Lecture 20. Enteric Fever. Typhus Fever.

Relapsing Fever
Enteric Fever
Salmonellosis and Typhoid Fever
Salmonellae are flagellated, gram-negative bacteria that cause a self-limited food-borne and
water-borne gastroenteritis (Salmonella enteritidis, Salmonella typhimurium, and others) or a life-
threatening systemic illness marked by fever (Salmonella typhi). In the United States, Salmonella
species cause approximately 500,000 reported cases of food poisoning, and many cases go
unreported. Because Salmonella species (other than S. typhi) infect most commercially raised
chickens and many cows, the major sources of Salmonella in the United States are feces-
contaminated meat and chicken that are insufficiently washed and cooked. In contrast, humans
are the only host of S. typhi, which is shed in the faeces, urine, vomitus, and oral secretions by
acutely ill persons and in the faeces by chronic carriers without overt disease. Therefore, typhoid
fever is a disease largely of developing countries where sanitary conditions are insufficient to
stop its spread. Typhoid fever is a protracted disease that is associated with bacteraemia, fever,
and chills during the first week; widespread reticuloendothelial involvement with rash, abdominal
pain, and prostration in the second week; and ulceration of Peyers patches with intestinal
bleeding and shock during the third week.
PATHOGENESIS. The typhoid bacilli are ingested through contaminated food or water. During
the initial asymptomatic incubation period of about 2 weeks, the bacilli invade the lymphoid
follicles and Peyer's patches of the small intestine and proliferate. Salmonellae invade intestinal
epithelial cells as well as tissue macrophages. Invasion of intestinal epithelial cells is controlled
by invasion genes that are induced by the low oxygen tension found in the gut. These genes
encode proteins involved in adhesion and in recruitment of host cytoskeletal proteins that
internalize the bacterium. Similarly, intramacrophage growth is important in pathogenicity, and
this seems to be mediated by bacterial genes that are induced by the acid pH within the
macrophage phagolysosome. Following this, the bacilli invade the blood stream causing
bacteraemia, and the characteristic clinical features of the disease like continuous rise in
temperature and 'rose spots' on the skin are observed. Immunological reactions (Widal's test) be-
gin after about 10 days and peak litres are seen by the end of the third week. Eventually, the
bacilli are localised in the intestinal lymphoid tissue (producing typhoid intestinal lesions), in the
mesenteric lymph nodes (leading to haemorrhagic lymphadenitis), in the liver (causing foci of
parenchymal necrosis), in the gall bladder (producing typhoid cholecystitis), and in the spleen
(resulting in splenic reactive hyperplasia).
PATHOLOGIC CHANGES. The lesions are observed in the intestines as well as in other
organs.
1. INTESTINAL LESIONS. Lesions Induced by S. enteritidis or S. typhimurium are limited to
the ileum and colon and include erosion of the epithelium and mixed inflammation in the lamina
propria. Variable numbers of polymorphonuclear neutrophils are found in the stools, depending
on the severity of the infections. S. typhi causes proliferation of phagocytes with enlargement of
reticuloendothelial and lymphoid tissues throughout the body, Peyers patches in the terminal
ileum become sharply delineated, plateau-like elevations up to 8 cm in diameter, with
enlargement of draining mesenteric lymph nodes. In the second week, the mucosa over the
swollen lymphoid tissue is shed, resulting in oval ulcers with their long axes in the direction of
bowel flow.

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Macroscopically, terminal ileum is affected most often, but lesions may be seen in the jejunum
and colon. The Peyer's patches show oval typhoid ulcers with their long axis along the length of
the bowel. The base of the ulcers is black due to sloughed mucosa. The margins of the ulcers are
slightly raised due to inflammatory oedema and cellular proliferation. There is never significant
fibrosis and hence fibrous stenosis seldom occurs in healed typhoid lesions. The regional lymph
nodes are invariably enlarged.
Microscopically. There is hyperaemia, oedema and cellular proliferation consisting of phagocytic
histiocytes (showing characteristic erythrophagocytosis), lymphocytes and plasma cells. Though
enteric fever is an example of acute inflammation, neutrophils are invariably absent from the
cellular infiltrate and this is reflected in the leucopenia with neutropenia and relative
lymphocytosis in the peripheral blood.
The spleen is enlarged, soft, and bulging, with uniformly pale red pulp, obliterated follicular
markings, and prominent sinus histiocytosis and reticuloendothelial proliferation. The liver shows
small, randomly scattered foci of parenchymal necrosis in which the hepatocytes are replaced by
a phagocytic mononuclear cell aggregate, called a typhoid nodule. These distinctive nodules also
occur in the bone marrow and lymph nodes. Gallbladder colonization, which may be associated
with gallstones, causes a chronic carrier state.
The main complications of the intestinal lesions of typhoid are perforation of the ulcers and
haemorrhage.
2. OTHER LESIONS. Besides the intestinal involvement, various other organs and tissues
showing pathological changes in enteric fever are:
(i) Mesenteric lymph nodeshaemorrhagic lymphadenitis.
(ii) Liverfoci of parenchymal necrosis.
(iii) Gall bladdertyphoid cholecystitis.
(iv) Spleen-splenomegaly with reactive hyperplasia.
(v) Kidneysnephritis.
(vi) Abdominal musclesZenker's degeneration.
(vii) Jointsarthritis.
(viii) Bonesosteitis.
(ix) MeningesMeningitis.
(x) TestisOrchitis.
Persistence of organism in the gall bladder or urinary tract may result in passage of organisms
in the faeces or urine creating a "carrier state' which is a source of infection to others.
Rickettsial Infections
Rickettsiae are vector-borne obligate intracellular bacteria that cause epidemic typhus (Rickettsia
prowazekii), scrub typhus (Rickettsia tsutsugamushi), and spotted fevers (Rickettsia rickettsii and
others). In contrast, Q fever, which is caused by the related organism Coxiella burnetii and
produces pneumonia and fever, is transmitted by aerosols. Ehrlichia chaffeensis, a newly
discovered in-tracellular organism related to the rickettsiae, causes an acute febrile illness similar
to the spotted fevers, but without a rash." It is tick transmitted and may predominantly affect
neutrophils or macrophages. Epidemic typhus, which is transmitted from person to person by
body lice, is particularly associated with wars and human suffering, when persons are forced to
live in close contact without changing clothes (e.g., a 1996 outbreak in a Burundi prison). Scrub
typhus, transmitted by chiggers, was a major problem for U.S. soldiers in the Pacific in World
War II and in Vietnam. RMSF, transmitted to humans by rodent and dog ticks, is most frequent in
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the south-eastern and south-western United States. Rickettsiae of RMSF enter the skin with the
bite or with scratching of the skin covered with insect faeces.
Pathogenesis. Regardless of the route of infection, rickettsiae predominantly infect endothelial
and vascular smooth muscle cells, causing a vasculitis that may be complicated by thrombi and
haemorrhages. Rickettsiae have an endotoxin but lack secreted toxins. In addition. R. rickettsii
activates host kallikrein and kinins and so causes local clotting. Rickettsiae bind to cholesterol-
containing receptors, are endocytosed into phagolysosomes, escape into the cytosol, and multiply
until they burst the cells. Antibody-dependent and cell-dependent immunity may prevent rein-
fection with rickettsiae but may not prevent reactivation of typhus after many years, which is
referred to as Brill-Zinsser disease. Instead, T lymphocyte- mediated immunity is most important
for clearing rickettsiae. One effect of cellular immunity may be release of cytokines that induce
nitric oxide-mediated, antirickettsial activity, not dissimilar to that described for activated
macrophages. Rickettsial infections are diagnosed by immunostaining of organisms or by
detection of antibodies in the serum. Against this background, we can turn to the morphology of
rickettsial infections with particular emphasis on typhus fever and RMSF.
MORPHOLOGY. Typhus Fever. In milder coses, the gross changes are limited to a rash and
small hemorrhages incident to the vascular lesions. In more severe cases, there may be areas of
necrosis of the skin with gangrene of the tips of the fingers, nose, scrotum, penis, and vulva. In
such cases, irregular ecchymotic haemorrhages may be found internally, principally in the brain',
heart muscle, testes, serosal membrane, lungs, and kidneys.
The most prominent microscopic changes are the small-vessel lesions that underlie the rash and
the focal areas of haemorrhage and inflammation in the various organs and tissues affected.
Endothelial proliferation and swelling in the capillaries, arterioles, and venules may narrow the
lumina of these vessels. Surrounding the involved vessels, a cuff of inflammatory mixed
leukocytes is usually present. The vascular lumina are sometimes thrombosed, but necrosis of the
vessel wall is unusual in typhus compared with RMSF. It is the vascular thromboses that lead to
the gangrenous necroses of the skin and other structures. In the brain, characteristic typhus
nodules are composed of focal microglial proliferations mixed with leukocytes.
Rocky Mountain Spotted Fever. An eschar at the site of the tick bite followed by a hemorrhagic
rash that extends over the entire body, including the palms of the hands and soles of the feet, is
the hallmark of RMSF. The vascular lesions that underlie the rash often lead to acute necrosis,
fibrin extravasations, and thrombosis of the small blood vessels, including arterioles. In severe
RMSF, foci of necrotic skin ore thus induced, particularly on the fingers, toes, elbows, ears, and
scrotum. Vascular necrosis and thrombosis are far more frequent with RMSF than with typhus
and may mimic the necrotizing vasculitis of the collagen vascular diseases. Despite frequent local
thrombi, systemic DIC is rare, even in the most severe cases; The perivascular inflammatory
response is similar to that of typhus, particularly in the brain, skeletal muscle, lungs, kidneys,
testes, and heart muscle. The vascular necroses in the brain may involve larger vessels and
produce focal areas of ischemic demyelinization or microin-forcts, A pneumonitis of primary
rickettsial origin is present in severely affected patients and often predisposes to a secondary
bacterial infection.
Other Rickettsial Infections. Coxiella infections (Q fever) mainly involve the lungs, producing an
interstitial pneumonitis that resembles viral pneumonia. In severe cases, small gronulomas may
appear in the spleen, liver, and bone marrow along with focal perivoscular inflammatory
infiltrates.
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Scrub typhus, or mite-borne infection, is usually a milder version of typhus fever. The rash is
usually transitory or may not appear. Vascular necrosis or thrombosis is rare, but there may be a
prominent inflammatory lymphadenopathy.
Relapsing Fever
Relapsing fever is caused by helical Borrelia spirochetes (B. recurrentis), which are transmitted
from person to person by body lice or from animals to humans by soft ticks. Louse-transmitted
Borrelia, associated with overcrowding due to poverty or war, caused multiple large epidemics in
Africa, Eastern Europe, and Russia in the first half of the 20th century, infecting 15 million
persons and killing 5 million, and is still a problem in some developing countries.
In both lice- and tick-transmitted borreliosis, there is a 1- to 2-week latent period after the bite as
the spirochetes multiply in the serum. Clinical infection is heralded by shaking chills, fever,
headache, and fatigue, followed by DIC and multiorgan failure. Cytokines include TNF-a. Spi-
rochetes are cleared from the blood by anti-Borrelia antibodies that target a single major surface
protein called the variable major protein. After a few days, bacteria bearing a different surface
antigen reach high densities in the blood, and symptoms return until a second set of host
antibodies clears these organisms. Other infectious agents that change surface molecules in
response to antibodies, which is called antigenic variation. The lessening severity of successive
attacks of relapsing fever and its spontaneous cure in many untreated patients have been
attributed to the limited genetic repertoire of Borrelia, enabling the host to build up cross-reactive
as well as clone-specific antibodies. Antibiotic treatment of Borrelia infections may cause a
massive release of endotoxin, resulting in a dangerous rise in temperature with rigors, fall in
blood pressure, and leukopenia (the Jarisch-Herxheimer reaction). Because reactions to endotoxin
are mediated by host TNF-a, anti-TNF antibodies can protect patients from the Jarisch-
Herxheimer reaction.
MORPHOLOGY. In fatal louse-borne disease, the spleen is moderately enlarged (300 to 400 gm)
and contains focal necroses and miliary collections of leukocytes, including neutrophils, and
numerous borreliae. There is congestion and hypercellularity of the red pulp with
erythrophagocytosis. The liver may also be enlarged and congested with prominent Kupffer cells
and septic foci. Scattered haemorrhages resulting from DIC may be found in serosal and mucosal
surfaces, skin, and viscera. Pulmonary bacterial super infection is a frequent complication.