This effect estimate was similar to the difference between patients with and without HGG in prior studies. The crossover design of the trial, in which each subject serves as his or her own control, allows sufficient power for the detection of a clinically significant effect of IVIG with only a small number of patients and is the major strength of this design. For example, a sample size of 10 patients in a crossover trial has more power to detect differences than double the sample size using a parallel group design. As we did not have multiple bacterial infections per patient, the power of the study was less than anticipated. To our knowledge, this is the first 
randomized, double-blind, placebo-controlled clinical trial of IVIG for HGG after lung transplantation. In a crossover design, we did not find a significant impact of IVIG on bacterial infections or other infectious episodes, despite observing expected increases in IgG levels following IVIG administration. Adverse events were mild and common during both IVIG and placebo periods. Previous studies have shown associations between the presence of HGG after lung transplant and worse outcomes. We previously Amikacin hydrate demonstrated that lung transplant recipients with severe HGG had a higher cumulative incidence of pneumonia compared to that of recipients without HGG,, but there was no significant increase in the risk of CMV disease. Those with severe HGG also had an increased risk of death. The incidence of severe HGG was about 15% in our prior studies, however other investigators have demonstrated even higher prevalences of HGG after lung transplantation. A recent study in pediatric lung transplant recipients found an association between HGG and the risk of infections and hospitalization. More recently, lower post-transplant IgG levels were associated with an increased risk of BOS. To our knowledge, there is only one other RCT of immunoglobulin replacement for HGG in thoracic organ transplantation. Yamani et al. studied the use of Cytogam in patients with IgG levels between 350 and 500 mg/dl in a randomized, double-blind placebo controlled trial with 13 patients randomized to Cytogam and 10 patients randomized to placebo. An average of only 1.4 doses were administered per patient, without a standard regimen. The investigators found a decrease in the number of episodes of CMV disease, but no other differences between the groups. These results may not be generalizable as this study 1) used Cytogam in patients who received valganciclovir for CMV prophylaxis for only 4 weeks after transplantation, 2) on average only administered 1�C2 doses of study drug for the entire study period, 3) only showed an effect on CMV infection, and 4) demonstrated no effect on bacterial infections. These data may be difficult to extrapolate to the chronic use of IVIG in lung transplant patients with HGG receiving more prolonged CMV prophylaxis. Our study had several limitations. While the crossover design Estradiol Benzoate provided more power than we would have had with.20 subjects studied in a parallel design, there were few outcomes and our findings could very well be attributable to inadequate power. For the crossover design to be valid, we needed to ensure clinical stability over the time of both treatment periods, necessarily limiting the duration of each. Longer studies with greater numbers of patients would be necessary to detect smaller differences in outcomes. The primary statistical analysis may be anti-conservative in small samples.