The decision by the New York City Office of Chief Medical Examiner to investigate deaths associated with infection by the 2009 pandemic influenza virus provides an opportunity to examine the pathogenesis of fatal pandemic influenza. Major findings include (1) tracheitis and/or bronchitis in all cases, with DAD-associated viral pneumonia as the primary pathology; (2) distribution of influenza viral antigen predominantly in the tracheobronchial epithelium and submucosal glands, and to a lesser extent in bronchiolar epithelium and alveolar epithelial cells and macrophages; (3) bacterial pneumonia in 55%; and (4) comorbidities in 91% of adult and adolescent decedents (with obesity in 72%). These pathologic findings are strikingly similar to those of published autopsy studies from the 1918 and 1957 pandemics and to a more limited extent from publications investigating seasonal influenza.23,25,27,28
Although pandemic and seasonal influenza generally cause self-limited illnesses, a small percentage of cases are fatal.25
In typical uncomplicated infections, viral replication apparently remains limited to the mucosal lining of the pharynx and upper tracheobronchial tree. Determinants of progression of a predominantly upper respiratory tract infection to fatal pulmonary disease are poorly understood but likely include a number of different factors such as age, immune and underlying health status, preexisting immunity to viral antigens (principally hemagglutinin), 29
and pharyngeal bacterial flora. The findings in this and other studies24
suggest that severe disease is associated with the development of influenza viral pneumonia,23,25,30
with or without secondary bacterial pneumonia.24,31,32
The pulmonary pathologic abnormalities observed in the 2009 fatalities reported here do not differ significantly from those reported by pathologists who performed meticulous autopsies during the 1918 and 1957 pandemics (reviewed in references 23
). For example, influenza viral antigen in the tracheobronchial epithelium, alveolar lining cells, and alveolar macrophages, as shown here by immunohistochemistry (), was first demonstrated by immunofluorescence in 1957 pandemic autopsy cases.23
Our observation that viral antigen in alveolar cells often did not colocalize with foci of DAD and alveolar hyaline membrane formation likely reflects the rapid asynchronous kinetics of influenza viral replication and clearance.25
It could also be consistent with recent speculation that at least some of the pulmonary abnormalities of fatal influenza viral pneumonia might be induced by the release of host inflammatory mediators, rather than by a direct viral cytopathic effect.33,34
Whether such pulmonary pathologic changes might also occur in patients with self-limited influenza infection is not known.
Bacterial pneumonia was observed in 55% of the fatalities described here. In comparison, postmortem cultures for bacteria were positive in more than 90% of 1918 pandemic autopsies and about 75% of 1957 autopsies. 23,25
Of the 13 decedents who died without having been hospitalized, 8 (62%) had evidence of bacterial pneumonia (), suggesting that community acquired bacterial pneumonia may play a significant role in the current pandemic. In addition, 8 of these 13 decedents also had DAD, confirming that these changes are not just secondary to prolonged mechanical respirator support but a component of the viral disease process as described in the 1918 and 1957 pandemics. Nine decedents had pulmonary thrombi including 5 with focal infarcts. Thrombi are common with DAD and have been described with influenza infection since 1918.20,35
One of the 2 infant deaths (case 3) also had bacterial pneumonia. A recent report by the Centers for Disease Control and Prevention described concurrent bacterial infection in 29% of referral specimens from influenza A/H1N1 fatalities.21
As this report notes, inadequate sampling, collection of specimens from unaffected portions of the lung, or prolonged illness or treatment may limit the detection of bacteria and explain the variations in percentages of detection.21
Regardless, these findings suggest that, even in an era of widespread and early antibiotic use, bacterial pneumonia remains an important factor in severe/fatal influenza. In coming months it will be important for clinicians to diagnose and treat bacterial pneumonias occurring in patients infected with the pandemic influenza virus. Unfortunately, there is insufficient clinical information about the natural history of severe influenza disease to fully inform clinicians about optimal prophylaxis and treatment approaches.
In addition to demonstrating the characteristics and constancy of pulmonary abnormalities in fatal pandemic influenza, this case series emphasizes an association between underlying illnesses and mortality. Epidemiologic studies conducted during the current pandemic13,35
have suggested obesity as an important risk factor for fatal outcomes. Nearly half of the patients in this case series had a BMI greater than 40. Enhanced susceptibility to fatal infection in obese persons might reflect associated independent risk factors such as compromised ventilatory function, hypertension, congestive heart failure, or diabetes mellitus.36
The presence of only a single decedent older than 60 years is also consistent with current reports that older individuals are less vulnerable to infection with the 2009 A/H1N1 virus than with seasonal influenza viruses, presumably because of immunologic protection induced by prior exposure to previously circulating human A/H1N1 viruses.37
It is not yet clear whether the comparatively few fatalities in older persons is due entirely to low incidence of infection by itself, or whether there may be lower case fatality as well. The frequent gastrointestinal symptomatology (39%) in these patients is an area that needs further study with respect to the underlying pathology of the gastrointestinal tract.
A potentially important diagnostic modality in the new influenza pandemic is CT imaging, which provided detailed information on antemortem pathologic changes in the lungs of 4 patients in this case series. Our findings suggest that CT can be a valuable tool in identifying patients who will require intensive medical support and to elucidate the pathogenesis of severe disease. At present we do not know to what extent the CT abnormalities seen in these fatal cases also occur in patients with milder infections, but this question, as well as differentiating viral from bacterial infections, can be investigated in clinical trials, in volunteer challenge studies, and with quantitative CT analysis.
Pandemic progression offers an opportunity to study pandemic influenza viral infection using techniques not available in past pandemics, including enhanced surveillance, rapid genetic analyses, improved radiographic imaging techniques, and better tools to evaluate the immune response and the natural history of uncomplicated and severe disease. A better understanding of secondary bacterial pneumonias will be crucial for the treatment of severely ill influenza patients. Our findings suggest that, although the spectrum of pulmonary pathologic abnormalities has remained similar from pandemic to pandemic during the past 120 years,24
the portion of the human population that is most susceptible to lethal infection differs with each new viral emergence, confirming the continuing importance of epidemiologic studies identifying risk groups and the continuing importance of careful autopsy pathology studies and the value of centralized evaluation of deaths by a medical examiner’s office.