Parainfluenza Virus Type 1 Induces Epithelial IL-8 Production via p38-MAPK Signalling

Human parainfluenza virus type 1 (HPIV-1) is the most common cause of croup in infants. The aim of this study was to describe molecular mechanisms associated with IL-8 production during HPIV-1 infection and the role of viral replication in MAPK synthesis and activation. An in vitro model of HPIV-1 infection in the HEp-2 and A549 cell lines was used; a kinetic-based ELISA for IL-8 detection was also used, phosphorylation of the mitogen-activated protein kinases (MAPKs) was identified by Western blot analysis, and specific inhibitors for each kinase were used to identify which MAPK was involved. Inactivated viruses were used to assess whether viral replication is required for IL-8 production. Results revealed a gradual increase in IL-8 production at different selected times, when phosphorylation of MAPK was detected. The secretion of IL-8 in the two cell lines infected with the HPIV-1 is related to the phosphorylation of the MAPK as well as viral replication. Inhibition of p38 suppressed the secretion of IL-8 in the HEp-2 cells. No kinase activation was observed when viruses were inactivated

Reducing occurrence and severity of pneumonia due to pandemic H1N1 2009 by early oseltamivir administration: a retrospective study in Mexico.

BACKGROUND: Anti-viral treatment has been used to treat severe or progressive illness due to pandemic H1N1 2009. A main cause of severe illness in pandemic H1N1 2009 is viral pneumonia; however, it is unclear how effective antiviral treatment is against pneumonia when administered >48 hours after symptom onset. Therefore, we aimed to determine how time from symptom onset to antiviral administration affected the effectiveness of antiviral treatment against pneumonia due to pandemic (H1N1) 2009. METHODS/PRINCIPAL FINDINGS: A retrospective medical chart review of 442 patients was conducted in a hospital in Mexico. Subjects had tested positive for pandemic H1N1 2009 virus by real-time reverse-transcriptase-polymerase-chain-reaction and were administered oseltamivir. Median time from symptom onset to oseltamivir administration was 5.0 days (range, 0-43). 442 subjects, 71 (16.1%) had severe pneumonia which required mechanical ventilation, 191 (43.2%) had mild to moderate pneumonia, and 180 (40%) did not have pneumonia. Subjects were divided into four groups based on time to oseltamivir administration: ≤2, 3-7, 8-14, and >14 days. Severity of respiratory features was associated with time to treatment, and multivariate analysis indicated that time to oseltamivir administration was associated with severity of respiratory features. A proportional odds model indicated that 50% probability for occurrence of pneumonia of any severity and that of severe pneumonia in patients who would develop pneumonia reached at approximately 3.4 and 21 days, respectively, after symptom onset. Patients with a shorter time to oseltamivir administration were discharged earlier from the hospital. CONCLUSIONS: Earlier initiation of oseltamivir administration after symptom onset significantly reduced occurrence and severity of pneumonia and shortened hospitalization due to pandemic H1N1 2009. Even when administered >48 hours after symptom onset, oseltamivir showed considerable potential for reducing pneumonia. Application of these results would benefit patients affected by future influenza pandemics

Laboratory data and physical findings for study patients at presentation^*.

<p>Grouping of patients was based on the number of days from symptom onset to oseltamivir administration: Group 1, ≤2 days; Group 2, 3–7 days; Group 3, 8–14 days; Group 4, >14 days.</p>†<p>WBC: white blood cell count,</p>‡<p>RBC: red blood cell count,</p>§<p>SpO₂: oxygen saturation measured by pulse oximetry in room air.</p><p>*Normal ranges are as follows: WBC, 4000–10 000; neutrophil count, 2200–8250; lymphocyte count, 1500–4000; RBC, 3.8–6.5; hemoglobin, 11.5–17.0; platelets, 150–400; albumin, 2.30–3.50; sodium, 138–150; respiratory rate, 12–20 per min in adults; SpO₂, 92–98% at sea level.</p><p>**One-way ANOVA.</p><p>SD denotes standard deviation.</p

Cumulative rate of hospital discharge as a function of the time of oseltamivir administration.

<p>The cumulative rate of hospital discharge in each group using Kaplan-Meier's method was calculated using data on death as censored data. The groups of patients with earlier oseltamivir administration were discharged from the hospital significantly earlier (p<0.001, Tarone's test). Grouping of patients was based on days from symptom onset to oseltamivir administration: Group 1, ≤2 ; Group 2, 3–7; Group 3, 8–14; Group 4, >14days.</p

Characteristics of study patients.

1<p>One-way ANOVA,</p>2<p>Chi-square test,</p>3<p>Kruskal-Wallis test,</p>4<p>Cochran-Armitage test.</p><p>Grouping of patients was based on the number of days from symptom onset to oseltamivir administration: Group 1, ≤2 days; Group 2, 3–7 days; Group 3, 8–14 days; Group 4, >14 days.</p><p>*Median number of days from symptom onset to oseltamivir administration among all study patients.</p><p>†Socioeconomic background, based on patient's approximate daily income: 0 = <$5 US, 1 =$6–$10, 2 =$11–$15, 3 =$16–$25, 4 =$26–$40, 5 = >$40.</p><p>‡COPD: chronic obstructive pulmonary disease.</p

Clinical features of the study patients on admission.

<p>Grouping of patients was based on the number of days from symptom onset to oseltamivir administration: Group 1, ≤2 days; Group 2, 3–7 days; Group 3, 8–14 days; Group 4, >14 days.</p><p>*Cochran-Armitage test.</p><p>†Chest radiological findings.</p

Model of the probability of occurrence of pneumonia.

<p>The probability of developing pneumonia is depicted using a proportional odds model. <i>p₁</i>, the probability of severe pneumonia; <i>p₂</i>, the probability of mild/moderate pneumonia; <i>x</i>, time until oseltamivir administration from symptom onset.</p><p></p><p></p>The solid line indicates the probability of occurrence of severe pneumonia (<i>p₁</i>). The dotted line indicates the probability of occurrence of any severity of pneumonia (mild to severe pneumonia, <i>p₁+p₂</i>).<p></p

Multivariate analysis of the severity of respiratory features using a proportional odds model.

<p>*Grouping of patients was based on the number of days from symptom onset to oseltamivir administration: Group 1, ≤2 days; Group 2, 3–7 days; Group 3, 8–14 days; Group 4, >14 days.</p>†<p>The odds ratio of socioeconomic level was presented when the level was upped by one unit as a continuous variable.</p>‡<p>AGE 1 (age <18 y), AGE 2 (age 18–50 y), AGE 3 (≥50 y).</p>§<p>Comorbidities are compared between present and absent.</p><p>χ2: Chi-square test.</p

Severity of respiratory features in each group.

<p>(P<0.001, Jonckheere's test).</p><p>Grouping of patients was based on the number of days from symptom onset to oseltamivir administration: Group 1, ≤2 days; Group 2, 3–7 days; Group 3, 8–14 days; Group 4, >14 days.</p><p>*Severe pneumonia: abnormal shadows on chest radiographs and required mechanical ventilation.</p>†<p>Moderate/mild pneumonia: abnormal shadows on chest radiographs but did not require mechanical ventilation.</p>‡<p>Upper respiratory tract infection: absence of pneumonia.</p