Scrub typhus

Scrub typhus epidemiology, pathogenesis, diagnosis, management, complications and mortality

1. Scrub Typhus Presenter : Dr. Dhileeban Maharajan Moderator : Dr. Salam Ranabir

2. introduction Most common re-emerging diseases in India Documented in India since 1930 First reported in Assam during second world war Scrub is the commonest Rickettsioses *50% of undifferentiated fever due to Rickettsioses (*Selected Areas)

3. Rickettsioses Obligate intracellular, gram-negative bacteria Rickettsia , Orientia , Ehrlichia , Neorickettsia , Neoehrlichia , and Anaplasma Divided into typhus group and spotted fever group Orientia spp. makes up the scrub typhus group Zoonoses where human beings are accidentally involved

4. Rickettsioses classification

5. Among the major groups of rickettsioses, commonly reported diseases in India are scrub typhus murine flea-borne typhus Indian Tick Typhus Q fever.

6. Scrub typhus Among Rickettsioses, scrub is the commonest Mite borne infectious disease Orientia tsutsugamushi Transmitted through Larval mites or “chiggers” Belonging to family Trombiculidae Only larval stages take blood meal

7. Rodents (wild rats - Rattus ) - Natural hosts for scrub typhus Field rodent and vector mites act as reservoir Between the two the infection perpetuates in nature Mite islands Chiggers, too small to be seen by the naked eye, Feed usually on rodents and accidentally on humans

8. Transmit infection during the prolonged feeding which can last 1-3 days Incidence of scrub typhus is higher among rural population

9. microbiology Obligate intracellular pathogens Rod shaped bacterium. Can be cultured in cell monolayers . Gram Staining - appear as gram negative bacteria. Highly virulent - need biosafety level 3 facilities Exhibit extensive genomic and antigenic heterogeneity Preferred Stain : Gimenez stain ( Orientia tstsugamushi )

10. Found throughout the mites body but greatest number in salivary glands. Does not have a vacuolar membrane - grows freely in the cytoplasm of infected cells Needs to infect eukaryotic cells in order to multiply Serotypes Karp Gilliam Kawazaki Boryon Kato

11. First described in China in 313 AD First isolated in Japan in 1930 Asia Pacific Rim 2/3 are Farmers Highest in 40 to 60 years 80% during summer and autumn Tsutsugamushi Triangle Regions where scrub typhus is endemic epidemiology

12. vectors 60 species of mites Chigger mites (0.2 to 0.4mm) Both Vector and Reservoir Transovarial transmission Transstadial transmission (Larval trombiculid mites - Chiggers)

13. Life cycle

14. Chigger Bite Bacteria multiply at Innoculation site Attach to Endothelial cells Stimulate Phagocytosis Escapes Phagosomes Replicate in cytoplasm Disseminate into multiple organs (Through endothelial cells and macrophages) Type 1 immune response Papule Ulcer Necrosis Eschar + Lymphadenopathy pathogenesis Cytokines

15. Ecology Geographically focal disease Mite islands

16. iNcubation period I ncubation period of 6–21 days Mild and self-limiting to fatal. Scrub typhus lasts for 14 to 21 days without treatment . Death may occur end of 2nd week due to complications .

17. Clinical manifestations

18. Common symptoms Fever (High Grade > 104 F; Median 14.4 days) Intense Generalized Headache Diffuse myalgias Nausea, Vomiting, Diarrhea Cough Symptoms

19. Maculopapular rash Blood-shot eyes Papule followed by an eschar at the site of chigger feeding

20. Rash 50% Develop Rash Nonpruritic Macular or maculopapular rash Face also involved Begins in the abdomen and spreads to extremities

21. eschar Only in 46% (5 to 80%) patients 1 cm in size Painless papule at chigger bite site Central necrosis Then characteristic black crust One or multiple eschars may develop

22. Relative bradycardia Lymphadenopathy - Tender lymph node, usually proximal to site of mite bite • Hepatomegaly and splenomegaly can be observed Signs

23. Respiratory- Cough Acute Respiratory Distress Syndrome Pathogenesis of ARDS in scrub typhus not known, thought to be immunological response of the lung to the infection without direct invasion of the organism Diffuse alveolar damage without evidence of vasculitis .

24. Neurological Involvement of blood vessels in the central nervous system may produce meningitis slight intellectual blunting to coma or delirium In severe cases, evolution to a multiple-organ dysfunction syndrome with hemorrhage can be observed

25. complications Overwhelming pneumonia with ARDS–like presentation Acute Kidney Injury Atypical pneumonia, Myocarditis, Congestive heart failure Pulmonary edema Circulatory collapse Disseminated intravascular coagulation (DIC).

26. Some patient recover spontaneously. Case-fatality rate for untreated classic cases is 70 % (the fatality rate ranges from 0 to 30 %.)

27. Diagnosis No laboratory test is reliable in early phase Usually recognized with symptoms signs laboratory features with epidemiological clues

28. Immunofluorescence and immunoperoxydase assays Rapid immunochromatographic Flow Assay (RFA) Dot blot immunoassay The Weil-Felix test Orientia tsutsugamushi can be cultivated on L929 cells. ELISA PCR (Polymerase Chain Reaction) Sequencing of the 56-kDa protein gene

29. Weil Felix ( Heterophile antibody test) Sharing of antigens between rickettsia and proteus is the basis Agglutinins to P.vulgaris strain OX19, OX2 and P.mirabilis OXK. Lacks sensitivity Serves as a useful and inexpensive diagnostic tool Should be carried out only after 5-7 days of onset of fever. Titre of 1:80 to be considered possible infection.

30. IgM and IgG ELISA Immunoglobulin M (IgM) capture assays for serum, are probably the most of sensitive tests available for rickettsial diagnosis Presence of IgM antibodies, indicate comparatively recent infection Significant IgM antibody titre is observed at the end of 1st week IgG antibodies appear at the end of 2nd week. The cut off value is Optical Density of 0.5.

31. Polymerase Chain Reaction (PCR) Rapid and specific test for diagnosis. Can be used to detect rickettsial DNA in whole blood and eschar samples. PCR is targeted at the gene encoding the major 56 Kda and/or 47 Kda surface antigen gene. The results are best within first week for blood samples because of presence of rickettsemia in first 7-10 days.

32. Immunofluoroscence Assay (IFA): This is a reference serological method and considered serological ‘gold standard’ Cost and requirement of expertise limit its wide use. Recommended only for research and in areas where sero -prevalence is high

33. Indirect Immunoperoxidase Assay (IPA): It gives comparable result as IFA but requires special instrument and experienced personnel for interpretation of the test.

34. Supportive laboratory investigations Thrombocytopenia in severe illness Elevation in hepatic enzymes Leukopenia or leukocytosis Infiltrates in chest X-ray (Mostly bilateral)

35. Differential diagnosis Malaria and dengue Leptospirosis Other rickettsial diseases Typhoid fever Anthrax Spider bite

36. Definition of Suspected/clinical case: Acute undifferentiated febrile illness of 5 days or more with or without eschar should be suspected as a case of Rickettsial infection. If eschar is present, fever of less than 5 days duration should be considered as scrub typhus. Other presenting features may be headache and rash, lymphadenopathy, multi-organ involvement like liver, lung and kidney involvement. Dengue, malaria, pneumonia, leptospirosis and typhoid – D/D

37. Definition of Probable case: A suspected clinical case showing titres of 1:80 or above in OX2, OX19 and OXK antigens by Weil Felix test An optical density (OD) > 0.5 for IgM by ELISA Considered positive for typhus and spotted fever groups of Rickettsiae .

38. Definition of Confirmed case: Rickettsial DNA is detected in eschar samples or whole blood by PCR Rising antibody titers on acute and convalescent sera detected by Indirect Immune Fluorescence Assay (IFA) or Indirect Immunoperoxidase Assay (IPA)

39. Paucity of evidence based on randomized controlled trials for the management of Scrub typhus Without waiting for laboratory confirmation of the Rickettsial infection, antibiotic therapy should be instituted when rickettsial disease is suspected treatment

40. At Primary level: Recognition of disease severity. Patients comes with complications, considers it as rickettsial infection , treatment with doxycycline should be initiated before referring. Referral to secondary or tertiary centre in case of complications like ARDS, acute renal failure, meningo -encephalitis, multi-organ dysfunction.

41. Community acquired pneumonia, doxycycline is to be initiated when scrub typhus is considered likely. In fever cases , duration of 5 days or more where malaria, dengue and typhoid have been ruled out Doxy should be started

42. Adults Doxycycline 200 mg/day in two divided doses for individuals above 45 kg for duration of 7 days. (Patients should be advised to swallow capsules with plenty of fluid during meals while sitting or standing) Azithromycin 500 mg in a single oral dose for 5 days.

43. Children Doxycycline in the dose of 4.5 mg/kg body weight/day in two divided doses for children below 45 kg Azithromycin in the single dose of 10mg/kg body weight for 5 days.

44. Pregnant women Azithromycin is the drug of choice in pregnant women, as doxycycline is contraindicated Azithromycin 500 mg in a single dose for 5 days. During pregnancy, scrub typhus may lead to spontaneous abortion, stillbirth, preterm delivery and small for gestational age infants

45. Secondary and Tertiary care: The treatment as specified above in uncomplicated cases. In complicated cases the following treatment is to be initiated – i ) Intravenous doxycycline (wherever available) 100mg twice daily in 100 ml normal saline to be administered as infusion over half an hour initially followed by oral therapy to complete 7-15 days of therapy.

46. Intravenous Azithromycin in the dose of 500mg IV in 250 ml normal saline over 1 hour once daily for 1-2 days followed by oral therapy to complete 5 days of therapy. Intravenous chloramphenicol 50-100 mg/kg/d 6 hourly doses to be administered as infusion over 1 hour initially followed by oral therapy to complete 7-15 days of therapy.

47. Management of the individual complications should be done as per the existing practices Doxycycline and/or Chloramphenicol resistant strains have been seen in South-East Asia. (These strains are sensitive to Azithromycin )

48. In endemic areas, wear full-length clothing, socks and shoes. Avoid walking barefoot . Apply , as necessary, insect repellents containing dibutyl phthalate, benzyl benzoate , diethyltoluamide , and other substances to the skin and clothing to prevent chigger bites. Do not sit or lie on bare ground or grass; use a suitable groundsheet or other ground cover . prevention

49. Community Rapid case identification by health-care workers. Public education on case recognition and personal protection Rodent control and improve living conditions

50. Pre-exposure chemoprophylaxis Recommended for short period, high- risk exposure. Weekly doxycycline started before and for 6 weeks after exposure is recommended. No vaccine is available for scrub typhus

51. FUTURE PROSPECTS Research and development should focus on following issues: ( i ) Vaccines for rickettsial diseases (ii) Rapid diagnostic card test combining antigen and antibody (iii) Intravenous preparation of doxycycline (iv) Robust surveillance and reporting system.

52. POINTS TO REMEMBER Scrub typhus is a re-emerging disease in India. Important cause of community acquired undifferentiated febrile illness Considered in the differential diagnosis of sepsis and multiorgan dysfunction syndrome. Search for an eschar in hidden areas of body Diagnosis is done by IgM scrub typhus ELISA. Doxycycline is the drug of choice.

53. Thank you