Typhoid Fever

Typhoid Fever
Introduction
History
Epidemiology
Genetics
Pathogenesis
Prevention
Food and water sanitation
Vaccine
Clinical Spectrum
Diagnosis
Treatment
Complications
Perforation
Other complications
Conclusions
Recommendations
Clinical Photos
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
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the mid-19th century that physicians began to distinguish it from typhus and malaria. (8) Sir William Oslers 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 Peyers 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 Peyers 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
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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 Peyers 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 waterborne 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.
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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 reemerged. (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)
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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
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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 dIvoire. (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.
Recommendations
1. Typhoid fever should be suspected in young children and infants with fevers of unknown origins in endemic regions.
2. Filtration and chlorination are the two important steps in ensuring a safe water supply. In urban areas safe drinking water should be made available though piped
systems or trucked tankers.
3. Appropriate food handling is essential: washing hands with soap before preparing and handling food; eating only cooked or still hot food; avoiding raw food,
shellfish, ice.
4. Appropriate systems for human waste disposal must be available for the entire community.
5. Countries with high rates of typhoid fever should consider mass immunization programs using new Vi and Ty21a vaccines for those more than 2 years of age.
6. In hospitals where microbiological facilities are available for the culture of salmonella spp., bone marrow samples, as well as blood and stool should be obtained in
patients when typhoid fever is suspected.
7. Testing should include stools of recovering patients at 3 months or urine in regions where schistosomiasis is common, to detect the carrier state.
8. The Widal test cannot be used in the diagnosis without assessing background antibody levels in the population. Better serologic tests should be available soon.
9. Antibiotic therapy should be based on the sensitivity spectrum of local S. typhi strains. Chloramphenicol, ampicillin or co-trimazole may be adequate agents if strains
are susceptible.
10. In regions where MDR strains are known to exist, fluroquinolones are the agents of choice.
11. In regions where MDR strains exist and where quinolone use has been extensive, testing for relative flouroquinolone resistance with nalidixic acid discs should be
undertaken.
12. Patients, with severe typhoid manifested by hypotension and/or altered state of consciousness, should receive short term high dose steroid therapy.
13. The treatment of typhoid perforation is aggressive resuscitation using broad spectrum antibiotics against enteric organisms, prompt surgery with examination of the
entire small bowel and right colon with resection (local or segmental) of all full thickness ulcers and perforations.

Brian Ostrow MD, FRCS(C)

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Guelph, Ontario, Canada

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Clinical Photos

Reference List
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