Typhoid fever is an acute systemic
illness caused by motile, gram-negative bacilli of the genus
Salmonella usually S. typhi or S. enteritidis.
The organisms are gram-negative,
flagellated, noncapsulated, non-sporulating, facultative anaerobic
bacilli, which have characteristic flagellar, somatic, and outer coat
antigens.
Typhoid fever, the most serious human
salmonellosis, is characterized by prolonged fever, bacteremia and
multiplication of the organisms within mononuclear phagocytic cells of
the liver, spleen, lymphnodes, and Payer’s patches.
Humans are the only natural reservoir
for S. typhi, and typhoid fever therefore must be acquired from
convalescing patients or from chronic carriers- specially older women
with gallstones or biliary scarring, in whom S. typhi may colonize
the gallbladder or biliary tree.
Mode of
infection:
Typhoid fever is spread primarily
through ingestion of contaminated water and food (especially dairy
products and shellfish), and much less commonly by direct
finger-to-mouth contact with faeces, urine, or other secretions.
Although concentrations of Salmonella
typhi in the water or food may be too low to cause infections, the
organisms may proliferate sufficiently when environmental conditions
are favourable to cause infection.
Shellfish in contaminated water filter
large volumes and concentrate the microbial content, a process that
accumulates enormous doses of S. typhi in raw shellfish.
Urine from patients with
pyelonephritis can be a significant source of S. typhi. Typhoid fever
has become rare in countries with modern control of sewage and of
water and milk supplies.
Throughout history of armies and
refugees have been especially susceptible.
Stages of
infection:Untreated typhoid fever progresses
through the following five stages:
Incubation (10-14 days); Active
invasion/bacteremia (1 week); Fastigium (1 week); Lysis (1 week) and
Convalescence (several weeks).
Following ingestion, bacilli must first
survive gastric acid.
Thus, patients who ingest antacids,
have had a gastrectomy, or have low gastric acidity for other reasons
require fewer organisms for infection.
Bacilli that survive gastric acidity
attach preferentially to the tips of villi in the small intestine,
onvade the mucosa immediately, or multiply in the lumen for several
days before penetrating the mucosa.
The bacilli then pass to the lymphoid
follicles of the intestine and the draining mesenteric lymph nodes.
Some organisms pass into the systemic circulation and are phagocytosed
by the reticuloendothelial cells of liver and spleen.
Bacilli invade and proliferate further
within the phagocytic cells of the intestinal lymphoid follicles,
mesenteric lymph nodes, liver, and spleen.
During this initial incubation period,
therefore, the bacilli are primarily sequestered in the intracellular
habitat of the intestinal and mesenteric lymphoid system.
Eventually the bacilli are released
from the reticuloendothelial cells, pass through the thoracic duct,
enter the blood stream, and produce a primary transient bacteremia and
clinical symptoms.
During this active invasion/bacteremic
phase, bacilli disseminate to and proliferate in many organs, but are
most numerous in organs that possess significant phagocytic activity,
namely liver, spleen and bone marrow.
The Peyer’s patches of the terminal
ileum and the gall bladder are also hospitable sites.
Bacilli invade the gall-bladder from
either blood or bile, after which they reappear in the intestine, are
excreted in the stool, or reinvade the wall of the intestine.
Clinical
presentation: Clinically, the patients develop fever,
diarrhea or constipation, vomiting, abdominal distention, myocarditis,
splenomegaly, leukopenia, and mental changes.
The patient’s temperature follows a
characteristic pattern. It remains normal during the incubation
period, undergoes daily stepwise elevations during active invasion,
remains high during fastigium, falls slowly (with fluctuations) during
lysis, and remains normal during convalescence. During the bacteremic
phase, patients typically have a spiking afternoon fever that
increases daily (up to 105C) before stabilizing in the second or third
week of illness. The high fever is often associated with prostration
and delirium.
In the final phase, usually 3 to 5
weeks after onset, the patient is febrile and exhausted, but recovers
if there are no complications.
Infection of Peyer’s patches leads to
lymphoid hyperplasia, which can resolve without scarring or can
progress to capillary thrombosis, with necrosis and ulceration.
S. typhi in the blood during the second
or third week of illness initiate prolonged bacteremia, often heralded
by the transient appearances of “rose spot”-macular lesions on the
limbs, lower abdomen, and chest that resemble petechial hemorrhages,
but are actually foci of hyperemia (capillary atony). Microscopically,
the macular lesions are edematous and infiltrated with histiocytes-an
appearance that reveals that they are sites of bacterial localization
and toxic injury.
Bacteria are seeded to the organs, including, spleen,
liver, kidneys, and gallbladder, and chronic cholecystis may be
established.
Bacteria shed from the gallbladder reinfect the
intestine, producing a tender abdomen and diarrheal disease, and they
may also produce hepatosplenomegaly.
Complication:
The most frequent and severe
complication is intestinal perforation with peritonitis.
Other
problems are bleeding and thrombophlebitis, usually of the saphenous
vein, cholecystitis, pneumonia and focal abscesses in various organs
and tissues.
The mortality from these complications
ranges from 2% to 10% without treatment.
About 20% of untreated convalescent
patients relapse.
Diagnosis:
Success of cultivation of salmonella
varies with stage and “tissue” (blood, urine, or stool).
Cultures of
blood may be positive during incubation and are usually positive
during active invasion and fastigium ; they are usually negative during
lysis and convalescence.
Culture of urine and stool grow salmonella
less frequently, but usually become positive toward the end of fastigium. Stool cultures remain positive until late convalescence.
The Widal agglutination test, using H (flagellar) or O (somatic)
antigens, becomes positive 10 or more days after onset, titers
continue to rise into convalescence.
Pathological features:
Image1
;
Image2
(Dr Tsutsumi)
The earliest pathologic changes are in
the stages of bacterial attachment and penetration.
Bacteria are
firmly attached to intestinal epithelium with an accompanying
degeneration of the brush borders.
Later as the salmonellae pass to
lymphoid follicles of the intestine, there is diffuse enterocolitis
and hypertrophy of Peyer’s patches.
This is followed by necrosis of
intestinal and mesenteric lymphoid tissues, focal granulomas in the
liver and spleen, and characteristic mononuclear inflammatory cells
(“typhoid nodules”) in many organs.
Typhoid nodules are primarily
aggregates of altered macrophages (“typhoid cells”) that phagocytose
bacteria, erythrocytes and degenerated lymphocytes.
These nodules also
contain plasma cells and lymphocytes, but not typically neutrophils.
The most common sites for typhoid
nodules are the intestine, mesenteric lymph nodes, spleen, liver, and
bone marrow. Less commonly, the kidney, testes, and parotid gland are
affected.
Although the pathologic changes of
typhoid fever may not correlate precisely with the clinical stages,
certain patterns are characteristic.
During the incubation stage there
is a mild enteritis, mesenteric lymphadenitis, and hyperplasia of
intestinal lymphoid tissue, primarily of Peyer’s patches of the ileum
and solitary lymphoid follicles of the cecum.
The lymphoid hyperplasia
may resolve or may progress to capillary thrombosis.
Thrombosis causes
the adjoining intestinal mucosa to enlarge during the phase of active
invasion and then become necrotic.
This process gives rise to the
characteristic lesions, which are elevated 0.1 to 0.4 cm above adjacent
mucosa.
While bacilli continue to proliferate,
dying bacilli release endotoxins that cause toxemia, beginning during
invasion and becoming maximal in fastigium.
The necrotic mucosa
sloughs, usually during lysis, producing ulcers that conform to
Peyer’s patches and are concentrated along the antimesenteric border.
The ulcers may bleed or perforate, usually during lysis. Most
perforations are near the ileocecal valve, measure less than 1 cm
across, and lead to peritonitis.
Interestingly, these areas become
repopulated with lymphoid cells and heal without scarring.
During active invasion the mesenteric
lymph nodes enlarge and develop typhoid nodules, focal hemorrhages,
and necrosis, changes which resemble those in the intestinal lymphoid
tissue.
The spleen becomes large and hyperemic and microscopically
shows typhoid nodules in the red pulp. The hyperplastic white pulp
exhibits areas of focal necrosis.
The enlarged liver displays
sinusoids lined with swollen Kupffer’s cells and histiocytes. Focal
necrosis of liver cells is common. The lack of neutrophils in typhoid
fever is conspicuous.
The intestinal ulcers and focal areas of
necrosis, are bounded only by chronic inflammatory cells, and the
patient is actually leukopenic.
Toxemia may cause other complications,
including ileus ; mild fatty liver; a flabby heart with dilated
ventricles, vacuolization of cardiac myocytes, and cardiac arrhythmia
that may cause sudden death; mild interstitial pneumonitis ; swelling
and degeneration of the proximal tubular epithelium of kidney; “ring”
hemorrhages in brain; capillary microthrombi ; and degeneration of
skeletal muscles.
During convalescence, the intestine
returns to normal, with minimal scarring of the mucosa. Adhesions are
rare.
Typhoid nodules in various organs are resorbed without
distortion of the architecture.
The capsule of the spleen, however,
may become fibrotic, giving the appearance of “sugar coating”.
Skeletal muscles regenerates and toxic
changes of heart disappear.
Treatment:
The most widely used antibiotic for
typhoid fever is chloramphenicol. However, this drug does not reduce
the relapse rate, and convalescent excretors and chronic carriers are
not cured. Moreover, some strains of S typhi are resistant, and
chloramphenicol may cause aplastic anemia. Other effective antibiotics
(some without these disadvantages) are ampicillin, amoxicillin, and
trimethoprim-sulfametholoxazole.
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