Autopsy Findings in Eight Patients With Fatal H1N1 Influenza

Abstract

A novel H1N1 influenza A virus emerged in April 2009, and rapidly reached pandemic proportions. We report a retrospective observational case study of pathologic findings in 8 patients with fatal novel H1N1 infection at the University of Michigan Health Systems (Ann Arbor) compared with 8 age-, sex-, body mass index-, and treatment-matched control subjects. Diffuse alveolar damage (DAD) in acute and organizing phases affected all patients with influenza and was accompanied by acute bronchopneumonia in 6 patients. Organizing DAD with established fibrosis was present in 1 patient with preexisting granulomatous lung disease. Only 50% of control subjects had DAD. Peripheral pulmonary vascular thrombosis occurred in 5 of 8 patients with influenza and 3 of 8 control subjects. Cytophagocytosis was seen in all influenza-related cases. The autopsy findings in our patients with novel H1N1 influenza resemble other influenza virus infections with the exception of prominent thrombosis and hemophagocytosis. The possibility of hemophagocytic syndrome should be investigated in severely ill patients with H1N1 infection.

Influenza virus H1N1 activates platelets through FcγRIIA signaling and thrombin generation

“…Consistent with the autopsies of H 1 N 1 -infected patients, which have documented platelets in the affected lungs, [33][34][35] we observed an accumulation of platelets in bronchoalveolar lavages of H 1 N 1 -infected mice (supplemental Figure 3). The interaction between platelets and H 1 N 1 may thus take place in blood during viremia in critically ill patients or in the inflamed lungs where immune complexes against H 1 N 1 are present, 23 when vascular permeability is increased 65 and/or when the integrity of lung capillaries is compromised.…”

“…Platelets are an important source of inflammatory mediators, which are either stored or can be produced de novo upon activation. 3,4 Intrigued by the presence of activated platelets in the blood of critically ill influenza H 1 N 1 infected patients, [33][34][35]37 we aimed to study the activation of platelets by the H 1 N 1 IAV.…”

“…17 Indeed, the autopsy of patients with fatal influenza infection revealed pulmonary vascular thrombosis. [33][34][35] Previous work indicating that incubation of human platelets with H 3 N 2 virus induces antibody-and complementdependent platelet lysis could also possibly explain the thrombocytopenia observed in patients. 36 Alternatively, the lower platelet count in IAV-infected patients might result from the direct or indirect platelet activation by the virus, promoting platelet-leukocyte aggregation.…”

Negative Regulation of Lung Inflammation and Immunopathology by TNF-α during Acute Influenza Infection

“…[3][4][5][6][7][8][9][10][11] TNF-␣, a classical proinflammatory cytokine, has recently been shown to play anti-inflammatory and antifibrotic roles in various models. [32][33][34][35][36][37][38][39][40][41][42][43] However, whether TNF-␣ plays an immunoregulatory role during influenza infection remains unclear.…”

“…1,2 It is now well established that lung immunopathology is one of the main causes of influenzarelated morbidity and mortality. [3][4][5][6][7][8][9][10][11] Influenza viruses are negative-stranded, enveloped RNA viruses belonging to the family Orthomyxoviridae that preferentially infect and replicate in bronchial epithelial cells. 7 Both innate and adaptive immune responses are key players in the host defense against influenza.…”