Typhoid Fever in Children

Post-COVID everyone seems to be posting the perfect picture of their travels to the far reaches of the world. While this is an exciting change, it allows transmission of illness to countries where they are not endemic. Recently, a pediatric patient presented to the ED who just returned from abroad with a gastroenteritis presentation. In addition to my passion for PEM, I also share a passion for global health. This inspired me to write a series of morsels related to concerning presentations in patients who have recently travelled. First out of the oven, an illness popularized by stories of Mary Mallon, or better known as Typhoid Mary.  She was the first person in the United States to be found to be an asymptomatic carrier of Salmonella Typhi, and as a result was quarantined for the last 30 years of her life (imagine that after struggling through the comparably short quarantine during COVID)! This disease process can present similarly but has several notable differences from the Salmonella gastroenteritis seen frequently in the US.  Let us take a moment to review Typhoid Fever in children:

Typhoid Fever: Basics 

  • Salmonella enterica serotype Typhi is the causative bacteria and represents 75% of cases of enteric fever (GBD 2017)
    • Salmonella enterica serotypes Paratyphi A, B and C cause Paratyphoid fever which has clinically indistinguishable features.
    • Paratyphoid fever is less common (25% of cases of enteric fever) and is typically less severe. (GBD 2017)
  • In a study from Australia, most infections in travelers were acquired in South/Southeast Asia and Oceania. The most common countries of acquisition were Bangladesh, India, Nepal, and Pakistan (Forster 2021)
  • For travelers, the peak incidence occurs at age 10 and those who are visiting to their country of birth. Neonates are protected if they are exclusively breastfed. (Forster, 2021)
  • Transmission is by Fecal-Oral route (Chiodini 2018)
  • Incubation period 6-30 days after exposure (Chiodini 2018)
  • Salmonella typhi produces an endotoxin although its clinical significance is not yet well understood (Gibani 2019)
  • Two typhoid vaccines are available for those > 6 m/o and are 50-80% effective. In the US 95% of vaccine-eligible pediatric patients who travel are unvaccinated (McAteer 2021)
  • Drug resistance has been developing over time. The first case of extensively-drug resistant (XDR) typhoid fever was seen in Pakistan in 2018. This is resistant to most commonly used drugs but sensitive to azithromycin and carbapenems (Chiodini 2018)

Typhoid Fever: Presentation

  • Insidious onset of fevers seen in nearly all cases of patients, gradually increasing in temperature over several days. This can be the sole feature in some cases. It can also be associated with headache, anorexia, and malaise. (Britto 2017, Chiodini 2018)
  • Abdominal pain is the second most common symptom in pediatric patients, followed by diarrhea. (Rauniyar 2021)
  • Up to 10% of patients may present with constipation as opposed to diarrhea. This is thought to be due to the inflammation of the Payer’s patches. (Rauniyar 2021, Zwar 2021)
  • Relative Bradycardia for the patient’s temperature is seen in Typhoid fever in up to 30% of children. (Britto 2017)
  • By the second week of symptoms, fevers are sustained closer to 40OC, and there are often worsening abdominal symptoms including distension. (Shah 2021) 

Typhoid Fever: Evaluation & Management

  • Physical exam features which can seen but are not specific include: 
    • Respiratory symptoms including a wheeze consistent with reactive airway disease can sometimes be auscultated in children. (Britto 2017)Tenderness or hepatomegaly/splenomegaly can be seen in up to 90% of pediatric patients. (Britto 2017)
    • The classic rash described as Rose spots or blanching, erythematous papules typically start around day 7-10. These are only seen in up to 20% of patients. (Shah 2021).
  • In any suspected case, lab work including CBC, CMP, CRP should be obtained. 
    • CBC can show a pancytopenia thought to be due to seeding of Salmonella to the bone marrow. (Britto 2017)Leukocyte count can be high or normal in children, as compared to adults where it is typically low. (Britto 2017)Eosinopenia is seen in 70% of children and is an indicator of disease severity. (Britto 2017)AST and ALT are often mildly elevated but do not exceed 2-3x the normal levels. (Shah 2021)
    • Hyponatremia may be present but is typically mild. (Shah 2021)
  • Obtain blood and stool cultures! Cultures are very important if they are diagnostic but can be highly variable depending on duration of symptoms
    • There are several rapid diagnosis tests available in endemic areas. Due to low sensitivities and cross-reactivity in those who are vaccinated, blood cultures are the preferred method to diagnosis .(Chiodini 2018)The sensitivity of blood cultures (66%) is highest in the first week and drops rapidly each subsequent week. (Mogsale 2016, Shah 2021)Stool cultures are only positive in 30% of cases if collected in 2nd-3rd week of illness which makes them a poor choice for definitive diagnosis. (Shah 2021)
    • Bone marrow aspiration cultures are considered the gold standard as they are highly sensitive especially later in the course. They are impractical and unnecessary in most clinical settings. (Shah 2021)
  • Consider alternative diagnosis with similar presentations such as malaria, as it has a similar distribution pattern to typhoid fever. A thick and thin smear can help to rule out malaria. 
  • Treatment: 
    • Rocephin is the recommend first line medication for most countries. (Chiodini 2018)
    • Use Azithromycin for travelers from areas of XDR Salmonella Typhi, per the CDC recommendation that currently refers to those with recent travels to Pakistan and Iraq. (Chiodini 2018)

Typhoid Fever: Complications

  • For uncomplicated courses, symptoms improve on their own within 2-4 weeks.
  • 10-15 % of patients develop complications during the 2nd-3rd week of symptoms. (Shah 2021)
  • Risk of mortality is 4x higher in those < 5 years as compared to those > 5 years of age due to their increased complication rate. (Britto 2017)
  • Gastrointestinal complications are most predominant: 
    • Paralytic ileus can be seen in infants and young children. (Britto 2017)
    • In older children, Salmonella typhi frequently causes enlarged mesenteric lymph nodes which likely contributes to abdominal pain. (Shah 2021)
    • GI hemorrhage can be seen if there is erosion of the bowel walls, and further erosion can also lead to bowel perforation. (Shah 2021)
    • Acalculous cholecystitis has been described in children which has led to rare reports of gallbladder perforation. (Obasi 2020)
    • Hepatic and splenic abscesses have been documented in children, and splenic rupture is particularly associated with cases of MDR typhoid fever. (Britto 2017)
  • Cardiac complications are rare but can be very serious. These include myocarditis, infective endocarditis, pericarditis, and pericardial effusions. They are more typically seen in older children. (Britto 2017)
  • Respiratory complications are more prevalent in adults, but occasional bronchopneumonia, pleural effusions and empyemas have been seen in children. (Britto 2017)
  • There have been several neurological complications associated with typhoid fever in pediatric patients (Britto 2017): 
    • It has an increased association with febrile seizures. This may be due to the height of the temperature, but there is a theory that the typhoid toxin could cause cortical irritation.
  • There have also been reports of Salmonella Typhi spondylodiscitis causing back pain in a pediatric patient as well as osteomyelitis. The MSK complications do not always share the same prodrome of fever, diarrhea and abdominal pain or they can be far removed from the initial infectious symptoms by several months. (Banerjee 2018, Rohilla 2019)

Moral of the Morsel

  • “Ken-ya tell me if you recently travelled?” Remember to think about Typhoid fever especially with travel to South/Southeast Asia and Oceania.
  • “30 days hath September  Salmonella Typhi!” It can take up to a full month after exposure for a person to start having symptoms!
  • Be suspicious! As the common method of diagnosis is by blood cultures which can take 1-2 days, always be suspicious with those with a travel history and presentation consistent with enteric fever. 
  • Rocephin, AKA Cef-Kill-It-All. This is the antibiotic of choice unless they have travelled to an area with a strain of XDR Salmonella Typhi. 
  • The Second Great Mimicker! While TB is referred to as the great mimicker, I think Salmonella Typhishould be nominated for second place. The list of complications ranges broadly from GI to Neuro to MSK! 

References

Banerjee B, Madiyal M, Madhava P, Agarwal M, Mukhopadyay C. Typhoid spondylodiscitis mimicking tuberculosis in a teenage girl. J Infect Public Health. 2018 Jan-Feb;11(1):136-137. PMID: 28602673

Britto C, Pollard AJ, Voysey M, Blohmke CJ. An Appraisal of the Clinical Features of Pediatric Enteric Fever: Systematic Review and Meta-analysis of the Age-Stratified Disease Occurrence. Clin Infect Dis. 2017 Jun 1;64(11):1604-1611. PMID: 28369224

Chiodini J. The CDC Yellow Book app 2018. Travel Med Infect Dis. 2017 Sep;19:75-77. PMID: 29074406

Forster D, Leder K. Typhoid fever in travellers: estimating the risk of acquisition by country. J Travel Med. 2021 Dec 29;28(8). PMID: 34619766. 

GBD 2017 Typhoid and Paratyphoid Collaborators. The global burden of typhoid and paratyphoid fevers: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Infect Dis. 2019 Apr;19(4):369-381. PMID: 30792131

Gibani et all. Investigation of the role of typhoid toxin in acute typhoid fever in a human challenge model. Nat Med. 2019 Jul;25(7):1082-1088. PMID: 31270506

McAteer J, Derado G, Hughes M, Bhatnager A, Medalla F, Chatham-Steverns K, Appiah G, Mintz E. Typhoid Fever in the US Pediatric Population, 1999-2015: Opportunities for Improvement. Clin Infect Dis. 2021 Dec 6;73(11): e4581-e4589. PMID: 33247585

Mogasale V, Ramani E, Mogasale VV, Park J. What proportion of Salmonella Typhi cases are detected by blood culture? A systematic literature review. Ann Clin Microbiol Antimicrob. 2016; 15: 32. PMID: 27188991

Obasi AA, Igboanugo AA. Gall Bladder Complications Resulting from Typhoid Fever in Children: Challenges of Management and Lessons Learned. 2020 Jan-Mar; 10(1): 35–38. PMID: 35531587.

Rauniyar G, Bhattacharya S, Chapagain K, Shah GS, Khanal B. Typhoid Fever among Admitted Pediatric Patients in a Tertiary Care Center: A Descriptive Cross-sectional Study. JNMA J Nepal Med Assoc. 2021 Sep 11;59(241):871-874. PMID: 35199732

Rohilla R, Bhatia M, Gupta P, Singh A, Shankar R, Omar BJ. Salmonella osteomyelitis: A rare extraintestinal manifestation of an endemic pathogen. J Lab Physicians. 2019 Apr-Jun; 11(2): 164–170. PMID: 31160858

Shah A. Diagnosis of Enteric Fever. Pediatr Inf Dis 2021; 3 (4):165-169. 10.5005/jp-journals-10081-1323

Zwar N, Torda A. Investigation of diarrhoea in a traveller just returned from India. BMJ. 2011 May 26:342:d2978. PMID: 21622512

Erica Scott
Erica Scott
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