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The Novel Human Influenza A(H7N9) Virus Is Naturally Adapted to Efficient Growth in Human Lung Tissue.

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The Novel Human Influenza A(H7N9) Virus Is Naturally Adapted to Efficient Growth in Human Lung Tissue.

MBio. 2013;4(5)

Authors: Knepper J, Schierhorn KL, Becher A, Budt M, Tönnies M, Bauer TT, Schneider P, Neudecker J, Rückert JC, Gruber AD, Suttorp N, Schweiger B, Hippenstiel S, Hocke AC, Wolff T

Abstract
ABSTRACT A novel influenza A virus (IAV) of the H7N9 subtype has been isolated from severely diseased patients with pneumonia and acute respiratory distress syndrome and, apparently, from healthy poultry in March 2013 in Eastern China. We evaluated replication, tropism, and cytokine induction of the A/Anhui/1/2013 (H7N9) virus isolated from a fatal human infection and two low-pathogenic avian H7 subtype viruses in a human lung organ culture system mimicking infection of the lower respiratory tract. The A(H7N9) patient isolate replicated similarly well as a seasonal IAV in explanted human lung tissue, whereas avian H7 subtype viruses propagated poorly. Interestingly, the avian H7 strains provoked a strong antiviral type I interferon (IFN-I) response, whereas the A(H7N9) virus induced only low IFN levels. Nevertheless, all viruses analyzed were detected predominantly in type II pneumocytes, indicating that the A(H7N9) virus does not differ in its cellular tropism from other avian or human influenza viruses. Tissue culture-based studies suggested that the low induction of the IFN-β promoter correlated with an efficient suppression by the viral NS1 protein. These findings demonstrate that the zoonotic A(H7N9) virus is unusually well adapted to efficient propagation in human alveolar tissue, which most likely contributes to the severity of lower respiratory tract disease seen in many patients. IMPORTANCE Humans are usually not infected by avian influenza A viruses (IAV), but this large group of viruses contributes to the emergence of human pandemic strains. Transmission of virulent avian IAV to humans is therefore an alarming event that requires assessment of the biology as well as pathogenic and pandemic potentials of the viruses in clinically relevant models. Here, we demonstrate that an early virus isolate from the recent A(H7N9) outbreak in Eastern China replicated as efficiently as human-adapted IAV in explanted human lung tissue, whereas avian H7 subtype viruses were unable to propagate. Robust replication of the H7N9 strain correlated with a low induction of antiviral beta interferon (IFN-β), and cell-based studies indicated that this is due to efficient suppression of the IFN response by the viral NS1 protein. Thus, explanted human lung tissue appears to be a useful experimental model to explore the determinants facilitating cross-species transmission of the H7N9 virus to humans.

PMID: 24105764 [PubMed - in process]

Phase II Trial of Biweekly Chemotherapy with Docetaxel and Cisplatin in High-Risk Patients with Unresectable Non-Small Cell Lung Cancer.

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Phase II Trial of Biweekly Chemotherapy with Docetaxel and Cisplatin in High-Risk Patients with Unresectable Non-Small Cell Lung Cancer.

Chemotherapy. 2013 Oct 9;59(3):159-166

Authors: Kim MJ, Kim SH, Kang JH, Kim HG, Cho YJ, Jeong YY, Kim HC, Lee JD, Hwang YS, Kim MG, Choi JY, Lee GW

Abstract
Purpose: We investigated the efficacy and toxicity of a biweekly schedule of docetaxel and cisplatin in high-risk patients with unresectable (stages IIIB-IV) non-small cell lung cancer (NSCLC). Methods: In this study, 48 high-risk patients with previously untreated locally advanced or metastatic NSCLC were treated with combination chemotherapy consisting of docetaxel 40 mg/m(2) and cisplatin 40 mg/m(2); both drugs were given biweekly, on days 1 and 15, every 4 weeks in an outpatient setting. Results: Complete response, partial response, and stable disease were observed in 1 (2.1%), 30 [62.5%, 95% confidence interval (CI) 47.9-77.1], and 4 (8.3%) patients. The median overall survival was 15.1 months (95% CI 11.7-18.5) and the median time to progression was 7.5 months (95% CI 6.4-8.6). The major toxicity was grade 3 anemia in 7 (14.6%) patients. Grade 3/4 neutropenia was observed in 5 (10.4%) patients. Among the nonhematologic toxicities, grade 3 infection and grade 3 diarrhea were observed in 5 (10.4%) and 4 (8.3%) patients, respectively. No treatment-related mortality was found. Conclusions: As a front-line chemotherapy for high-risk patients with unresectable NSCLC in an outpatient setting, the biweekly schedule of docetaxel and cisplatin showed feasible efficacy with acceptable hematologic toxicities, comparable to the results of previous studies of triweekly or weekly schedules. Additional large randomized studies are needed to optimize the schedule and dosage of combination therapy with docetaxel and cisplatin in high-risk patients with unresectable NSCLC. © 2013 S. Karger AG, Basel.

PMID: 24107481 [PubMed - as supplied by publisher]

Dysregulation in lung immunity - The protective and pathologic Th17 response in infection.

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Dysregulation in lung immunity - The protective and pathologic Th17 response in infection.

Eur J Immunol. 2013 Sep 23;

Authors: Way EE, Chen K, Kolls JK

Abstract
Th17 cytokines can play both protective and pathologic roles in the airways. An emerging theme in Th17 cytokine biology is that these responses can mediate tissue pathology when downstream effector cells are dysfunctional, such as neutrophils lacking functional NADPH oxidase in the case of chronic granulomatous disease, or epithelial cells lacking appropriate ion transport as in the case of cystic fibrosis. In this Mini-Review we highlight recent advances in the protective and pathologic roles of Th17 cytokines in the context of infection at the pulmonary barrier.

PMID: 24130019 [PubMed - as supplied by publisher]

Invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease.

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Invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease.

Multidiscip Respir Med. 2013 Sep 4;8(1):59

Authors: Tutar N, Metan G, Koç A, Yilmaz I, Bozkurt I, Simsek ZO, Buyukoglan H, Kanbay A, Oymak F, Gulmez I, Demir R

Abstract
BACKGROUND: Invasive pulmonary aspergillosis (IPA) is an infection often occurring in neutropenic patients and has high mortality rates. In recent years, it has been reported that the incidence of IPA has also increased in patients with chronic obstructive pulmonary disease (COPD). The purpose of this study is to investigate the clinical and demographic characteristics and treatment responses of IPA in patients with COPD.
METHODS: Seventy-one patients with a positive culture of Aspergillus from lower respiratory tract samples were examined retrospectively. Eleven (15.4%) of these patients, affected with grade 3 or 4 COPD, had IPA.
RESULTS: Aspergillus hyphae were detected in lung biopsy in three (27.3%) out of 11 patients and defined as proven IPA; a pathological sample was not taken in the other eight (72.7%) patients, and these were defined as probable IPA. Aspergillus isolates were identified as six cases of Aspergillusfumigatus and three of Aspergillusniger in nine patients, while two isolates were not identified at species level. While five patients required intensive care unit admission, four of them received mechanical ventilation. The most common finding on chest X-ray and computed tomography (CT) (respectively 63.6%, 72.7%) was infiltration. Amphotericin B was the initial drug of choice in all patients and five patients were discharged with oral voriconazole after amphotericin B therapy. Six patients (54.5%) died before treatment was completed.
CONCLUSIONS: IPA should be taken into account in the differential diagnosis particularly in patients with severe and very severe COPD presenting with dyspnea exacerbation, poor clinical status, and a new pulmonary infiltrate under treatment with broad-spectrum antibiotics and steroids.

PMID: 24135224 [PubMed - as supplied by publisher]

Activity, Severity and Impact of Respiratory Disease in Primary Antibody Deficiency Syndromes.

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Activity, Severity and Impact of Respiratory Disease in Primary Antibody Deficiency Syndromes.

J Clin Immunol. 2013 Oct 18;

Authors: Hurst JR, Workman S, Garcha DS, Seneviratne SL, Haddock JA, Grimbacher B

Abstract
PURPOSE: Some patients with primary antibody deficiency (PAD) syndromes develop bronchiectasis. In immunocompetent patients with bronchiectasis, key clinico-pathophysiological relationships exist between exacerbation frequency, lung function, health-status, infection and inflammation. It is not known whether such relationships are present in PAD. It is also not known how local and systemic inflammation in PAD compares with that in immunocompetent (non-PAD) bronchiectasis patients.
METHOD: We assessed symptoms, exacerbation frequency, health-status, lung function, CT, airway and systemic inflammation and infection in 33 PAD patients and 20 immunocompetent controls with bronchiectasis.
RESULTS: Despite less severe airflow obstruction, PAD patients had similar health-status impairment and greater airway (sputum log10 IL-6 2.71 vs. 1.81 pg/ml, p = 0.001) and greater systemic inflammation than immunocompetent bronchiectasis controls (serum log10 CRP 0.77 vs. 0.36 mg/l, p = 0.001). In PAD, cross-sectional markers of disease severity (CT and lung function) did not relate to inflammatory markers of disease activity, however there was a relationship between FEV1 decline rate and systemic inflammation (IL-6; r = 0.42, p = 0.036) and the magnitude of the systemic inflammatory response was related to that in the airway. Correlation between generic SF36 and respiratory SGRQ questionnaires (r = -0.79, p < 0.001) suggests that much health-status impairment in PAD relates to respiratory involvement. Health-status was associated with dyspnoea (rho = 0.77, p < 0.001), respiratory infection frequency (rho = 0.48, p = 0.016), lung function (FEV1: r = -0.60, p = 0.001) and rate of lung function decline (r = 0.41, p = 0.047).
CONCLUSION: The major findings of this analysis are that in patients with PAD, cross-sectional markers of disease severity such as lung function and CT extent of disease do not reflect disease activity as assessed by airway and systemic inflammation. In addition, there is a relationship between the rate of progression of lung disease and the severity of the systemic inflammatory response which itself is related to that in the airway. Much of the quality of life impact in PAD relates to respiratory involvement, specifically the severity of airflow obstruction, respiratory exacerbation frequency and dyspnoea. Finally, patients with PAD had greater airway and systemic inflammation than a control population with non-PAD bronchiectasis which may suggest a dysregulated airway immune response.

PMID: 24136152 [PubMed - as supplied by publisher]

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