Leukopenia and lack of ribavirin predict poor outcomes in patients with haematological malignancies and respiratory syncytial virus infection.

Objectives: Respiratory syncytial virus (RSV) infection causes morbidity and mortality in cancer patients. However, studies describing this infection in patients with haematological malignancies are scarce. We sought to evaluate the clinical impact of RSV infection on this patient population. Methods: We reviewed the records of patients with haematological malignancies and RSV infections cared for at our institution between January 2000 and March 2013. Results: Of the 181 patients, 71 (39%) had AML, ALL or myelodysplastic syndrome, 12 (7%) had CML or CLL, 4 (2%) had Hodgkin lymphoma, 35 (19%) had non-Hodgkin lymphoma and 59 (33%) had multiple myeloma. Most patients [117 (65%)] presented with an upper respiratory tract infection (URTI) and 15 (13%) had a subsequent lower respiratory tract infection (LRTI). The overall LRTI rate was 44% and the 90 day mortality rate was 15%. Multivariable regression analysis showed that having both neutropenia and lymphocytopenia (adjusted OR = 7.17, 95% CI = 1.94-26.53, P < 0.01) and not receiving ribavirin-based therapy during RSV URTI (adjusted OR = 0.03; 95% CI = 0.01-0.11, P < 0.001) were independent risk factors for LRTI. Having both neutropenia and lymphocytopenia at RSV diagnosis was also a risk factor for death at 90 days after RSV diagnosis (adjusted OR = 4.32, 95% CI = 1.24-15.0, P = 0.021). Conclusions: Patients with haematological malignancies and RSV infections, especially those with immunodeficiency, may be at risk of LRTI and death; treatment with ribavirin during RSV URTI may prevent these outcomes.

Challenges in Determining Genotypes for Pharmacogenetics in Allogeneic Hematopoietic Cell Transplant Recipients.

As part of a pharmacogenetic study, paired blood and oral fluid samples were tested for the IL28B polymorphism (rs12979860) before and after hematopoietic cell transplantation (HCT) to evaluate changes in the genotype and investigate the utility of genotyping in oral fluid in HCT recipients. In 54 patients with leukemia >18 years of age, samples were collected approximately 7 days before HCT and 60 days after HCT. IL28B polymorphism testing was performed using real-time PCR with allele-specific probes. Twenty-four patients had the same genotype as their donors. In 30 patients, the genotype was different from that of the donor. In the oral fluid samples, 4 retained the recipient's genotype, and 18 had a genotype that matched that of the donor. In the remaining 8 patients, the results could not be characterized and appeared to be a combination of both, suggesting mixed proportions of donor and recipient cells. The assumption was that the sloughed epithelial cells of the mouth are of recipient origin. However, oral fluid is a mixture that contains varying numbers of cells of the recipient and immunomodulatory cells from the donor. Therefore, the use of oral fluid after HCT for clinical pharmacogenetics purposes needs further investigation.

Human metapneumovirus infections in hematopoietic cell transplant recipients and hematologic malignancy patients: A systematic review.

Over the past decade, reported incidence of human metapneumovirus (hMPV) has increased owing to the use of molecular assays for diagnosis of respiratory viral infections in cancer patients. The seasonality of these infections, differences in sampling strategies across institutions, and small sample size of published studies make it difficult to appreciate the true incidence and impact of hMPV infections. In this systematic review, we summarized the published data on hMPV infections in hematopoietic cell transplant recipients and patients with hematologic malignancy, focusing on incidence, hMPV-associated lower respiratory tract infection (LRTI), mortality, prevention, and management with ribavirin and/or intravenous immunoglobulins. Although the incidence of hMPV infections and hMPV-associated LRTI in this patient population is similar to respiratory syncytial virus or parainfluenza virus and despite lack of directed antiviral therapy, the mortality rate remains low unless patients develop LRTI. In the absence of vaccine to prevent hMPV, infection control measures are recommended to reduce its burden in cancer patients.

Utility of the Enzyme-Linked Immunospot Interferon-γ-Release Assay to Predict the Risk of Cytomegalovirus Infection in Hematopoietic Cell Transplant Recipients.

The ability to distinguish allogeneic hematopoietic cell transplant (allo-HCT) recipients at risk for cytomegalovirus (CMV) reactivation from those who are not is central for optimal CMV management strategies. Interferon γ (IFN-γ) produced by CMV-challenged T cells may serve as an immune marker differentiating these 2 populations. We prospectively monitored 63 CMV-seropositive allo-HCT recipients with a CMV-specific enzyme-linked immunospot (ELISPOT) assay and for CMV infection from the period before transplantation to day 100 after transplantation. Assay results above certain thresholds (50 spots per 250 000 cells for immediate early 1 or 100 spots per 250 000 cells for phosphoprotein 65) identified patients who were protected against CMV infection as long as they had no graft-versus-host disease and/or were not receiving systemic corticosteroids. Based on the multivariable Cox proportional hazards regression model, the only significant factor for preventing CMV reactivation was a CMV-specific ELISPOT response above the determined thresholds (adjusted hazard ratio, 0.21; 95% confidence interval, .05-.97; P = .046). Use of this assay as an additional tool for managing allo-HCT recipients at risk for CMV reactivation needs further validation in future studies. Application of this new approach may reduce the duration and intensity of CMV monitoring and the duration of prophylaxis or treatment with antiviral agents in those who have achieved CMV-specific immune reconstitution.

Parainfluenza virus infections in hematopoietic cell transplant recipients and hematologic malignancy patients: A systematic review.

Parainfluenza viral infections are increasingly recognized as common causes of morbidity and mortality in cancer patients, particularly in hematopoietic cell transplant (HCT) recipients and hematologic malignancy (HM) patients because of their immunocompromised status and susceptibility to lower respiratory tract infections. Advances in diagnostic methods, including polymerase chain reaction, have led to increased identification and awareness of these infections. Lack of consensus on clinically significant endpoints and the small number of patients affected in each cancer institution every year make it difficult to assess the efficacy of new or available antiviral drugs. In this systematic review, we summarized data from all published studies on parainfluenza virus infections in HM patients and HCT recipients, focusing on incidence, risk factors, long-term outcomes, mortality, prevention, and management with available or new investigational agents. Vaccines against these viruses are lacking; thus, infection control measures remain the mainstay for preventing nosocomial spread. A multi-institutional collaborative effort is recommended to standardize and validate clinical endpoints for PIV infections, which will be essential for determining efficacy of future vaccine and antiviral therapies.

Infection with novel respiratory syncytial virus genotype Ontario (ON1) in adult hematopoietic cell transplant recipients, Texas, 2011-2013.

BACKGROUND: Respiratory syncytial virus (RSV) can cause severe respiratory disease in adult hematopoietic cell transplant (HCT) recipients. RSV subgroups A and B have evolved into multiple genotypes. We report on a recently described RSV genotype (ON1) in a cohort of adult HCT recipients in Texas. METHODS: Twenty adult HCT recipients were enrolled as a part of an efficacy trial of ribavirin therapy. RSV identification and genotyping was performed using molecular techniques. RSV-specific neutralizing antibody (NAb) responses were measured. RESULTS: ON1 genotype was detected in 3 of 6 patients in the 2011-2012 season and in 8 of 14 patients in 2012-2013 season. Other genotypes detected were NA1 and BA. NAb levels were low at enrollment. Eight of 9 patients who cleared the RSV infection within 2 weeks mounted a ≥4-fold NAb response, compared with 2 of 8 who shed the virus for >2 weeks. The clinical course of those infected with ON1 was comparable to the course for individuals infected with other genotypes. CONCLUSION: This is the first report of RSV ON1 genotype in the United States, and ON1 genotype was dominant genotype in adult HCT recipients. Interestingly, faster viral clearance was associated with a ≥4-fold NAb response, likely indicating a reconstituted immune system.