CHILDREN TREATED WITH OSELTAMIVIR DEVELOP RESISTANT INFLUENZA A VIRUSES

Oseltamivir-resistant influenza A mutations in children being treated for influenza with oseltamivir arise more frequently than previously thought, according to a recent report. Furthermore, children can be a source of viral transmission, even after five days of treatment. Maki Kiso of the University of Tokyo and colleagues found that 18% of children treated with oseltamivir developed mutant drug-resistant viruses as soon as four days after the initiation of treatment.

The researchers obtained samples of influenza A viruses from 50 children, age 2 months to 15.8 years, who were treated with oseltamivir. They then “sequenced the genes for neuraminidase and haemagglutinin and studied the mutant neuraminidases for their sensitivity to oseltamivir.”

Neuraminidase mutations developed in nine children by day 4 of treatment; no mutations were found in children age 7 or older. Six of the nine patients had Arg292Lys mutations, two had Glu119Val mutations, and one had an Asn294Ser mutation. The researchers also found that “over a quarter of the children who shed virus for three days or more had drug resistant influenza viruses.”

The researchers offered several explanations for their findings. The first was their use of rigorous detection techniques. “Molecular cloning of the neuraminidase genes from clinical specimens would identify viruses that might be overlooked in assays done on mixed populations of mutant and parental viruses.” Second, they noted that the virus may have been replicated at a high level in children treated with oseltamivir, which may have resulted in a high frequency of resistant viruses. Third, children in Japan—where the study was conducted—are given oseltamivir at a dosage of 4 mg/kg daily, “whereas in other countries, the drug is given according to weight groups.”

Kiso M, Mitamura K, Sakai-Tagawa Y, et al. Resistant influenza A viruses in children treated with oseltamivir: descriptive study. Lancet. 2004;364:759-765.

AIR POLLUTION AFFECTS LUNG DEVELOPMENT

Children living in polluted communities are five times more likely to have clinically low lung function levels. In 1993, W. James Gauderman, PhD, and colleagues, recruited 1,759 fourth–grade children from 12 communities in southern California. Parents and legal guardians completed a baseline questionnaire. Then, over an eight-year period, researchers analyzed FVC, FEV₁, and maximal midexpiratory flow rate (MMEF). They set up air-pollution-monitoring stations to measure average hourly levels of ozone, nitrogen dioxide, particulate matter, and acid vapor.

Children living in the most populated communities had significant reductions in their FEV₁, as compared to children living in communities with cleaner air. “The estimated proportion of children with a low FEV₁ was 1.6% at the lowest level of exposure to PM_2.5 and was 4.9 times as great at the highest level of exposure to PM_2.5.”

Overall, they found that the average FEV₁ in girls increased from 1,988 mL at age 10 to 3,332 mL at age 18; the average FEV₁ in boys increased from 2,082 mL at age 10 to 4,464 mL at age 18. “Similar patterns of growth over the eight-year period were observed for FVC and MMEF.” Deficits in lung function were positively correlated with the level of exposure to nitrogen dioxide, acid vapor, PM_2.5, and elemental carbon.

Researchers were uncertain how exposure to pollutants leads to reduced lung function. They suspect, however, that pollutants may reduce the growth of alveoli or that airway inflammation may play a role.

Guaderman WJ, Avol E, Gilliland F, et al. The effect of air pollution on lung development from 10 to 18 years of age. N Engl J Med. 2004;351:1057-1067.

SURVIVAL IN PATIENTS WITH ADENOCARCINOMA OF THE LUNG

Never-smokers with adenocarcinoma of the lung have improved survival when compared to current smokers, a recent study found. Luke T. Nordquist, MD, and colleagues examined the records of 132 never-smokers and 522 current smokers with adenocarcinoma to identify demographic and survival differences between the two groups. Demographic factors examined included age at diagnosis, stage at presentation, gender, tumor histology and smoking status, and number of metastatic sites. The researchers believed that “an understanding of these differences could then be utilized for better prognostication and therapeutic benefit.”

After examining the data they found significant differences in demographic factors and survival between the two groups. Never-smokers with adenocarcinoma were predominantly female and older. About 78% of those in the never-smoker category were female, compared with 54% in the current smoker category. Mean age for never-smokers was 63.5 years, compared with 59.4 years for current smokers. In addition, 23% of never-smokers hit the five-year survival mark, compared with 16% of current smokers. The researchers attributed the difference in survival, in part, to the possibility that current smokers have increased incidence of comorbidities and are therefore more susceptible to poorer prognosis and survival.

According to the authors, because “multiple chemicals in cigarette smoke are presumed to induce carcinogenesis in smokers,” the incidence of adenocarcinoma in never-smokers might suggest “an alternate mechanism of carcinogenesis and therefore a distinct natural history and tumor biology.” Further investigation of adenocarcinoma in never-smokers “could lead to development of cohort-specific treatment strategies.”

In an accompanying editorial, Peter J. Mazzone, MD, MPH, Tarek Mekhail, MD, MSc, and Alejandro C. Arroliga, MD, FCCP, noted that although it is possible that there are distinct mechanisms of carcinogenesis in never-smokers and current smokers, the study by Nordquist et al had several limitations. Among them were the self-reported nature of smoking status and the fact that both groups conatined more women than men. In addition, the study did not include factors such as performance status and treatments received, both of which are determinants of survival.

Nordquist LT, Simon GR, Cantor A, et al. Improved survival in never-smokers vs current smokers with primary adenocarcinoma of the lung. Chest. 2004;126:347-351.
Mazzone PJ, Mekhail T, Arroliga AC. Is lung cancer in the nonsmoker a different disease? Chest. 2004;126:326-329.

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