symptoms continue unchanged with the onset of gastrointestinal symptoms. Acute migratory arthralgia or arthritis may last days or weeks and may persist as the disease progresses. The involved joints, in decreasing order of frequency, are knees, ankles, hips, fingers, wrists, elbows, hands, and spine. Examination may reveal joint pain, swelling, limited range of motion, and warmth. Fever sometimes is present. Spondylitis, with or without sacroiliitis, may develop. Permanent joint destruction and deformity are uncommon occurrences but can be severe. Arthrocentesis may reveal an inflammatory arthritis, with cell counts of 6000 to 75,000/mm 3 , often with a polymorphonuclear leukocyte predominance. Synovial biopsy may show PAS-positive macrophages.
Central Nervous System
Whipple disease can be confined to the brain but usually is accompanied by other manifestations. CNS and neurologic manifestations, such as headache, diplopia, meningoencephalitis, depression, confusion, and personality changes, are uncommon manifestations but may be significant. The spectrum of potential CNS involvement is listed in Box 46.2 .
