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The circulating dsDNA viral microbiome in allogeneic hematopoietic stem cell transplant recipiets

Hill JA, Mayer BT, Xie H, et al. The cumulative burden of double-stranded DNA virus detection after allogeneic HCT is associated with increased mortality. Blood. 2017; 129:2316–2325.

Hill and colleagues accessed a repository of plasma samples that had been collected from 2007–2014 on a weekly basis from adults and children undergoing allogeneic hematopoietic stem cell transplantation (HCT) to quantify the amount of viral dsDNA in plasma by quantitative polymerase chain reaction (qPCR). The samples were obtained through day 100 and there was a mean of 13 samples per patient. As part of routine management, Herpes simplex virus (HSV) seropositive patients received acyclovir through day 100 and those who were Varicella zoster virus (VZV) seropositive received it through day 365. After June 2008, cytomegalovirus (CMV) seropositive cord blood recipients received ganciclovir pre-transplant and high dose valganciclovir after transplantation.

Of the total of 404 allogeneic HCT recipients, 125 involved cord blood, 125 were Human Leukocyte Antigen (HLA) mismatched, and 125 were HLA matched. CMV was detected at some point in 65% of patients, followed in frequency by BK Virus (BKV) (54%), Human heresvirus (HHV)-6B (46%), adenovirus (10%), and Epstein-Barr Virus (EBV) (10%). The median time to first viral detection was on day 20. The following were the median viral loads expressed as copies/ml: CMV—191, BKV—3090, HHV-6B—741, adenovirus—1023, and EBV—195. More than one virus was isolated from 90% of patients during the 100 day period, 62% had ≥2 viruses detected, 28% had >3, and 5% had 4 or 5. Two viruses were simultaneously detected at some point in 37% while 12% had 3 or 4 simultaneous detections. Having a cord blood or HLA mismatched HCT, myeloablative conditioning, and acute graft versus host disease were independent risk factors for detection of multiple viruses at some point.

The cumulative burden of viral exposure was determined by calculating the average area under the curve (AUC) (log₁₀ copies/ml) for each individual virus. There was a possible (P = .054) association of an absolute lymphocyte count <200 cells/mm³ and maximum viral AUC. After taking into account immune reconstitution and graft versus host disease, the optimal predictor of early (day 0–100) and late (day 101–365) mortality was the maximum cumulative viral load AUC value. Of note is that end-organ disease and death due to dsDNA viral infection, which occurred in 34 (8.4%) and 8 (2.0%) patients, respectively, was relatively uncommon,.

Infection with DNA viruses is an important cause of morbidity and mortality in HCT patients, with CMV being chief among these in terms of the combination of frequency and potential severity. The fact that the reactivation of these dsDNA viruses relatively infrequently led to end organ disease likely was in large part the result of prophylactic and preemptive therapeutic strategies. The finding that the cumulative viral load AUC was the strongest predictor of mortality despite this lack of any apparently direct adverse effect in all but a small proportion of patients is of interest and raises the possibility that indirect effects, such as an increased production of pro-inflammatory cytokines, plays a role. There remains, however, the “chicken-and-egg problem”—does increased reactivation of dsDNA viruses lead to increased mortality or is it just a reflection of loss of host control due to confounding factors that instead contribute to the death of the patient?

Another monogenic defect in innate immunity resulting in severe infection: IFIH1 and respiratory viruses

Asgari S, Schlapbach LJ, Anchisi S, et al. Severe viral respiratory infections in children with IFIH1 loss-of-function mutations. Proc Natl Acad Sci U S A. 2017;114:8342–8347.

Asgari and colleagues evaluated 120 children who had been previously healthy but who were admitted to intensive care because of respiratory failure caused by common viral respiratory tract infections. They identified, using both unbiased exome and transcriptome sequencing, loss-of-function (LOF) variants in the Interferon-induced helicase C domain-containing protein 1 (IFHI1) gene in 8 of the children, 4 of whom had a rare (0.64% allele frequency splicing variant, rs3573204 which was heterozygous in 3 and homozygous in one. This results in a frame shift and stop codon such that the encoded protein lacks the C-terminal regulatory domain necessary for binding viral dsRNA. Two additional LOF variants were detected in a total of 4 patients. All 8 children had bronchiolitis which was complicated by pneumonia in 2. Six were infected by respiratory syncytial virus and 2 by human rhinovirus.

IFHI1 is a cytoplasmic innate immunity receptor that senses viral RNA metabolites and dsDNA and leads to activation of a series of antiviral responses, such as the induction of proinflammatory cytokines and type I interferons. The investigators demonstrated that IFHI1 expression restricts replication of human respiratory syncytial virus and rhinoviruses in vitro. Evaluation of the IFHI1 variants demonstrated that the resultant proteins are less stable than the wild type protein and that the lack ATPase activity which is necessary for its function. Asgari and colleagues conclude that “IFHI1 deficiency causes a primary immunodeficiency manifested in extreme susceptibility to common respiratory RNA viruses.”

Of note is that the same LOF variants described here provide protection against the development of type 1 diabetes mellitus as well as some other autoimmune diseases.

Almost simultaneously with the publication discussed here, Lamborn and colleagues described a homozygous missense mutation in a child with recurrent viral respiratory tract infections [1]. This mutation resulted in decreased expression of MDA5, which is also an intracellular receptor for viral dsRNA. In 2015, a previously healthy child who developed a severe, life-threatening infection with H1N1 (pH1N1) 2009 influenza A virus was found to have compound null mutations in IRF7, a transcription factor important for the amplification type I and II interferons [2].

These findings contribute to the body of work that points to the fact that individuals (not only children) who develop unusual or unusually severe primary viral and other infections have a significant likelihood of having a monogenic defect in innate immunity [3]. Another in an increasingly long line supportive of this notion is a recent report that inborn errors in RNA polymerase III was associated with and caused severe disease, including pneumonia and encephalitis in 4 children with varicella zoster virus infection [4].

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