Influenza in 2009: Title and subTitle BreakNew Solutions, Same Old Problems

In 1941, the Commission on Influenza of the Armed Forces Epidemiological Board (AFEB) established a comprehensive national research plan to address the most important unanswered scientific questions about influenza.¹ The commission prioritized assessment of vaccine and immune serum prophylaxis efficacy but also defined a much broader scope of collaborative work across the academic, public health, and military sectors. The plan included evaluation of isolation and quarantine practices, environmental controls, and the effectiveness of masks to control infection; field studies to define the clinical, microbiologic, pathologic, and epidemiologic correlates of infection and disease for specific virus subtypes; and evaluation of treatment regimens, including prophylaxis for bacterial superinfections.

As clinicians and public health practitioners contend with the 2009 influenza A(H1N1) virus pandemic, the health care community should be grateful to the commission for accurately anticipating the requirements for effective control and for pioneering the investigations that ultimately led to the vaccines and drugs that can be used today. Nevertheless, answers to most of the questions posed almost 7 decades ago remain incomplete, at best. Like a laborious mosaic, pieces of the influenza picture only slowly emerge and often are surprising with awesome or unimagined discoveries that require new hypotheses and innovative avenues of inquiry.

For clinicians, the most urgent gaps are those related to the prediction, treatment, and supportive care of individuals at increased risk for serious complications of infection. The reports in this issue of JAMA that describe critically ill patients in Canada² and Mexico,³ and earlier reports from other sites,^{4 - 6} challenge traditional views about management of severe influenza and help fill in some of the missing pieces. For example, patients with a 5- to 6-day history of influenzalike illness, hypoxemia, or signs of progressive respiratory compromise appear to be at risk for rapid deterioration and should be treated with empirical antiviral therapy, admitted to the hospital, and monitored carefully. Clinicians should not be falsely reassured by previous good health, young age, and absence of major comorbidities because these characteristics do not exclude the potential for respiratory failure and death. Likewise, major comorbidities, tobacco use, pregnancy, and possibly obesity may increase the risk. On the other hand, a majority of patients can survive intensive care for this illness, even if antiviral treatment was not initiated within 48 hours of clinical onset. Meticulous attention to complicating conditions including bacterial superinfection, pulmonary embolism, and adverse events associated with prolonged mechanical ventilation is essential.^{2 - 6} Respiratory isolation also remains an important priority, given that nosocomial transmission was the source of infection in 10% of the Canadian patients who required intensive care.²

Despite these helpful insights, many clinical dilemmas remain. The overarching need is to define the viral, immunologic, clinical, and epidemiologic determinants of individual susceptibility and protection, and then to quantify the benefit expected from new vaccines and treatments among individuals in various risk strata. Optimizing antiviral treatment regimens is critical. The approved antivirals are difficult to administer to critical care patients, and few data are available to individualize dosages and the duration of necessary treatment. Monotherapy is problematic, especially where drug resistance has emerged.

Borrowing from the lessons of HIV treatment, clinical trials to evaluate combination antiviral regimens in critically ill patients with high influenza viral loads must be an urgent priority.⁷ Given the high proportion of critically ill patients receiving corticosteroid treatment, controlled clinical trials to determine the harms or benefits from this intervention are needed immediately. If antivirals become scarce, drug resistance emerges, or critical care options are curtailed or nonexistent, a SARS-like scenario could emerge whereby clinicians will try using unproven or unconventional treatments without a structured process to evaluate their effectiveness.⁸ Multicenter trials to systematically assess the most sensible options, such as immunoglobulin infusion, cytokine inhibitors treatment, etc, should be planned now so they could be rapidly deployed when pandemic influenza or some other serious new threat emerges.

One of the most ominous implications of the emerging experience with 2009 influenza A(H1N1) in hospitals is the requirement for long lengths of stay and highly intensive treatments.^{2 - 6} In developed countries, these resources have little capacity for surges in patient volume, and in most developing countries they are scarce or nonexistent. The reported experience from Canada is illustrative.² If community attack rates are higher this winter season than when the pandemic virus first appeared, serious shortages of life-saving critical care interventions are probable. Data to develop, test, and validate risk prediction and outcome models that improve allocation of these scarce resources are an especially large need that will occur when facilities are short of beds, personnel, intensive care equipment, and supplies.⁹

The duration and correlates of viral transmissibility among infected patients and health care personnel, as well as the attributable impact of isolation practices, need to be established. From this perspective, the randomized effectiveness trial demonstrating the noninferiority of surgical masks compared with N95 respirators is timely and a key addition to the evidence base for occupational safety decisions.¹⁰ The demand for respirators will exceed supply, and reserving them for aerosol-generating procedures and other higher-risk situations makes sense, provided surgical masks, hand hygiene, respiratory etiquette, and appropriate patient isolation measures are in routine use elsewhere.^{10 - 13} The influenza attack rate of 23% among nurses enrolled in the trial may reflect nonoccupational exposures or may indicate that neither masks nor respirators are very effective in clinical practice—reflecting another important data gap. Similar studies are needed to define evidence-based practices for patient isolation practices involving masks as well as environmental controls, including surface and fomite disinfection, use of UV lights, ventilation strategies, and other control measures.

The Commission on Influenza was formed at a time of great concern about an expected pandemic and its potential effects on military troops preparing to engage in World War II. Urgency compelled the development of a work plan that drove influenza research and vaccine development.¹ Regrettably, much of the original scientific agenda was never accomplished once the urgency waned. Influenza eventually took a back seat to other health priorities, and investments to answer fundamental virologic, epidemiologic, and clinical questions, modernize vaccine approaches, and develop a better pipeline of treatments were scant.

Recent global infectious disease threats have once again created urgency and improved preparedness has ensued. The SARS outbreak was an important reminder that new infections can emerge and rapidly globalize with devastating socioeconomic consequences. As a result, global surveillance has expanded and businesses are more engaged in preparedness. The avian influenza A(H5N1) outbreaks served as an alert that influenza can have an extremely high mortality rate even when it is not highly transmissible to humans. In response, government leaders and global health agencies initiated major investments in vaccine modernization, drug procurement, and public health preparedness. Now the 2009 influenza A(H1N1) pandemic exposes true vulnerabilities: the attenuated capacity for health care system surge, enormous global disparity in access to prevention and care, and how much more must be learned to truly understand and control this formidable foe on the frontlines of health care, worksites, and communities.

Influenza can be prevented, and the unnecessary toll it takes on families and businesses around the world, year after year, can be mitigated. The evidence needed to prevent influenza has changed little since 1941. What has changed is the evolution of extraordinarily powerful scientific approaches and tools that can be applied to find solutions. What is currently unknown is certainly now knowable, if the investments are expanded and sustained in basic, translational, and public health sciences necessary for success, even when urgency fades.^{14 - 17} The past decade has provided ample warning. Clearly, it is time for a Global Commission on Influenza Work Plan 2009 and for all sectors to commit to, and to invest in, completion of the work plan on the fastest possible trajectory.