Typhoid fever is an important infectious disease and considered as a global health problem since long time. It is said that Alexander the Great died because of Typhoid or malaria. The last description of his final illness from royal diaries is consistent with diagnosis of typhoid fever though relevant date is lacking.
      WHO has estimated that approximately 17 million cases and 600,000 annual deaths occur each year worldwide due to typhoid. A study quoted that typhoid fever incidence is very high in Southeast Asia (> 100 cases per 100,000 per year) (24). In endemic areas prevalence of bacteremia in febrile child is as high as 2-3%. Typhoid fever has great social and economic burden in developing countries because of hospitalization, its complications, income loss etc.
      Most common age of presentation is 3-19 years in endemic areas but typhoid fever has been reported in less than 3 years of age from India and Bangladesh. Causative organism for typhoid fever is Salmonella typhi, a gram-negative bacterium. It is estimated that this organism is about 50,000 years old (1).

Pathogenesis: After infection S. typhi reaches small intestine and penetrates its mucosal epithelium via enterocytes to reach lamina propria. Macrophages ingest the bacteria without killing it. During acute infection, S. typhi multiplies in mononuclear phagocytic cell system from where organism reaches the blood stream. Some of the bacteria reach mesenteric lymphnodes causing mesenteric adenitis which drain into thoracic duct through lymphatic channels and bacteria gains entry into the circulation. S. Typhi reach reticuloendothelial system e.g., spleen, liver, bone marrow within 24 hours of ingestion where it resides for about 8-14 days. Incubation period may be as low as 3 days and as high as 60 days. During clinical illness, low but sustained level of secondary bacteremia (1-10 bacteria per ml of blood) is maintained.

Transmission: Humans serve as the natural host as well as reservoir. Faeco-oral contamination is the most common route of infection. Consuming raw fruit and vegetables contaminated with sewage water, shellfish, and ice creams are the significant risk factors for contracting S. typhi infection. Epidemiological studies have suggested that small inocula are sufficient for water borne transmission but large inocula is required for food borne organism transmission. Recently several transmissions in homosexual men have been reported from USA (9).

Clinical features: Symptomatology of typhoid fever is highly variable ranging from mild illness with low-grade fever, dry cough, and malaise to severe illness associated with complications. Depending on age of the patient clinical manifestations vary.

• School going children and adolescents: Onset is usually insidious. Fever, myalgia, anorexia, headache and abdominal pain are the initial features. In early phase diarrhea is common but later constipation ensues. Patient may develop cough, epistaxis and lethargy. Within a week of onset, fever increases in stepwise fashion and becomes unremitting and high grade. During second week of illness all the symptoms increase in severity and patient may appear toxic, lethargic, and disoriented. Delirium and Stupor may occur. On examination relative bradycardia (disproportionate to the degree of fever) is characteristic. Hepatosplenomegaly with abdominal distention and generalized tenderness are common findings. Few patients with typhoid fever may develop macular or maculopapular, discrete erythematous rash, raised from skin, blanching on pressure on about 7-10th day of illness (rose spots) usually seen on chest and abdomen in crops. On healing they leave small hyperpigmented areas. S. Typhi can be cultured from these lesions (60% yield). Chest examination may reveal scattered rhonchi and crepitations. Without complications all signs and symptoms subsides within 2-4 weeks except malaise and lethargy, which may persist for 1-2 months.
  
• Infants and young children: Typhoid fever usually presents as mild fever, malaise and diarrhea and is commonly labeled as acute gastroenteritis in this age group, however sepsis may occur.
  
• Neonatal typhoid fever: S. typhi can be transmitted vertically. Antenatally it can cause (may lead) to chorio-amnionitis, miscarriage, fetal death (58) and premature delivery. Neonatal typhoid usually presents within 72 hours of delivery with hypo or hyperthermia, vomiting, diarrhea, abdominal distention, convulsions, hepatomegaly and jaundice. Poor feeding and weight loss may be significant.

Factors influencing the severity of typhoid fever and overall outcome: Various factors may affect the severity as well as outcome of the typhoid fever, e.g., Age at presentation, vaccination status, size of inoculum, virulence of the organism, host factors (eg, HIV), treatment received or other drugs (eg – antacids / H2 Blockers). HIV infected patients are at higher risk. A study from AIIMS, New Delhi concluded that Helicobacter pylori infection is associated with increased risk of acquiring typhoid fever. Illiteracy, nuclear family, non-use of soap and ice creams were also implicated as high risk for typhoid fever.

Complications: 10-20% of patients have occult blood in stools, 3% having malena and 0.5-3% of patients may develop intestinal perforation, followed by peritonitis presenting as sudden tachycardia, hypotension, abdominal distention with guarding, rigidity and rebound tenderness. Hypothermia usually occurs after the first week of disease. Perforation size may range from pinpoint to several centimeters. Gram-negative sepsis may ensue. X-ray abdomen may suggest free air in abdomen. Altered sensorium has high case fatality rate. Study from Malaysia showed that children with splenomegaly, thrombocytopenia and leucopenia are more likely to develop complications (20). Short duration of symptoms, inadequate antimicrobial treatment, male sex and leucopenia were the independent risk factors for enteric perforation from a study done in Turkey (23). Intestinal bleeding usually occurs from multiple, variable sized punched out ulcers in the distal ileum and proximal colon.

Other complications include – Pneumonia by superinfection with organisms other than Salmonella typhi, bronchitis (10%), toxic myocarditis, neurological complications including raised intracranial pressure, cerebral thrombosis, acute cerebellar ataxia, chorea, aphasia, deafness, psychosis, transverse myelitis, peripheral neuritis, optic neuritis, meningitis, encephalomyelitis, Guillian-Barre syndrome, cranial nerve palsies. Other reported complications are – Disseminated intravascular coagulation (DIC), thrombocytopenia, Hemolytic Uremic syndrome (HUS), Hepatitis, Splenic and bone marrow granulomas, glomerulonephritis, pancreatitis, splenic / liver abscess, cutaneous leukocytoclastic vasculitis, Suppurative lymphadenitis, cutaneous ulcerations, thrombosis, phlebitis, fatal bone marrow necrosis, pyelonephritis, nephrotic syndrome, endocarditis, orchitis, osteomyelitis and suppurative arthritis especially in children with hemoglobinopathies.

Culture:

Definitive diagnosis of typhoid fever is made only on isolation of S. typhi from blood, bone marrow etc. in presence of characteristic clinical features.

• Blood culture is the mainstay of diagnosis. More than 80% of patients with acute typhoid fever have the causative organism in their blood.
  
• Bone marrow aspiration culture in the gold standard for definitive diagnosis particularly for patients, who had already received treatment, had long history of illness and negative blood culture with recommended volume of blood.



Points to remember during blood culture:
• Sample should be inoculated at the time of withdrawing blood.
• Blood culture bottles with sample should not be stored or transported at low temperature.
• Sterile technique employment is mandatory.
• Volume of blood to be withdrawn
• 10-15 ml – school children and adults.
• 2-4 ml – Toddlers and preschool children. (Because of more bacteremia).
• Optimum ratio of blood volume to culture media 1:10 – 1:12 as sensitivity decreases with less blood volume.
• Negative blood culture results should always be interpreted in relation with volume of blood sent to the laboratory.
• Serum can also be cultured (clot culture).
  
• Stool culture is useful in carriers. If it is positive it suggests typhoid       fever only in presence of clinical features.
  
• Duodenal aspirate culture results are also satisfactory but not used       frequently because of low acceptability.
  

Serological tests:

A)    Felix-Widal test: This test measures agglutinating antibody levels against “O” and “H” antigens. Usually “O” antibodies appear on 6th – 8th day and “H” antibodies on D10 – D12 after onset of disease. If possible paired titration with convalescent sera should be performed. Widal assay is moderately sensitive and specific. In 30% of blood culture proven cases, Widal test is negative.

Limitations of Widal test:

1. Previous antimicrobial treatment may block antibodies response and Widal may be falsely negative.
2. S. Typhi shares “O” and “H” antigens with other Salmonella serotypes and has cross reacting epitopes with other entero-bacteriacae so false positive test may occur.
3. Widal may also be false positive in Malaria, Typhus, sepsis with other organisms, cirrhosis etc.
4. In endemic areas like India there is low background baseline antibody levels found in normal populatio and cut off is variable between areas and time. So it is important to establish a cut off level of baseline antibody levels in the defined geographical area and population, and positive report should be interpreted only in the light of antibodies levels more than threshold. It is unnecessary to perform Widal test in blood culture positive cases.

It is clear that there is a need for quick and reliable diagnostic test as an alternate to Widal in view of above mentioned limitations.

Newer diagnostic methods:

1. IDL tubex test: Rapid and simple test and can defect IgM 09 antibodies within 2 minutes. It detects IgM and not IgG, suggestive of recent infection. Infection with other serotypes including S. paratyphi gives negative result. A study showed that in a single blood sample collected on admission to hospital, sensitivity of tubex test was 69.8% as compared with bone marrow culture and 86.5% as compared with blood culture (22).



2. Typhidot test: Developed in Malaysia, detects both IgM and IgG against a 50 KD Antigen of Salmonella typhi. It takes 3 hours to perform. Multinational clinical evaluation suggests that it is a simple, rapid, economic test with high specific (75%), sensitive (95%) and high negative and positive predictive values.
Limitations: In endemic areas after the age of 2 years after typhoid infection, IgG antibodies are formed so this test cannot differentiate acute and convalescent cases. It may give false positive results because of previous infection with S. typhi or current re-infection in which secondary immune response significantly boosts (augments) IgG production and IgM becomes undetectable. To increase the diagnostic efficacy a modified version of typhidot has been developed, called as Typhidot-M in which IgG is totally inactivated in the serum sample and only IgM is detected. Trials showed that it is better than Widal and blood culture methods. It may prove very useful in areas of high endemicity of typhoid fever and has potential to replace Widal test because of its rapidity, and accuracy in diagnosis of typhoid fever. Typhidot was recently evaluated in Vellore and it showed 100% sensitivity and 80% specificity when bacteremic patients were analysed.


3. IgM dipstick test: Originally developed in Netherlands, it is based on binding of S. typhi specific IgM antibodies to S. typhi. It can be done on serum or whole blood and requires incubation for 3 hours at room temperature. Evaluation studies done in Kenya, Egypt, Vietnam and Indonesia suggest that this method is 65-77% sensitive and 95-100% specific. It is a rapid and simple alternative for diagnosis of typhoid fever where culture facilities are not available. Moreover this test does not require trained personnel, equipments or electricity treatment can be offered promptly.



4. Point to remember: Specific antibodies usually appear after a week after onset of signs and symptoms so careful interpretation is necessary.

Management of typhoid fever:Can be subdivided into general management & specific measurements.

1. General: Supportive case includes
   
• Maintenance of adequate hydration.
• Antipyretics.
• Appropriate nutrition.
2. Specific: Antimicrobial therapy is the mainstay treatment. Selection of antibiotic should be based on its efficacy, availability and cost. With the emergence of resistant strains of S. typhi choosing an appropriate empirical antibiotic is difficult. Following drugs are used in treatment:

• Chloramphenicol (50 mg/kg/day qid PO or 75 mg/kg/day 6 hourly IV)
• Ampicillin (200 mg/kg/day 4-6 hourly IV)
• Amoxicillin (100 mg/kg/day tid PO)
• Trimethoprim Sulphamethoxazole (10 mg/kg/ of TMP and 50 mg/kg/ of SMZ bid PO)

Studies from Asia have shown that fluroquinolones are equally effective in children and can be used with the dose of 15 mg/kg/day bid PO / IV. Various quinolones are available in the market e.g., ofloxacin, ciprofloxacin, pefloxacin etc but no one is superior to another and all are equally efficacious. Recently a study from Vellore (India) reported treatment failure in typhoid fever with ciprofloxacin. Similar findings were also noted in the study from Pakistan. One study from Ludhiana also reported declining response to fluroquinolones in acute typhoid fever. This study recommended addition of 3rd generation cephalosporins (e.g., ceftriaxone) or aminoglycoside in the treatment regime. In Orissa 2% - 5% resistance to ciprofloxacin was found because of its indiscriminate use either singly or in combination. However there are few reassuring evidences also, which suggest that sensitivity to chloramphenicol is reappearing.
       In case of quinolone resistance – Azithromycin, 3rd generation cephalosporins (ceftriaxone) or high doses of fluroquinolones may be tried. There were suspicions that quinolones may damage articular cartilage in growing weight bearing joints but a recent study from Glasgow concluded that there are no adverse effects on growth or incidence of arthralgia / arthritis associated with ciprofloxacin in less than 6 years of age.

Duration of treatment: Most of the children become afebrile within 7 days of treatment, but therapy should be continued for at least 14 days in uncomplicated typhoid fever or 5-7 days after defervescence. Patient should be closely monitored for complications, as timely interventions reduce morbidity as well as mortality. If patient develops altered sensorium, delirium, stupor or obtundation, then CSF examination is warranted to rule out meningitis. If normal then patient should be treated as typhoid meningitis and high dose dexamethasone (steroids) are indicated with antibiotics. (Initially 3 mg/kg show IV (over half an hour), after 6 hours – 1 mg/kg and then 6 hourly for 7 doses). It is shown to reduce mortality by 80-90%. Data suggest that very short courses of therapy may be adequate in uncomplicated typhoid fever. These drugs include:

• Oral Cefixime (20 mg/kg/day) bid for 7 days.
• Ceftriaxone 50 mg/kg/day od IM for 5 days
• Oral ofloxacin 15 mg/kg/day bid for 2 days
• Cefopodoxime & Azithromycin are also effective.

Carriers: 1-5% of patients with acute typhoid fever develop carrier state (chronic carrier) usually because of gall bladder infection. Risk of chronic carrier state increases with increasing age. Female sex has more predilection for carrier state.

Treatment of carrier: Cholecystitis requires cholecystectomy. For eradication, Amoxicillin or ampicillin (100 mg/kg/day) with probenecid (23 mg/kg) or Trimethoprim – Sulphamethoxazole combination can be used for 6 weeks. Quinolones are also effective and given for 28 days.

Prevention: Typhoid fever can be prevented by some simple measures:

• Ensuring access to safe water and appropriate human excreta disposal.
• Promotion of safe food handling practices.
• Basic hygiene measures implementation and reinforcement.
• Hand washing before and after preparing and eating food.
• Avoidance of seafood e.g., shellfish, ice-cream etc.
• Health education with community participation and public awareness in one of the most important measure to prevent typhoid fever.

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