SummaryBackgroundWhile CMV viral load (CMV-VL) is commonly used to guide preemptive therapy in the post-transplant setting, there is little data correlating viremia with clinical endpoints. We therefore investigated the association of CMV-VL with mortality in the first year after hematopoietic cell transplantation (HCT).MethodsThis cohort study included patients who received an allogeneic HCT between 01 January 2007 and 28 February 2013, were CMV seropositive or had a seropositive donor, and underwent weekly plasma CMV monitoring by PCR through day 100 post-transplant. Cox proportional hazards models were used to estimate the association of CMV-VL at different thresholds with overall by 1 year post-transplant, adjusting for the use of preemptive therapy and other factors such as neutropenia, and graft-versus-host disease. Secondary endpoints were non-relapse mortality and CMV end organ disease by 1 year post-transplant.FindingsAmong 926 patients, the cumulative overall mortality was 30·0% (95% CI 26·9–33·0) by 1 year. CMV-VL of ≥250 IU/ml was associated with increased risk of early (day 0–60 post-transplant) death (adjusted HR 18·1, 95% CI 8·8–37·4). The risk was attenuated after day 60 (adjusted HR 1·8, 95% CI 1·4–2·4). Similar associations were observed for higher CMV-VL thresholds. CMV-VL was also associated with increased risk of non-relapse mortality and demonstrated a dose-response relationship. The adjusted HR (95% CI) for CMV-VL of any positive CMV-VL below 500, 501–1000, and >1000 IU/ml were 1·4 (0·9–2·1), 2·6 (1·3–4·9), and 5·0 (3·1–8·1), respectively.InterpretationCMV viremia is associated with increased risk of overall and non-relapse mortality in the first year after HCT, independent of the use of preemptive therapy and with evidence of a postitive dose-response relationship. These data establish the suitability of viral load as a surrogate clinical endpoint for clinical trials for CMV vaccines, biologics, and drugs.FundingMerck & Co., Inc., National Institute of Health (K23-AI097234, K24HL093294, HL088021, CA78902, CA18029, HL122173)

The epidemiology of herpes zoster (HZ) in contemporary autologous hematopoietic cell transplant (HCT) recipients, and the impact of acyclovir/valacyclovir (ACV/VACV) prophylaxis, is not well described. In this observational study from 2002–2010, we retrospectively identified 1,000 varicella zoster virus (VZV) seropositive autologous HCT recipients with up to five years of follow up. The incidence of HZ and use of ACV/VACV prophylaxis were determined through review of medical records and mailed questionnaires. Risk factors for HZ were determined by multivariable Cox regression. Over a period of five years post-autologous HCT, 194 patients developed at least one HZ episode with a cumulative incidence of 21%; 159/194 (82%) were not on prophylaxis at the time of HZ. A second episode of HZ occurred in 31/194 (16%) patients. Patients taking ACV/VACV had reduced risk for HZ (adjusted hazard ratio [aHR], 0.59; 95% CI, 0.37–0.91), whereas those older than the median age (≥55.5 years) had increased risk (aHR 1.42, 95% CI 1.05–1.9). Disseminated VZV was reported in 8% and post-herpetic neuralgia in 13% of patients. We demonstrate a high burden of HZ late after autologous HCT, despite long-term antiviral prophylaxis. Improved prevention strategies are needed to provide sustained protection against HZ after autologous HCT.

Parainfluenza virus (PIV) infection can progress from upper respiratory tract infection (URTI) to lower respiratory tract disease (LRTD) in immunocompromised hosts. Risk factors for progression to LRTD and presentation with LRTD without prior URTI are poorly defined. Hematopoietic cell transplant (HCT) recipients with PIV infection were retrospectively analyzed using standardized definitions of LRTD. PIV was detected in 540 HCT recipients; 343 had URTI alone and 197 (36%) had LRTD (possible, 76; probable, 19; proven, 102). Among 476 patients with positive nasopharyngeal samples, the cumulative incidence of progression to probable/proven LRTD by day 40 was 12%, with a median time to progression of 7 days (range, 2 to 40). In multivariable analysis monocytopenia (hazard ratio, 2.22; P = .011), steroid use ≥1mg/kg prior to diagnosis (hazard ratio, 1.89; P = .018), co-pathogen detection in blood (hazard ratio, 3.21; P = .027), and PIV type 3 (hazard ratio, 3.57; P = .032) were associated with increased progression risk. In the absence of all 4 risk factors no patients progressed to LRTD, whereas progression risk increased to>30% if 3 or more risk factors were present. Viral load or ribavirin use appeared to have no effect on progression. Among 121 patients with probable/proven LRTD, 64 (53%) presented LRTD without prior URTI, and decreased lung function before infection and lower respiratory co-pathogens were risk factors for this presentation. Mortality was unaffected by the absence of prior URTI. We conclude that the risk of progression to probable/proven LRTD exceeded 30% with ≥3 risk factors. To detect all cases of LRTD, virologic testing of lower respiratory samples is required regardless of URTI symptoms.

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