Pandemic (H1N1) 2009 and Oseltamivir Resistance in Hematology/Oncology Patients

To the Editor: Tramontana et al. (1) recently described characteristics and oseltamivir resistance in hematology and oncology patients infected with pandemic (H1N1) 2009 virus. Such cases merit further study because concurrent medical problems in immunosuppressed patients may obscure and delay diagnosis and management of pandemic (H1N1) 2009 infections. Moreover, severe complications of such infection may be more likely to develop in immunosuppressed patients (2). During the winter of 2009, oseltamivir-resistant pandemic (H1N1) 2009 virus infection was diagnosed for 4 patients at Duke University Medical Center. We describe the clinical features of the infections, the challenges associated with diagnosis of pandemic (H1N1) 2009 virus infection, and the clinical outcome for the infected patients. 
 
Four immunocompromised patients who received chemotherapy and immunotherapy for solid-organ and hematologic malignancies were hospitalized at our tertiary care medical center during October–November 2009, a period of peak activity of pandemic (H1N1) 2009 in surrounding communities in North Carolina (3). These 4 case-patients experienced symptoms attributable to pandemic (H1N1) 2009 from 0 to 14 days after hospital admission, and the diagnosis of pandemic (H1N1) 2009 was made 0–28 days after symptom onset. Illness, diagnosis, and treatment of the patients are summarized in the Table. One patient reported contact with a family member who had influenza-like illness. Three other patients likely acquired pandemic (H1N1) 2009 in the hospital. An investigation could not conclusively establish whether transmission of pandemic (H1N1) 2009 occurred between case-patients and healthcare workers or visitors (4). All 4 case-patients ultimately died; 2 patients recovered from pandemic (H1N1) 2009 after antiviral drug therapy but died of underlying disease and subsequent bacterial infections. One case-patient did not receive antiviral drugs because the diagnosis was made posthumously. 
 
 
 
Table 
 
Clinical, diagnostic, and therapeutic patient information for 4 patients hospitalized for hematologic and oncologic conditions, North Carolina, USA, 2009* 
 
 
 
We learned valuable lessons regarding diagnosis and management of pandemic (H1N1) 2009 in immunocompromised patients. First, pandemic (H1N1) 2009 infection can be difficult to diagnose in immunocompromised hospitalized patients. Such patients do not exhibit consistent symptoms or signs for pandemic (H1N1) 2009. Consistent with Tramontana et al. (1), fever was the most common feature, followed by progressive dyspnea and intermittent cough. None of our patients reported sore throat. Moreover, such nonspecific symptoms may be inadvertently attributed to concurrent medical problems common in immunocompromised patients such as bone marrow suppression, adverse effects of drugs or chemotherapy, recent surgical procedures, opportunistic infections, or line-related bloodstream infections. 
 
Second, respiratory viruses may be imported and subsequently transmitted to hospitalized patients despite standard infection prevention measures (5). Clinicians should remain vigilant for hospital-onset respiratory viral infections and have a low threshold for diagnostic testing, particularly during periods of increased influenza or respiratory virus activity in the community. 
 
Early suspicion and prompt testing may have reduced the delay in the diagnosis and management of these patients with pandemic (H1N1) 2009. However, the initial nasal wash specimen from patient 1 was negative for pandemic (H1N1) 2009 virus antigen, whereas the initial bronchoscopy and nasal wash specimens from patient 4 also were negative for such antigens on laboratory testing. This underscores the limitations of current testing and that the sensitivity of pandemic (H1N1) 2009 diagnostic testing remains poor and needs further improvement. Thus, in patients suspected of having pandemic (H1N1) 2009 or in those who are critically ill, lower tract respiratory specimens should tested to improve diagnostic sensitivity, and clinicians should consider using immunoassay and culture methods. 
 
All 4 patients described in this case series had viral isolates containing H275Y mutation in the neuraminidase gene of pandemic (H1N1) 2009 virus, which is specifically associated with high-level resistance to oseltamivir. Increasing data show that immunocompromised patients are at increased risk for development of drug-resistant influenza infections after oseltamivir prophylaxis or while receiving oseltamivir treatment (6). Fortunately, this resistance trait remains rare. 
 
Existing evidence suggests oseltamivir-resistant pandemic (H1N1) 2009 virus is stable and retains similar transmissibility and virulence as the wild-type virus (7). Therefore, in immunosuppressed patients, in which the influenza mortality rate is high, clinicians should also suspect drug-resistant influenza infection if the patient does not improve. Before she died of underlying hematologic illness, patient 2 clinically improved after treatment with intravenous zanamivir (obtained through an emergency application for an investigational–new drug). As reported in other studies, pandemic (H1N1) 2009 virus was found in her nasal washes, 1 week after she received zanamivir for 10 days (8). 
 
Some data suggest that pandemic (H1N1) 2009 virus has a predilection to affect the lower respiratory tract and is associated with more illness and death than is seasonal influenza (9). All 4 case-patients with in this series developed dyspnea, and 3 of the 4 ultimately died of refractory respiratory failure. Our observations suggest that oseltamivir-resistant pandemic (H1N1) 2009 virus is also associated with poor prognosis and may retain the same tropism for lower respiratory tract involvement as wild type. 
 
These case-patients illustrated the complexity of the diagnosis and management of such infections in hospitalized immunocompromised patients. Vigilance and heightened clinical suspicion are needed to facilitate early diagnosis, treatment and prevention measures to limit transmission of pandemic (H1N1) 2009 virus or similar viral pathogens.

Four immunocompromised patients who received chemotherapy and immunotherapy for solid-organ and hematologic malignancies were hospitalized at our tertiary care medical center during October-November 2009, a period of peak activity of pandemic (H1N1) 2009 in surrounding communities in North Carolina (3). These 4 case-patients experienced symptoms attributable to pandemic (H1N1) 2009 from 0 to 14 days after hospital admission, and the diagnosis of pandemic (H1N1) 2009 was made 0-28 days after symptom onset. Illness, diagnosis, and treatment of the patients are summarized in the Table. One patient reported contact with a family member who had infl uenza-like illness. Three other patients likely acquired pandemic (H1N1) 2009 in the hospital. An investigation could not conclusively establish whether transmission of pandemic (H1N1) 2009 occurred between case-patients and healthcare workers or visitors (4). All 4 case-patients ultimately died; 2 patients recovered from pandemic (H1N1) 2009 after antiviral drug therapy but died of underlying disease and subsequent bacterial infections. One case-patient did not receive antiviral drugs because the diagnosis was made posthumously.
We learned valuable lessons regarding diagnosis and management of pandemic (H1N1) 2009 in immunocompromised patients. First, pandemic (H1N1) 2009 infection can be diffi cult to diagnose in immunocompromised hospitalized patients. Such patients do not exhibit consistent symptoms or signs for pandemic (H1N1) 2009. Consistent with Tramontana et al. (1), fever was the most common feature, followed by progressive dyspnea and intermittent cough. None of our patients reported sore throat. Moreover, such nonspecifi c symptoms may be inadvertently attributed to concurrent medical problems common in immu-nocompromised patients such as bone marrow suppression, adverse effects of drugs or chemotherapy, recent surgical procedures, opportunistic infections, or line-related bloodstream infections.
Second, respiratory viruses may be imported and subsequently transmitted to hospitalized patients despite standard infection prevention measures (5). Clinicians should remain vigilant for hospital-onset respiratory viral infections and have a low threshold for diagnostic testing, particularly during periods of increased infl uenza or respiratory virus activity in the community.
Early suspicion and prompt testing may have reduced the delay in the diagnosis and management of these patients with pandemic (H1N1) 2009. However, the initial nasal wash specimen from patient 1 was negative for pandemic (H1N1) 2009 virus antigen, whereas the initial bronchos-  copy and nasal wash specimens from patient 4 also were negative for such antigens on laboratory testing. This underscores the limitations of current testing and that the sensitivity of pandemic (H1N1) 2009 diagnostic testing remains poor and needs further improvement. Thus, in patients suspected of having pandemic (H1N1) 2009 or in those who are critically ill, lower tract respiratory specimens should tested to improve diagnostic sensitivity, and clinicians should consider using immunoassay and culture methods. All 4 patients described in this case series had viral isolates containing H275Y mutation in the neuraminidase gene of pandemic (H1N1) 2009 virus, which is specifi cally associated with high-level resistance to oseltamivir. Increasing data show that immunocompromised patients are at increased risk for development of drug-resistant infl uenza infections after oseltamivir prophylaxis or while receiving oseltamivir treatment (6). Fortunately, this resistance trait remains rare.
Existing evidence suggests oseltamivir-resistant pandemic (H1N1) 2009 virus is stable and retains similar transmissibility and virulence as the wild-type virus (7). Therefore, in immunosuppressed patients, in which the infl uenza mortality rate is high, clinicians should also suspect drug-resistant infl uenza infection if the patient does not improve. Before she died of underlying hematologic illness, patient 2 clinically improved after treatment with intravenous zanamivir (obtained through an emergency application for an investigational-new drug). As reported in other studies, pandemic (H1N1) 2009 virus was found in her nasal washes, 1 week after she received zanamivir for 10 days (8).
Some data suggest that pandemic (H1N1) 2009 virus has a predilection to affect the lower respiratory tract and is associated with more illness and death than is seasonal infl uenza (9). All 4 case-patients with in this series developed dyspnea, and 3 of the 4 ultimately died of refractory respiratory failure. Our observations suggest that oseltamivir-resistant pandemic (H1N1) 2009 virus is also associated with poor prognosis and may retain the same tropism for lower respiratory tract involvement as wild type.
These case-patients illustrated the complexity of the diagnosis and management of such infections in hospitalized immunocompromised patients. Vigilance and heightened clinical suspicion are needed to facilitate early diagnosis, treatment and prevention measures to limit transmission of pandemic (H1N1) 2009 virus or similar viral pathogens.