Influenza: May 2006
de Jong MD, Tran TT, Truong HK, et al. Oseltamivir resistance during treatment of influenza A (H5N1) infection. N Engl J Med. 2005;353:2667-2672. This is a report from Vietnam concerning studies in 8 patients with avian influenza.
The first patient was a 13-year-old girl whose mother died of this infection 1 day after oseltamivir treatment. This strain of influenza A (H5N1) was susceptible to oseltamivir. The next day, the child was admitted and treated with oseltamivir (75 mg on admission, 6 hours later, and 24 hours after admission); this was followed by 75 mg twice daily. The child subsequently had a progressive infiltrate, pulmonary failure, intubation, and she died on the seventh day of oseltamivir treatment. Laboratory studies of the child's virus showed oseltamivir resistance with the H274Y mutation in a strain recovered on the fourth day of treatment. This child also had persistent positive culture results for H5N1 until death.
The rest of the report concerns a total of 8 patients, including the 13-year-old child described previously (patient 1) and this patient's mother (patient 2).
All 8 patients were treated with oseltamivir, and there appeared to be 2 distinctly different courses. Four of the patients (patients 1-4) had persistence of positive viral culture results at high titers and 2 had verified oseltamivir resistance. By contrast, patients 5-8 had negative culture results after oseltamivir and survived. These data are summarized in Table 1 .
Conclusion: The study authors concluded that at least some patients had incomplete viral suppression with the recommended doses of oseltamivir. This results in continued replication, sometimes with oseltamivir resistance. They suggest that higher doses and longer duration of therapy or combination therapy need further evaluation.
Comment: The role of oseltamivir in the treatment of influenza pneumonia is not well established. The initial trials were for seasonal flu and concluded that early treatment, within 48 hours of onset of symptoms, was required to demonstrate a beneficial response. An antiviral effect could be demonstrated with later administration, but this did not translate to a clinical benefit. A limitation in these studies is the absence of prior trials to test the utility of oseltamivir in patients with influenza pneumonia, in part reflecting the rarity of this complication and confusion with the contribution of bacterial superinfection. The study authors conclude that persistent viral replication as indicated by high titers of influenza virus with infection involving influenza A (H5N1) suggests that ongoing replication may contribute to the pathologic events. In the mouse model, oseltamivir treatment at the pneumonia stage confers benefit, providing at least some support for this hypothesis. The counterargument is that the hemorrhagic pneumonia leading to acute respiratory distress syndrome (ARDS) with influenza pneumonia, which was a characteristic feature in the 1918-1919 pandemic and in the lethal cases reported with H5N1, is a reflection of the "cytokine storm," and this inflammatory response needs to be the subject of any therapeutic attack.
Bonner AB, Monroe KW, Talley LI, Klasner AE, Kimberlin DW. Impact of the rapid diagnosis of influenza on physician decision-making and patient management in the pediatric emergency department: results of a randomized, prospective, controlled trial. Pediatrics. 2003;112:363-367. This is a randomized trial to determine the impact of rapid diagnosis of influenza on physician decision making and patient treatment.
Methods: Patients 2 months to 21 years of age who presented to an urban emergency department were screened for cough, fever, coryza, and other symptoms suggesting influenza. All patients had a rapid test for influenza (FluOIA, Biostar, Louisville, Colorado) and they were randomized to (1) physician notified of the result of the rapid flu test or (2) physician not aware of these results. Both groups were followed to determine outcomes in terms of diagnostic testing and antibiotic prescribing.
Results: There were 418 patients enrolled, and 202 had positive test results for influenza. Physicians who were aware of these results had a significant reduction of ordering diagnostic tests, charges associated with these tests, antibiotics prescribed, and length of stay in the emergency department. These results are summarized in Table 2 .
Conclusion: The investigators concluded that the rapid diagnosis of influenza in the emergency department had a substantial positive effect on diagnostic testing, antibiotic use, and emergency department charges.
Comment: This is an older paper, which we don't usually review, but it seemed to have an important message in terms of treatment of patients with influenza and the use of the rapid diagnostic tests.
de Jong MD, Tran TT, Truong HK, et al. Oseltamivir resistance during treatment of influenza A (H5N1) infection. N Engl J Med. 2005;353:2667-2672. This is a report from Vietnam concerning studies in 8 patients with avian influenza.
The first patient was a 13-year-old girl whose mother died of this infection 1 day after oseltamivir treatment. This strain of influenza A (H5N1) was susceptible to oseltamivir. The next day, the child was admitted and treated with oseltamivir (75 mg on admission, 6 hours later, and 24 hours after admission); this was followed by 75 mg twice daily. The child subsequently had a progressive infiltrate, pulmonary failure, intubation, and she died on the seventh day of oseltamivir treatment. Laboratory studies of the child's virus showed oseltamivir resistance with the H274Y mutation in a strain recovered on the fourth day of treatment. This child also had persistent positive culture results for H5N1 until death.
The rest of the report concerns a total of 8 patients, including the 13-year-old child described previously (patient 1) and this patient's mother (patient 2).
All 8 patients were treated with oseltamivir, and there appeared to be 2 distinctly different courses. Four of the patients (patients 1-4) had persistence of positive viral culture results at high titers and 2 had verified oseltamivir resistance. By contrast, patients 5-8 had negative culture results after oseltamivir and survived. These data are summarized in Table 1 .
Conclusion: The study authors concluded that at least some patients had incomplete viral suppression with the recommended doses of oseltamivir. This results in continued replication, sometimes with oseltamivir resistance. They suggest that higher doses and longer duration of therapy or combination therapy need further evaluation.
Comment: The role of oseltamivir in the treatment of influenza pneumonia is not well established. The initial trials were for seasonal flu and concluded that early treatment, within 48 hours of onset of symptoms, was required to demonstrate a beneficial response. An antiviral effect could be demonstrated with later administration, but this did not translate to a clinical benefit. A limitation in these studies is the absence of prior trials to test the utility of oseltamivir in patients with influenza pneumonia, in part reflecting the rarity of this complication and confusion with the contribution of bacterial superinfection. The study authors conclude that persistent viral replication as indicated by high titers of influenza virus with infection involving influenza A (H5N1) suggests that ongoing replication may contribute to the pathologic events. In the mouse model, oseltamivir treatment at the pneumonia stage confers benefit, providing at least some support for this hypothesis. The counterargument is that the hemorrhagic pneumonia leading to acute respiratory distress syndrome (ARDS) with influenza pneumonia, which was a characteristic feature in the 1918-1919 pandemic and in the lethal cases reported with H5N1, is a reflection of the "cytokine storm," and this inflammatory response needs to be the subject of any therapeutic attack.
Bonner AB, Monroe KW, Talley LI, Klasner AE, Kimberlin DW. Impact of the rapid diagnosis of influenza on physician decision-making and patient management in the pediatric emergency department: results of a randomized, prospective, controlled trial. Pediatrics. 2003;112:363-367. This is a randomized trial to determine the impact of rapid diagnosis of influenza on physician decision making and patient treatment.
Methods: Patients 2 months to 21 years of age who presented to an urban emergency department were screened for cough, fever, coryza, and other symptoms suggesting influenza. All patients had a rapid test for influenza (FluOIA, Biostar, Louisville, Colorado) and they were randomized to (1) physician notified of the result of the rapid flu test or (2) physician not aware of these results. Both groups were followed to determine outcomes in terms of diagnostic testing and antibiotic prescribing.
Results: There were 418 patients enrolled, and 202 had positive test results for influenza. Physicians who were aware of these results had a significant reduction of ordering diagnostic tests, charges associated with these tests, antibiotics prescribed, and length of stay in the emergency department. These results are summarized in Table 2 .
Conclusion: The investigators concluded that the rapid diagnosis of influenza in the emergency department had a substantial positive effect on diagnostic testing, antibiotic use, and emergency department charges.
Comment: This is an older paper, which we don't usually review, but it seemed to have an important message in terms of treatment of patients with influenza and the use of the rapid diagnostic tests.
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