Adjuvant immunosuppression in the management of severe influenza: friend or foe?

www.ccmjournal. org 457 The pathogenesis and clinical outcome of influenza virus infection are affected by variations in the virus, the host, and the host’s response to infection (1, 2). Significant research has been directed at understanding the various components of the host’s innate and adaptive responses to influenza (2, 3). Antibodies and pattern recognition receptions, such as Toll-like receptors and retinoic acid-inducible gene I, which can recognize influenza infection and result in the production of proinflammatory cytokines and type I interferons, are the first lines of defense from influenza infection (4). These responses initiate the adaptive immune response, which includes induction of virusspecific Band T-cell responses (3). Although these immune responses are critical for the control and clearance of influenza, defects in the adaptive immune response, whether genetic or iatrogenic (i.e., lymphocyte depletion following hematopoietic stem cell or solid organ transplantation), can result in prolonged replication, progression to the lower airway, and enhanced morbidity and mortality in the patient. Excessive or dysbalanced immune response, on the other hand, may be detrimental to recovery (2). Overproduction of cytokines and chemokines, including tumor necrosis factor α, interleukin-6, interleukin-8, and interferons, can result in, among other complications, excessive recruitment of neutrophils and mononuclear cells (2). If the infection involves the lungs, this excess inflammation may result in lung damage, more severe disease, and mortality. As such, modulation of the immune system may be necessary to optimize the outcomes of severe influenza infection but comes at the risk of causing severe disease with associated morbidity and mortality (5). Novel antibodies directed at the hemagglutinin stem region and the ectodomain of the influenza matrix protein 2 domain and novel therapies, such as protease-activated receptor-2 agonists, type I interferons, and other immunomodulatory agents such as statins, that may derive their benefit through modulation of the host immune responses, are promising adjuvants that are being studied to optimize the immune response in an individual (1, 6, 7). Optimally, any immunomodulatory therapy would limit inflammation to the point that it is sufficient to lead to clearance of the virus but prevent the deleterious effects of the inflammatory response. In this issue of Critical Care Medicine, Wang et al (8) have investigated the role of the addition of sirolimus and corticosteroids to traditional antiviral therapy in the management of laboratory-confirmed influenza A/H1N1 pdm infection with lower airway involvement. In this single center, prospective, controlled study, the investigators provided standard oseltamivir 75 mg twice daily for 10 days to all patients with polymerase chain reaction (PCR)-confirmed influenza A/ H1N1 pdm and respiratory failure requiring ventilatory support. All 38 patients were also given oral prednisolone 20 mg daily for 14 days. Half of the patients (n = 19) were randomized to also receive sirolimus 2 mg daily for 14 days. Patients were otherwise managed with standard, low tidal volume ventilator management strategies and supportive care, including antimicrobials at the discretion of the primary provider. The two groups of patients were comparable at baseline, with similar Acute Physiology and Chronic Health Evaluation II scores (26 vs 29.2), Sequential Organ Failure Assessment scores (5.7 vs 5.4), PaO 2 /FIO 2 (106.5 vs 16.3 mm Hg), or A-aO 2 (456.1 vs 508.8 mm Hg) gradients. Patients who received sirolimus had better PaO 2 /FIO 2 ratios at day 3 and day 7 (167.5 vs 106.8 [p = 0.025] and 241.6 vs 147.0 [p = 0.008], respectively), shorter duration of ventilator use (13.8 ± 22.3 vs 33 ± 44.8 d, p = 0.03), and higher likelihood of having a negative PCR of lower airway specimens at day 7 (12 of 16 [75%] vs 3 of 15 [33.3%], p < 0.05) among survivors. There was a trend to less hypotension (1 [5.3%] vs 6 [31.6%], p = 0.09) in patients who received sirolimus. The intervention was well tolerated without differences in rates of hospital-acquired pneumonia (3 of 19 [15.8%] vs 6 of 19 [31.6%]) or ICU mortality (3 [15.8%] vs 8 [42.1%], p = 0.15) between the two groups. The study did not collect serial quantitative virology nor did it assess the immunologic impact (i.e., serum or bronchoalveolar lavage cytokine levels) of the intervention. In many regards, these results are surprising in context of existing data on the impact of steroids and immunosuppressive therapy on the course of influenza infection. The majority of studies, published to date, would suggest that steroids are associated with worse outcomes in patients with influenza, particularly if pneumonia is present. Early use of high-dose corticosteroids in patients with severe influenza infection has been associated with increased mortality (58% vs 27% and 33.7% vs 16.8% mortality) (9, 10). Steroids may predispose to prolonged viral replication, resulting in more direct cytopathic effect on the infected lungs, as well as increasing the risk of bacterial and Copyright © 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0b013e3182a63779 Michael G. Ison, MD, MS, FIDSA Division of Infectious Diseases; Division of Organ Transplantation; and Northwestern University Transplant Outcomes Research Collaboration Northwestern University Feinberg School of Medicine Chicago, IL