Evidence from autopsies on the pathogenesis and pathological findings of the 2009 pandemic influenza A(H1N1) – implications for clinical care and disease burdenArchived

Predictive clinicopathological features derived from systematic autopsy examination of patients who died with A/H1N1 influenza infection in the UK 2009–10 pandemic Lucas S. Health Technol Assess 2010; 14(55):83–114

2009 Pandemic influenza A(H1N1) Pathology and pathogenesis of 100 fatal cases in the United States.  Shieh W-J, Blau DM, Denison AM, Deleon-Carnes M, Adem P, Bhatnager J et al. Am J Pathol 2010; 177: 166-175. doi: 10.2353/ajpath.2010.100115.

The first study, conducted in Europe during the 2009 pandemic addressed several objectives concerning the pathogenesis of the disease caused by the influenza A(H1N1) 2009 viruses. Specifically the author worked with a national group of histopathologists to:

• Gather the available clinical pathology information from autopsies performed on cases with known or suspected influenza A(H1N1) 2009 infection;
• Evaluate co-morbidities present in these deceased patients correlating them with the A(H1N1) 2009-related pathology and treatment-associated pathology;
• Determine the relative contributions of co-morbidities and estimate the significant features associated with death;

The letters asked for autopsy reports with the following case definitions of the autopsied deceased:From pathologists - primarily, those with H1N1 infection, proven before or after death, and those in whom swine flu was unproven but most likely to have been present; secondarily, those in whom H1N1 was a minor pathology, as well as those in whom it was the immediate cause of death.

From coroners and fiscal procurators - primarily, mention of ‘swine flu’, ‘swine influenza’ or ‘H1N1 infection’ in any part of the cause of death; secondarily, any age from infancy to old age.

The sample was 68 autopsy reports of deaths in 19 children (0–15 years) and 49 adults (16 years and older).  This sample represents approximately 15% of the known deaths from A(H1N1)2009 in the country.  The median age for children at death was 6 years and for adults 41 years. The deaths in children were associated with congenital diseases (47%, 9/19), particularly of the heart and central nervous system. The autopsied children were not obese. The deaths in adults were associated with pregnancy (three cases in the study) obesity (50% of the adult cases had a body mass index ≥ 30 kg/m2) and chronic respiratory disease (12%, 6/49 adults). Nearly all the deaths (94%, 64/68) were a consequence of the A(H1N1) 2009 infection in the respiratory tract. However, in more than 41% of the deaths, bacterial secondary infection was the significant complication, Pneumococcus spp. being the most common agent identified (25%, 7/28) though Group A Streptococci were also indentified with smaller numbers of Staphlococcus aureus and Haemophilus influenzae in both adults and children.  The author concluded that the major co-morbidities associated with death from influenza A(H1N1) 2009 infection were obesity, chronic respiratory disease and pregnancy. Congenital disease in children and learning difficulties in adults were also important, but diabetes was not.

The second study had some similarities to the first one with the observations made from the beginning of the 2009 pandemic about the pathological evaluation of respiratory specimens from initial influenza-associated deaths from the US with laboratory-confirmed  A(H1N1) 2009virus infection.  The advantages of the American study included the fact that tissue samples were investigated centrally at the Centers for Disease Control and Prevention using multiple laboratory methods, including histopathological evaluation, special stains, molecular and immuno-histochemical assays, viral culture and electron microscopy.  The results suggested both similarities and differences in viral tropism and tissue damage compared with seasonal influenza. The most prominent histopathological feature observed was diffuse alveolar damage in the lung in all case-patients examined which corresponded with the viral pneumonia and immuno-localization of viral antigens. Alveolar lining cells, including type I and type II pneumocytes, were the primary infected cells. The universal finding was diffuse alveolar damage with pulmonary thromboemboli in about 15% of cases. No myocarditis or encephalitis was observed in the cases with cardiac or brain samples available (30% and 19% respectively).  Bacterial co-infections were identified in about a quarter of the cases as in the European study with  Pneumococcus spp.  and other streptococcal species predominating.  The availability of a series of high class colour photo-micrographs with a variety of special stainings in the US study contributes ot its usefullness.  

ECDC Comment (25th February 2011):

The detailed American study indicated diffuse alveolar damage in all the cases and this was consistent with the reported clinical syndrome of acute respiratory distress syndrome including oedema, hyaline membranes, inflammation and fibrosis with evidence of viruses in the lung parenchyma. This has similarities with what is found in fatal cases of human influenza A(H5N1) infection with infection confined to the lower respiratory tract.(1) However there were also similarities with seasonal influenza with viral localisation in the upper respiratory tract: the trachea, bronchi and bronchioles.(2)  These finding describes at the microscopic level how, when human infection with A(H1N1)2009 results in severe disease, it is a more difficult clinical challenge than the previous seasonal infection. That is consistent with the clinical findings of disease causing severe respiratory distress in a few that is then very difficult to treat.(3) What is not at all clear is what are the under-lying mechanisms that has made the A(H1N1)2009 so difficult in some patients, though there are some suggestions.(4)  Whether these features of A(H1N1) 2009 disease persist beyond the 2010/2011season, and whether A(H1N1)2009 itself persists as a seasonal influenza will be important in determining the future burden of influenza epidemics for Europe.  It also means that previous estimates of the burden of disease due to seasonal influenza are likely to have to be revisited at least.(5)

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