Typhoid Fever, Causes, Symptoms, Diagnosis, Treatment

Typhoid Fever and paratyphoid fever is a serotype typhi is a gram-negative bacterium that is responsible for typhoid fever and has been a burden on developing nations for generations. It is important for public health problems globally and major causes of morbidity in the developing world []. Typhoid and paratyphoid fever are acute and often life-threatening febrile illnesses caused by systemic infection with the bacterium Salmonella enterica serotype typhi and paratyphi, respectively. Classical symptoms include gradual onset of sustained fever, chills, hepatosplenomegaly, and abdominal pain. In some cases, patients experience rash, nausea, anorexia, diarrhea or constipation, headache, relative bradycardia and reduced level of consciousness []. While both diseases share clinical features, paratyphoid fever tends to have a more benign course of illness. Without effective treatment, typhoid fever has a case-fatality rate of 10–30%. This number is reduced to 1–4% in those receiving appropriate therapy [].

Typhoid (cloudy) fever is a systemic infection, caused mainly by Salmonella typhi found only in man. It is characterized by a continuous fever for 3-4 weeks, relative bradycardia, with the involvement of lymphoid tissue and considerable constitutional symptoms. In western countries, the disease has been brought very close to eradication levels. In the UK, there is approximately one case per 100,000 population per year. Each year, the world over, there are at least 13-17 million cases of typhoid fever, resulting in 600,000 deaths. 80% of these cases and deaths occur in Asia alone. In southeast Asian nations, 5% or more of the strains of the bacteria may already be resistant to several antibiotics [].

Enteric fever is a systemic infection caused by the human-adapted pathogens Salmonella enterica serotype Typhi (S. Typhi) and S. Paratyphi A, B, and C. These organisms are important causes of febrile illness among crowded and impoverished populations with inadequate sanitation who are exposed to unsafe water and food, and also pose a risk to travelers visiting endemic countries []. The extra-intestinal infections caused by Salmonella are very fatal. The incidence of typhoid fever remains very high in impoverished areas and the emergence of multidrug resistance has made the situation worse

Pathophysiology of Typhoid Fever

Salmonella enterica serotype Typhi is usually contracted by ingestion of food or water that is contaminated with the excrements of those that carry the organism and must survive the gastric pH barrier in the stomach prior to adherence in the small intestine.  An infectious dose of Salmonella enterica serotype typhi in healthy individuals ranges between 1000 and 1 million organisms but can be related to the host’s defense mechanisms. 

Salmonella enterica serotype typhi enter the submucosal region of the small bowel by either direct penetration into the epithelial tissue mediated by the cystic fibrosis transmembrane conductance regulator (CFTR) or via the M-cell, a specialized lymphoid epithelial cell. Once within the submucosa, the bacterium causes hypertrophy of the Peyer’s patches. 

Dissemination of the organism from the Peyer’s patches occurs via the lymphatic system and the bloodstream. Cellular replication within the reticuloendothelial system is a hallmark of the disease and eventually causes the systemic symptoms that a clinician will observe. Following replication, organisms will reside in the macrophages of the liver, spleen and bone marrow.  Classically, Salmonella enterica serotype typhi can be cultured from the bone marrow even after anti-microbial therapy has been initiated. 

Approximately 1% to 5% of patients will become chronic carriers of Salmonella enterica serotype typhi despite adequate antimicrobial therapy.  A chronic carrier is defined as a patient that has excretion of the bacterium in the stool or urine for greater than 12 months after an acute infection and is typically is of the female gender or has cholelithiasis.  Those in the chronic carrier state will typically have high levels of antibodies to the Vi antigen and will not develop the clinical disease. The most famous of these chronic carriers was Mary Mallon who was diagnosed as a “healthy carrier” of the disease in 1906 after transmitting the disease to several households in which she served as the cook.  The term “Typhoid Mary” became prominent during public health campaigns and is still used in modern culture today. 

Causes of Typhoid Fever

Bacteria

  • The Gram-negative bacterium that causes typhoid fever is Salmonella enterica subsp. enterica.[rx] The two main types of the subspecies enterica are ST1 and ST2, based on MLST subtyping scheme, which is currently widespread globally.[rx]

Transmission

  • Unlike other strains of Salmonella, no animal carriers of typhoid are known.[rx] Humans are the only known carriers of the bacteria.[rx]S. e. subsp. enterica is spread through the fecal-oral route from individuals who are currently infected and from asymptomatic carriers of the bacteria.[rx] An asymptomatic human carrier is an individual who is still excreting typhoid bacteria in their stool a year after the acute stage of the infection.[rx]

Fecal-oral transmission route

  • The bacteria that cause typhoid fever spread through contaminated food or water and occasionally through direct contact with someone who is infected. In developing nations, where typhoid fever is established (endemic), most cases result from contaminated drinking water and poor sanitation. The majority of people in industrialized countries pick up typhoid bacteria while traveling and spread it to others through the fecal-oral route.
  • This means that Salmonella typhi is passed in the feces and sometimes in the urine of infected people. You can contract the infection if you eat food handled by someone with typhoid fever who hasn’t washed carefully after using the toilet. You can also become infected by drinking water contaminated with the bacteria.

Symptoms of Typhoid Fever

Classically, the progression of untreated typhoid fever is divided into four distinct stages, each lasting about a week. Over the course of these stages, the patient becomes exhausted and emaciated.[rx]

  • In the first week – the body temperature rises slowly, and fever fluctuations are seen with relative bradycardia (Faget sign), malaise, headache, and cough. A bloody nose (epistaxis) is seen in a quarter of cases, and abdominal pain is also possible. A decrease in the number of circulating white blood cells (leukopenia) occurs with eosinopenia and relative lymphocytosis; blood cultures are positive for Salmonella enterica subsp. enterica or S. paratyphi. The Widal test is usually negative in the first week.[rx]
  • The two major symptoms – of typhoid are fever and rash. Typhoid fever is particularly high, gradually increasing over several days up to 104 degrees Fahrenheit or 39 to 40 degrees Celsius. The rash, which does not affect every patient, consists of rose-colored spots, particularly on the neck and abdomen.
  • In the second week – the person is often too tired to get up, with high fever in plateau around 40 °C (104 °F) and bradycardia (sphygmothermic dissociation or Faget sign), classically with a dicrotic pulse wave. The abdomen is distended and painful in the right lower quadrant, where a rumbling sound can be heard. Diarrhea can occur in this stage, but constipation is also common.
  • The spleen and liver are enlarged – (hepatosplenomegaly) and tender, and liver transaminases are elevated. The Widal test is strongly positive, with antiO and antiH antibodies. Blood cultures are sometimes still positive at this stage. The major symptom of this fever is that it usually rises in the afternoon up to the first and second week.

In the third week of typhoid fever, a number of complications can occur

  • Intestinal hemorrhage due to bleeding in congested Peyer’s patches occurs; this can be very serious but is usually not fatal.
  • Intestinal perforation in the distal ileum is a very serious complication and is frequently fatal. It may occur without alarming symptoms until septicemia or diffuse peritonitis sets in.
  • Encephalitis
  • Respiratory diseases such as pneumonia and acute bronchitis
  • Neuropsychiatric symptoms (described as “muttering delirium” or “coma vigil”), with picking at bedclothes or imaginary objects
  • Metastatic abscesses, cholecystitis, endocarditis, and osteitis
  • The fever is still very high and oscillates very little over 24 hours. Dehydration ensues, and the patient is delirious (typhoid state). One-third of affected individuals develop a macular rash on the trunk.
  • Platelet count goes down slowly and the risk of bleeding rises.
  • By the end of the third week, the fever starts subsiding.
  • weakness
  • abdominal pain
  • constipation
  • headaches
  • Rarely, symptoms might include confusion, diarrhea, and vomiting, but this is not normally severe.

Diagnosis of Typhoid Fever

  • Diagnosis is made by any blood –  bone marrow, or stool cultures and with the Widal test (demonstration of antibodies against Salmonella antigens O-somatic and H-flagellar). In epidemics and less wealthy countries, after excluding malaria, dysentery, or pneumonia, a therapeutic trial time with chloramphenicol is generally undertaken while awaiting the results of the Widal test and cultures of the blood and stool.[21]
  • The Widal test – is time-consuming and prone to significant false-positive results. The test may also be falsely negative in the early course of illness. However, unlike the Typhidot test, the Widal test quantifies the specimen with titers.
  • Typhidot is a medical test – consisting of a dot ELISA kit that detects IgM and IgG antibodies against the outer membrane protein (OMP) of the Salmonella enterica subsp. enterica. The typhoid test becomes positive within 2–3 days of infection and separately identifies IgM and IgG antibodies.
  • The test is based on the presence of specific IgM and IgG antibodies –  to a specific 50Kd OMP antigen, which is impregnated on nitrocellulose strips. IgM shows recent infection whereas IgG signifies remote infection. The most important limitation of this test is that it is not quantitative and the result is only positive or negative.

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Laboratory diagnosis of typhoid

Diagnostic test Sensitivity range (%) Specificity range (%) Comments
Microbiological tests
Blood culture 40-80 NA Widely regarded as the gold standard, but sensitivity may be low in endemic areas with high rates of antibiotic use—hence true specificity is difficult to estimate
Bone marrow cultures 55-67 30 Greater sensitivity but invasive and thus of limited clinical value, especially in ambulatory management
Urine culture 0-58 NA Variable sensitivity
Stool culture 30 NA Sensitivity lower in developing countries and not used routinely for follow-up
Molecular diagnostics
Polymerase chain reaction 100 100 Promising, but initial reports indicated similar sensitivity to blood cultures and lower specificity
Nested polymerase chain reaction 100 100 Promising and may replace blood culture as the new “gold standard”
Serological diagnosis
Widal test (tube dilution and slide agglutination) 47-77 50-92 Classic and inexpensive. Despite mixed results in endemic areas, still performs well for screening large volumes. May need standardization and quality assurance of reagents
Typhidot 66-88 75-91 Lower sensitivity than Typhidot-M
Typhidot-M 73-95 68-95 Higher sensitivity and specificity than classic Typhidot in some series, but other evaluations suggest that the performance may not be as robust in community settings as in hospital
Tubex 65-88 63-89 Promising initial results but has yet to be evaluated in larger trials in community settings
Others
Urine antigen detection 65-95 NA Preliminary data only

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Treatment of Typhoid Fever

General principles for the management of typhoid

  • Rapid diagnosis and institution of appropriate antibiotic treatment
  • Adequate rest, hydration, and correction of the fluid-electrolyte imbalance
  • Antipyretic therapy as required (such as paracetamol 120-750 mg taken orally every 4-6 hours)
  • Adequate nutrition: a soft, easily digestible diet should be continued unless the patient has abdominal distention or ileus
  • Close attention to hand washing and limitation of close contact with susceptible individuals during the acute phase of infection
  • Regular follow-up and monitoring for complications and clinical relapse (this may include confirmation of stool clearance in non-endemic areas or in high-risk groups such as food handlers)

Oral Rehydration Therapy

The rediscovery of oral rehydration therapy in the 1960s provided a simple way to prevent many of the deaths of diarrheal diseases in general.

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Anti-microbial therapy

Antibiotic Route Adult dosage/day Dosage:mg/kg/day Duration (in days)
First-line antibiotics :
Chloramphenicol Oral, IV 500 mg qid 50 mg/kg in 4 doses @ 14
Trimethoprim-Sulfamethoxazole Oral, IV 160/800 mg bid 4-20 mg/kg: in 2 doses 14
Ampicillin/Amoxycillin Oral, IM, IV 1000-2000 mg qid 50-100 mg/kg: in 4 doses 14
Second-line antibiotics:
Fluoroquinolones
Ciprofloxacin Oral/IV 500 mg bid/200 mg bid NA 10-14
Norfloxacin Oral 400 mg bid NA 10
Pefloxacin Oral, IV 400 mg bid NA 10
Ofloxacin Oral 400 mg bid NA 14
Ceph alosporins
Ceftriaxone IM, IV 1-2 gm bid 50-75 mg/kg: in 1-2 doses 7-10
Cefotaxime IM, IV 1-2 gm bid 40-80 mg/kg: in 2-3 doses 14
Cefoperazone IM, IV 1-2 gm bid 50-100 mg/kg: in 2 doses 14
Cefixime Oral 200-400 mg od/bid 10 mg/kg: in 1-2 doses 14
Other antibiotics:
Aztreonam IM 1 gm/bd-qid 50-70 mg/kg: 2-4 5-7
Azithromycin Oral 1 gm od 5-10 mg/kg:1 5
Preferred therapy for the management of typhoid fever.
Antimicrobial agents Route of administration Children Adult
Ceftriaxone IM/IV 50 mg/kg per day IV; for 7–10 days 1–2 g per day IV; for 7–10 days
Ciprofloxacin, levofloxacin or other FQ† Oral/IV – FQ given in full doses as recommended; for 7–10 days
Azithromycin Oral Used in complicated cases 500 mg twice a day for 5 days
Cefixime–ofloxacin Oral – 200–200 mg; for 7–14 days

High-dose therapy is based on antimicrobial susceptibility profile of the infected typhoidal Salmonella strain, as majorities are nonsusceptible to quinolones. Least preferred as the majority of the isolates show intermediate resistance to quinolones.

FQ: Fluoroquinolone; IM: Intramuscular; IV: Intravenous.

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The Use of Glucocorticosteroids

  • It has been advocated for the treatment of severe typhoid fever based on a randomized, double-blind, placebo-controlled trial carried out in Indonesia. This study showed a significant reduction in mortality in patients with severe typhoid fever (ie. associated delirium, obtundation, stupor, coma, or shock) treated with chloramphenicol and dexamethasone as compared with chloramphenicol-treated control patients (case-fatality rate, 10% versus 56%) [].
  • Although the case fatality rate in the control group was high and the study has never been repeated, on the basis of this study, dexamethasone, 3 mg/kg intravenously, followed by eight doses of 1 mg/kg every 6 hours, should be considered for the treatment of severe typhoid with altered mental status or shock. Steroid treatment beyond 48 hours may increase the relapse rate [].
  • Corticosteroids are administered for severe toxemia and fever and may produce a dramatic response in the patient with profound sepsis.

Vaccines

Three types of typhoid vaccines are available

  • Phenol-inactivated vaccine;
  • Live, attenuated S typhi strain,
  • Ty21a; Purified Vi capsular polysaccharide vaccine.

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Typhoid fever vaccines

Vaccine Age Route Dosage Revaccination
Killed whole-cell vaccine 5 years subcutaneous 0.5 ml (0.25 ml for children < 10y)
x 2 times,
4 weeks apart		 3 years
Vi CPS 2 years subcutaneous 0.5 ml 3 years
Ty21 a, live 6 years Oral 1 capsule every other day, total of 3 capsule 5 years s

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  • Each of these vaccines offers 55% to 85% protection for 3 to 5 years. The main differences relate to their side effects. Local pain at the injection site and mild to moderate systemic reactions are commonly encountered with the phenol-inactivated vaccine.
  • The live-attenuated oral vaccine may cause mild gastrointestinal distress, but because of its low toxicity and ease of administration, it should be used for travelers to areas of high risk. There are little data available regarding the protective efficacy of the oral vaccine for travelers.
  • The purified capsular Vi vaccine has significantly fewer adverse effects than the killed whole-cell parenteral vaccines. Its efficacy has not been established in travelers, but it is used as an alternative to the oral typhoid vaccine. Lin et al report efficacy of more than 90% for a new typhoid vaccine with the capsular polysaccharide of S typhi, Vi conjugated to nontoxic recombinant Pseudomonas aeruginosa exotoxin A (Vi-rEPA).
  • Two injections of this vaccine, given 6 weeks apart, prevented blood-culture positive typhoid fever during a period of 27 months in 5525 children, 2 to 5 years old in Dong Thap Province of Vietnam, where typhoid is highly endemic [].

Prevention of Typhoid Fever

  • Sanitize water – Boil or disinfect any water that will be used for drinking, washing or preparing food, making ice, or brushing teeth. Better yet, try to drink only bottled water (carbonated is safer than regular) or other drinks that come in cans or bottles, but wipe the outside of the can or bottle before drinking from it. Tell kids to avoid tap water, fountain drinks, and ice cubes, and remind them to not swallow any water in the shower or bath.
  • Cook all food – Fully cook all food, and avoid food from street vendors and food stored or served at room temperature. Instead, serve packaged foods or meals that are freshly cooked and served to steaming hot.
  • Avoid raw food – Avoid raw, unpeeled fruits and vegetables that may have been washed with contaminated water, especially lettuce and fruits like berries that can’t be peeled. Bananas, avocados, and oranges make better choices, but be sure you peel them yourself. For safety’s sake, you may want your kids to avoid raw foods entirely.
  • Wash hands well and often – Wash with soap and clean, warm water, especially after kids use the bathroom or before they eat or prepare food. If no soap and water are available, use an alcohol-based hand sanitizer.
  • Wash your hands – Frequent hand-washing in hot, soapy water is the best way to control infection. Wash before eating or preparing food and after using the toilet. Carry an alcohol-based hand sanitizer for times when water isn’t available.
  • Avoid drinking untreated water – Contaminated drinking water is a particular problem in areas where typhoid fever is endemic. For that reason, drink only bottled water or canned or bottled carbonated beverages, wine, and beer. Carbonated bottled water is safer than uncarbonated bottled water is. Ask for drinks without ice. Use bottled water to brush your teeth, and try not to swallow water in the shower.
  • Avoid raw fruits and vegetables – Because raw produce may have been washed in unsafe water, avoid fruits and vegetables that you can’t peel, especially lettuce. To be absolutely safe, you may want to avoid raw foods entirely.
  • Choose hot foods – Avoid food that’s stored or served at room temperature. Steaming hot foods are best. And although there’s no guarantee that meals served at the finest restaurants are safe, it’s best to avoid food from street vendors — it’s more likely to be contaminated.

Prevent Infecting Others

If you’re recovering from typhoid fever, these measures can help keep others safe:

  • Take your antibiotics – Follow your doctor’s instructions for taking your antibiotics, and be sure to finish the entire prescription.
  • Wash your hands often – This is the single most important thing you can do to keep from spreading the infection to others. Use hot, soapy water and scrub thoroughly for at least 30 seconds, especially before eating and after using the toilet.
  • Avoid handling food – Avoid preparing food for others until your doctor says you’re no longer contagious. If you work in the foodservice industry or a health care facility, you won’t be allowed to return to work until tests show that you’re no longer shedding typhoid bacteria.

Avoiding Infection

Typhoid is spread by contact and ingestion of infected human feces. This can happen through an infected water source or when handling food. The following are some general rules to follow when traveling to help minimize the chance of typhoid infection:

  • Drink bottled water, preferably carbonated.
  • If bottled water cannot be sourced, ensure water is heated on a rolling boil for at least one minute before consuming.
  • Be wary of eating anything that has been handled by someone else.
  • Avoid eating at street food stands, and only eat food that is still hot.
  • Do not have ice in drinks.
  • Avoid raw fruit and vegetables, peel fruit yourself, and do not eat the peel.

References

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