Proposed Sequence of Events

Mucosal Penetration

After ingestion, the organisms pass through the upper gastrointestinal tract to the small intestine, where they either invade directly or multiply for several days before invading. Since fewer than 5% of the villi have organisms attached, it is hypothesized that there are specific receptor sites on the villi, but these receptors have not been identified. Stool cultures are positive for several days after S. Typhi ingestion and then become negative until after the onset of clinical illness. Human volunteer studies have shown that invasion can take place in the jejunum, and animal studies suggest that it occurs in the ileum. The M cells, epithelial cells that overlie the Peyer's patches, are the potential sites where S. Typhi is internalized and transported to the underlying lymphoid tissues.62 After penetration, the organisms pass to the intestinal lymphoid follicles and the draining mesenteric lymph nodes; some also pass into the systemic circulation where they are filtered out by the reticuloendothelial cells of the liver and spleen. The salmonellae are able to prevent acidification of the phagosomes, survive, and multiply within the mononuclear phagocytic cells of the lymphoid follicles, lymph nodes, liver, and spleen. At this stage, there are subtle degenerative, proliferative, and granulo-matous changes in the villi, crypt glands, and lamina propria of the small bowel and in the mesenteric lymph glands. These changes are reversible and unassociated with clinical symptoms.

Dissemination and Organ Invasion

At a critical point (which is probably a function of number of bacteria, bacterial virulence, and the host's immune response), a sufficient number of organisms and possibly other mediators that induce clinical symptoms are released from this sequestered intracellular habitat in the intestinal and mesen-teric lymph system and pass through the thoracic duct and into the general circulation. This marks the end of the incubation period, which may last from 3 to 60 days, but is usually 7 to 14 days.

During this bacteremic phase, the organisms may invade any organ but are most commonly found in the liver, spleen, bone marrow, gallbladder, and Peyer's patches in the terminal ileum.56,63 They invade the gallbladder either directly from the bloodstream or from the bile and then reappear in the intestine, where they are excreted in the stool and reinvade through the intestinal wall. At most tissue sites the organisms are again taken up by, and multiply within, the mononuclear phagocytic cells.

Pathology

The basic histologic finding in typhoid fever is infiltration of tissues by macrophages (typhoid cells) containing bacteria, erythrocytes, and degenerated lymphocytes. Aggregates of these macrophages are called typhoid nodules (Fig. 17-2). They are most commonly found in the intestine, mesenteric lymph nodes, spleen, liver, and bone marrow, but may be found in the kidneys, testes, and parotid glands.

Intestine

In the intestine, there are four classic pathologic stages. Hyperplastic changes begin during the first week of illness and primarily involve Peyer's patches of the ileum and solitary lymphoid follicles of the cecum, but may involve any lym-phoid tissue in the intestine. Almost all infiltrative cells are mononuclear; typhoid nodules are common. If the hyperplasia does not resolve, necrosis of the intestinal mucosa develops, usually after 7 to 10 days of clinical illness (Fig. 17-3). Sloughing of the mucosa follows and results in the development of an ulcer, which may bleed (see Fig. 17-3). The ulcers conform in shape and distribution to the location of the lymphoid follicles are largest in the ileum, and are almost always found on the antimesenteric border of the intestines. These ulcers may perforate into the peritoneal cavity.64 Perforations are single and measure less than 1 cm in 80% of cases, and 90% are found within 60 cm of the ileocecal valve. When healing takes place, it is usually complete, without scarring.

Mesenteric Lymph Nodes, Spleen, and Liver

In the mesenteric lymph nodes, the sinusoids are enlarged and distended by large collections of macrophages and reticuloendothelial cells. The nodes become soft and swollen and often contain areas of focal necrosis. The spleen is enlarged, red, soft, and congested. Its serosal surface may have

FIGURE 17-3 Peyer's patches in the ileum showing several stages in a single specimen. A, Active ulceration. B, Necrosis. C, The sloughing of necrotic tissue has left the muscularis bare. (Courtesy of the Armed Forces Institute of Pathology, Neg. No. 64-3208-2.)

a fibrinous exudate. Microscopically, the red pulp is congested and contains typhoid nodules. The liver is usually enlarged. Hypertrophy and hyperplasia of the Kupffer cells produce the typhoid nodules. There is frequently focal hepatic necrosis and cloudy swelling of hepatocytes. The gallbladder is usually slightly hyperemic and may, in rare instances, show evidence of cholecystitis.

Other Organs

These are less frequently involved during typhoid fever and usually have lesions attributed to toxic factors. The heart may be flabby with dilated ventricles, and microscopically there is often a nonspecific pattern of necrosis with degeneration and fatty infiltration of the myocardial cells. The lungs may develop an interstitial pneumonitis and bronchitis, and skeletal muscles may show Zenker's degeneration. The most common lesion found in the kidneys is swelling and albuminous degeneration of the proximal tubular epithelium, but interstitial nephritis, glomerulonephritis, and pyelonephritis have been noted. Central nervous system changes have been poorly described, but ring hemorrhages, capillary thrombi, perivenous demyelinating leukoencephalitis, and meningitis have been reported. Occasionally, focal lesions such as osteomyelitis, brain abscess, and spleen and liver abscesses have been reported. These lesions are almost always characterized by a polymorphonuclear instead of a mononuclear response. Salmonellae stimulate phagocytosis of neutrophils, red blood cells, and platelets by histiocytes within the bone marrow stroma.65 This may be one of the mechanisms behind the pancytopenia commonly seen in typhoid fever.

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