An Update on Management of Adenovirus

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An Update on Management of Adenovirus

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1. An Update on Management of Adenovirus Michael G. Ison, MD MS Transplant Infectious Diseases & Compromised Host Program Massachusetts General Hospital Boston, Massachusetts

2. Overview Introduction to Adenovirus Virology & Pathophysiology Epidemiology & Clinical Significance Clinical Syndrome Diagnosis and Monitoring Management Options Conclusion & Questions

3. Virology & Pathophysiology

4. Adenovirus: Basic Virology First identified in 1953 > 51 adenovirus strains identified 6 subgroups recognized

5. Adenovirus: Basic Virology Non-enveloped 65-80 nm icosahedral viruses

6. Adenovirus: Transmission Inhaled aerosolized droplets Direct spread to conjunctiva Fecal-oral spread Virus shed for months after initial infection in stool in immunocompetant No clear seasonal pattern Early spring and autumn in some studies

7. Adenovirus: Transmission Receptor CAR MHC class I ?2 domain (AdV 2 & 5) Sialic acid (subgroup D) ?v3 and ?v5 integrins cofactor for efficient infection

8. Adenovirus: Replication Receptor binding Endocytosis into cell Acidifcation of the endosome results in degradation of the capsid Penton base facilitates released from the endosome and transported to the nucleus EIA region of the adenovirus genome is activated Early proteins are made Receptor binding Endocytosis into cell Acidifcation of the endosome results in degradation of the capsid Penton base facilitates released from the endosome and transported to the nucleus EIA region of the adenovirus genome is activated Early proteins are made

9. Epidemiology & Clinical Significance

10. Adenovirus: Non-Military Impact Long-term care facilities Children (esp Day care facilities) Swimming pools Job Corps training camps Immunosuppressed patients

11. Adenovirus: Military Significance Outbreaks in military since the 1950s Adenovirus caused 10% of all recruits to be hospitalized in 1958 50-80% attack rate Risk factors: Stresses of training Environmental factors Mixing of susceptible young adults in close contact settings

12. Adenovirus: Military Significance

13. Adenovirus: Military Significance

14. Adenovirus: Military Significance

15. Adenovirus: Impact of Vaccination Oral, live attenuated Ad4/Ad7 vaccine Major difference by center (Ft. Dix 16.7 cases/100 recruits vs. Ft. Polk 2.3 cases/100 recruits)Major difference by center (Ft. Dix 16.7 cases/100 recruits vs. Ft. Polk 2.3 cases/100 recruits)

16. Adenovirus: Impact of Vaccination

17. Adenovirus: Impact of Vaccination Trend toward more cases of adenoviral respiratory infections 3 cases/1000 recruits/wk 1998 & 1999 6/1000 recruits/wk in 2000 & 2001 2 fatal cases/year Epidemic adenoviral outbreaks in military basic training camps each yr 22,800 illness in 2000

18. Clinical Syndrome

19. Adenovirus: Clinical Presentation Common Manifestations Upper respiratory tract infections Conjunctivitis Gastroenteritis Hemorrhagic cystitis Rare manifestations/complications Pneumonia Hepatitis Nephritis Meningoencephalitis

20. Adenovirus: Clinical Presentation Presenting symptoms: Fever (typically =102F) Nasal congestion (96%) Sore throat (71%) Cough (68%) Gastrointestinal disturbances (46%) Risk factors for infection: Autumn recruitment Home state: Kansas and New Mexico Smoking +

21. Adenovirus: Clinical Presentation 3 days of reduced activity 10 days of respiratory disease 50% seek medical care 20% are hospitalized; of those admited:1 35% 1 d 37% 2 d 15% 3 d 6% 4 d 7% 5 d 10% develop viral pneumonia AdV responsible for 90% of pneumonias in military recruits

22. Diagnosis and Monitoring

23. Diagnosis & Monitoring Cell culture: A549, HEK, Hep-2 Immunoflourescence Enzyme Immunoassay Latex Agglutination Serology PCR Virus may be shed for prolonged time after recovery

24. Management Options

25. Management: Available Agents

26. Management: Vidarabine Marginal Activity In Vitro 50-200 g/mL Activity dependent on cell line used Improved efficacy when combined with adenosine deaminase inhibitor Clinically effective in the management of 2 cases of AdV-associated hemorrhagic cystitis in BMT patients2,3

27. Management: ddC

28. Management: ddC

29. Management: Mycofenolate In vitro data of activity vs. adenovirus No clinical data

31. Management: Ganciclovir Effective therapy for adenovirus-induced hemorrhagic cystitis Valganciclovir study: No difference in frequency or level of viral replication in treated vs. untreated patients

32. Management: Ribavirin (Virazole) Guanosine analogue Both the base and the D-ribose sugar are necessary for antiviral activity Virustatic Parts of its antiviral efficacy through immunomodulatory mechanisms Oral, IV, and inhaled formulations Adverse Events Anemia Teratogen

33. Ribavirin: Clinical Studies 35 mg/kg loading dose followed by 25 mg/kg Q8 for 10 days Bordigoni: 35 allo-HSCT Morality All therapies: 68.2% Ribavirin: 76.9% Cidofovir: 33.3% Virus clearance: 11 d (7-35 d)

34. Ribivirin: Clinical Studies

35. Ribavirin: Conclusions IC50 is high for most isolates Only active against subgroup C viruses in vitro May not be clinically active in vivo

36. Management: Cidofovir (Vistide) Cytosine analogue (HPMPC) Inhibits DNA polymerase Virustatic IV only; typically administered with probenecid May be given weekly Adverse Events Renal failure/proteinuria Neutropenia Increased intraocular pressure/anterior uveitis (?)

37. Cidofovir: in vivo Studies Adenovirus 4, 5,8,and 37 were used with topical CDV drops. Adenovirus 4, 5,8,and 37 were used with topical CDV drops.

38. Cidofovir: Clinical Studies

39. Cidofovir: Clinical Studies w/ PCR

40. Cidofovir: Clinical Studies w/ PCR

41. Cidofovir: Lipid Ester Formulation Ether lipid ester prodrugs of CDV result in analogs that: Have enhanced activity Are orally active Have equal efficacy vs. CMV & orthopoxviruses as IV CDV

42. Cidofovir: Lipid Ester Formulation

43. Cidofovir: Conclusions IC50 is achievable for most isolates in vitro Appears to be clinically active in vivo Lipid ester formulations may be better tolerated and are orally bioavailable

44. Management: HPMPA

45. Adenovirus: Conclusions Adenovirus is a significant pathogen in the military Could undermine the overall state of preparedness of the US military No randomized studies of available antiviral agents Ribavirin of questionable benefit except in serogroup C cases Cidofovir and its lipid derivatives may be more beneficial

46. Adenovirus: Future Directions Vaccination Highly effective in preventing disease Under development Clinical Studies of Available Compounds Cidofovir shows the most promise Ribavirin an option in group C infections Development & testing of new agents (esp lipid esters of cidofovir)

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