Viral Infections in the Immunocompetent Host

1. Viral Infections in the Immunocompetent Host Corey Casper, M.D., M.P.H. Division of Infectious Disease, Department of Medicine The University of Washington Vaccine and Infectious Disease Institute, Fred Hutchinson Cancer Research Center

2. Outline • Classification of Viruses • Classical vs. Other Schemes • Diagnosis of Viral Infections • Common Viral Infections for the Infectious Disease Consultant

3. Classification of Viruses

4. Classification of Viruses • Classic Taxonomy • Nucleic Acid Structure • DNA vs. RNA • Single vs. Double Stranded • Envelope • Presence or absence • Organization of genome • Example: Paramyxoviruses • Mode of transcription • Example: Retroviruses • “Functional Taxonomy” • Group viruses by primary organ system involved in the pathology of disease • Example: Respiratory Viruses • Group viruses with similar treatments • Example: Herpesviruses

5. Your Mother Knows Best? • Which of the following viruses would you be most likely to acquire from touching a toilet seat? True MedCon Call! • HIV • Calicivirus • Herpes Simplex Virus-2 • Parainfluenza

6. Viral Structure

7. Player or Bystander? • A 63 y.o. man presents from an outside hospital with fever and headache for 2 weeks. Multiple blood, urine, CSF, and sputum cultures have been negative. Chest X-ray, full body CT and peripheral smear are all unremarkable. You are consulted by the medical team to assess whether the patient’s symptoms could be attributable to infection with CMV. Which of the following studies would support that diagnosis? • 1,000 copies of CMV DNA by PCR from the peripheral blood • Positive CMV IgM • Positive urine CMV shell-vial culture • None of the above

8. Diagnosis of Viral Infections - Direct

9. Diagnosis of Viral Infections - Indirect

10. Diagnostic Virology: Culture • Clinical specimen collected and either sent directly to lab or placed in viral culture medium • Specimens then grown on number of different cell lines depending on type of virus suspected • Diagnosis either by looking for CPE, or adding fluorescently-tagged antibodies to viral antigens • “Shell vial” culture: Diagnosis of CMV or BK • Advantages: Specific, sensitivity testing? • Disadvantages: Slow, not as sensitive as molecular diagnostics, not possible for all viruses

11. Diagnostic Virology: DFA Fluorescent label Antibody to Viral Protein Clinical Specimen

12. Diagnostic Virology: EIA Fluorescent label Antibody to Human Antibodies Sera Containing Antibodies to Viral Protein Viral Protein

13. Diagnostic Virology: PCR • Advantages: • Rapid • Sensitive • Quantitative • Disadvantages • Too sensitive? • Specificity • Costly Source: http://www.nupedia.com/newsystem/upload_file/678/pcr.png

14. Case 1: HPI • 18 y.o. woman from Sitka, Alaska who presents with fevers and abdominal pain for 2 weeks • Initially presented to ED in AK 2 weeks PTA with dysuria and mild abdominal pain • Treated with TMP-SMX without improvement • Re-presented 3 days later with severe abdominal pain, headache and temperature to 102F. Had diffuse vesicular rash • Admitted to hospital where she had the following labs/studies: • Normal CBC, SMA-7, negative UA, negative CXR and KUB • AST 110, ALT 124, nml INR, GGT, Amylase, Alk Phos • Hospital Course: • Subsequent multiple blood and urine cultures negative • CT of chest, abdomen and pelvis negative • Exploratory laparotomy found lesions on the liver as on the following slide • Persistent fevers and abdominal pain despite Cefotetan, Doxycycline and Metronidazole • Transferred to UWMC

15. Case 1: Hepatic Lesions

16. Case 1: Physical Exam on Transfer to UWMC • T 38.9, HR 110, RR 22, BP 118/72 • Abd: Diffuse TTP, no rebound or guarding • Skin: Adjacent rash • GU: Nml genitalia

17. The Herpesvirus Family • HHV-1 : Herpes Simplex 1 (HSV-1) • Clinical: Oral Herpes • HHV-2 : Herpes Simplex 2 (HSV-2) • Clinical: Genital Herpes • HHV-3 : Varicella Zoster Virus (VZV) • Clinical: Chickenpox, Zoster • HHV-4 : Epstein Barr Virus (EBV) • Clinical: Mono, lymphoma • HHV-5: Cytomegalovirus (CMV) • Clinical: Retinitis, Pneumonitis, etc • HHV-6/7: Roseolavirus • Clinical: Exanthem subitum • HHV-8: Kaposi’s Sarcoma-Associated Herpesvirus (KSHV) • Clinical: KS, multicentric Castleman’s disease, primary effusion lymphoma

18. Herpesvirus Family Characteristics • Large, Enveloped DNA-viruses • Envelope: • Transmission via mucosal surfaces • Fomite acquisition is uncommon • Large • Smart! • Evolved many complex mechanisms for immune evasion and pathogenesis • DNA • Use similar cellular machinery to human DNA, so therapy must find novel areas of difference (in contrast to HIV) • Ubiquitous • Except for HSV-2 and HHV-8, all infect more than 50% of most populations worldwide • Latency allows for life-long infection • Intermittent reactivation and lifelong shedding can make understanding clinical symptoms and diagnostic tests challenging • Long term infection with some herpesvirus can lead to cancer

19. Herpesvirus Therapy: DNA Synthesis Inhibitors • Aciclovir and ganciclovir require viral TK to make dGMP, then cellular kinases make dGTP which terminates DNA synthesis • Cidofovir and foscarnet do not require TK • Ribavirin depletes intracelluar GTP Source: Naesens and de Clercq Herpes 2001

20. Case 2 • 34 y.o. nurse presents with 3 weeks of coughing, post-tussive emesis, sinus congestion and malaise in January

21. Respiratory Viruses: Clinical • Heterogeneous group of viruses • DNA and RNA, enveloped and “naked” • Similar clinical presentations • Seasonality is important

22. What goes around comes around… • http://depts.washington.edu/rspvirus/respiratory.htm

23. Viruses in Health Care Workers, 2007-2008

24. Respiratory Viruses: Pearls

25. Influenza: Virus Strains • Type A - moderate to severe illness - all age groups - humans and other animals - Subtypes of type A determined by hemagglutinin and neuraminidase • Type B - milder epidemics - humans only - primarily affects children • Type C - rarely reported in humans - no epidemics

26. Influenza Virus • Neuraminidase • Antigenic Determinant • Confer virulence • Allow viral mobility through • Respiratory tract • Hemagglutinin • Binds virus to cell • Confers target specificity RNA • M2 protein • only on type A • Allows H+ ions to enter virus to lower • pH for viral uncoating

27. Influenza Antigenic Changes • Hemagglutinin and neuraminidase antigens change with time • Changes occur as a result of point mutations in the virus gene (“antigenic drift”), or due to exchange of a gene segment with another subtype of influenza virus (“antigenic shift”) • Impact of antigenic changes depend on extent of change (more change usually means larger impact)

28. Making a Global Influenza Pandemic OR

29. Influenza Clinical Features • Incubation period 2 days (range 1-4 days) • Severity of illness depends on prior experience with related variants • Abrupt onset of fever, myalgia, sore throat, nonproductive cough, headache

30. Influenza Complications • Pneumonia • primary influenza • secondary bacterial • Reye syndrome • Myocarditis • Death 0.5-1 per 1,000 cases

31. Influenza: Treatment & Prophylaxis • M2 Inhibitors • Amantadine and rimantidine • “Effective” against Influenza A • 2007, >97% of influenza was resistant • SWINE FLU IS RESISTANT • Inhibit viral replication • Single mutation confers resistance, occurs with every 1,000-10,000 replications • Neuraminidase inhibitors • Oseltamivir (oral pill) and Zanamivir (inhaled) • Effective against Influenza A and B • 98% of H1N1 strains (except SWINE FLU) were resistant in 2008-9! • Combination therapy? • Oseltamavir, rimantidine and ribavirin have been shown to have combined efficacy

32. Respiratory Viruses: Adenovirus • Common cause of URI and keratoconjuntivitis. Has been occasionally associated with pneumonia in community outbreaks, diarrhea in children, and hepatitis. • May cause cystitis or nephritis in transplant patients • Treatment: Supportive. IV cidofovir may be effective in the immunocompromised

33. Respiratory Viruses: Parainfluenza • Four subtypes • PIV3 seen most commonly in severe infections • In children, leading cause of croup. Can be a cause of severe lower respiratory tract illness in some children or transplant patients • Treatment is supportive, but aerosolized ribavirin may be used in life-threatening cases

34. Respiratory Viruses: Metapneumovirus • Recently identified from retrospective series of unidentified respiratory illnesses. • Serologic studies suggest most are infected by 5 years of age, peak 6-12 months • Mild URI in most, with rare progression to severe LRTI • Wheezing is a common initial presentation • Treatment is supportive

35. Respiratory Viruses: Coronaviruses • Large family of viruses with multiple animal hosts • Generally cause non-specific symptoms such as fevers, myalgias, fatigue. May progresses to non-productive cough and dyspnea. • Diagnosis is by PCR, and treatment is supportive • SARS • Newly identified virus associated with severe LRTI in Asia in 2003. Thought to be transmitted by contact with small mammals (civets) in Asia, spread between humans through respiratory droplets and feces • Development of respiratory failure occurs in minority of cases, but may be more common in Asian persons

36. PCR for Respiratory Virus Detection • Problem of inadequate specimens for immunoblot or DFA • PCR is more sensitive and perhaps equally as specific • Molecular Virology Lab now offers multiplex PCR for detection of 12 viruses Kuypers, et al 2006

37. Gastrointestinal Viruses • Most common viruses to cause gastrointestinal illnesses are Norovirus, calicivirus, rotavirus, astrovirus, and adenovirus • Present with diarrhea, fever and/or abdominal pain. Children more often affected, although incidence high in institutional or “closed” settings (i.e. cruise ships) • Transmission via fecal-oral route • Diagnosis: • PCR of stool, or plasma PCR if disseminated disease suspected (adenovirus)

38. Case 3 • 21 year old UW student presents with fever to 39, headache, stiff neck and photophobia shortly after returning for Fall Quarter • Student health service concerned about risk of meningitis epidemic

39. Case 3: Continued • Physical examination revealed the following:

40. Enteroviruses • Large group of viruses including the subgroups: poliovirus, echovirus, and coxsackieviruses • Worldwide pathogens with most infections in summer and fall • Chronic meningoencephalitis among persons with agammaglobulinemia • Diagnosis • PCR of stool, oropharynx or CSF

41. Enteroviruses: Coxsackievirus • Common causes of aseptic meningitis • Heterogeneous and non-distinct exanthems (skin rashes). Exception: Hand-Foot-Mouth (Coxsackievirus A16) with oral vesicles and papules/vesicles on palms and soles. • Complications: • Group A • herpangina (dysphagia with lesions on soft palate) • Group B • Myopericarditis

42. Case 4 • 62 y.o. man taken to HMC from cruise ship docked at Pier 66 with fevers, altered mental status, and weakness in the left leg

43. FLAVIVIRUSES • Heterogeneous group of zoonotic / arthropod transmitted viruses • West Nile Virus • Dengue • Yellow Fever • Japanese Encephalitis • St. Louis Encephalitis • Tick-Borne Encephalitis • Diagnosis • Serology • IgM during acute illness or IgG in convalescence • Serum should be collected 8-10 days after illness onset. • Follow up with a convalescent serum specimen obtained at least 2 weeks after the first specimen. • CSF should be collected within 8 days of illness onset. IgM may appear in CSF earlier than in serum. • IgM does not cross the blood brain barrier: its presence in CSF indicates neuroinvasive disease. • IgM antibody can persist for more than • Non-specific (but this may be a good thing!) • PCR • Less sensitive, but useful in immunocompromised hosts

44. Flaviviruses: West Nile Virus • Rapidly emerging virus across U.S. since 1999 • WA one of the few states without any documented infections • Transmitted from reservoirs in birds to human via mosquitoes • Majority of infections are without symptoms or only with fever and malaise, but most severe complication is neurological (encephalitis and muscle weakness)

45. West Nile Distribution, 2008

46. Flaviviruses: Dengue • Tropical virus transmitted by Aedes aegypti (day biting) mosquito • Illness characterized by high fever, headache (often retro-orbital), myalgias/arthralgias and rash • Hemorrhagic fever or shock may occur shortly after resolution of fever. May be more common in persons previously exposed.

47. Flaviviruses: Yellow Fever • Endemic to sub-Saharan Africa and South America • Transmitted by mosquito bites • Symptoms range from constitutional to severe. Symptomatic patients likely to experience headache, altered mental status, icterus, and many have diffuse hemorrhage • Preventable by vaccine, which may cause vaccine-induced encephalitis among young infants or the elderly

48. Other Flaviviruses • Japanese Encephalitis • High fevers and altered mental status • Endemic to regions in Asia where mosquitoes interact with pigs and birds • St. Louis Encephalitis • Fevers and altered mental status, especially among the elderly. • Seen in North, Central and South America as well as the Caribbean. • Tick-Borne Encephalitis • Infection via Ixodes species ticks • Europe and Asia • History: persons with outdoor exposure. • Presents with fever, but may progress to altered mental status and paralysis.

49. Case 5 • 28 year old latina sheep-sheerer from Oregon presents to UWMC with increasing lesion on hand

50. Poxviruses: Orthopox • Monkeypox: recently spread by prairie dogs • Cowpox: cause “milkers nodules” on hands of dairy workers • ORF: nodule on hands, arms or face after exposure to ruminants • Smallpox • Diagnosis • Electron Microscopy