Steven A. Pergam

Reduced mortality after allogeneic hematopoietic cell transplantation

BACKGROUND Over the past decade, advances have been made in the care of patients undergoing transplantation. We conducted a study to determine whether these advances have improved the outcomes of transplantation. METHODS We analyzed overall mortality, mortality not preceded by relapse, recurrent malignant conditions, and the frequency and severity of major complications of transplantation, including graft-versus-host disease (GVHD) and hepatic, renal, pulmonary, and infectious complications, among 1418 patients who received their first allogeneic transplants at our center in Seattle in the period from 1993 through 1997 and among 1148 patients who received their first allogeneic transplants in the period from 2003 through 2007. Components of the Pretransplant Assessment of Mortality (PAM) score were used in regression models to adjust for the severity of illness at the time of transplantation. RESULTS In the 2003-2007 period, as compared with the 1993-1997 period, we observed significant decreases in mortality not preceded by relapse, both at day 200 (by 60%) and overall (by 52%), the rate of relapse or progression of a malignant condition (by 21%), and overall mortality (by 41%), after adjustment for components of the PAM score. The results were similar when the analyses were limited to patients who received myeloablative conditioning therapy. We also found significant decreases in the risk of severe GVHD; disease caused by viral, bacterial, and fungal infections; and damage to the liver, kidneys, and lungs. CONCLUSIONS We found a substantial reduction in the hazard of death related to allogeneic hematopoietic-cell transplantation, as well as increased long-term survival, over the past decade. Improved outcomes appear to be related to reductions in organ damage, infection, and severe acute GVHD. (Funded by the National Institutes of Health.).

West Nile virus neuroinvasive disease

Since 1999, there have been nearly 20,000 cases of confirmed symptomatic West Nile virus (WNV) infection in the United States, and it is likely that more than 1 million people have been infected by the virus. WNV is now the most common cause of epidemic viral encephalitis in the United States, and it will likely remain an important cause of neurological disease for the foreseeable future. Clinical syndromes produced by WNV infection include asymptomatic infection, West Nile Fever, and West Nile neuroinvasive disease (WNND). WNND includes syndromes of meningitis, encephalitis, and acute flaccid paralysis/poliomyelitis. The clinical, laboratory, and diagnostic features of these syndromes are reviewed here. Many patients with WNND have normal neuroimaging studies, but abnormalities may be present in areas including the basal ganglia, thalamus, cerebellum, and brainstem. Cerebrospinal fluid invariably shows a pleocytosis, with a predominance of neutrophils in up to half the patients. Diagnosis of WNND depends predominantly on demonstration of WNV‐specific IgM antibodies in cerebrospinal fluid. Recent studies suggest that some WNV‐infected patients have persistent WNV IgM serum and/or cerebrospinal fluid antibody responses, and this may require revision of current serodiagnostic criteria. Although there is no proven therapy for WNND, several vaccines and antiviral therapy with antibodies, antisense oligonucleotides, and interferon preparations are currently undergoing human clinical trials. Recovery from neurological sequelae of WNV infection including cognitive deficits and weakness may be prolonged and incomplete. Ann Neurol 2006;60:286–300

Safety and Efficacy of CMX001 as Salvage Therapy for Severe Adenovirus Infections in Immunocompromised Patients

No therapeutic agent has yet been established as the definitive therapy for adenovirus infections. We describe the clinical experience of 13 immunocompromised patients who received CMX001 (hexadecyloxypropyl cidofovir), an orally bioavailable lipid conjugate of cidofovir, for adenovirus disease. We retrospectively analyzed 13 patients with adenovirus disease and viremia treated with CMX001; data were available for ≥ 4 weeks after initiation of CMX001 therapy. Virologic response (VR) was defined as a 99% drop from baseline or undetectable adenovirus DNA in serum. The median age of the group was 6 years (range, 0.92-66 years). One patient had severe combined immunodeficiency, 1 patient was a small bowel transplant recipient, and 11 were allogeneic stem cell transplant recipients. Adenovirus disease was diagnosed at a median of 75 days (range, 15-720 days) after transplantation. All patients received i.v. cidofovir for a median of 21 days (range, 5-90 days) before CMX001 therapy. The median absolute lymphocyte count at CMX001 initiation was 300 cells/μL (range, 7-1500 cells/μL). Eight patients (61.5%) had a ≥ 1 log10 drop in viral load after the first week of therapy. By week 8, 9 patients (69.2%) demonstrated a VR, with a median time to achieve VR of 7 days (range, 3-35 days). The change in absolute lymphocyte count was inversely correlated with the change in log10 viral load only at week 6 (r = -0.74; P = .03). Patients with VR had longer survival than those without VR (median 196 days versus 54.5 days; P = .04). No serious adverse events were attributed to CMX001 during therapy. CMX001 may be a promising therapeutic option for the treatment of severe adenovirus disease in immunocompromised patients.

Pregnancy Complications Associated with Hepatitis C: Data from a 2003–2005 Washington State Birth Cohort

OBJECTIVE The objective of the study was to determine the effect of hepatitis C virus (HCV) on selected maternal and infant birth outcomes. STUDY DESIGN This population-based cohort study using Washington state birth records from 2003 to 2005 compared a cohort of pregnant women identified as HCV positive from birth certificate data (n = 506) to randomly selected HCV-negative mothers (n = 2022) and drug-using HCV-negative mothers (n = 1439). RESULTS Infants of HCV-positive mothers were more likely to be low birthweight (odds ratio [OR], 2.17; 95% confidence interval [CI] 1.24, 3.80), to be small for gestational age (OR, 1.46; 95% CI, 1.00, 2.13), to need assisted ventilation (OR, 2.37; 95% CI, 1.46, 3.85), and to require neonatal intensive car unit (NICU) admission (OR, 2.91; 95% CI, 1.86, 4.55). HCV-positive mothers with excess weight gain also had a greater risk of gestational diabetes (OR, 2.51; 95% CI, 1.04, 6.03). Compared with the drug-using cohort, NICU admission and the need for assisted ventilation remained associated with HCV. CONCLUSION HCV-positive pregnant women appear to be at risk for adverse neonatal and maternal outcomes.

Intensive strategy to prevent CMV disease in seropositive umbilical cord blood transplant recipients.

Seropositive umbilical cord blood transplant (UCBT) recipients are at increased risk for CMV complications. To reduce CMV complications, we adopted an intensive strategy that consisted of ganciclovir administered before transplantation (5 mg/kg intravenously daily from day -8 to day -2), high-dose acyclovir (2 g, 3 times daily) after transplantation, and biweekly monitoring with a serum CMV PCR for preemptive therapy. Hazard rates and cumulative incidence of CMV complications along with days treated were compared in high-risk CMV-seropositive UCBT recipients who received the intensive strategy and a historical cohort who received a standard strategy. Of 72 seropositive patients, 29 (40%) received standard prophylaxis and 43 (60%) the new intensive approach. The hazard rate (HR) for CMV reactivation was lower for patients receiving the intensive strategy (HR 0.27, 95% confidence interval 0.15-0.48; P < .001) and led to fewer cases of CMV disease by 1 year (HR 0.11, 95% confidence interval 0.02-0.53; P = .006). In patients who reactivated, the intensive strategy also led to fewer days on CMV-specific antiviral therapy (median 42% [interquartile range 21-63] vs 70% [interquartile range 54-83], P < .001). Use of an intensive CMV prevention strategy in high-risk CMVseropositive UCBT recipients results in a significant decrease in CMV reactivation and disease.

The Serum Galactomannan Index Predicts Mortality in Hematopoietic Stem Cell Transplant Recipients With Invasive Aspergillosis

We examined the relationship between serum and bronchoalveolar lavage (BAL) galactomannan index (GMI) values and mortality in allogeneic hematopoietic cell transplant recipients with invasive pulmonary aspergillosis. Using a clinical sign and symptom-initiated approach, we found that the serum but not the BAL GMI level correlated with 42- and 180-day patient mortality.

Varicella Zoster Virus (VZV) in Solid Organ Transplant Recipients

-herpesvirus family. VZV is presentworldwide and is highly infectious. Primary infection leadsto acute varicella or ‘chickenpox,’ usually from exposureeither through direct contact with a skin lesion or throughairborne spread from respiratory droplets (1,2). After initialinfection, VZV establishes lifelong latency in cranial nerveanddorsalrootganglia,andcanreactivateyearstodecadeslater as herpes zoster (HZ) or ‘shingles’ (3). More than90% of adults in the United States acquired the disease inchildhood, while the majority of children and young adultshave been vaccinated with the live virus vaccine (2,4).Primary varicella typically presents with fever, constitu-tional symptoms and a vesicular, pruritic, widely dissem-inated rash that primarily involves the trunk and face (5).Thesymptomsusuallyresolvewithin7–10days,butinrarecases primary varicella leads to more severe disease andvisceral invasion. Complications, such as hepatitis, pancre-atitis, pneumonitis and encephalitis are infrequent but canbelife-threatening;adultsandveryyoungchildrenaremorelikely to develop such complications from primary infection(6,7). Rates of hospitalization and mortality due to varicellahave dropped with the institution of routine childhood vari-cella vaccination (8,9).Nearly all patients with HZ develop an exanthem of vesic-ular lesions in a dermatomal distribution. The annual inci-dence of HZ in the general population is 1.5–3.0 cases per1000 persons (2), and is estimated to occur in up to 20%of individuals during their lifetime (10). Secondary compli-cations such as bacterial superinfection and postherpeticneuralgia (PHN), or chronic neuropathic pain at the site ofHZ, lead to increased morbidity (11).Over 90% of adult solid organ transplant (SOT) recipientswill be seropositive for VZV. Rates are lower in pediatrictransplants(12,13),butimmunitywillincreaseasuptakeofvaricella vaccine improves. Varicella is rare in adult SOT re-cipients,butcanbedevastating,withvisceralinvolvement,severe skin disease, and disseminated intravascular coag-ulation (14–19). HZ is a frequent infectious complication inSOT recipients with an incidence of approximately 8–11%during the first 4 years posttransplant (20–22). Invasive dis-ease and dissemination similar to that seen in primary VZVinfection are uncommon but have been reported in SOTand other immunocompromised populations, and level ofimmunosuppression may alter the risk of developing thesecomplications (17,23,24). Rates of PHN in SOT recipi-ents may also be higher than in immunocompetent popu-lations (22).

Safety and Immunogenicity of Heat-Treated Zoster Vaccine (ZVHT) in Immunocompromised Adults

BACKGROUND Safety and immunogenicity of heat-treated zoster vaccine (ZVHT) were assessed in immunocompromised adults. METHODS In a randomized, double-blind, placebo-controlled, multicenter study, 4 doses ZVHT or placebo were administered approximately 30 days apart to adults with either solid tumor malignancy (STM); hematologic malignancy (HM); human immunodeficiency virus (HIV) with CD4(+) ≤200; autologous hematopoietic stem-cell transplant (HCT) or allogeneic-HCT recipients. Varicella-zoster virus (VZV) T-cell responses by interferon-γ enzyme-linked immunospot (IFN-γ ELISPOT) and VZV antibody concentrations by glycoprotein enzyme-linked immunosorbent assay (gpELISA) were measured at baseline and approximately 28 days after each dose. RESULTS No safety signals were found in any group. IFN-γ ELISPOT geometric mean fold rises (GMFR) after dose 4 in STM, HM, HIV, and autologous-HCT patients were 3.00 (P < .0001), 2.23 (P = .004), 1.76 (P = .026), and 9.01 (P = NA), respectively. Similarly, antibody GMFR were 2.35 (P < .0001), 1.28 (P = .003), 1.37 (P = .017), and 0.90 (P = NA), respectively. T-cell and antibody responses were poor after 4 doses of ZVHT in allogeneic-HCT patients. CONCLUSION ZVHT was generally safe and immunogenic through 28 days post-dose 4 in adults with STM, HM, and HIV. Autologous-HCT but not allogeneic-HCT patients had a rise in T-cell response; antibody responses were not increased in either HCT population. Study identification. V212-002 Clinical Trials Registration. NCT00535236.

Herpes zoster incidence in a multicenter cohort of solid organ transplant recipients

S.A. Pergam, C.W. Forsberg, M.J. Boeckh, C. Maynard, A.P. Limaye, A. Wald, N.L. Smith, B.A. Young. Herpes zoster incidence in a multicenter cohort of solid organ transplant recipients.
Transpl Infect Dis 2011: 13: 15–23. All rights reserved

Early emergence of an H275Y mutation in a hematopoietic cell transplant recipient treated with intravenous peramivir

C. Renaud, S.A. Pergam, C. Polyak, R. Jain, J. Kuypers, J.A. Englund, L. Corey, M.J. Boeckh. Early emergence of an H275Y mutation in a hematopoietic cell transplant recipient treated with intravenous peramivir.
Transpl Infect Dis 2010: 12: 513–517. All rights reserved