The differential diagnosis, recent treatment guidelines by the Indian Academy of Paediatrics IAP and prevention of typhoid fever are elucidated in this article. 

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Typhoid

Acute widespread infection of the reticuloendothelial system known as enteric fever prefers the gallbladder and intestinal lymphoid tissue. The term encompasses typhoid fever produced by salmonella typhi (about 80 per cent of all cases globally) and paratyphoid fever caused by salmonella paratyphi A or B. (20 per cent of all cases). The bacteria is non-lactose fermenting and gram-negative.

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Typhoid suspicion

Case of typhoid infection suspicion based only on clinical evidence. Patient with three days of fever, relative bradycardia, acute frontal headache, beginning constipation, and escalating intermittent fever.

Suspect case of typhoid:  A patient with a fever (38° C or higher) that has continued for at least three days and increased in a stepladder pattern, relative bradycardia, severe frontal headache, early constipation, and a positive serodiagnosis or antigen detection test but no S. Typhi isolation. There should be no malarial parasites in the peripheral blood smear, and the patient's lymphocyte count should be normal or low.

Confirmed case of typhoid: A patient with fever (38°C or above) that has persisted at least three days, with a laboratory-confirmed positive culture (blood, bone marrow, bowel fluid) of S. Typhi or with a positive serodiagnosis ('O' titre more than 1/60 or 'H' titre greater than 1/320.

Chronic carrier: Chronic carrier is defined as a person who excretes S. Typhi in faeces or urine (or has recurring positive bile or duodenal string culture) for more than a year after the beginning of acute typhoid fever.

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Differential diagnosis 

Any condition characterised by fever, stomach discomfort, and hepatosplenomegaly. Notable ones include:

• Malaria
• Visceral leishmaniasis (Kala-Azar)
• Dengue fever
• Short-term viral fevers
• Hepatointestinal amoebiasis

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Diagnosis

Primarily clinical: The most frequent cause of fever with no specific reason.

Clinical diagnosis: The incubation period is usually 7-14 days (ranging from 5-21 days).

1st week: Nonspecific features of malaise, headache, rising remitting fever (stepwise fashion) with initial constipation followed by diarrhoea, mild cough with conjunctivitis.

2nd week: Patient is toxic & apathetic; sustained high temperature with relative bradycardia; rose spots on upper thorax: distended abdomen: hepatomegaly and/or splenomegaly

3rd week: Patient delirious with abdominal distension & profuse pea soup diarrhoea. Intestinal bleeding, hepatosplenomegaly, and intestinal perforation (more frequently among adults than children) due to ileocecal lymphatic hyperplasia of the Peyer's patches may occur during the third week of illness, along with secondary bacteremia and peritonitis.

Infant to children up to 5 years: Fever, vomiting, and diarrhoea.
1. Older children: Fever trending upwards (step ladder pattern) over 5–7 days, anorexia, abdominal pain, cough followed by toxic look, lethargy, tender abdomen, soft splenomegaly, hepatomegaly, and relative bradycardia.
2. Rash: Rose spots described in Western textbooks are almost never seen in Indian children.

Laboratory diagnosis:

1. Hemogram: Total leukocyte count: normal or low, with neutrophilia and thrombocytopenia. Eosinopenia is strikingly concordant with typhoid fever. There may be a slight increase in transaminases. Leukopenia with a left shift is typically seen in adults, while leukocytosis is more common in children.
2. Culture and sensitivity: It is the most crucial investigation for diagnosis and the gold standard. Automated blood culture devices such as BACTEC enhance recovery and are cost-effective over time. Salmonella is an organism that may be easily cultured, and antibiotic sensitivity findings are crucial for therapy.
3. Blood culture: 90 per cent yield in the first week, decreasing to 40 per cent in the fourth week. Send paired cultures with a total blood volume of 5–10 mL and a broth: blood ratio of 1:5. In the latter phases of pyrexia of unknown origin (PUO), bone marrow culture is a crucial examination since it stays positive even after antibiotic treatment. Due to low yield, stool and urine cultures are not suggested.
4. Serology: It is important to note that these tests are not diagnostic and should not be used to make treatment choices for patients.
5. Widal test: In the second week of illness, it detects the presence of immunoglobulin M (IgM) and IgG antibodies against H (flagellar antigen) and O (somatic antigen) of S. Typhi and paratyphi A and B. Slides are inferior to the tube approach. Antibody titers of both O and H in the range of 1:160 or above are considered positive. It is traditional to see a fourfold increase in titer in matched samples collected one week apart; however, this approach is impractical. Due to its limited sensitivity and specificity, widal may provide false-positive results for malaria, rickettsial infection, and other Enterobacteriaceae infections. It may be falsely negative in individuals who have been treated with antibiotics before.
6. Typhidot/enzyme immune assay (EIA) test: It works by detecting IgM and IgG antibodies against the S. Typhi-specific 50 kd outer membrane protein antigen. Specificity is just 37%, and anamnestic responses are possible with other illnesses. A 2017 assessment of the Cochrane database indicated that quick diagnostic serologic assays need additional thorough validation.
7. Never rely on serological testing to diagnose or rule out enteric fever.
8. It is essential to rule out malaria, dengue, and other potential causes of feverish sickness in patients with acute febrile illness lasting longer than 3 days.

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Treatment

Management guidelines:

1. In bacteraemic patients, automated blood cultures may provide positive findings in as little as four hours, with definitive identification and susceptibility data available within 48 hours.
2. Two sets of blood cultures are preferable prior to initiating antibiotic therapy and in patients currently on antibiotics who are not responding to treatment.
3. Begin empirical therapy for probable enteric fever with oral cefixime or intravenous ceftriaxone, depending on the severity of the condition, after submitting baseline testing, including blood cultures.
4. In the absence of a positive blood culture or if a blood culture reveals no growth, reevaluate the diagnosis and discontinue or alter antibiotic treatment if the patient does not have typhoid.
5. In typhoid fever, fever defervescence is protracted and may take between 5 and 7 days to improve. Monitor the frequency and level of fever for improvement before changing antibiotics.
6. The patient's appetite and overall health may improve prior to a decrease in fever.
7. Observe for problems such as abdominal distension, pain, vomiting, change in GCS, and laboratory parameters such as cytopenia.

Effective antibiotic treatment shortens the duration of the disease and decreases death due to complications. As there is no easy confirmatory test for enteric fever, empirical therapy is recommended in endemic regions at the time of onset. Oral antimicrobials may be administered to individuals with fever for three to four days and suggestive symptoms in the absence of an obvious infection focus and, if applicable, a negative malaria smear. In the absence of a straightforward diagnostic test, there is no alternative to the administration of antimicrobials on a case-by-case basis. Ensure enough hydration, the use of antipyretics for fever, and cautious follow-up.

Choice of antimicrobial:

Resistance to routinely used medications complicates the choice of antimicrobials. Culture and susceptibility findings are critical for guiding individual patient therapy and monitoring regional resistance trends, but they are often unavailable in endemic regions due to a lack of microbiological expertise.

High incidences of fluoroquinolone resistance are now being observed in both South Asia and Africa. Cephalosporins with a broader range of activity, oral cefixime and parenteral ceftriaxone, and oral azithromycin are now suggested. Cefixime and ceftriaxone are linked to increased relapse rates. Resistance to each of the three agents is emerging.

The Indian Academy of Pediatrics (IAP) has released standard treatment guidelines 2022 for enteric fever.

Selecting an empirical treatment for typhoid fever
Patient's condition	First-line choice	Second-line choice
Outpatient department	Cefixime	Azithromycin (penicillin                                                                                                                 allergy)
Severe illness Indoor patient   Any complications	Ceftriaxone	Cefotaxime   Aztreonam

 

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Warning signs to watch out for

Adults

1. On first inspection, two or more of the following Quick Sepsis-related Organ Failure Assessment (qSOFA) criteria are met:

• Altered mental state
• Respiratory rate of fewer than 22 breaths per minute
• Systolic blood pressure of less than 100 mm Hg

 2. The patient may be at risk for severe sepsis and need more intensive treatment.

Children

• The appearance of illness and toxicity
• Inability to take orally administered medications
• Persistent vomiting
• Signs of severe dehydration
• Abdominal distension with or without discomfort
• Jaundice
• Drowsiness or altered awareness
• Signs of gastrointestinal bleeding (such as passing new blood in stools or melaena)
• Signs of haemodynamic shock, such as discoloured skin and diminished capillary return
• Seizures

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Duration of treatment

Treat for a minimum of 7 days after defervescence, or for a total of 14 days, whichever comes first. Azithromycin is administered for a total of seven days. Steroids are only prescribed for serious illnesses. If the patient comes with shock, coma, or altered sensorium, dexamethasone may be administered at a dosage of 3 mg/kg followed by 1 mg/kg every six hours for two days. Usage cautiously, since prolonged steroid use might raise the relapse rate and induce severe consequences.

If after day 7 of antibiotics defervescence has not happened but the kid seems less toxic, the length between fever spikes has increased, or the child responds rapidly to antipyretics, the same antibiotics may be maintained until day 10.

Clinical failure:

After seven days of optimum therapy, the absence of defervescence and the presence of a rise in fever spikes indicate clinical failure. In this situation, rule out: Infections including malaria and hepatitis A; Drug fever or thrombophlebitis; If the kid was culture negative, the diagnosis should be reevaluated with a thorough history, physical examination, and other tests.

Special therapeutic concerns:

1. A culture-positive result empowers the practitioner, instils confidence even in cases of late defervescence, and saves the needless use of azithromycin, which must be kept on hand as a backup medication.

2. Quinolones are contraindicated in children and should not be used to treat enteric fever.

3. Aminoglycosides, such as amikacin, have no function in therapy since their site of action is extracellular whereas Salmonella is an intracellular bacterium.

4. In the age of antimicrobial resistance (AMR), it is crucial that labs provide drug sensitivity reports that include minimum inhibitory concentrations (MICs) and their interpretation. MIC 1 for ceftriaxone is linked with a favourable clinical result in cases of enteric fever. In India, increasing ceftriaxone MICs have been documented. According to the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST), the MIC breakpoints for ceftriaxone resistance are [>4] and [>2], respectively. Azithromycin is the treatment of choice for isolates resistant to ceftriaxone. Meropenem may be prescribed if the kid is hemodynamically unstable or if the illness is severe.

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Relapse

Enteric fever has a recurrence incidence between 5 and 20% even after proper therapy. Relapse is the return of fever 2–3 weeks after its initial remission. Usually, it is milder. Relapse is treated with the same medicine as initial treatment. Relapse can only be distinguished from reinfection by molecular typing.

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Carrier state

It is defined as the presence of Salmonella in the stool or urine of an asymptomatic individual more than three months after an incident of enteric fever. It is rare in children, hence screening for S. typhi carriage after sickness is not suggested. Reduce the risk of close contact by administering trimethoprim-sulfamethoxazole (10 mg/kg/day for 6–12 weeks) or high-dose amoxicillin (75–100 mg/kg/day for 4–6 weeks).

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Prevention

There are vaccinations available for the prevention of typhoid: 

1. A single dose of Vi polysaccharide vaccination for children older than 2 years. Protection must be renewed every three years by vaccination.
2. Children under the age of six months may get a single dose of the typhoid conjugate vaccination. Offers at least three years of protection to adults, children, and newborns older than six months. The immunisation schedule is now under investigation.
3. Neither vaccine is 100 per cent effective, necessitating repeated vaccinations since the efficiency of vaccines declines over time.
4. Vaccinate everyone, including all household members of a confirmed case (adults and children older than six months), all healthcare staff and food handlers.

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This is the next article of our monsoon series. To read the earlier articles of the series, click here:Managing dengue fever: What you should know; Malaria in monsoon: Recent updates ;Leptospirosis: A commonly misdiagnosed disease; Know cholera: Diagnosis and treatment approach; Chikungunya: An overview of diagnosis and treatment

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Click here to see references

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

About the author of this article: Dr Monish Raut is a practising super specialist from New Delhi.