During April 2009–June 2010, thirty-seven (0.5%) of 6,740 pandemic (H1N1) 2009 viruses submitted to a US surveillance system were oseltamivir resistant. Most patients with oseltamivir-resistant infections were severely immunocompromised (76%) and had received oseltamivir before specimen collection (89%). No evidence was found for community circulation of resistant viruses; only 4 (unlinked) patients had no oseltamivir exposure.
During April, 2009
During April 2009
Oseltamivir resistance was determined by either NI or pyrosequencing for the H275Y mutation. NI was performed on virus isolates with a chemiluminescent substrate; viruses with elevated IC50 values for oseltamivir were identified as resistant, based on previously set criteria (
A comparison group of hospitalized patients infected with oseltamivir-susceptible pandemic (H1N1) 2009 was identified from the Influenza Hospitalization Network (FluSurv-NET). FluSurv-NET includes 10 states that participate in the Emerging Infections Program, a population-based surveillance for hospitalized patients with influenza infection (California, Colorado, Connecticut, Georgia, Maryland, Minnesota, New Mexico, New York, Oregon, Tennessee), plus 6 states (Iowa, Idaho, Michigan, North Dakota, Oklahoma, South Dakota) added in response to the 2009 pandemic, as previously described (
We considered identical matches on all 4 variables as a high probability match, e.g., a patient from FluSurv-NET who had a pandemic (H1N1) 2009 virus specimen submitted to national antiviral resistance surveillance who had an oseltamivir-susceptible pandemic (H1N1) 2009 virus infection. We validated our linking methods with Oregon data (n = 41); all 4 patients identified as high probability matches were true matches. For validation purposes, we identified 4 specimens that were matched on county, age, and sex but not on specimen collection date up to 7 days, e.g., moderate probability matches; 1 patient was hospitalized, 2 were outpatients, and 1 specimen was from a medical examiner (patient not hospitalized). The Oregon surveillance specimens that were neither high nor moderate probability matches were surveillance specimens from outpatients and cluster investigations (M. Vandermeer, pers. comm.).
Overall, 6,740 virus isolates and specimens were submitted to surveillance systems; 37 (0.5%) viruses were oseltamivir resistant (
Most patients infected with oseltamivir-resistant pandemic (H1N1) 2009 viruses were hospitalized (81%), had a severe immunocompromising condition (76%), and had been exposed to oseltamivir before collection of the specimen tested for antiviral resistance (89%) (
| Characteristic | Oseltamivir-resistant infections | Oseltamivir-susceptible infections | |||
| Total from national surveillance,
n = 37 | Total from FluSurv-NET states,‡ n = 17 | National surveillance cases from FluSurv-NET counties, n = 401 | National surveillance cases matched in FluSurv-NET, n = 65 | ||
| Median age, y (range) | 18 (1–74) | 21 (5–74) | 22 (0–89) | 31 (0–82) | |
| Female sex | 18 (49) | 6 (35) | 177 (50) | 38 (58) | |
| Hospitalized | 30 (81) | 16 (100) | 65 (16) | 65 (100) | |
| ICU admission | 13/30 (43) | 7/12 (58) | – | 14 (23) | |
| Deaths, all cause§ | 7/31 (23) | 2/12 (17) | – | 3 (5) | |
| Oseltamivir exposure¶ | 31 (89) | 16 (94) | – | 6 (14) | |
| Underlying medical condition | 33 (89) | 17 (100) | – | 49 (75) | |
| Severe/Immunosuppression# | 28 (76) | 17 (100) | – | 7 (11)** | |
| Pregnancy | 1 (2.7) | 0 | – | 5 (7.7) | |
| Asthma and CLD | 10 (27) | 2 (18) | – | 21 (34) | |
| CVD | 8 (22) | 4 (24) | – | 5 (8) | |
| Diabetes mellitus | 5 (14) | 2 (13) | – | 12 (18) | |
| Chronic kidney disease | 4 (11) | 3 (19) | – | 5 (8) | |
| No underlying medical conditions | 4 (11) | 0 | – | 13 (21) | |
| Median time from oseltamivir initiation to specimen collection, d (range) | 11 (2–37) | 14 (3–37) | – | 1.5 (1–4)†† | |
*Values are no. (%) except as indicated. FluSurv-NET, Influenza Hospitalization Network; ICU, intensive care unit; CLD, chronic lung disease; CVD, cardiovascular disease, excluding hypertension; –, not applicable. †Missing data were excluded from analysis; denominators are included where they varied from cohort size. ‡Of the 16 oseltamivir-resistant cases from states participating in FluSurv-NET, 5 had county information and were from FluSurv-NET counties. None were high probability matches to a FluSurv-NET hospitalized patient and none were from Oregon. FluSurv-NET captured only 1 hospitalization for each patient infected with pandemic (H1N1) 2009 virus during the year. Repeat hospitalizations were not recorded, although many sites noted repeat hospitalizations for patients with immunosuppressive conditions (L. Kamimoto, pers. comm.). §Among oseltamivir-resistant cases, 4 deaths were reported to national surveillance as directly caused by influenza. Cause of death was not recorded for patients infected with oseltamivir-susceptible pandemic (H1N1) 2009 virus. ¶Patients with oseltamivir exposure received oseltamivir, either as chemoprophylaxis or treatment, before the collection date of the pandemic (H1N1) 2009 virus specimen tested for antiviral resistance. #For patients with oseltamivir-resistant pandemic (H1N1) 2009, severe immunosuppression was defined as any of the following: receiving treatment for any cancer within 6 months before onset of influenza illness, currently receiving immunosuppressive medication, including systemic corticosteroids, as part of prevention strategies for transplant (bone marrow or solid organ) rejection, or for management of pulmonary or autoimmune conditions, or having a diagnosis of AIDS, not just HIV infection. For patients within FluSurv-NET, we included any patient with a medical record of the syndromes above or if immunosuppressed or immunosuppression was recorded in the medical chart. **Among the 7 hospitalized patients from FluSurv-NET with oseltamivir-susceptible pandemic (H1N1) 2009 and an immunosuppressive condition, 3 (43%) were receiving chronic systemic corticosteroids; 1 for systemic lupus erythematosus and the other 2 for unknown reasons. The immunosuppressive condition was not known for 4 patients, but immunosuppression was recorded from the medical record. ††n = 6.
Among the 28 patients infected with oseltamivir-resistant pandemic (H1N1) 2009 virus, with a severe immunocompromising condition and a complete case form, 24 (86%) had a malignancy reported, 23 had a hematologic malignancy and were receiving chemo- or immunosuppressive therapy at the time of their infection, and 10 (38%) were recipients of a hematopoietic stem cell transplant (SCT). One patient had AIDS and a lymphoma of the central nervous system. Among the 3 immunosuppressed patients without a malignancy, 2 were recipients of solid organ (renal) transplants, and another had received SCT <6 months before influenza illness (reason for SCT could not be confirmed).
Among 1,982 national surveillance oseltamivir-susceptible specimens from the 16 FluSurv-NET states, 1,607 (81%) had county information; among these, 401 (25%) specimens were from FluSurv-NET counties, and 65 patients from FluSurv-NET were high probability matches to patients identified in antiviral resistance surveillance data (
Infections with oseltamivir-resistant pandemic (H1N1) 2009 viruses were rare in the United States during April 2009
Although the number of patients with oseltamivir-resistant pandemic (H1N1) 2009 virus infections was small in the United States during this period, this is the largest case series published and confirms findings from reports with smaller samples (
We thank all state and local public health officials and laboratory staff who assisted in compiling this report. We also thank the principal investigators and staff from FluSurv-NET, including the Emerging Infections Program Network, for enabling access to pertinent data compiled in this report.
Dr Graitcer is an Epidemic Intelligence Service Officer assigned to the Influenza Division at the Centers for Disease Control and Prevention, Atlanta, Georgia, USA. His primary research interests include influenza and emergency medicine.