We report a case series of hospitalized cancer patients with influenza A pandemic (H1N1) 2009 virus infection and their outcomes. Patients with hematologic malignancies accounted for 50% of deaths of persons with pandemic influenza in Victoria during the first 3 months of the pandemic (15
). The strongest effects of illness from pandemic influenza among hospitalized cancer patients in the present series occurred in HSCT recipients. Nine of the 10 cancer patients admitted to intensive care were HSCT recipients. Furthermore, of 7 deaths from pandemic (H1N1) 2009 in this series of hospitalized cancer patients, 6 occurred in HSCT recipients (comprising 37.5% of these patients). Our observations are similar to those seen with seasonal influenza. In a series of hematology patients with respiratory virus infection, including seasonal influenza, from 1 large cancer center, the largest number of infections and deaths occurred in recipients of allogeneic HSCTs (21
). Our observations support the importance of existing recommendations for control of transmission of influenza infection in HSCT recipients during an influenza pandemic (22
Half of the 24 cancer patients who had not received an allogeneic HSCT had underlying multiple myeloma (n = 8) and chronic lymphocytic leukemia (n = 4). There was also a paucity of patients with solid tumors (n = 2). The severity of illness from influenza in patients who have underlying multiple myeloma and chronic lymphocytic leukemia has not previously been widely appreciated, although a high rate of pneumonic illness from influenza has previously been demonstrated at 1 center (21
). Patients with multiple myeloma have impaired cell-mediated immunity, in addition to humoral immune deficits (6,23,24
). All 4 patients with multiple myeloma admitted to intensive care had previously received an autologous HSCT, which likely further compromised immunologic function. They also had been diagnosed with myeloma for several years.
Bacterial co-pathogens that cause pneumonia were not identified in our study cohort. However, patients received broad-spectrum antibacterial agents on admission. In contrast, a small number of investigators have identified bacterial superinfections in up to 30% of fatal cases of pandemic influenza (3,25
). For patient 17 in this series, a diagnosis of pulmonary aspergillosis was made after autologous HSCT, an association previously reported with seasonal influenza in allogeneic HSCT recipients (26
When there is a circulating strain of influenza not contained in the recent influenza vaccine, postexposure oseltamivir prophylaxis is an attractive strategy that can prevent the development of influenza infection (27–29
). Postexposure prophylaxis of healthcare workers and family members may reduce the likelihood of exposure through prevention of influenza infection in close contacts of HSCT recipients. Our observations that would support post-exposure oseltamivir prophylaxis are 1) 4 of 5 allogeneic HSCT recipients who died or were admitted to intensive care had either nosocomial or household acquisition; 2) 5 of 11 HSCT recipients who had pneumonia before beginning oseltamivir therapy died; 3) none of the patients in this study were known to have received postexposure prophylaxis at the time of symptom onset, despite use of this strategy during the study period (29
); and 4) 3 patients acquired the infection in the hospital from unidentified sources. This nosocomial transmission occurred despite heightened awareness during this pandemic, which demonstrates the difficulties of effective containment in the hospital setting (28,29
The finding of oseltamivir-resistant influenza virus in 4 of 7 patients with a positive pandemic (H1N1) 2009–specific RT-PCR result after >
4 d of oseltamivir therapy is a cause for concern. In Australia, oseltamivir-resistant pandemic (H1N1) 2009 has been described in another immunocompromised patient, a renal transplant recipient (30
). No oseltamivir-resistant pandemic (H1N1) 2009 strains have been detected in nonhospitalized patients in Australia (B. Wang and A. Hurt, pers. comm.). The risk of pandemic influenza developing the H275Y mutation that confers oseltamivir resistance is considered to be higher in immunocompromised patients (10,12
). Immunocompromised patients have also been overrepresented in deaths associated with oseltamivir-resistant seasonal influenza (31,32
). If repeat NAT on respiratory specimens had been routinely performed for all treated patients in the present series, rates of oseltamivir resistance may have been even higher than we observed. Our findings indicate an urgent need to optimize oseltamivir dosing in immunocompromised patients. Further research into the role of combination antiviral therapy should be considered (33,34
). Immunocompromised patients should have serial screening for ongoing viral shedding and oseltamivir resistance. The oseltamivir-resistant H275Y mutants remain susceptible to the alternative NA inhibitor zanamivir, and therefore the use of this drug should be considered in patients who are shedding these viruses (10
Only 1 of the patients who was in intensive care and had oseltamivir-resistant pandemic (H1N1) 2009 virus survived. The effects of oseltamivir-resistant influenza virus in this patient are uncertain. The deterioration of her condition after initial stabilization may have been related to development of oseltamivir-resistance and persistent influenza viral replication similar to that seen in a recent case report (30
). Others have shown development of resistance to oseltamivir within 3 d of therapy (30
), and we observed resistance develop within 4 d for 1 patient. Undoubtedly, other explanations for her biphasic illness are possible. Immune recovery with resolution of neutropenia may have enabled viral clearance and recovery.
Universal chemoprophylaxis for HSCT recipients during an outbreak with an influenza strain that is not contained in the available influenza vaccine has been recommended by international guidelines supported by North American and European Blood and Marrow Transplant groups, Infectious Diseases Society of America, and the US Centers for Disease Control and Prevention (22
). One of the study centers instituted universal chemoprophylaxis for patients admitted to receive an allogeneic HSCT after 2 cases of nosocomial-acquired infection before engraftment (P. Ferguson, pers. comm.). Although the strategy led to apparent success, with no further nosocomial infections observed, we have concern about this approach based on 1) the high rate of oseltamivir resistance (4/30 [13.3%] administered oseltamivir) observed in this study; 2) overrepresentation of postexposure prophylaxis in cases of oseltamivir-resistant pandemic (H1N1) 2009 influenza (12
); 3) the potential that pandemic (H1N1) 2009 H275Y mutant viruses may transmit and spread throughout the community, similar to outcomes recently observed with seasonal influenza A (H1N1) viruses with the same H275Y mutation (8,11,35
); and 4) the paucity of hospital-acquired cases seen in this series during heightened surveillance and control measures of a pandemic. A more judicious approach may be surveillance, infection control measures, and early treatment until vaccination becomes available (12,22,28
). Additionally, education of patients and their close contacts to facilitate early treatment and avoidance of exposure is essential. When a vaccine becomes available, close contacts of those infected, their family members, and healthcare workers should be vaccinated.
One of the strengths of this study is the relatively high coverage of the major hematology centers in a single state, which reduces the effect of bias on patient ascertainment. However, patients whose treatment was managed in the community were excluded, and this information will be essential to our understanding as to which co-factors predict clinical progression and outcomes for pandemic (H1N1) 2009 infection in immunocompromised patients.
A high rate of oseltamivir resistance developed in critically ill HSCT recipients, particularly in those who continued to shed pandemic (H1N1) 2009 virus after 4 d of oseltamivir treatment. Consequently, surveillance, infection control measures, and early treatment of those at greatest risk of pandemic (H1N1) 2009 infection may prove more useful than universal chemoprophylaxis during an outbreak with an influenza strain that is not contained in the available influenza vaccine. Continued surveillance for oseltamivir-resistant influenza virus strains is needed, particularly in the immunocompromised.