Typhoid Fever
Introduction
Typhoid or enteric fever is an ancient disease, which has afflicted mankind
since human populations grew large enough to contaminate their water and food
supplies. It is caused by Salmonella enterica serovar typhi (previously known
as salmonella typhi), a pathogen specific only to humans, as well as by certain
non-typhoid salmonella (NTS), particularly Paratyphoid strains A, B, C. These
waterborne gram negative aerobes are associated with poor sanitation and fecal
contamination of water and food supplies. The syndrome needs to be distinguished
from that caused by many other organisms. Today there are as many as 16-30
million cases per year, almost exclusively in the developing world, with a
mortality rate of 10%. Recent developments in the mapping of the Salmonella
genome have provided insights into its pathogenicity and how antibiotic resistance
and human immunity develop. Typhoid fever is important surgically because
abdominal complications such as intestinal perforation, bleeding, cholecystitis
and pancreatitis represent the most serious complications of the illness.
Typhoid perforation of the ileum is one of the most common causes of bowel
perforation in the developing world. (1) Excellent reviews
are available for both adult (2-6) as well
as pediatric disease. (7) This Review will focus on recent
developments in our understanding of this disease.
History
Typhoid fever was not well understood in the ancient world, probably because
its symptoms are not primarily diarrheal, but rather systemic and non-specific.
It was only in the mid-19th century that physicians began to distinguish it
from typhus and malaria. (8) Sir William Osler’s clinical
description remains unsurpassed. Typhoid fever was frequently associated with
military campaigns and was a significant cause of death in the American Civil
War and Boer War where deaths from typhoid exceeded those from combat. (9)
With recognition that fecal contamination of food and water supplies was the
main mode of transmission of the illness and measures taken to prevent these
(10;11), typhoid fever has been restricted,
in industrialized countries, to localized epidemics (12;13)
and infections in travelers returning from endemic areas. (14)
Epidemiology
In contrast to that seen in the rich countries, typhoid fever remains an important
cause of illness in the developing world where annual incidences in Papua
New Guinea and Indonesia may reach 1200/100,000 population. A recent epidemiologic
study showed that south-east and south-central Asia are the regions of highest
endemicity with rates greater than 100/100,000 cases per year; the rest of
Asia, Africa, Latin America, the Caribbean and Oceania (except Australia and
New Zealand) are the next highest with incidence rates of 10-100/100,000 and
Europe, North America and the rest of the developed world have low rates of
disease. (15) Typhoid fever represents the 4th most common
cause of death in Pakistan. (16)
The majority of patients, 60-90%, are treated as outpatients and, therefore,
hospital based studies will underestimate true incidence. Two hospital based
case-control studies from Vietnam found that risk of infection was related
to recent contact with an infected person, lack of education and drinking
untreated water. (17;18) S. paratyphi
A, which normally causes about 15-20% of cases of typhoid fever in Asia, increasingly
is becoming a pathogen in India (19) and China (20),
possibly due to vaccination against S. typhi. Recent epidemiologic studies
also show the rise of multi-drug resistant (MDR) organisms. (21)
In a study of 1100 hospitalized children in Pakistan, the mortality rate of
1.6% was found to be related to younger age and MDR infection. (22)
Traditionally the age range considered to be at greatest risk was 5-25 years.
However this has been questioned in a study from a private laboratory in Bangladesh,
which found that the 57% of S. typhi isolates were in children less than 5
years of age and 27% less than 2 years. (23) This has significant
implications for vaccination policies.
Genetics
In 2001 the entire genome of a MDR isolate of S. typhi was sequenced. (24)
This showed that Salmonella share more than 70-80% of genes with other enteric
bacteria, like E. coli. Another feature of S. typhi genome is the presence
of over 200 inactivated genes which are felt to be related to the adaptation
of the bacteria to the human host and possibly its ability to invade human
tissue. Drug resistance is encoded in a transmissible plasmid. The development
of additional horizontal genes in the salmonella pathogenicity islands (SPI)
represented the separation of the E. Coli and Salmonella lineages and allows
for the targeting of intestinal epithelial cells by Salmonella. (25)
Pathogenesis
Much of the genetic and cellular studies on the pathophysiology of invasive
Salmonella infection have been carried out in the murine model using S. typhimurium,
which causes invasive disease in mice but not in humans. As opposed to the
Salmonella spp. associated with human diarrheal illness, S. typhi and those
strains that cause typhoid fever are able to achieve cellular invasion.
The pathophysiology of typhoid fever is a complex process which proceeds through
several stages. (24;26;27)
The disease begins with an asymptomatic incubation period of 7-14 days, (inversely
related to the size of the infecting dose), during which bacteria invade macrophages
and spread throughout the reticuloendothelial system. The first week of symptomatic
disease is characterized by progressive elevation of the temperature followed
by bacteremia. The second week begins with the development of rose spots,
abdominal pain and splenomegaly. The third week is marked by a more intense
intestinal inflammatory response particularly in the Peyer’s patches
with associated necrosis which can result in perforation and hemorrhage. These
clinical stages are associated with complex cellular events just now being
understood.
First, ingested bacteria must survive the acidic environment of the stomach.
The known increased risk of typhoid fever with concomitant Helicobacter pylori
infection (28) may express itself via the hypochlorhydria
associated with chronic H.pylori infection. (29) Invading
organisms pass through the intestinal epithelial cells and come into contact
with phagocytic cells in the Peyer’s patches of the intestinal wall.
However the macrophages do not kill the bacteria. Thence, bacterial replication
is primarily intracellular. Salmonella avoids encapsulation in lysosomes by
diverting normal cellular mechanisms. (30) Bacteria inject
effector proteins into the cells of the innate immune system (macrophages
and natural killer cells) though a type III protein secretion system (TTSS)
which stimulate both pro and anti-inflammatory responses. (31)
Over the asymptomatic incubation period of 7-14 days the bacteria proliferate
and spread through the blood stream to other cells in the reticuloendothelial
system in the liver, spleen, bone marrow and gall bladder. As replication
inside phagocytic cells continues, bacteria are shed into the blood stream
in sustained but low concentrations and the clinical syndrome of fever, headache
and abdominal pain begins. The gallbladder is felt to be a significant site
(32) for ongoing exposure of intestinal epithelial cells
to the pathogen. The inflammatory response to this process of repeated exposure
is felt to give rise to the necrosis which is a prominent feature of the disease.
(33) This occurs in areas of greatest macrophage concentration
such as the Peyer’s patches and explains why intestinal bleeding and
perforation are the most frequent complications. Elsewhere typhoid nodules,
foci of macrophages and lymphocytes proliferate. As the infection progresses
the typical changes of sepsis accumulate in the heart, brain and kidneys.
If not interrupted this process may lead to circulatory failure and death
from overwhelming sepsis.
Prevention
Infected or asymptomatic carrier humans represent the reservoir for S. typhi.
Therefore identification and treatment of these individuals represents one
strategy for interruption of transmission.
Food and water sanitation
There is no doubt that lack of clean drinking water and unsanitary conditions
for the production and preparation of food represent the main reasons for
the ongoing endemicity of typhoid fever in the developing world. Poor water
quality, sanitation and hygiene account for some 1.7 million deaths a year
world-wide (3.1% of all deaths and 3.7% of all DALY's), mainly through infectious
diarrhea. Nine out of 10 such deaths are in children. (34)
Poverty, uncontrolled urbanization and inadequate infrastructure all contribute
to the contamination of water supplies. (35) Filtration
and chlorination together are effective methods of interrupting the transmission
of water-borne diseases. (36;37)
Vaccine
The other approach to the control and eradication of typhoid fever has been
through vaccination. Acquired immunity to S. typhi infection is both humoral
and cellular but is incomplete, allowing for subsequent infections and restricting
the efficacy of vaccines. (38;39) Older,
parenteral whole-cell vaccines resulted in significant local and systemic
reactions. (40) Two new vaccines are in current use: a parenteral
capsule polysaccharide vaccine based on the Vi antigen and an oral live attenuated
vaccine containing strain Ty21a. The first, while resulting in local pain
in 86% of children, requires 1 injection with a booster in 3 years and confers
protection within 7-10 days of inoculation. On the other hand the Ty21a vaccine
requires several doses, is only moderately immunogenic and its efficacy is
reduced by simultaneous anti-malarial therapy, (although a report from Gabon
showed that simultaneous anti-malarial prophylaxis with atovaquone/proguanil
does not have this effect (41)). A systematic review for
the Cochrane Database showed these two vaccines had significantly reduced
efficacy (efficacy rates approx.50%) in comparison to the older whole-cell
vaccines, but fewer side effects.(42) Current vaccines do
not afford protection against Paratyphoid strains. The search for better vaccines
continues. (43)
The use of vaccines for travelers to endemic areas has been recommended for
some time; (44) even if the travel is for short periods.
(45) Malaria remains the most common febrile disease of
returning travelers to Italy requiring hospital admission. (46)
Mass vaccination campaigns have been used to lower the risk of disease in
India and Thailand, but their use in the rest of the developing world is otherwise
limited. A report from the ongoing epidemic in Tajikistan advocated mass vaccination.
(47) A recent report from an urban slum community in Delhi,
India showed the high costs of typhoid fever and recommended more widespread
vaccination. (48) The current Vi and Ty21a vaccines are
not licensed for use in children less than 2 years, in whom its efficacy is
unproven, and therefore are deemed unsuitable for expanded immunization programs
which target infants in their first year of life. (49) They
are also costly. All these factors have restricted mass vaccination for typhoid
in endemic countries.
The World Health Organization appears to advocate mass vaccination in endemic
areas. (50;51) However this is seldom
implemented. The Diseases of the Most Impoverished (DOMI) project is undertaking
a randomized cluster vaccination program in Asia which should help to clarify
the effects of mass typhoid vaccination. (52)
Clinical Spectrum
Traditionally the age range considered at greatest risk is 5-25 years of age,
although young children and infants may also be infected. In these the disease
may present as a non-specific febrile illness until diagnostic tests are positive.
Akpede from Nigeria provides an excellent review of the management of these
cases, including those with HIV. (53)
After the initial 7-14 day asymptomatic phase, the clinical features of typhoid
fever begin with the onset of a remitting diurnal fever, anorexia, headache,
lethargy, confusion, cough and abdominal pain. (54) Constipation
is considered a feature, although diarrhea and vomiting is recognized, particularly
with young children and those infected with HIV. Relative bradycardia is said
to be a feature; increased heart rate is correlated with later stages and
with mortality. (55) The clinical signs are few: rose spots
(pink macules which blanch on pressure, are present on the thorax and abdomen
of 60% of light-skinned patients but are considerably more difficult to detect
in dark-skinned patients); abdominal tenderness (acute abdomen if perforation);
splenomegaly more common than hepatomegaly; rales (with a normal chest xray);
conjunctivitis and apathy. Assessment of hemodynamic and mental status is
important and correlates with severity of illness. In contrast to other investigators
Haq et al. found clinical factors strongly correlated with diagnostic accuracy.
(56)
Thielman gives a very good differential diagnosis of other infectious which
may mimic typhoid fever. (3) In Africa, malaria is probably
the most important disease from which typhoid must be distinguished. (57;58)
Non resolution gives rise to complications which are discussed below. Typhoid
fever patients suffer a relapse rate of 5-10% and 1-3% will become asymptomatic
carriers, potentially infecting others. Relapses take the form of a milder
disease and are less common after quinolone therapy. Carriers excrete S. typhi
in the stool more than 3 months after treatment. In Egypt, carrier state is
associated with urinary pathology such as Schistosomiasis and may be evidenced
by urinary excretion. (6) Carriers require treatment with high dose quinolones
(ciprofloxacin 750mg q12h) for 4 weeks. Carrier state associated with cholelithiasis
is a risk for gall bladder cancer and requires cholecystectomy. (59)
Diagnosis
The lack of specificity of the clinical spectrum, added to the difficulty
of achieving a definitive bacteriologic or serologic diagnosis, frustrates
clinicians managing typhoid fever.(60;61)
Laboratory tests are non-specific but haemoglobin, white cell and platelet
counts are usually reduced. Liver function tests are mildly elevated.
Culture of the infectious agent may be obtained from stool, urine, blood,
bone marrow or bile. Bone marrow is the most sensitive source (80-95%) and
positive blood cultures (60-80%) are facilitated by increasing the volume
sampled. (62) Detection of S. typhi DNA by polymerase chain
reaction (PCR) has recently been shown to be a very sensitive index of infection.
(63)
Serologic tests have a long but limited history of use in typhoid fever. The
Widal test, useful only for infection with S. typhi, detects O (surface) and
H (flagellar) antigens. However, baseline titers in the general population
must be determined for each geographic region. (64-66)
When used as a single test in endemic areas, it lacks sensitivity and specificity.
(67) A 4 fold rise in O, H or Vi titers provides support
for the diagnosis of typhoid fever, but is not useful in the acute situation.
As a result, numerous other serologic tests are being developed (2):
ELISA; (68-70) salivary IgA;(71)
a modified Widal test to detect IgM; (72) and dipstick assay.(73)
Treatment
It is recommended that treatment of typhoid fever begin on the basis of clinical
findings prior to definitive diagnosis. Sadly in endemic regions, facilities
for definitive diagnosis, based on blood or bone marrow culture or serologic
tests may be entirely lacking. Supportive measures such as oral or intravenous
rehydration, antipyretics, appropriate nutrition and blood transfusion are
important.
Mortality from typhoid fever showed a marked decline from 20% to 1% after
the introduction of chloramphenicol in 1948. (74) Chloramphenicol
however does not prevent relapse unless given for 2-3 weeks; the carrier state
is not eradicated; nor is it useful against MDR strains. (75)
Ampicillin and sulfonamides, co-trimazole, became the next antibiotics to
be used, but multi-drug resistant MDR organisms developed.(76-78)
In some regions with high MDR prevalence, sensitivity to chloramphenicol has
re-emerged. (79) MDR strains are noted to be more virulent
and associated with increased mortality and complications.
The flouroquinolones - ofloxacin and ciprofloxacin, the third generation cephalosporins
-ceftriazone and cefixime, and azithromycin, a macrolide antibiotic, are the
drugs of choice for MDR typhoid fever. Flouroquinolones achieve excellent
penetration in macrophages and bile, important sites of infection. In the
developed countries they have been used infrequently in patients less than
18 years of age, because of potential arthropathy. However there is increased
evidence for their safety in this population. However, resistance to flouroquinolones
has also developed and represents a significant threat to the treatment of
typhoid fever. (80) The presence of nalidixic acid resistance
is a marker for decreased susceptibility to flouroquinolones and should be
tested for when dealing with MDR strains.(81-83)
Nalidixic acid resistant strains may show a slower response to flouroquinolones
and require higher doses (ciprofloxacin 1500mg/d instead of 1000mg/d). Switching
to ceftriaxone or azithromycin may be preferable in these patients. (84)
These agents should be given for at least 7 days.
The standard duration of treatment has been for 10-14 days, but uncomplicated
typhoid fever has been shown to respond to shorter courses of flouroquinolones,
ie. 2-3 days of treatment.(85) Thaver (75),
in a systematic review for the Cochrane database comparing flouroquinolones
with other antibiotics, concluded that the scientific data derived from RCTs
was poor, and that there was little to recommend flouroquinolones over 1st
line drugs, (chloramphenicol, ampicillin and co-trimazole). Flouroquinolones
reduced failure rates when compared to third generation cephalosporins. The
study recommended large multi-center outpatient trials comparing flouroquinolones
and 1st line therapy in children to settle this question. Thaver et al admit
their conclusions differ from those of Parry (5) and standard
textbooks which recommend flouroquinolones as modern 1st line therapy. (3;4)
Since there is great regional variability with regard to antibiotic sensitivity
and the presence of MDR strains and because misuse of antibiotics is a potent
cause of the development of MDR strains (86), it is essential
that physicians working in regions where typhoid fever is endemic, ascertain
the nature and prevalence of the different strains and base appropriate recommendations
for first and second line therapy on this information.
The WHO recommends the following regimes for uncomplicated typhoid fever.
Table 1 page 20 (2)
In severe disease the following regimes are recommended. Table 2 page 23 (2)
Complications
Complications occur in 10-15% of patients, particularly those who have been
ill for more than 2 weeks. Gastrointestinal hemorrhage, perforation and encephalopathy
are the most important. GI hemorrhage is most common but usually resolves
without surgery. Severe typhoid may be defined as occurring
in those patients with hypotension despite rehydration and mental confusion
or altered state of consciousness. These patients may benefit from high dose
dexamethasone therapy (3mg/kg followed by 8 doses of 1mg/kg q6h) with a marked
reduction in mortality. (87) This is one of the few instances
where high dose steroids are of value in sepsis. (88)
Perforation
The surgeon is typically consulted in typhoid fever when perforation is suspected.
It may present suddenly as an acute abdomen or more commonly as worsening
in an already sick patient with increasing abdominal signs, rising pulse and
falling blood pressure. (89) The presence of free air on
abdominal xrays is pathognomonic.
These are very sick patients who require vigorous resuscitation and the addition
of metronidazole to combat gram-negative anaerobes and gentamycin for aerobes.
Conservative therapy has been abandoned with improved mortality rates. (90)
Mortality increased when time to presentation is delayed and also with delayed
time to surgery after perforation. (91) Mortality rates
vary from 14% in Nigeria (89) to 34% in Cote d’Ivoire.
(92) Single perforations are most common (70%) and in the
terminal ileum, but multiple perforations may occur.(93)
At operation the entire small bowel and proximal colon should be carefully
examined for perforation. Debate exists as to the various methods of closure
from simple suture, to wedge resection and closure to segmental resection
and primary anastomosis. (94;95) It is
not clear to me that any conclusion can be drawn from the evidence. Obviously
multiple perforations lend themselves to segmental resection.
Other complications
Numerous other complications are seen with typhoid fever. (4)
see Table 163-1 The most important surgical ones being: hepatic or splenic
abscess(96), splenic rupture (97) and
pancreatitis. Encephalomyelitis (98), osteomyelitis (99),
glomerulonephritis and renal failure (100) may all occur.
Myocarditis is a common cause of circulatory collapse.
Conclusions
Despite intensive scrutiny and major advances in genetic research and understanding
the details of cellular inflammation, typhoid fever remains a major cause
of death and disease in the developing world. Its eradication awaits the provision
of sanitary water supplies and proper disposal of human sewage. Its eradication
would probably be accelerated by programs of mass vaccination in endemic regions.
Appropriate antibiotic therapy may postpone the further development of MDR
strains. In the meantime, surgeons will continue to be asked to care for desperately
sick typhoid patients with intestinal perforations and other complications.
