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									  Le Polmoniti Virali:
  diagnosi e terapia

             Roberto Luzzati
SC Malattie Infettive, Ospedale Maggiore
 Azienda Ospedale/Università - Trieste
• 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
    Viruses linked to community-acquired pneumonia
                  in 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
              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
              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
Lancet March 23, 2011
         CMV pneumonia in the
       immunocompromised host
CMV reactivation, as a consequence of impaired cell-mediated immunity,
  is frequent in immunocompromised patients

CMV is present in the lungs in approximately 75% of patients with HIV and
   PCP. Virus detection does not necessarily mean viral disease

-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
             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,

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

•   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
                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
• 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

Only one patient exhibited a positive cytopathic effect in BAL fluid

                                             Crit Care Med 2009 37: 1850-1857
 Prevalence and mortality of CMV infection in
nonimmunosuppressed patiens in ICU: a review
               (13 studies, 1258 pts)
                                            (overall 17%)



                          Crit Care Med 2009; 37: 2350-2358
 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
                         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
Herpes simplex virus
               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
              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
Clin Microb Infect, 2006; 12:1050-59
Is it unknown how HSV reaches the lower respiratory tract and if it replicates

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
• 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

                        Am J Respir Crit Care Med Vol 175. pp 935–942, 2007
                   RISK FACTORS FOR HSV

S: Multivariate analysis

                  Am J Respir Crit Care Med Vol 175. pp 935–942, 2007
                   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

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
                      HSV viral load

Patients with HSV BPn had a            To predict HSV BPn, a virus load cutoff
higher normalized median virus         value of 8104 copies/106 cells had 81%
load than those without                sensitivity (95% CI, 69–90%) and
(p 0.0001).                            83% specificity (95% CI, 71–91%).

                 Am J Respir Crit Care Med 2007; 175: 935–942
        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
H1N1 Influenza
Seasonal influenza compared to pandemic


     Deaths        Requiring                  symptoms



  Seasonal influenza               Pandemic Influenza

- 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
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
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
Infect Dis Clin N Am 24 (2010) 203–228
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
  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
•   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

•   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
Use of early corticosteroid therapy on ICU admission in patients affected by
    Severe pandemic H1N1 influenza A infection (ESICM H1N1 Registry)


                                             Martin-Loeches I et al, Int Care Med 2011

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