Pandemic influenza: was the concern warranted?

In this issue of Blood, Choi et al describe influenza in hematopoietic cell transplant (HCT) recipients to identify risk factors, compare the impact of pandemic 2009 A1/H1N1 with seasonal A1 and seasonal B on clinical outcomes, and probe the impact of early or late antiviral therapy on complications.¹  They found that lower respiratory disease, hypoxia, and prolonged viral shedding were more likely with pandemic 2009 influenza than with seasonal influenza, but survival rates did not differ.

In the US, it was estimated that nearly 60 million illnesses, more than 250 000 hospitalizations, and 12 000 deaths were because of pandemic 2009 A1/H1N1 virus.²  While those numbers sound quite sobering, most illness was mild and the rate of influenza-associated mortality was similar to that of seasonal influenza. Some claimed that the fears of a devastating impact were overblown. The lack of more severe illness was surprising because in animals replication of 2009 H1N1 virus in the lungs was higher than seasonal viruses, morbidity was greater, and pathologic changes appeared to be similar to the highly virulent 1918 virus.^3,4 

Although in general the 2009 H1N1 virus was not associated with greater morbidity than seasonal influenza in the general population, some individuals were affected more than others. Attack rates were highest in the young, pregnant women and young adults were more vulnerable to severe illness, and three-fourths of deaths occurred in individuals with underlying illnesses.^5,6  It has been suggested that cross-reactive immunity from prior influenza infections by other strains in older individuals may have had some protective effect, which would explain the vulnerability of younger individuals. The common thread is that immunocompromised persons unable to mount effective primary or recall immune responses would be particularly vulnerable and certainly the HCT recipient is the poster child for an inability to mount effective immune responses early after HCT or even later, especially with graft-versus-host disease or poor graft function.

Shortcomings of the Choi study include the retrospective design, the long span needed to collect the cases, the changes in viral diagnostic assays over time (with differing sensitivities of case identification), changes in transplant practices over time, perhaps the vigor in case ascertainment that varies over time, and the relatively small number of cases. The strengths of the Choi study are the excellent characterization of the infections, the comparison between influenza types, the focus on important clinical outcomes, and identification of severity risk factors. The suggestion that high-dose steroids may be beneficial is provocative, but the authors have earlier noted the conflicting data on this point,⁷  and randomized trials are clearly needed. Not evaluated in the Choi study was the possible effect of influenza on the subsequent development of noninfectious lung injury or alloreactive syndromes.

Multiple studies have documented substantial morbidity and mortality with seasonal influenza and other community respiratory viruses in HCT recipients. The Choi study emphasizes the importance of early antiviral therapy. Many influenza experts recommend presumptive initiation of therapy for individuals with influenza-like symptoms during times of influenza activity in the community.⁸  Consensus guidelines recommend additional measures to protect HCT recipients.⁹  Upper respiratory infection (URI) symptoms before start of conditioning should lead one to consider postponement until the URI resolves, if possible, because of the risk for progression to pneumonia. Immunization of patients beyond 6 months after transplant should be performed. Healthcare workers and family members should be immunized to reduce the risk for transmission to the HCT patient. HCT recipients less than 6 months after HCT should receive chemoprophylaxis with neuraminidase inhibitors during community influenza outbreaks. Chemoprophylaxis should be considered for all influenza-exposed HCT recipients during the first 2 years or beyond 2 years if substantially immunocompromised after HCT regardless of vaccination history because of the possibility of suboptimal immunologic response to immunization. Children < 9 years old, less than 6 months after HCT, and receiving their first influenza vaccination, should be given 6 weeks of chemoprophylaxis after the first dose of vaccine. Awareness of drug resistance patterns of circulating influenza strains is advisable and should guide the choice of prophylactic agent.

Seasonal influenza visits every year. What is sobering is how poorly prepared we are for influenza every year. Immunization rates in the general population and among high-risk patients are suboptimal. Failure of many health care workers to get immunized is disappointing. Infection control plans in cancer, leukemia, and HCT inpatient and outpatient facilities are often poorly formulated or not effectively implemented. We clearly can and should do better.⁸  The Choi study reminds us of the importance of redoubling our efforts to protect our patients not only for pandemics but for a predictable event every winter.