Le Polmoniti Virali:
diagnosi e terapia
Roberto Luzzati
SC Malattie Infettive, Ospedale Maggiore
Azienda Ospedale/Università - Trieste
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
Viruses linked to community-acquired pneumonia
in children and adults
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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
Cytomegalovirus
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
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
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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
Infect Dis Clin N Am 24 (2010) 147–158
Infect Dis Clin N Am 24 (2010) 147–158
Diagnosis
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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.
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CMV antigen (pp65). Sensitive and quantitative, requires sufficient leukocytes in the
peripheral blood.
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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
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Shell vial culture: low sensitivity and time consuming
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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.
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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
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
Titolo….
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%)
12%
20%
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
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The mainstay of anti-CMV therapy is ganciclovir 5 mg/kg (intravenous) every 12
hours for the duration of infection.
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Valganciclovir, the oral equivalent, is metabolized to ganciclovir in vivo and is as
effective as parenteral ganciclovir.
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Foscarnet and cidofovir are alternative CMV therapies, are administered
intravenously and are nephrotoxic.
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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.
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The decision to treat CMV CAP is based on severity, that is, the degree of
hypoxemia.
Herpes simplex virus
Herpes simplex virus
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After primary infection in the upper respiratory tract, the viral genome is
incorporated into trigeminal nerve sensory ganglia.
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Upon reactivation during stressful conditions (pregnancy, pneumonia), the
neurotropic virus may travel along axons to provoke epithelial lesions, such
as herpes labialis and gingivostomatitis.
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Oropharyngeal reactivation often results in symptomless viral shedding,
detectable by PCR (2-5%).
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Most healthy individuals develop antibodies against the virus after their
initial infection
Herpes simplex virus
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HSV can be isolated from the respiratory tract of asymptomatic adults (up
to 5%).
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HSV has been recovered from the upper an lower respiratory tract of 22 and
16% of ICU patients respectively.
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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.
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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
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
• 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
RISK FACTORS FOR HSV
BRONCHOPNEUMONITIS
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
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
HSV viral load
Patients with HSV BPn had a
higher normalized median virus
load than those without
(p 0.0001).
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%).
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
hospitalisation
Deaths
Requiring
hospitalisation
Clinical
symptoms
Asymptomatic
Seasonal influenza
Clinical
symptoms
Asymptomatic
Pandemic Influenza
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
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
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
2010;362:1708-1719
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
Therapy
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Neuraminidase inhibitors: oral oseltamivir, zanamivir by inhalation.
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There is now widespread resistance to oseltamivir, greatly diminishing the therapeutic options in
influenza and avian influenza (H5N1).
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At present, oseltamivir remains effective against most strains of swine influenza (H1N1).
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Oseltamivir is usually given for 5 days, in severe cases, for 10 days.
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For severely ill hospitalized unable to take oral medications, peramivir is available for IV
administration.
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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.
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Combination therapy: oseltamivir, amantadine and ribavirin.
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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)
HR=1.3
Martin-Loeches I et al, Int Care Med 2011