Dimpy P. Shah

Management of Respiratory Viral Infections in Hematopoietic Cell Transplant Recipients and Patients With Hematologic Malignancies

Despite preventive strategies and increased awareness, a high incidence of respiratory viral infections still occur in patients with hematologic malignancies (HMs) and in recipients of hematopoietic cell transplant (HCT). Progression of these viral infections to lower respiratory tract may prove fatal, especially in HCT recipients. Increasing evidence on the successful use of ribavirin (alone or in combination with immunomodulators) for the treatment of respiratory syncytial virus infections in HM patients and HCT recipients is available from retrospective studies; however, prospective clinical trials are necessary to establish its efficacy with confidence. The impact on progression to pneumonitis and/or mortality of treating parainfluenza virus infections with available (ribavirin) or investigational (DAS181) antiviral agents still needs to be determined. Influenza infections have been successfully treated with neuraminidase inhibitors (oseltamivir or zanamivir); however, the efficacy of these agents for influenza pneumonia has not been established, and immunocompromised patients are highly susceptible to emergence of antiviral drug resistance, most probably due to prolonged viral shedding. Infection control measures and an appreciation of the complications following respiratory viral infections in immunocompromised patients remain crucial for reducing transmission. Future studies should focus on strategies to identify patients at high risk for increased morbidity and mortality from these infections and to determine the efficacy of novel or available antiviral drugs.

Immunodeficiency scoring index to predict poor outcomes in hematopoietic cell transplant recipients with RSV infections

We developed an immunodeficiency scoring index for respiratory syncytial virus (ISI-RSV) infection, based on a cohort of 237 allogeneic hematopoietic cell transplant (allo-HCT) recipients, that can predict the risk of progression to lower respiratory tract infection (LRTI) and RSV-associated mortality. A weighted index was calculated using adjusted hazard ratios for immunodeficiency markers. Based on the ISI-RSV (range, 0-12), patients were stratified into low (0-2), moderate (3-6), and high (7-12) risk groups. A significant trend of increasing incidence of LRTI and RSV-associated mortality was observed as the risk increased from low to moderate to high (P < .001). Patients in the high-risk group had the greatest benefit of ribavirin-based therapy at the upper respiratory tract infection stage and the highest risk for progression to LRTI and death when antiviral therapy was not given (6.5 [95% confidence interval (CI), 1.8-23.6] and 8.1 [95% CI, 1.1-57.6], respectively). The ISI-RSV is designed to stratify allo-HCT recipients with RSV infection into groups according to their risk for progression to LRTI and RSV-associated mortality. Identification of high-risk groups using this index would distinguish patients who would benefit the most from antiviral therapy, mainly with aerosolized ribavirin. The ISI-RSV should be validated in a multi-institutional study.

An Adaptive Randomized Trial of an Intermittent Dosing Schedule of Aerosolized Ribavirin in Patients With Cancer and Respiratory Syncytial Virus Infection

A continuous dosing schedule of aerosolized ribavirin has been used for respiratory syncytial virus (RSV) upper respiratory tract infection and lower respiratory tract infection (LRTI) but is associated with high cost and inconvenient administration. We conducted an adaptive randomized trial to evaluate the effectiveness of an intermittent dosing schedule of ribavirin versus that of a continuous dosing schedule of ribavirin in preventing RSV LRTIs in 50 hematopoietic stem cell transplant recipients or patients with hematologic malignancies. LRTI occurred in 3 patients (9%) receiving the intermittent schedule and in 4 (22%) receiving the continuous schedule, with a 0.889 posterior probability. Because the intermittent schedule is easy to administer and has a higher efficacy than the continuous schedule, we recommend the intermittent schedule for patients who are at risk for RSV LRTI. Clinical Trials Registration. NCT00500578.

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.

Immune response to hepatitis B vaccination in drug using populations: A systematic review and meta-regression analysis

Injecting and non-injecting drug users are at increased risk of contracting HBV infection, and show lower antibody response to hepatitis B vaccination compared to the general population. This systematic review and meta-regression analysis aimed to estimate seroprotection rates and identify host or vaccine factors associated with varying immune response following hepatitis B vaccination in drug using populations. Original research articles were searched using online databases (Medline, PubMed, and Embase) and from reference lists of eligible articles. HBV vaccine intervention studies reporting seroprotection rates in drug users, published in English during or after 1989 were eligible. Of 978 citations reviewed, 11 studies were eligible and included for final analysis. The reported seroprotection rates ranged from 54.5% to 97.1%. The studies were significantly heterogeneous (Q=180.850, p=0.000). Measurement of anti-HBs antibody at 2 months after the third vaccine dose (RR=2.62, 95%CI=1.16-5.94, p=0.026) was significantly associated with higher seroprotection rates compared to measurement at 1 month and 6 month following third vaccine dose. Age, gender, current drug use, vaccine dose and schedule, anti-HBc, anti-HCV and anti-HIV antibody seropositivity, and proportion of IDU study population did not show a significant association with seroprotection rates. Recommendations for future research include the definition of a standardized time point for the measurement of anti-HBs antibody levels, to enhance comparability of the immune response between different studies. Studies should strive to accurately report all potentially relevant factors affecting immune response to vaccine. Long-term follow up studies are needed to assess the seroprotection status in drug using populations receiving hepatitis B vaccine by standard or accelerated schedules.

Fecal colonization and infection with Pseudomonas aeruginosa in recipients of allogeneic hematopoietic stem cell transplantation.

Pseudomonas aeruginosa, especially multidrug‐resistant (MDR) isolates, is an important pathogen in allogeneic hematopoietic stem cell transplant (HCT) recipients. The ability to identify patients at risk for these infections and administer appropriate empiric therapy, particularly during episodes of neutropenia, may improve outcomes and also direct infection control and antimicrobial stewardship efforts. Many transplant centers obtain routine surveillance stool cultures (SSCs) from HCT recipients to test for colonization with vancomycin‐resistant enterococci, and extended‐spectrum beta lactamase‐producing Enterobacteriaceae. Our center initiated the performance of SSCs for P. aeruginosa, because of a perceived increase in the frequency of infection with MDR strains. The aim of this study was to determine the utility of this practice.

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.

Vaccination guidelines after hematopoietic stem cell transplantation: practitioners' knowledge, attitudes, and gap between guidelines and clinical practice

Hematopoietic stem cell transplant (HCT) recipients are more susceptible to infections from vaccine‐preventable diseases than the general population. Despite the development of international consensus guidelines addressing immunization after HCT, studies have shown that deviations from recommended immunization practices commonly occur.

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.

Outcomes of Influenza Infections in Hematopoietic Cell Transplant Recipients: Application of an Immunodeficiency Scoring Index

Hematopoietic cell transplant (HCT) recipients have lower immune response to influenza vaccination and are susceptible to lower respiratory tract infection (LRI) and death. We determined clinical characteristics and outcomes of laboratory-confirmed influenza, including 2014/H3N2 infection, in 146 HCT recipients. An immunodeficiency scoring index (ISI) was applied to identify patients at high risk for LRI and death. Thirty-three patients (23%) developed LRI and 7 (5%) died within 30 days of diagnosis. Most patients received antiviral therapy (83%); however, only 18% received it within 48 hours of symptom onset. The incidence of LRI was significantly higher in the ISI high-risk group than it was in the low-risk group (P < .001). Receiving early antiviral therapy was associated with a substantial reduction in LRI for all ISI risk groups with the greatest risk reduction observed in the high-risk group. When compared with previous seasons, no significant differences in patient outcomes were observed during the 2014/H3N2 season; however, antiviral therapy was more promptly initiated in the latter season. The ISI that was originally developed for respiratory syncytial virus may help identify HCT recipients at risk for progression to LRI and mortality after influenza infection. These patients should be monitored more closely. Early initiation of antiviral therapy for influenza in HCT recipients, regardless of the ISI risk group, may improve morbidity as well as mortality.