Lung Pathology in Fatal Novel Human Influenza A (H1N1) Infection

Mauad, Thaís; Hajjar, Ludhmila Abrahão; Callegari, Giovanna D.; Silva, Luiz F F da; Schout, Denise; Galas, Filomena Regina Barbosa Gomes; Alves, Venâncio Avancini Ferreira; Malheiros, Denise Maria Avancini Costa; Auler, José Otávio Costa; Ferreira, Aurea F.; Borsato, Marcela R. L.; Bezerra, Stephania M.; Gutierrez, Paulo Sampaio; Caldini, Élia Garcia; Pasqualucci, Carlos Augusto; Dolhnikoff, Marisa; Saldiva, Paulo Hilário Nascimento

doi:10.1164/rccm.200909-1420oc

Cited by 480 publications

(497 citation statements)

References 32 publications

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“…Autopsy findings in fatal cases of 2009 H1N1 have been reported from several countries. [11][12][13][14][15] The authors of the present study also reported the pathological and virological findings of two autopsy cases of 2009 H1N1 in Japan. 16,17 Both cases revealed that the 2009 H1N1 virus infected type II pneumocytes and caused diffuse alveolar damage (DAD).…”

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confidence: 82%

Histopathological and immunohistochemical findings of 20 autopsy cases with 2009 H1N1 virus infection

et al. 2012

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, were histopathologically analyzed. Hematoxylin-eosin staining, immunohistochemistry for type A influenza nucleoprotein antigen, and real-time reverse transcription-PCR assay for viral RNA were performed on formalin-fixed and paraffin-embedded specimens. In addition, the D222G amino acid substitution in influenza virus hemagglutinin, which binds to specific cell receptors, was analyzed in formalinfixed and paraffin-embedded trachea and lung sections by direct sequencing of PCR-amplified products. There were several histopathological patterns in the lung according to the most remarkable findings in each case: acute diffuse alveolar damage (DAD) with a hyaline membrane (four cases), organized DAD (one case), acute massive intra-alveolar edema with variable degrees of hemorrhage (three cases), neutrophilic bronchopneumonia (five cases) and tracheobronchitis with limited histopathological changes in alveoli (four cases). In two cases, the main findings were due to preexisting disease. Influenza virus antigen was only detected in the respiratory tract in 10 cases by immunohistochemistry. The antigen was detected in type II pneumocytes (three cases) in the epithelial cells of the trachea, bronchi and glands (six cases), and in the epithelial cells in both of the above (one case). The four cases with acute DAD presented with antigen-positive type II pneumocytes. In one case, the D222G substitution was detected in the lung as a major sequence, although 222D was prominent in the trachea, suggesting that selection of the viral clones occurred in the respiratory tract. In five

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confidence: 82%

Histopathological and immunohistochemical findings of 20 autopsy cases with 2009 H1N1 virus infection

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“…TLR9 activation in DCs strongly induces the release of type‐1 IFNs and pro‐inflammatory cytokines and upregulates the co‐stimulatory molecules (e.g., CD80/86);3, 14 TLR7/8 activation induces IFNs, the pro‐inflammatory IL‐6, TNF‐α, CCL2/MCP‐1, and CXCL8/IL‐8 and promotes DC maturation;3, 11, 17 TLR3 in epithelial cells causes tissue inflammation in influenza pneumonia through IL‐6, TNF‐α, and CXCL8/IL‐8 induction and effector cell recruitment 3, 7, 8. Limited available reports had described upregulations of the “viral‐sensing” TLRs in association with the inflammatory cytokines in patients with severe A/H1N1pdm09 influenza 27, 28, 29. Interestingly, the “bacterial‐sensing” TLRs (2 and 4) were also reported to be suppressed 27, 28.…”

Section: Discussionmentioning

confidence: 99%

“…TLR's active role in cytokine induction was supported by our ex vivo experiments, which showed significant differences in cellular cytokine responses between patients with influenza and controls upon TLR‐specific ligand stimulation (e.g., CpG DNA‐TLR9 and imiquimod‐TLR7; the resultant response pattern governed by the ligand tested, cell type studied, and disease stage at the time of sampling/“immune exhaustion”) and a dynamic change in their responsiveness during clinical recovery 20, 32. Perpetuating, uncontrolled pro‐inflammatory cytokine responses can lead to immunopathological damage in severe influenza (Data S1); and further stimulation of TLRs in a more advanced disease stage may exacerbate tissue inflammation 5, 6, 7, 8, 11, 17, 20, 22, 29. Whether TLR blockade alone can reduce inflammation is uncertain as compensatory mechanisms might exist 4, 5, 15.…”

Section: Discussionmentioning

confidence: 99%

Role of human Toll‐like receptors in naturally occurring influenza A infections

Lee

Wong

Hui

et al. 2013

Influenza Resp Viruses

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BackgroundWe investigated the roles of Toll‐like receptors (TLRs) in naturally occurring influenza.MethodsA prospective, case – control study was conducted. Adults hospitalized with virologically confirmed influenza A infections (onset <48 hours, before treatment) were compared with age‐/gender‐matched controls. TLRs (2, 3, 4, 7, 8, 9) expression in monocytes and dendritic cells (DCs – total, myeloid, plasmacytoid) was quantitated using flow cytometry. Gene expression of RLRs (RIG‐1, MDA‐5) was evaluated using real‐time PCR. Concomitant signaling molecules expression, plasma cytokine/chemokine concentrations, and respiratory tract viral loads were measured. PBMCs were cultured and stimulated ex vivo with TLR‐specific ligands for cytokine responses.ResultsForty two patients with influenza (24 A/H3N2, 18 A/H1N1pdm09) and 20 controls were studied. Patients' mean age was 68 ± 16 years; 81% had respiratory/cardiovascular complications. There were increased cellular expressions of TLR9, TLR8, TLR3, and TLR7 during influenza; TLR2 and TLR4 were suppressed. Results were similar for both virus strains. Higher TLR expression levels at presentation significantly correlated with lower viral loads (Spearman's rho: −0·46 to −0·69 for TLR9, TLR8, and TLR3; P‐values <0·05). Multivariate regression models (adjusted for age, comorbidity, disease severity, time from onset) confirmed their independent associations. Increased signaling molecules (phospho‐MAPKs, IκB) and inflammatory cytokines (IL‐6, sTNFR‐1, CCL2/MCP‐1; CXCL10/IP‐10, IFN‐γ) correlated with increased TLR expression. RLRs were upregulated simultaneously. PBMCs of patients with influenza showed significant, dynamic changes in their cytokine responses upon TLR stimulation, compared with controls.ConclusionsOur results suggest that TLRs play an important role in early, innate viral inhibition in naturally occurring influenza. Inflammatory cytokine responses are concomitantly induced. These findings support investigation of TLR targeting as a novel intervention approach for prophylaxis against influenza.

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“…The clinical manifestations of 2009 pandemic influenza A (H1N1) greatly varied. While the mild‐form 2009 pandemic influenza A (H1N1) with nonspecific symptoms/signs such as fever, sore throat, and myalgia are usually found, severe cases with fatal outcome have not been uncommonly encountered 5 , 6 , 7 , 8 , 9 , 10 . The first case of pandemic influenza A (H1N1) was identified in Taiwan on May 20, 2009 11 .…”

Section: Introductionmentioning

confidence: 99%

2009 pandemic Influenza A (H1N1): clinical and laboratory characteristics in pediatric and adult patients and in patients with pulmonary involvement

Lee

Liu

Wang

et al. 2012

Influenza Resp Viruses

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Please cite this paper as: Lee and Liu et al. (2012) 2009 pandemic Influenza A (H1N1): clinical and laboratory characteristics in pediatric and adult patients and in patients with pulmonary involvement. Influenza and Other Respiratory Viruses 6(601), e152–e161. Background To better understand clinical and laboratory characteristics in children, adults, and patients with lung involvement suffering 2009 pandemic influenza A (H1N1). Methods A total of 442 patients with 2009 pandemic influenza A (H1N1) were retrospectively analyzed. Results Comparing to their adult counterpart (n = 55), pediatric patients (n = 387) had significantly higher frequencies of fever, rhinorrhea, cough, sore throat, nausea/vomiting, and longer length of fever; lower frequencies of chest pain and dyspnea; higher incidence of lymphopenia; and lower incidence of elevated serum C‐reactive protein. Among the 227 patients with radiographs available, lung involvement was found in 19 (8·4%) (52·6% consolidation and 47·4% interstitial infiltrations), including 18 children and one adult. One child with lung consolidation died of multiorgan failure. Significant findings in patients with lung involvement included predominant young age (≤10 years), prolonged fever, and delayed oseltamivir therapy (≥48 hours after onset of illness); higher frequencies of dyspnea, nausea/vomiting, and altered consciousness; and higher incidences of leukopenia, elevated serum creative kinase, and lactic dehydrogenase. Conclusions Among patients with 2009 pandemic influenza A (H1N1), we found significant difference in clinical manifestations between children and adults, and significant differences in clinical and laboratory manifestations between patients with lung involvement and those without. On the basis of data from this study and the existing literature, early treatment with oseltamivir is recommended for patients with 2009 pandemic influenza A (H1N1), regardless of age.

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Lung Pathology in Fatal Novel Human Influenza A (H1N1) Infection

Cited by 480 publications

References 32 publications

Histopathological and immunohistochemical findings of 20 autopsy cases with 2009 H1N1 virus infection

Histopathological and immunohistochemical findings of 20 autopsy cases with 2009 H1N1 virus infection

Role of human Toll‐like receptors in naturally occurring influenza A infections

2009 pandemic Influenza A (H1N1): clinical and laboratory characteristics in pediatric and adult patients and in patients with pulmonary involvement

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