Enteric fever

Introduction
Epidemiology and pathogenesis
Clinical features
Differential diagnoses
Complications
Investigations
Management
Prevention
Vaccination
management of carriers

1. ENTERIC FEVER By Dr. Prabhakar Postgraduate in pediatrics Dept of pediatrics S V M C, T irupati

2. Overview Introduction Epidemiology and pathogenesis C linical features Differential diagnoses Complications I nvestigations Management Prevention V accination

3. Genus: Salmonella Only one species- Salmonella Enterica > 2000 serotypes Sallmonella Enterica subspecies Enterica Serotype Typhi Serotype Paratyphi

4. typhoid (90%) paratyphoid fevers (10%). Enteric fever This is an acute generalized infection of the intestinal lymphoid tissue, gall-bladder and reticuloendothelial system.

5. https://en.wikipedia.org/wiki/Typhoid_fever History The name  S typhi  is derived from the ancient Greek  word - typhos ,  an ethereal smoke or cloud that was believed to cause disease and madness.  William Budd 1838, English country doctor  The  American Civil War  -1861 to 1865 Karl Joseph Eberth -1880,   Georg Theodor August Gaffky 1984,   Almroth Edward Wright - 1896 

6. Strongly endemic Endemic Sporadic cases Incidence of typhoid fever https://en.wikipedia.org/wiki/Typhoid_fever#/media/File:Fievre_typhoide.png

7. 33-60 million cases and 6 lakh deaths occur annually due to typhoid fever world wide. Around 5 million cases occur annually in India

8. AGENT HOST ENVIRONMENT Disease

9. AGENT- Salmonella typhi – majorcause S.paratyphi A , S.paratyphi B Family- Enterobactericeae Gram negative bacilli Motile with peritrichate flagella Non acid-fast Non capsulated Non spore forming Facultative anerobe

10. The Enteric bacilli have 3 important antigens: O antigen (body or somatic) Less immunogenic Cross reacts H antigen or flagellar antigen, Strongly anigenic Rapid rise of Ab in infection/ immunisation Lasts longer and specific Vi antigen (virulence antigen) S. Typhi and S.Paratyphi C Poorly immunogenic Disappears….. May persist in chronic carriers

11. HOST Humans are only reservoir and only known susceptible host Peak incidence ---- 5 to 15 years. 10% of cases occur in infant age group. No sex predliction Children constitute 40-50% MDR typhoid cases with higher case fatality rate

12. Case definition Confirmed case of typhoid fever A patient with fever (38°C and above) that has lasted for at least three days, with a laboratory-confirmed positive culture (blood, bone marrow, bowel fluid) of S. typhi . Probable case of typhoid fever A patient with fever (38°C and above) that has lasted for at least three days, with a positive serodiagnosis or antigen detection test but without S. typhi isolation . Chronic carrier Excretion of S. typhi in stools or urine (or repeated positive bile or duodenal string cultures ) for longer than one year after the onset of acute typhoid fever. Short-term carriers also exist but their epidemiological role is not as important as that of chronic carriers . Some patients excreting S. typhi have no history of typhoid fever

13.  " Typhoid Mary "(Mary Mallon ) 1907- was the first asymptomatic typhoid carrier to be identified by medical science Typhoid Mary in a 1909 newspaper illustration

14. Environmental Source of infection Primary - faeces, urine of cases, carriers Secondary – contaminated water, food, fingers and flies.

15. Spread of infecion Water contamination Food contamination Houseflies Predisposing factors Over crowding Poor personal hygiene Poverty and illiteracy Poor sanitary and water supply suituations Open defecation

16. Pathogenesis Bacteremia – Metastatic infection

17. PATHOGENESIS Ingestion Invade body through gut mucosa in terminal ileum. Pass through intestinal mucosa S. Typhi enter mesenteric lymphoid system Lymphatics Bloodstream (Asymptomatic bacteremia , Culture negative) Colonize Reticuloendothelial system (replicate in macrophages) Shed back into blood (Secondary bacteremia -Symptoms appear)

18. Virulence factors Genes – regulate invasion of Payer’s patches Inoculum size 25% for 10 5 50% for 10 7 75% for 10 9 Gastric pH Vi polysaccharide antigen Concommitant H. Pylori infection Immunocompetence

19. Clinical features Incubation period- 3 to 60 days – depending on size of inoculum…… Symptoms occur in 1-2 weeks Clinical picture exhibits a wide range of clinical severity and varies according to age Mild pyrexia ------------> fatal severe disease

20. In neonates infection is transmitted vertically Mother has chorioamnionitis- may lead to abortion or premature delivery. Presents with Hypothermia or hyperthermia Vomiting Diarrhoea Abdominal distention Seizures Jaundice Hepatomegaly Failure to thrive

21. In infants and children up to 5 years Disease may be mild Presenting only as diarrhea Or mimicking a viral illness In in older children and adolescents, the onset is insidious.

22. Initial symptoms –over 2-3 days fever(95%) coated tongue(76%) anorexia(70%) Vomiting Hepatomegaly Splenomegaly diarrhoea malaise myalgia , headache abdominal pain Diarrhoea - constipation cough and epistaxis Severe lethargy Relative bradycardia seen in older children and adults

23. CLINICAL FEATURES • First week : malaise, headache, cough & sore throat in prodromal stage . The disease classically presents with step-ladder fashion rise temperature (40 - 41°C) over 4 to 5 days, accompanied by headache, vague abdominal pain, and constipation or pea soup Diarrhoea . • Second week : Between the 7th -10th day of illness, mild hepatosplenomegally occurs in majority of patients. Relative bradycardia may occur and rose-spots may be seen . • Third week: The patient will appear in the "typhoid state" which is a state of prolonged apathy, toxemia , delirium, disorientation and/or coma. Diarrhoea will then become apparent. If left untreated by this time, there is a high risk (5-10%) of intestinal hemorrhage and perforation . • Rare complications : Hepatitis , Pneumonia, Thrombophlebitis, Myocarditis, Cholecystitis , Nephritis , Osteomyelitis, and Psychosis. 2-5 % patients may become Gall-bladder carriers

24. http://www.japi.org/november_2015/16_apir_api_recommendations_for.html

25. 2 nd week High Fever sustained Fatigue, anorexia, cough, abdominal symptoms increase in severity Patients appear acutely ill, disoriented and lethargic. Delirium and stupor may be observed. Coma may intervene

26. Rose spots Appear on 7-10 days In 10-20% individuals Macular – 2-4 mm size 15-20 in number Appear in crops in periumbilical and anterior chest Better appreciated in fair skinned people Lasts 2-3 days Leave a slight brownish discoloration of the skin on healing.

27. If course remains uncomplicated symptoms start abating by 2-4 wks. although lethargy and malaise may persist for 1-2 months Relapse rate 5-20 % 2 to 3 weeks after fever subsides or stopping antibiotics - mimics original illness but milder and shorter duration

28. Complications

29. Hemorrhage and Perforation Intestinal haemorrhage (<1%) and perforation (0.5-1%) are infrequent among children. Intestinal perforation may be preceded by a marked increase in abdominal pain, tenderness, vomiting, and features of peritonitis Intestinal perforation and peritonitis may be accompanied by a sudden rise in pulse rate, hypotension, marked abdominal tenderness and guarding and subsequent abdominal rigidity. A rising white blood cell count with a left shift and free air on abdominal radiographs

30. http://www.japi.org/november_2015/16_apir_api_recommendations_for.html

31. DIFFERENTIAL DIAGNOSIS Salmonella infection and gastroenteritis - Salmonellae , the dysentery group may occasionally cause an invasive illness resembling typhoid fever with bacteremia. however, the GIT Symptoms are more acute than the general manifestations, and the pyrexia much lower and of shorter duration .

32. DIFFERENTIAL DIAGNOSIS

33. LAB INVESTIGATIONS

34. Lab investigations.. Complete blood count Hb -normal. Severe anaemia is unusual if present should suspect Intestinal haemorrhage WBC Count -normal TC –Leukopenia seen in 20-25%cases. DC -Eosinopenia present in 70-80%cases. PLC - normal. Thrombocytopenia marker of severe ileus, DIC

35. Blood Cultures in Typhoid Fevers Bacteremia occurs early in the disease Blood Cultures are positive in 1 st week in 90% 2 nd week in 75% 3 rd week in 60% 4 th week and later in 25 % Sensitivity is highest in first week of illness. Reduces with advancing illness

36. Amount of blood - 5ml in children 10 ml in adults Incubated at 37 degrees for 7 days Interpretation- If bottles show positive growth on 1,2,3 days then the bottles should be cultured. All the bottles should be subcultured on 7 th day before being declared as negative.

37. Bone marrow culture S.Typhi is an intracellular pathogen in reticuloendothelial cells of body including bonemarrow . Median Bacterial count-9CFU/ml compared to blood 0.3 CFU/ml (Bone marrow:peripheral blood ratio of bacteremia - 4.8 in 1 st week 158 in 3 rd week Sensitivity -80 %-95% Advantages-good even in late disease despite prior antibiotic therapy .

38. Other methods in Isolation of Enteric Pathogens Stool Culture during second week Urine Culture during third week Bile culture- obtained by duodenal aspiration Culture of –rose spots - pus from suppurative lesions -CSF -Sputum

39. SEROLOGICAL TESTS

40. SEROLOGICAL TESTS WIDAL TEST -widely used -measures agglutinating ab levels against ‘O’,’H’ antigens ‘ O’antibody Appear IgM 6-8 days ‘ H’antibody 10-12 days IgM,IgG

41. Timing of test – after 5-7 days of fever Method – Cut off value for diagnosis- level of both ‘O’,’H’ antibodies- 1 in 160 dilution TUBE METHOD SLIDE METHOD TIME – 6 HOURS 2-5 MINUTES BETTER TEST , CAN DETECT 1:1280 CONCENTRATION CAN DETECT ONLY 1:320 CONCENTRATION

42. Demonstration of a rise in titer of antibodies , by testing paired blood samples 10-14 days apart is preferred. Anamnestic response- persons who have had prior infection or immunization may develop an Anamnestic response during an unrelated fever. differentiated by repetition of test after 1 week

43. Rise in antibody titres Prior infection Stage of disease Symptomatic or subclinical infections High titres in endemic areas Immunization Treated cases Amnestic reactions ‘O’ antigen cross reaction ‘O’ antigen doesn’t last long ‘H’ antigen lasts longer…but rises slowly

44. False Positive seen in Infections with other Samonella serotypes Infections with other Enterobacteriaceae Malaria Typhus Sepsis with other organisms Cirrhosis Prior vaccination with whole cell vaccine-TAB

45. False Negative In 30% blood culture proved cases, Widal test is negative.

46. Typhidot A Enzyme immunoassay that detects IgG , IgM antibodies against a 50KD outer membrane protein distinct from O,H & Vi. Advantages: Simple, rapid, economical test. High sensitivity & high specificity Disadvantages: Can't differentiate between acute and convalescent cases; false positives common due to previous infections >>> Typhidot M – detects only IgM

47. IDL Tubex test Detecting antibody to 09 antigen, specific to serogroup D Salmonella. Advantages: Detects IgM (current infection) Easy to perform, 2 minutes time Good specificity Interpretation: Positive result – group D Salmonella infection. Salmonella Paratyphi A – negative result.

48. IgM Dipstick Test

49. IgM Dipstick Test Timing of test- a week after onset of symptoms Advantages : no training needed no specialized equipment rapid ,simple method – serum/ whole blood used- incubated for 3 hrs

50. ANTIGEN DETECTION TESTS ENZYME IMMUNO ASSAY COUNTER IMMUNO ELECTROPHORESIS COAGGLUTINATION TESTS Detects serum / urinary somatic / flagellar ag / Vi ag

51. PCR High sensitivity and specificity ? P revious infections ? Vaccinations ? False positivity ? Status in Chronic carriers ……for research purposes

52. Loop mediated isothermal amplification  ( LAMP ) is a single tube technique for the amplification of  DNA . microwave-accelerated metal-enhanced fluorescence ("MAMEF")

53. TREATMENT OF TYPHOID FEVER

54. MANAGEMENT SUPPORTIVE CARE - FLUIDS - NUTRITION -ANTIPYRETICS SPECIFIC ANTIMICROBIAL THERAPY -ANTIBIOTICS

55. DIET- fluids and electrolytes –monitored -oral nutrition with soft digestible diet ACTIVITY - encouraged rest till recovery SURGICAL CARE -for intestinal perforation

56. UNCOMPLICATED TYPHOID-IAP GUIDELINES SUSCEPTIBILITY ANTIBIOTIC FIRST LINE ORAL DRUG DAILY DOSE (mg/kg/ day) DAYS ALTERNATIVE/ 2 ND LINE ANTIBIOTIC- ORAL DRUG DAILY DOSE (mg / kg/day DAYS FULLY SENSITIVE 3 RD GENERATION CEPHALO- SPORIN CEFIXIME 15-20 14 CHLORAM- PHENICOL AMOXICILLIN TMP-SMX 50-75 75-100 8TMP 40SMX 14-21 14 14 MULTI DRUG RESIS TANT 3 RD GENERATION CEPHALO- SPORIN CEFIXIME 15-20 14 AZITHROMYCIN 10-20 14

57. SEVERE TYPHOID FEVER –IAP GUIDELINES SUSCEPTIBILITY ANTIBIOTIC FIRST LINE PARENTRAL DRUG DAILY DOSE (mg/kg/ day) DAYS ALTERNATIVE/ 2 ND LINE ANTIBIOTIC- PARENTRAL DRUG DAILY DOSE (mg / kg/day DAYS FULLY SENSITIVE CEFTRIAXONE CEFOTAXIME 50-75 14 CHLORAM- PHENICOL AMPICILLIN TMP-SMX 100 100 8TMP 40SMX 14-21 MULTI DRUG RESIS TANT CEFTRIAXONE CEFOTAXIME 50-75 14 AZTREONAM 50-100 14

58. PREVENTION

59. Enteric fever is a WASH disease Unsafe water sanitation and food with poor hygiene practices

60. How can Typhoid be avoided? Avoid risky foods or drinks Get vaccinated Use only clean water Ask for drinks without ice unless you know where it’s coming from Only eat foods that have been thoroughly cooked Avoid foods and drinks from street vendors

61. CONTROL OF SANITATION PROTECTION AND PURIFICATION OF DRINKING WATER SUPPLY IMPROVEMENT OF BASIC SANITATION PROMOTION OF FOOD HYGIENE

62. Simple hand hygiene and washing can reduce several cases of Typhoid

63. Best prevention Scrub of them off your hands Best prevention Scrub them off your hands

64. IMMUNIZATION PARENTERAL WHOLE CELL INACTIVATED VACCINE ORAL LIVE ATTENUATED Ty21a VACCINE POLYSACCHARIDE SUBUNIT VACCINE (Vi Ag) VI-CAPSULAR POLYSACCHARIDE CONJUGATE VACCINES

65. WHOLE CELL VACCINE Heat-inactivated phenol-preserved whole-cell typhoid vaccines available since the 1890s. moderatelyefficacious ( 51–88%) protection persisted for up to 7 years. high levels of reactogenicity ; fever (up to 30% ) headache (up to 10%), and severe local pain (up to 35 %),

66. LIVE ORAL TYPHOID VACCINE attenuated organism highly immunogenic but non pathogenic ENTERIC COATED CAPSULES: Dose - 1capsule on alternate days -3daysin children >6yrs protection starts after 1week of full course precautions ingested on empty stomach with cold/lukewarm drink, taken as a whole avoid antimalarial drugs for 24hrs

67. Ty21a —Oral live attenuated vaccine

68. LIQUID FORMULATION 3dose regimen on alternate days orally ADVANTAGES easy administration.extremely safe LIMITATIONS too many precautions cant be given <6yrs,children with congenital / acquired immunodeficiency

69. CAPSULAR POLYSACCHARIDE VACCINE Vi antigen capsular polysaccharide, responsible for virulence of bacteria non immunogenic <2yrs as t cell independent. I nduces I gM response without IgG response. no immunological memory ROUTE i.m . deltoid or thigh muscle SCHEDULE one dose 0.25ml. repeat every 3yrs

70. seroconversion 95-100%. protective efficacy 66-77%. protection begins within 14days of vaccination ADVANTAGES one dose, better compliance, less reactogenic , no interference with widal test, safe in immunocompromised children LIMITATIONS not effective in<2yrs age, no immunological memory, no boosting effect.protective efficacy is not very good

71. Vi-CPS — parenteral vaccine

72. Vi-capsular polysaccharide conjugate vaccines The limitations of the currently available typhoid vaccines include non-effectiveness below the age of 2 years , limited efficacy (of around 60%), T cell independent response which lacks immune memory and is not boostable , No protection against paratyphoid fever. Conjugation of the Vi antigen with a protein carrier is hence desirable as it would induce a T cell dependent immune response .

73. Vi-PS Conjugate vaccine conjugated with Pseudomonas aeruginosa exotoxin A Vi-PS Conjugate Vaccine Conjugated with Tetanus ® Toxoid ( Pedatyph ) by Bio-Med Pvt. Ltd . Vi-polysaccharide conjugate vaccine conjugated with ® Tetanus Toxoid from Bharat Biotech ( Typbar -TCV )

74. Who should get the Typhoid Vaccine? Travelers to parts of the world where Typhoid Fever is very common. People who work with or come in contact with a carrier of the disease. Laboratory analysts who work with the Salmonella Typhi bacteria.

75. Management of carriers An individual is considered to be a chronic carrier if he or she is asymptomatic and continues to have positive stool or rectal swab cultures for S. typhi a year following recovery from acute illness . The rate of carriage is slightly higher among female patients, patients older than 50 years, and patients with cholelithiasis or schistosomiasis . If cholelithiasis or schistosomiasis is present the patient probably requires cholecystectomy or antiparasitic medication in addition to antibiotics in order to achieve bacteriological cure

76. amoxicillin or ampicillin (100 mg per kg per day) plus probenecid ( 23 mg per kg for children ) or TMP-SMZ (160 to 800 mg twice daily ) Given for 6 weeks 60% cure rate

77. 750 mg of ciprofloxacin or 400 mg of norfloxacin twice daily for 28 days 80 % cure rate

78. Carriers should be excluded from any activities involving food preparation and serving, as should convalescent patients and any persons with possible symptoms of typhoid fever . Vi antibody determination has been used as a screening technique to identify carriers among food handlers and in outbreak investigations. Vi antibodies are very high in chronic S. typhi carriers

79. Issues concerned with prevention and control of enteric fever in India are: Lack of reliable data Lack of appropriate diagnostic facilities and relying on suboptimal tests Irrational use of antibiotics and OTC antibiotics Challenging living conditions Inability to implement vaccines in UIP

80. Summary India- highly endemic Wide clinical spectrum – varied presentation Blood culture vs. serological diagnosis Widal interpretation The timely and appropriate management of enteric fever reduces morbidity and mortality. General supportive measures, prompt recognition and treatment of complications ensure a favorable outcome. Third-generation cephalosporins are recommended for first-line treatment . Long time to recover Clean practices Vaccines Chronic carriers

81. References: IAP Textbook of Pediatric Infectious Diseases, 1 st ed. IAP Textbook of Pediatrics, 6 th ed. IAP Guidebook on Immunization 2013-14 Nelson Textbook of Pediatrics 20 th ed. The diagnosis, treatment and prevention of typhoid fever by WHO Enteric fever – is it so easy to handle- by Dr Bhaskar Naik