S Typhi Has Been A Major Human Pathogen For Thousands of Years, Thriving in Conditions of Poor
S Typhi Has Been A Major Human Pathogen For Thousands of Years, Thriving in Conditions of Poor
S Typhi Has Been A Major Human Pathogen For Thousands of Years, Thriving in Conditions of Poor
primarily by Salmonella enterica, subspecies enterica serovar typhi and, to a lesser extent,
related serovars paratyphi A, B, and C.
The protean manifestations of typhoid fever make this disease a true diagnostic challenge. The
classic presentation includes fever, malaise, diffuse abdominal pain, and constipation. Untreated,
typhoid fever is a grueling illness that may progress to delirium, obtundation, intestinal
hemorrhage, bowel perforation, and death within 1 month of onset. Survivors may be left with
long-term or permanent neuropsychiatric complications.
S typhi has been a major human pathogen for thousands of years, thriving in conditions of poor
sanitation, crowding, and social chaos. It may have responsible for the Great Plague of Athens at
the end of the Pelopennesian War.[1] The name S typhi is derived from the ancient Greek typhos,
an ethereal smoke or cloud that was believed to cause disease and madness. In the advanced
stages of typhoid fever, the patient's level of consciousness is truly clouded. Although antibiotics
have markedly reduced the frequency of typhoid fever in the developed world, it remains
endemic in developing countries.[2]
S paratyphi causes the same syndrome but appears to be a relative newcomer. It may be taking
over the typhi niche, in part, because of immunological naivete among the population and
incomplete coverage by vaccines that target typhi.
Note that some writers refer to the typhoid and paratyphoid fever as distinct syndromes caused
by the typhi versus paratyphi serovars, while others use the term typhoid fever for a disease
caused by either one. We use the latter terminology. We refer to these serovars collectively as
typhoidal salmonella.
Pathophysiology
All pathogenic Salmonella species, when present in the gut are engulfed by phagocytic cells,
which then pass them through the mucosa and present them to the macrophages in the lamina
propria. Nontyphoidal salmonellae are phagocytized throughout the distal ileum and colon. With
toll-like receptor (TLR)5 and TLR-4/MD2/CD-14 complex, macrophages recognize pathogen-
Chronic carriers are responsible for much of the transmission of the organism. While
asymptomatic, they may continue to shed bacteria in their stool for decades. The organisms
sequester themselves either as a biofilm on gallstones or gallbladder epithelium or, perhaps,
intracellularly, within the epithelium itself.[7] The bacteria excreted by a single carrier may have
multiple genotypes, making it difficult to trace an outbreak to its origin.[8]
Risk factors
Typhoidal salmonella have no nonhuman vectors. An inoculum as small as 100,000 organisms of
typhi causes infection in more than 50% of healthy volunteers.[9] Paratyphi requires a much
higher inoculum to infect, and it is less endemic in rural areas. Hence, the patterns of
transmission are slightly different.
The following are modes of transmission of typhoidal salmonella:
Paratyphi is more commonly transmitted in food from street vendors. It is believed that some
such foods provide a friendly environment for the microbe.
Paratyphi is more common among newcomers to urban areas, probably because they tend to be
immunologically nave to it. Also, travellers get little or no protection against paratyphi from the
current typhoid vaccines, all of which target typhi.[13, 14]
Typhoidal salmonella are able to survive a stomach pH as low as 1.5. Antacids, histamine-2
receptor antagonists (H2 blockers), proton pump inhibitors, gastrectomy, and achlorhydria
decrease stomach acidity and facilitate S typhi infection.[4]
Between 1999 and 2006, 79% of typhoid fever cases occurred in patients who had been outside
of the country within the preceding 30 days. Two thirds of these individuals had just journeyed
from the Indian subcontinent. The 3 known outbreaks of typhoid fever within the United States
were traced to imported food or to a food handler from an endemic region. Remarkably, only
17% of cases acquired domestically were traced to a carrier.[22]
International
Typhoid fever occurs worldwide, primarily in developing nations whose sanitary conditions are
poor. Typhoid fever is endemic in Asia, Africa, Latin America, the Caribbean, and Oceania, but
80% of cases come from Bangladesh, China, India, Indonesia, Laos, Nepal, Pakistan, or
Vietnam.[23] Within those countries, typhoid fever is most common in underdeveloped areas.
Typhoid fever infects roughly 21.6 million people (incidence of 3.6 per 1,000 population) and
kills an estimated 200,000 people every year.[24]
In the United States, most cases of typhoid fever arise in international travelers. The average
yearly incidence of typhoid fever per million travelers from 1999-2006 by county or region of
departure was as follows:[22]
Canada - 0
Africa - 7.6
Asia - 10.5
Mortality/Morbidity
With prompt and appropriate antibiotic therapy, typhoid fever is typically a short-term febrile
illness requiring a median of 6 days of hospitalization. Treated, it has few long-term sequelae and
a 0.2% risk of mortality.[22] Untreated typhoid fever is a life-threatening illness of several weeks'
duration with long-term morbidity often involving the central nervous system. The case fatality
rate in the United States in the pre-antibiotic era was 9%-13%.[25]
Race
Typhoid fever has no racial predilection.
Sex
Fifty-four percent of typhoid fever cases in the United States reported between 1999 and 2006
involved males.[22]
Age
Most documented typhoid fever cases involve school-aged children and young adults. However,
the true incidence among very young children and infants is thought to be higher. The
presentations in these age groups may be atypical, ranging from a mild febrile illness to severe
convulsions, and the S typhi infection may go unrecognized. This may account for conflicting
reports in the literature that this group has either a very high or a very low rate of morbidity and
mortality.[21, 26
History
A severe nonspecific febrile illness in a patient who has been exposed to typhoidal salmonella
should always raise the diagnostic possibility of typhoid fever (enteric fever).
Classic typhoid fever syndrome
The clinical syndromes associated with S typhi and paratyphi are indistinguishable. Typhoid
fever begins 7-14 days after ingestion of the organism . The fever pattern is stepwise,
characterized by a rising temperature over the course of each day that drops by the subsequent
morning. The peaks and troughs rise progressively over time.
Over the course of the first week of illness, the notorious gastrointestinal manifestations of the
disease develop. These include diffuse abdominal pain and tenderness and, in some cases, fierce
colicky right upper quadrant pain. Monocytic infiltration inflames Peyer patches and narrows the
bowel lumen, causing constipation that lasts the duration of the illness. The individual then
develops a dry cough, dull frontal headache, delirium, and an increasingly stuporous malaise.[2]
At approximately the end of the first week of illness, the fever plateaus at 103-104F (39-40C).
The patient develops rose spots, which are salmon-colored, blanching, truncal, maculopapules
usually 1-4 cm wide and fewer than 5 in number; these generally resolve within 2-5 days. [2]
These are bacterial emboli to the dermis and occasionally develop in persons with shigellosis or
nontyphoidal salmonellosis.[27]
During the second week of illness, the signs and symptoms listed above progress. The abdomen
becomes distended, and soft splenomegaly is common. Relative bradycardia and dicrotic pulse
(double beat, the second beat weaker than the first) may develop.
In the third week, the still febrile individual grows more toxic and anorexic with significant
weight loss. The conjunctivae are infected, and the patient is tachypneic with a thready pulse and
crackles over the lung bases. Abdominal distension is severe. Some patients experience foul,
green-yellow, liquid diarrhea (pea soup diarrhea). The individual may descend into the typhoid
state, which is characterized by apathy, confusion, and even psychosis. Necrotic Peyer patches
may cause bowel perforation and peritonitis. This complication is often unheralded and may be
masked by corticosteroids. At this point, overwhelming toxemia, myocarditis, or intestinal
hemorrhage may cause death.
If the individual survives to the fourth week, the fever, mental state, and abdominal distension
slowly improve over a few days. Intestinal and neurologic complications may still occur in
surviving untreated individuals. Weight loss and debilitating weakness last months. Some
survivors become asymptomatic S typhi carriers and have the potential to transmit the bacteria
indefinitely.[21, 28, 29, 2, 4]
Week 1
Week 2
Week 3
Very
Very common
Week 4
Post
Recover
10%-20%
n
Systemic
Stepladder
fever
pattern or insidious
onset fever
Acute high fever
Chills
Rigors
Anorexia
Diaphoresis
Neurologic
Malaise
commona
or death 3%-4%
(15% of chronic
Very rareb
Almost allc
Uncommon
Almost all
Very common
Almost
y phase relapse;
Almost
untreate
d cases)
Typhoid
carriers;
all
Insomnia
all
Very
Confusion/delirium
common
Very
Common
d
Psychosis
Catatonia
Frontal
headache
Very rare
Very rare
Very
state
long-term
(common
neurologic
sequelae
(extremel
common
Common
rare);
common
gallbladde
(usually
mild)
cancer
(RR=167;
carriers)
Meningeal signs
Parkinsonism
Ear, nose, and throat
Coated tongue
Raree
Very rare
Rare
Very
common
Sore throatf
Pulmonary
Mild cough
Bronchitic cough
Rales
Pneumonia
Common
Common
Common
Rare
Rare
Common
(lobar)
(basal)
Cardiovascular
Dicrotic pulse
Myocarditis
Pericarditis
Rare
Rare
Extremel
Common
y rareg
Thrombophlebitis
Gastrointestinal
Very rare
Constipation
Very
Common
Diarrhea
Bloating
common
Rare
Very
with
tympany
common
Diffuse
mild
(84%)[35]
Very
abdominal pain
Sharp right lower
common
Rare
quadrant pain
Gastrointestinal
hemorrhage
usually
trace
intestinal
perforation
Hepatosplenomegal
Rare
Common
y
Jaundice
Common
Gallbladder pain
Very rare
Urogenital
Urinary retention
Common
Hematuria
Rare
Renal pain
Rare
Musculoskeletal
Myalgias
Very rare
Arthralgias
Very rare
Rheumatologic
Arthritis
(large Extremely rare
joint)
Dermatologic
Rose spots
Miscellaneous
Abscess (anywhere)
a
Rare
Extremel
Extremel
Extremel
y rare
y rare
y rare
Very common: Symptoms occur in well over half of cases (approximately 65%-95%).
Very
rare:
Almost
Symptoms
all:
Common:
Rare:
occur
Symptoms
Symptoms
Symptoms
in
less
occur
occur
occur
than
in
in
in
5%
of
cases.
almost
all
cases.
35%-65%
of
cases.
5%-35%
of
cases.
Blank cells: No mention of the symptom at that phase was found in the literature.
Extremely
rare:
Symptoms
have
been
described
in
occasional
case
reports.