1. Enteric Fever Richelle C Charles, MD.

2. Outline Definitions: Typhoid and Enteric fever Etiology Epidemiology Transmission and Pathogenesis Clinical manifestations Diagnosis and Management Prevention and control

3. Definition: Enteric and typhoid fever Enteric fever denotes typhoid or paratyphoid fever Salmonella enterica serotype Typhi causes typhoid fever Salmonella enterica serotypes Paratyphi A, B and C are the causative agents of paratyphoid fever The terms “enteric fever” and “typhoidal illness” may sometimes be used to refer to syndrome of high grade and prolonged fevers in the absence of localizing symptoms or signs. –Examples: Tularemia, Yersiniosis, Brucellosis

4. Etiologic agent and pathogenesis

5. Nomenclature of Salmonellae Salmonella enterica: Gram-negative bacillus The multiple strata of clinical, microbiologic, and serologic designations applied to Salmonella infections lead to confusion.

6. Nomenclature of Salmonellae CLINICAL Salmonella strains are differentiated as typhoidal or non-typhoidal –Typhoidal strains cause enteric fever in all human hosts –Non-typhoidal Salmonella (NTS) are classically associated with inflammatory diarrhea in human hosts Classically this distinction reflects systemic illness vs. gastroenteritis but the lines can blur. –NTS may cause invasive infection that includes prolonged bacteremia (with or without pyogenic foci) that may mimic systemic illness with typhoidal strains –host factors influence susceptibility to invasive NTS (Specific immunodeficiencies associated with systemic disease) –characteristics of bacterial strain may influence likelihood for invasive NTS

7. Figure 5 The Lancet 2012 379, 2489-2499DOI: (10.1016/S0140-6736(11)61752-2)

8. Nomenclature of Salmonellae TAXONOMIC Most pathogenic Salmonella belong to a single subspecies designated Salmonella enterica subspecies enterica.

9. Nomenclature of Salmonellae. SEROLOGIC Salmonella are usually classified serologically. The serogroup is assigned based on the O antigen alone, while the serotype designation, from which the name (eg….) is derived, is based on both the O and H antigens.

10. Examples clinical and serologic classification of pathogenic Salmonella. ClinicalSerotype (O and H) Formal DesignationSerogroup (O) TyphoidalTyphi S. enterica subsp. enterica ser. Typhi D Paratyphi A S. enterica subsp. enterica ser. Paratyphi A A Paratyphi B (schottmuelleri) S. enterica subsp. enterica ser. Paratyphi B B Paratyphi C (hirschfeldii) S. enterica subsp. enterica ser. Paratyphi C C Non- typhoidal Typhimurium S. enterica subsp. enterica ser. Typhimurium B Enteriditis S. enterica subsp. enterica ser. Enteriditis D Newport S. enterica subsp. enterica ser. Newport C

11. Epidemiology

12. Burden in high incidence areas Incidence of Enteric Fever annually –22-27 million S. Typhi –5 million S. Paratyphi A (Increasing-- 1:5 cases in Asia) –S. Paratyphi B and C are less common causes of enteric fever globally. In high incidence areas, most infection occurs in young children Typically the leading cause of bacteremia (> 75%) in such areas

13. Typhoid Fever: Distribution

14. Transmission, Risk Factors and Patterns of Infection Sources of Infection S. Typhi and Paratyphi A and B are human restricted –no environmental or animal reservoir (*S. Paratyphi C can be shed by animals) –Source of infection is organisms shed in the stool of infected humans Pre-antibiotic era individuals shed bacteria during acute illness and typically for weeks during convalescence 3-5% of infected individuals develop chronic asymptomatic carriage (shedding bacteria > 1 year).

15. In endemic areas, what is the proportion infection transmitted via water source versus person-to- person transmission? a) 50:50 b) 20:80 c) 80:20

16. Transmission, Risk Factors and Patterns of Infection Mode of transmission Typhoidal S. enterica are acquired via ingestion of fecally- contaminated water or food. Molecular epidemiologic studies based on high resolution genotyping show waterborne transmission as the most likely route of transmission in majority of cases of enteric fever. –Despite spatial and temporal case clustering, the distribution of S. typhi genotypes was random –Households with multiple cases of enteric fever, only 20% shared a common bacterial genotype Baker S, Open Biol 2011

17. Transmission, Risk Factors and Patterns of Infection S. Typhi may persist for weeks after passage in water, and may persist in a variety of contaminated food items (e.g. dehydrated formula and iced beverages) ID50 in human volunteers ~ 10 7 bacteria (as few as 10 3 organisms can cause disease) Contact with a known case in <20% Consistent risk factors include drinking non- boiled water and foods prepared outside the home

18. Typhoid fever in the U.S. Sporadic disease (<1/100,000 person- years) In the U.S. ~80% of reported cases occur in returned travelers. Risk dependent on location, approaching 1 per 1000 in travelers arriving from India. Lynch MF, JAMA. 2009;302(8):859.

19. Typhoid fever in the U.S. Most published outbreaks between 1960-1999 are foodborne –Majority associated with asymptomatic chronic carriers employed as food handlers (Olsen SJ (2003) Epidemiol Infect 130: 13- 21). In the U.S. 0.2% fatalities in reported cases. Mary Mallon

20. Clinical Pathogenesis Invasion: –Asymptomatic (80-90%) or transient diarrhea (10-20%). Intracellular infection which disseminates throughout reticuloendothelial system Low grade bacteremia. –Median of 1 culturable bacteria per mL blood –Median of 10 culturable bacteria per mL bone marrow Pre-patent phase (Latency) of infection lasts ~1-2 weeks (3-60 days depending on number of organisms ingested) Modified from Monack, D. 2004 Nature Reviews Microbiology 2, 747-765.

21. Clinical Manifestations Non-specific –90% - mild, require outpatient treatment –10% - severe, classic ‘enteric fever’ Clinical FeatureApprox. Frequency* Flu-like symptoms Fever> 95 % Headache80 % Chills40 % Cough30 % Myalgia20 % Arthralgia< 5 % Abdominal symptoms Anorexia50 % Abdominal pain30 % Diarrhea20 % Constipation20 % Physical signs Hepatomegaly10 % Splenomegaly10 % Abdominal tenderness5 % Rash< 5 % Generalized adenopathy < 5 %

22. Clinical Manifestations Classic descriptions of enteric fever are based on series of hospitalized patients –Classically the first week is relatively indolent –By the second week of illness patients become toxic –Some degree of abdominal pain, diarrhea, or constipation is common –Some suggestion of encephalopathy is common –Life threatening complications around third week (i.e. encephalopathy, GI hemorrhage or perforation –Resolution over 3-4 weeks. Relapse in 10-20%. –Severe disease in adolescents and young males. –Life threatening complications typically after 1 week of escalating fevers and include intestinal perforation and encephalopathy.

23. Diagnosing Enteric Fever Currently there is no optimal assay for diagnosing patients with acute typhoid or paratyphoid fever This deficiency limits our ability to do the following: –To diagnose acute cases required for clinical management –Target administration of appropriate antimicrobials –Measure disease burden within a defined area –Measure the effectiveness of various intervention strategies.

24. Enteric Fever: Diagnostics Cultured based diagnostics –Blood cultures are limited by low number of organisms Sensitivity 40%-80% dependent on volume of culture –stool cultures positive in 50% of children, 30% of adults –BM culture gold standard but invasive – 80 to 95% sensitivity Serologic based diagnostics –Widal test most commonly used but lacks sensitivity and specificity –Rapid serologic tests (e.g. Tubex® or Typhidot® ) suffer similar problems Often left with need for empiric treatment

25. Test (culture site) SensitivitySpecificityComments Microbiologic Blood30-70%100% A number of advantages Sensitivity increases with volume Bone marrow80-95%100%Considered gold standard but impractical Stool30-50% Urine15-50% GenomicPCR50-95%variableIssues of sensitivity not solved Host response Widal70-100%30-85%Specificity decreases in endemic zones IDL Tubex® (Anti-LPS IgM) 60-85%55-80% Many small studies in general less sensitive but more specific than Widal Typhidot® (Anti-OMP IgG/IgM) 75-90%50-90% TPTest IgA Assay >90% Sensitive, specific, minimal laboratory requirements Selected diagnostic tests

26. Management Antibiotic management –reduces the mortality rate of enteric fever from 10-15% to less than 1% –shortens the duration of fever from 3-4 weeks to 3-5 days

27. Antibiotics Ciprofloxacin (and ofloxacin) remain effective for nalidixic-acid susceptible strains. –Short courses of 5-7 days are acceptable in uncomplicated cases. Third generation cephalosporins –Longer time to fever clearance and more clinical failures and rates of relapse with courses <7 days Azithromycin –Only rare reports of resistance –Excellent oral drug for uncomplicated infection caused by NaR strains. –Excellent response and low failure rates –Low rates of relapse after seven day course

28. Emergence of antibiotic resistance Wain (2015)Lancet 385:1136-45 Complications and mortality both are higher in cases of MDR strains (resistant to chloramphenicol, ampicillin, and co-trimoxazole) of Salmonella Typhi or Salmonella Paratyphi

29. Asymptomatic carriage 3-5% of infected individuals develop chronic infection in the gall bladder which may persist for decades May be reservoirs of infection within a community

30. Asymptomatic Carriage Gallstones are thought to be the principal risk factor for developing chronic carriage. – Gallstones detected in approximately 90% of chronic carriers. –Gallstones allow attachment of the bacteria and biofilm formation, which in turn protects the bacteria from the antimicrobial and emulsifying action of bile.

31. May contribute to transmission of infection May act as vehicles for introducing S. Typhi or S. Paratyphi A into previously uninfected communities. Asymptomatic carriage

32. Prevention and Control

33. Typhoid Control Major preventative strategy is the provision of safe water and adequate sanitation. –Municipal public infrastructure level Development of appropriate facilities for waste disposal and sewage treatment Development of safe water supplies –Household level – washing hands, food and water safety Reportable, control in areas where disease is sporadic includes identification of carriers (from household contacts) and restriction of carriers from food handling

34. Typhoid Vaccines Table 4: Vaccines for Typhoid Fever (11,22). Vacc.TypeRouteDose and Interval Minimum Age Protection against S. Typhi Boosting Interval in Travelers Licensed in # Nations Ty21a live- attenuated Oral 4 doses Administer one dose every other day until complete 5*50-80% every 5 years 56** Vi capsule antigen Polysacch.IM1250-80% every 2 years > 90** *5 years and older per WHO, 6 years and older per Advisory Committee on Immunization Practices. **As of March 2010

35. Typhoid Vaccines WHO recommends vaccination in highly endemic areas but not adopted into NIP. Vaccines are primarily used by persons from non-endemic areas

36. Limitations of current vaccines Limited immunity in young children (<2 years) Lack of cross protection against other causes of enteric fever, primarily S. Paratyphi A A number of conjugate Vi vaccines are in various stages of development to improve both immunogenicity in young children under 2 years of age and to induce longer lasting protection, A paratyphoid A conjugate vaccine containing the O-specific polysaccharide of S. Paratyphi A has also recently been reported

37. Obstacles to typhoid control Currently there is no optimal assay for diagnosing patients with acute typhoid or paratyphoid fever Limited data to assess true burden of disease Increasing antimicrobial resistance Lack of effective vaccines for children under the age of 2