We thank Drs. Khan and Sewell for their interest and relevant comments regarding our study. As pointed out in their letter, adverse reactions after IVIG administration have been observed in patients with severe infections. However, these severe adverse effects were described in patients with hypogammaglobulinemia who received their usual replacement treatment of IVIG during an intercurrent infection, who differ from the broad population of patients with sepsis of our study. Moreover, in the same observational study of more than 13 500 IVIG infusions, the incidence of adverse events was 0.8%, and none of these reactions were reported as severe (1). In our meta-analysis, adverse reactions were reported in only 6 studies. Of interest, most of these adverse effects were considered mild to moderate, and when severe (dyspnea or shock) they were thought to be secondary to the primary disease rather than to the treatment regimen. Neutropenia was also not reported as a consequence of IVIG use. However, ensuring the safety of participants with independent data safety monitoring committees and diligent reporting of adverse events within clinical trials is very important in general, as well as for future prospective trials evaluating the use of IVIG.

Costs and potential supply problems associated with the use of IVIG in a broad population of patients with severe sepsis and septic shock are crucial if considering recommending the use of IVIG. Albeit, important costs and supply should not supersede overall benefits, such as improvements in survival and quality of life; a clear survival benefit in any population should be given priority over other indications with lower evidence of a clinical benefit (2, 3). On the other hand, the estimated cost of IVIG (1 g/kg) is currently about half that of activated protein C in the same population. We agree that good management of IVIG supply should be prioritized by basing the use of IVIG on current evidence of clinical benefit. For these reasons and the potential benefit of the therapy, we believe that IVIG should be further evaluated in adult patients with severe sepsis and septic shock receiving current standard of care therapy.