Le Polmoniti Virali: diagnosi e terapia

1. Le Polmoniti Virali:diagnosi e terapia Roberto Luzzati SC Malattie Infettive, Ospedale Maggiore Azienda Ospedale/Università - Trieste

2. WHY? • Increasing attention to the severe respiratory syndrome associated with severe acute respiratory syndrome (SARS), avian flu and H1N1 pandemic influenza • Availability of efficient and rapid virologic diagnostic tests • Increasing immunocompromised patients • A large proportion of ventilator-associated pneumonia (VAP) and community acquired penumonia (CAP) episodes are of unknown origin

3. Viruses linked to community-acquired pneumoniain children and adults • Respiratory syncytial virus • Influenza A, B, and C viruses • Human metapneumovirus • Parainfluenza viruses types 1, 2, 3, and 4 • Adenovirus • Rhinovirus • Human bocavirus* • Coronavirus (including SARS) • Enteroviruses • Varicella-zoster virus • Hantavirus • Parechoviruses • Epstein-Barr virus • Human herpesvirus 6 and 7 • Herpes simplex virus • Mimivirus • Cytomegalovirus • Measles * MOSTLY IN DEVELOPING COUNTRIES Lancet March 23, 2011

4. Viral pneumonia • Individual PCR assays as well as multiplex assays have been used to detect viruses • Detection of microbial nucleic acid in respiratory tract secretions remains an area of ongoing study • It is unclear if positive results indicate upper rather than lower respiratory tract infection, colonization, or true infection of the lung Mandell, 2010

5. Viral Pneumonia In ten studies of adults with CAP (n=2910 episodes) in which PCR was used to test for respiratory viruses, evidence of viral infection was detected in 22% of cases Lancet March 23, 2011

6. Lancet March 23, 2011

7. Cytomegalovirus

8. CMV pneumonia in the immunocompromised host CMV reactivation, as a consequence of impaired cell-mediated immunity, is frequent in immunocompromised patients HIV CMV is present in the lungs in approximately 75% of patients with HIV and PCP. Virus detection does not necessarily mean viral disease Transplant -highest risk among seronegative transplants receiving an organ from a seropositive donor -CMV reactivation in CMV-seropositive -Among solid organ transplant patients higher incidence in lung transplant patients (53%-75%): CMV Pneumonia vs acute rejection -prophylactic or preemptive treatment with ganciclovir. Transpl Infect Dis 2003; 5:112-120

9. CMV CAP in immunocompetent host CMV seroprevalence ranges from from 65% among 40–49- year olds to 91% in those at least 80 years of age • Influenza, CMV and adenovirus are most frequent cause of severe viral CAP in immunocompetent pts • The severity of presentation varies from mild to severe hypoxemia • CXR: minimal or no infiltrates or bilateral interstitial infiltrates • Differential diagnosis: human and swine influenza, adenovirus, SARS, PCP Infect Dis Clin N Am 24 (2010) 147–158

10. Infect Dis Clin N Am 24 (2010) 147–158

11. Infect Dis Clin N Am 24 (2010) 147–158

12. Diagnosis • Serology.Acute infection: a single elevated IgM titer or a 4-fold increase in IgG titers. False positive IgM in patients with rheumatoid factors (RFs), EBV, HHV-6 infection. • CMV antigen (pp65). Sensitive and quantitative, requires sufficient leukocytes in the peripheral blood. • Polymerase chain detection (PCR). High sensitivity, rapid turnover time, not fully standardized, it does not distinguish between asymptomatic or latent infection and active infection. In immunocompetent hosts with primary CMV CAP, CMV PCR is usually negative • Shell vial culture: low sensitivity and time consuming • CMV cytopathology: demostrating characteristic large cells (cytomegalic cells) with intranuclear basophilic inclusions and cytoplasmic eosinophilic inclusions,with hematoxylin-eosin, Giemsa, Wright, or Papanicolaou stains in tissue specimens. • CMV intranuclear inclusions are surrounded by a clear halo giving them the typical appearance of an ‘‘owl’s eye,’’ but dense granular cytoplasmic inclusions, although not present in all cells, are diagnostic of CMV active infection Infect Dis Clin N Am 24 (2010) 147–158

13. CMV and VAP • CMV has been documented as the sole pathogen causing VAP on pathologic examination of pulmonary samples of 25 of 86 patients. Anesthesiology 1996; 84:280-287 • In a mouse model has been shown a casualty between CMV reactivation and pulmonary diseases,supported by the fact that prophylactic treatment with ayclovir prevent CMV reactivation and CMV associated lung fibrosis in immunocompetent mice with sepsis. Crit Care Med 2006; 34: 842-849

14. Titolo…. • 242 non-immunosoppressed ICU patients (MV > 2 days) underwent weekly pp65 antigenemia and BAL viral cultures when pneumonia was suspected • 39 (16.1%) developed an active CMV infection • ICU mortality (54% vs 37%) and in-hospital mortality (59 vs 41%) were increased in pts with active CMV infection, as compared with those without CMV infection • Further studies are needed to evaluate the role of antiviral treatments to reduce both the incidence and the outcome impact of avctive CMV infection Crit Care Med 2009 37: 1850-1857

15. Titolo…. Only one patient exhibited a positive cytopathic effect in BAL fluid Crit Care Med 2009 37: 1850-1857

16. Prevalence and mortality of CMV infection in nonimmunosuppressed patiens in ICU: a review (13 studies, 1258 pts) Crit Care Med 2009; 37: 2350-2358 (overall 17%) 12% 20%

17. Prevalence and mortality of CMV infection in nonimmunosuppressed patiens in ICU: a review • CMV is frequently observed in non-immunosoppressed critically ill pts (17%) • Previous exposure to CMV, ICU stay > 5 days, severe sepsis/shock, and high disease severity were important factors in whether the pt developed active CMV infection • The mortality rate associated with active CMV infection was 1.93 times (95% CI 1.29-2.88) as high as that for patients without CMV infection BUT a cause-effect relationship cannot be established yet • A large prospective cohort study is needed to define who is at the highest risk for developing active CMV infection and its effect on mortality. Crit Care Med 2009; 37: 2350-2358

18. CMV Therapy • The mainstay of anti-CMV therapy is ganciclovir 5 mg/kg (intravenous) every 12 hours for the duration of infection. • Valganciclovir, the oral equivalent, is metabolized to ganciclovir in vivo and is as effective as parenteral ganciclovir. • Foscarnet and cidofovir are alternative CMV therapies, are administered intravenously and are nephrotoxic. • In immunocompetent hosts, a complete course of therapy with ganciclovir/ valganciclovir is usually not necessary because patients usually improve after 1 to 2 weeks of therapy. • The decision to treat CMV CAP is based on severity, that is, the degree of hypoxemia.

19. Herpes simplex virus

20. Herpes simplex virus • After primary infection in the upper respiratory tract, the viral genome is incorporated into trigeminal nerve sensory ganglia. • Upon reactivation during stressful conditions (pregnancy, pneumonia), the neurotropic virus may travel along axons to provoke epithelial lesions, such as herpes labialis and gingivostomatitis. • Oropharyngeal reactivation often results in symptomless viral shedding, detectable by PCR (2-5%). • Most healthy individuals develop antibodies against the virus after their initial infection

21. Herpes simplex virus • HSV can be isolated from the respiratory tract of asymptomatic adults (up to 5%). • HSV has been recovered from the upper an lower respiratory tract of 22 and 16% of ICU patients respectively. • The presence of HSV-1 in the upper respiratory tract is a major risk factor for recovery of the virus from the lower respiratory tract. • This suggests that viral reactivation or infection in the oropharynx reaches the lower respiratory tract by aspiration. Lancet 2003; 362:1536-1541

22. Clin Microb Infect, 2006; 12:1050-59

23. Is it unknown how HSV reaches the lower respiratory tract and if it replicates there. The presence of HSV in the lower respiratory tract has been associated with: -more severe disease -prolonged length of stay in the ICU -increased duration of mechanical ventilation -greater mortality Am J Respir Crit Care Med 2007; 175: 865–867

24. All consecutive nonimmunocompromised pts (receiving MV for > 5 days) with suspected lung infection: BAL, oropharyngeal swabs and bronchial biopsy (macroscopic bronchial lesions) • HSV bronchopneumonitis: suspected lung infection + HSV in BAL and HSV-specific nuclear inclusions in cells recovered during lavage or bronchial biopsies • HSV bronchopneumonitis was diagnosed in 42 (21%) of the 210 pts with suspected lung infection and a mean duration of MV of 14 + 6 days Am J Respir Crit Care Med Vol 175. pp 935–942, 2007

25. RISK FACTORS FOR HSVBRONCHOPNEUMONITIS S: Multivariate analysis Am J Respir Crit Care Med Vol 175. pp 935–942, 2007

26. Diagnostic pathway Broncoscopy and biopsy of lesions Search for typical nuclear inclusion bodies and cytopatic effect of the virus in alveolar and bronchial cells and macrophages obtained in washings or biopsies Demonstration of HSV1- DNA in the respiratory tract may be too sensitive and may not help to differentiate harmless shedding from invasive infection Hematogenic spread with viremia and positive HSV 1-PCR in blood would more likely be a cause of herpetic alveolitic and pneumonia Am J Respir Crit Care Med 2007;175: 865–867

27. HSV viral load To predict HSV BPn, a virus load cutoff value of 8104 copies/106 cells had 81% sensitivity (95% CI, 69–90%) and 83% specificity (95% CI, 71–91%). Patients with HSV BPn had a higher normalized median virus load than those without (p 0.0001). Am J Respir Crit Care Med 2007; 175: 935–942

28. Therapy and Outcome • No significant difference in patient outcome or decrease viral load was found in patients with or without acyclovir treatment • There is not evidence that antiviral therapy is beneficial in presumed-HSV pneumonia in the critically ill, as shown by decreased morbidity and mortality • Since the pathogenic role of HSV remains unclear, only a randomized controlled trial comparing a specific antiviral agent with placebo could attempt to answer this question. Am J Respir Crit Care Med 2007; 175: 935–942

29. H1N1 Influenza

30. Clinicalsymptoms Asymptomatic Seasonal influenza compared to pandemic Deaths Requiring hospitalisation Clinicalsymptoms Deaths Requiring hospitalisation Asymptomatic Seasonal influenza Pandemic Influenza

31. CLINICAL ASPECTS OF PANDEMIC 2009 INFLUENZA A (H1N1) VIRUS INFECTION • Most illnesses caused by the 2009 H1N1 virus have been acute and self-limited • with the highes attack rate reported among children and young adults • About 21% of all persons and 45% of those beetwen the ages of 10 and 19 • years had become infected • The overall case fatality rate has been less than 0.5% and the wide range of • estimates (0.0004 to 1.47%) reflects uncertainty regarding case ascertainment and • number of infections • In contrast to seasonal influenza, most of the serious illnesses due to H1N1 virus • occurred among children and non-elderly adults (90% of deaths occurred in • those under 65 years of age) Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic (H1N1) 2009 Influenza. N Engl J Med 2010;362:1708-1719

32. Risk Factors for Complications of or Severe Illness with 2009 H1N1 Virus Infection About one quarter to one half of patients who were hospitalized or died had NO reported coexisting medical conditions Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic (H1N1) 2009 Influenza. N Engl J Med 2010;362:1708-1719

33. Causes of Hospitalization and ICU requirement (1) an acute viral pneumonitis in previously relatively healthy younger adults rapidly progressive and resulted in severe hypoxemia. (2) severe and prolonged exacerbation of chronic obstructive pulmonary disease (COPD) and asthma; (3) bacterial pneumonia, particularly Streptococcus pneumoniae, group A streptococci and Staphylococcus aureus, following an episode of influenza; (4) bronchiolitis and croup in infants and young children. Current Opinion in Infectious Diseases 2010, 23:139–144

34. Infect Dis Clin N Am 24 (2010) 203–228

35. Lung-Tissue Specimen Obtained at Autopsy from a 13-Year-Old Boy after a 7-Day Clinical Course of 2009 H1N1 Virus Infection Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic (H1N1) 2009 Influenza. N Engl J Med 2010;362:1708-1719

36. Antiviral Therapy in Specific Subgroups of Patients Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic (H1N1) 2009 Influenza. N Engl J Med 2010;362:1708-1719

37. Therapy • Neuraminidase inhibitors: oral oseltamivir, zanamivir by inhalation. • There is now widespread resistance to oseltamivir, greatly diminishing the therapeutic options in influenza and avian influenza (H5N1). • At present, oseltamivir remains effective against most strains of swine influenza (H1N1). • Oseltamivir is usually given for 5 days, in severe cases, for 10 days. • For severely ill hospitalized unable to take oral medications, peramivir is available for IV administration. • Viral shedding is prolonged in hospitalized patients, occurring for at least 7 days after symptom onset in 33–47% of patients, despite treatment with oseltamivir. • Combination therapy: oseltamivir, amantadine and ribavirin. • The role of steroid therapy is not established. Current Opinion in Infectious Diseases 2010, 23:139–144

39. Use of early corticosteroid therapy on ICU admission in patients affected by Severe pandemic H1N1 influenza A infection (ESICM H1N1 Registry) HR=1.3 Martin-Loeches I et al, Int Care Med 2011