Systemic Corticosteroids and Early Administration of Antiviral Agents for Pneumonia with Acute Wheezing due to Influenza A(H1N1)pdm09 in Japan

BACKGROUND: Pneumonia patients with wheezing due to influenza A(H1N1)pdm09 were frequently treated with systemic corticosteroids in Japan although systemic corticosteroid for critically ill patients with pneumonia caused by influenza A(H1N1)pdm09 has been controversial. Applicability of systemic corticosteroid treatment needs to be evaluated. METHODS/PRINCIPAL FINDINGS: We retrospectively reviewed 89 subjects who were diagnosed with influenza A(H1N1)pdm09 and admitted to a national hospital, Tokyo during the pandemic period. The median age of subjects (45 males) was 8 years (range, 0-71). All subjects were treated with antiviral agents and the median time from symptom onset to initiation of antiviral agents was 2 days (range, 0-7). Subjects were classified into four groups: upper respiratory tract infection, wheezing illness, pneumonia with wheezing, and pneumonia without wheezing. The characteristics of each group was evaluated. A history of asthma was found more frequently in the wheezing illness (55.6%) and pneumonia with wheezing (43.3%) groups than in the other two groups (p = 0.017). Corticosteroid treatment was assessed among subjects with pneumonia. Oxygen saturation was lower in subjects receiving corticosteroids (steroid group) than in subjects not receiving corticosteroids (no-steroid group) (p<0.001). The steroid group required greater oxygen supply than the no-steroid group (p<0.001). No significant difference was found by the Kaplan-Meier method between the steroid and the no-steroid groups in hours to fever alleviation from the initiation of antiviral agents and hospitalization days. In logistic regression analysis, wheezing, pneumonia and oxygen saturation were independent factors associated with using systemic corticosteroids. CONCLUSION: Patients with wheezing and a history of asthma were frequently found in the study subjects. Systemic corticosteroids together with early administration of antiviral agents to pneumonia with wheezing and possibly without wheezing did not result in negative clinical outcomes and may prevent progression to severe pneumonia in this study population

Rationale and Design of a Prospective, Multicentre, Stop Tyrosine Kinase Inhibitor Trial of Paediatric Patients with Chronic Myeloid Leukaemia with Sustained Complete Molecular Response (STKI-14)

Chronic myeloid leukaemia (CML) is a relatively rare disease in children, accounting for 2–3% of all paediatric leukaemia cases. Generally, children with CML can avoid hematopoietic stem cell transplantation and achieve molecular responses with tyrosine kinase inhibitors (TKI). However, CML stem cells are thought to survive in many patients, even after TKI treatment. Many aspects of the toxic effects of prolonged exposure to TKIs during childhood remain unclear, particularly those regarding growth impairment. This lack of clarity underscores the importance of the present clinical trial, which aims to clarify the feasibility of treatment-free remission (TFR) in children following TKI treatment. We aim to examine the long-term out-comes and complications of TKIs before and after cessation to better understand the unknown complications that could arise in adulthood. This trial targets patients who were diagnosed with CML at an age younger than 20 years, were in the chronic or accelerated phase at initial diagnosis and remained in complete molecular remission for at least 2 years after TKI administration. We will examine the utility of TKI cessation and assess the treatment results of patients who resumed TKI therapy after losing a major molecular response. We will also investigate factors related to the feasibility of a TFR after TKI cessation

One-Step Detection of the 2009 Pandemic Influenza A(H1N1) Virus by the RT-SmartAmp Assay and Its Clinical Validation

<div><h3>Background</h3><p>In 2009, a pandemic (pdm) influenza A(H1N1) virus infection quickly circulated globally resulting in about 18,000 deaths around the world. In Japan, infected patients accounted for 16% of the total population. The possibility of human-to-human transmission of highly pathogenic novel influenza viruses is becoming a fear for human health and society.</p> <h3>Methodology</h3><p>To address the clinical need for rapid diagnosis, we have developed a new method, the “RT-SmartAmp assay”, to rapidly detect the 2009 pandemic influenza A(H1N1) virus from patient swab samples. The RT-SmartAmp assay comprises both reverse transcriptase (RT) and isothermal DNA amplification reactions in one step, where RNA extraction and PCR reaction are not required. We used an exciton-controlled hybridization-sensitive fluorescent primer to specifically detect the HA segment of the 2009 pdm influenza A(H1N1) virus within 40 minutes without cross-reacting with the seasonal A(H1N1), A(H3N2), or B-type (Victoria) viruses.</p> <h3>Results and Conclusions</h3><p>We evaluated the RT-SmartAmp method in clinical research carried out in Japan during a pandemic period of October 2009 to January 2010. A total of 255 swab samples were collected from outpatients with influenza-like illness at three hospitals and eleven clinics located in the Tokyo and Chiba areas in Japan. The 2009 pdm influenza A(H1N1) virus was detected by the RT-SmartAmp assay, and the detection results were subsequently compared with data of current influenza diagnostic tests (lateral flow immuno-chromatographic tests) and viral genome sequence analysis. In conclusion, by the RT-SmartAmp assay we could detect the 2009 pdm influenza A(H1N1) virus in patients' swab samples even in early stages after the initial onset of influenza symptoms. Thus, the RT-SmartAmp assay is considered to provide a simple and practical tool to rapidly detect the 2009 pdm influenza A(H1N1) virus.</p> </div

Treatment and clinical time course of study subjects.

*<p>Wheezing was defined as a continuous high pitched sound emitting from the chest during expiration on auscultation.</p>†<p>Pneumonia was diagnosed on the basis of infiltrative shadows on chest radiograph.</p>‡<p>Antiviral medication was switched oseltamivir to zanamivire and vice versa.</p>§<p>The dose of corticosteroid was equivalent to methylprednisolone 1.0–1.5 mg/body weight (kg)/time, 2–4 times/day, in subjects under 15 years of age, and 40–80 mg/time, 2–4 times/day in those over 15 years of age.</p>¶<p>At least one medication of shortacting β2-agonist, longacting β2-agonist, inhaled isoproterenol, inhaled disodium cromoglycate, aminophylline, and leukotriene receptor antagonists.</p>∥<p>Oxygen was administered using a nasal cannula or face mask.</p>**<p>Antibiotics.</p

Background and clinical characteristics of study subjects.

*<p>Wheezing was defined as a continuous high pitched sound emitting from the chest during expiration on auscultation.</p>†<p>Pneumonia was diagnosed on the basis of infiltrative shadows on chest radiograph.</p>‡<p>Asthma includes active asthma and inactive asthma.</p>§<p>Other comorbidities include smoking , alcoholism, diabetis meritis, chronic heart diseases , obesity.</p>¶<p>SpO₂: oxygen saturation measured by pulse oximetry in room air.</p>∥<p>Pathogenic bacteria co-infection was detected by throat swabs and/or sputum.</p><p>Definition of abbreviations: WBC, white blood cell count; LDH, lactate dehydrogenase; ALP, alkaline phosphatase; AST, aspartate amino transferase; ALT, alanine aminotransferase; CRP, C-reactive protein; IgE, Immunoglobulin E.</p

Clinical factors for using systemic corticosteroids treatment among the study subjects by multiple logistic regression analysis.

<p>n = 89.</p>*<p>Wheezing was defined as a continuous high pitched sound emitting from the chest during expiration on auscultation.</p>†<p>Pneumonia was diagnosed on the basis of infiltrative shadows on chest radiograph.</p>‡<p>SpO₂: oxygen saturation measured by pulse oximetry in room air on admission.</p

Study population.

<p>A total of 104 patients were diagnosed with pandemic influenza A(H1N1)pdm09. Five patients (one of whom died) were admitted to the ICU and were excluded from the study. The remaining 99 patients were the study subjects. Among them, 89 subjects presented with respiratory disorders and 10 presented with symptoms other than respiratory disorders, including encephalopathy. The subjects with respiratory disorders were classified into the following four groups: upper respiratory tract infection (n = 22), wheezing illness (n = 9), pneumonia with wheezing (n = 30), and pneumonia without wheezing (n = 28). The total number of subjects with pneumonia was 58.</p

Systemic corticosteroids treatment in the relation0 to clinical time course assessed by Kaplan-Meier methods.

<p>Kaplan-Meier curves of the number of hours to fever alleviation (A) and hospitalization days (B) according to systemic corticosteroid treatment among subjects with viral pneumonia in steroid (n = 46) and non-steroid (n = 12) groups There were no significant differences between the groups in terms of either hours to fever alleviation (log rank test, p = 0.835) or hospitalization days (log rank test, p = 0.626).</p

Clinical presentation of subjects with pneumonia according to systemic corticosteroid treatment.

<p>N = 58.</p>*<p>No-steroid and steroid group denote group of subjects who were not treated and treated with systematic corticosteroids.</p>†<p>Wheezing was defined as a continuous high pitched sound emitting from the chest during expiration on auscultation.</p>‡<p>Pathogenic bacteria co-infection was detected by throat swabs and/or sputum.</p>§<p>SpO₂: oxygen saturation measured by pulse oximetry in room air.</p>¶<p>The number of days from symptom onset to the initiation of administration of antiviral agent either oseltamivir or zanamivir.</p>∥<p>At least one medication of short-acting β2-agonist, long-acting β2-agonist, inhaled isoproterenol, inhaled disodium cromoglycate, aminophylline, and leukotriene receptor antagonists.</p>**<p>Oxygen was administered using a nasal cannula or face mask.</p>††<p>The time (hours) to alleviation of fever to less than 37°C after the administration of antiviral agents.</p><p>Definition of abbreviation: WBC, white blood cell count; LDH, lactate dehydrogenase; CRP, C-reactive protein.</p