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Immunomodulation in 2009 H1N1

By Amesh A. Adalja, MD, February 18, 2011

Before the 2009 pandemic, there was speculation about the potential for immunomodulation to improve the clinical course of severe influenza (see, for instance, CBN Report, July 23, 2010). Corticosteroids, macrolides, statins, diabetic medications (metformin, pioglitazone), fibrates, and cox-2 inhibitors all were identified as likely candidates. However, the only evidence to support this theory was anecdotal reports on use in humans and laboratory-animal data. Now, a team of researchers in Spain has published results of a study1 of the use of several types of immune modulators in patients infected with 2009 H1N1.

Immune Modulation in Infectious Diseases

The clinical manifestations of infectious diseases result from both the direct effects of the pathogen and the effects of the host’s immune response. For instance, sepsis is the syndrome that results from the systemic inflammatory responses to a severe infection. Much of the morbidity of infectious diseases is due to an excessive immune response that produces overwhelming inflammation. Previous studies have shown that certain immunomodulatory drugs—including corticosteroids, macrolide antimicrobials, and other compounds—have the ability to lessen morbidity and mortality of specific infectious diseases by modifying the host immune response.

The standard treatment algorithms for several infectious diseases include immunomodulators:

  • For moderate to serve hypoxia secondary to pneumocystis pneumonia, corticosteroids may be used with antimicrobials to dampen the inflammatory response caused by fungal cell death.
  • For pneumococcal, tuberculous, and Haemophilus influenzae meningitis, corticosteroids are administered in conjunction with antimicrobial therapy to dampen the inflammatory response from bacterial cell death.
  • For sepsis and ventilator-associated pneumonia, the immunomodulatory antimicrobial, clarithromycin, reduces mortality and facilitates more rapid weaning from ventilators.

A Prospective Cohort Study of 197 Patients

This new study, by Viasus and colleagues,1 was a prospective cohort study of immunomodulatory therapies in patients hospitalized with 2009 H1N1 infections. The researchers enrolled 197 patients at 13 tertiary care hospitals in Spain between June and November 2009. For inclusion in the study, patients had to have PCR-confirmed 2009 H1N1 influenza and X-ray–confirmed pneumonia, and they had to have been admitted for at least 24 hours. Patients who were initially admitted to the ICU were excluded. Patients were considered to have received immunomodulatory therapy if they were taking corticosteroids, macrolides, or statins upon admission. The primary outcome was development of severe disease, as indicated by ICU admission or death.

Of the 197 patients studied, 68 received some form of immunomodulatory therapy—corticosteroids (37), macrolides (31), or statins (12). Eleven patients were on long-term statin therapy. Of note, patients who received these therapies were older and had higher pneumonia severity indices than those who were not taking immunomodulators. Multilobar pneumonia, respiratory failure, bacterial coinfection, and rapid oseltamivir treatment did not differ between the groups (25% vs. 18.5%), and, as expected, those taking statins had higher rates of co-morbid illnesses.

No Benefits to Immunomodulators

Immunomodulators were not found to decrease disease severity. On the contrary, those who received corticosteroids were more likely to develop severe disease and to acquire nosocomial bacterial infections, and those patients took longer to stabilize. Patients taking statins also took longer to stabilize, perhaps because they had a greater burden of co-morbid conditions.

Results May Not Be Generalizable

The following limitations of this study may limit its value:

  • Because corticosteroids are immunosuppressive, it may not be appropriate to group them with other immunomodulatory drugs.
  • Other agents, such as diabetic medications, fibrates, or cox-2 inhibitors, were not studied.
  • This was not a randomized, double-blind, controlled trial in which interventions could be tightly managed and the control and treatment groups matched.
  • Patients already on statins may not derive the same benefit as those newly initiated to the therapy.
  • The rate of antiviral use was relatively low and immunomodulation may work best in the setting of optimized antiviral therapy.

However, the study results should prompt further investigation. Use of immunomodulation to reduce severe influenza is a hypothesis that deserves careful investigation through rigorously designed and executed studies.


  1. Viasus D, Pano-Pardo JR, Cordero E, et al. Effect of immunomodulatory therapies in patients with pandemic influenza A (H1N1) 2009 complicated by pneumonia. JInfect 2011; doi:10.1016/j.jinf.2011.01.014. Accessed February 14