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Clinical Infectious Diseases 01/2013; · 9.15 Impact Factor
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ABSTRACT: Respiratory virus infections cause significant morbidity and mortality in immunocompromised patients. Timely diagnosis is needed to provide optimal clinical care. Diagnostic tests routinely available at most institutions are limited by poor sensitivity and a slow turnaround time. We collected 90 respiratory samples from 87 immunocompromised patients (56 bronchoalveolar lavage and 34 nasopharyngeal aspirate samples) in order to compare the performance of routine respiratory virus testing available at our institution to the FilmArray respiratory panel assay, a novel diagnostic tool which utilizes multiplex PCR to test for 21 respiratory pathogens with a 1-h turnaround time. Samples with discordant results and 13 samples with concordant results underwent further verification testing by laboratory-developed real-time PCR. The FilmArray assay identified viral pathogens in more samples than did clinical testing (30/90 versus 16/90; McNemar P = 0.001). Most of the additional viral pathogens identified by the FilmArray respiratory panel assay that were confirmed by verification testing were pathogens not assessed by routine clinical tests, including rhinovirus/enterovirus, human metapneumovirus, and coronavirus. The FilmArray respiratory panel assay allowed for increased identification of respiratory viral pathogens in this cohort of immunocompromised patients.
Journal of clinical microbiology 07/2012; 50(10):3216-21. · 4.16 Impact Factor
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ABSTRACT: Lung transplant recipients are at high risk of invasive fungal disease (IFD), particularly invasive aspergillosis and candidiasis. The antifungal strategy that optimally balances effective reduction of IFD with a minimum of toxicity remains undefined; universal triazole prophylaxis is common at lung transplantation (LT) centers, despite the well-known toxicities and costs of this approach.
We implemented an antifungal strategy in March 2007 targeted at LT recipients at highest risk for IFD based on our institutional epidemiology. All patients received inhaled amphotericin B during their initial LT hospitalization, bilateral lung transplant recipients received 7 to 10 days of micafungin, and only patients with growth of yeast or mold in their day-of-transplant cultures received further oral antifungal therapy tailored to their fungal isolate.
IFD events were assessed in sequential cohorts composed of 82 lung transplant recipients before and 83 patients after the implementation of this targeted antifungal strategy. We observed a sharp decline in IFD; in the second cohort, 87%, 91%, and 96% of patients were free of IFD, invasive candidiasis, and invasive aspergillosis at 1 year. Only 19% of patients in the second cohort received systemic antifungal therapy beyond the initial LT hospitalization, and no patients experienced antifungal drug-related toxicity or IFD-associated mortality.
The targeted antifungal strategy studied seems to be a reasonable approach to reducing post-LT IFD events while limiting treatment-related toxicities and costs.
Transplantation 07/2012; 94(3):281-6. · 4.00 Impact Factor
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Joshua A Hill,
Sophia Koo,
Belisa B Guzman Suarez,
Vincent T Ho,
Corey Cutler,
John Koreth,
Philippe Armand,
Edwin P Alyea,
Lindsey R Baden,
Joseph H Antin,
Robert J Soiffer, Francisco M Marty
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ABSTRACT: Human herpesvirus-6 (HHV-6) frequently reactivates after allogeneic hematopoietic stem cell transplantation (HSCT); its most severe manifestation is the syndrome of posttransplantation acute limbic encephalitis (HHV-6-PALE). The epidemiology, risk factors, and characteristics of HHV-6-PALE after unrelated cord-blood transplantation (UCBT) are not well characterized. We analyzed 1344 patients undergoing allogeneic HSCT between March 2003 and March 2010 to identify risk factors and characteristics of HHV-6-PALE. The cohort included 1243 adult-donor HSCT and 101 UCBT recipients. All patients diagnosed with HHV-6-PALE had HHV-6 DNA in cerebrospinal fluid (CSF) specimens in addition to symptoms and studies indicating limbic encephalitis. Nineteen cases (1.4%) of HHV-6-PALE were identified during this study: 10 after UCBT (9.9%) and 9 after adult-donor HSCT (0.7%), for an incidence rate of 1.2 cases/1000 patient-days compared to 0.08 cases/1000 patient-days (P < .001), respectively. Risk factors for HHV-6-PALE on multivariable Cox modeling were UCBT (adjusted hazard ratio [aHR], 20.0; 95% confidence interval [CI], 7.3-55.0; P < .001), time-dependent acute graft-versus-host disease (aGVHD) grades II to IV (aHR, 7.5; 95% CI, 2.8-19.8; P < .001), and adult-mismatched donor (aHR, 4.3; 95% CI, 1.1-17.3; P = .04). Death from HHV-6-PALE occurred in 50% of affected patients undergoing UCBT and no recipients of adult-donor cells. Patients receiving UCBT have increased risk for HHV-6-PALE and greater morbidity from this disease.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 05/2012; 18(11):1638-48. · 3.15 Impact Factor
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ABSTRACT: Sirolimus is used in allogeneic hematopoietic stem cell transplants (HSCTs) for prevention and treatment of graft-versus-host disease (GVHD). Posaconazole is used in this population for invasive fungal disease (IFD) prophylaxis and treatment. As posaconazole strongly inhibits CYP3A4, concurrent administration of sirolimus, a CYP3A4 substrate, and posaconazole has been reported to increase sirolimus drug exposure substantially. Coadministration of posaconazole and sirolimus is contraindicated by the manufacturer of posaconazole. We identified 15 patients who underwent HSCTs at our institution receiving a steady-state dose of sirolimus who subsequently started posaconazole therapy from January 2006 to March 2009. We recorded baseline characteristics, drug administration details, and potential adverse effects related to either drug. All patients underwent HSCTs for treatment of hematologic malignancy. All patients were initially prescribed sirolimus for GVHD prophylaxis and continued therapy after developing GVHD. Twelve patients (80%) received posaconazole for IFD prophylaxis in the setting of GVHD and 3 (20%) for IFD treatment. Patients received sirolimus and posaconazole concurrently for a median of 78 days (interquartile range [IQR] 25-177; range, 6-503). The median daily dose of sirolimus (2 mg/day) before initiation of posaconazole was reduced 50% to a median daily dose of 1 mg/day at steady state. Six patients experienced sirolimus trough levels greater than 12 ng/mL during coadministration, but only 1 patient experienced an adverse event potentially associated with sirolimus exposure during the first month of coadministration. This patient's sirolimus dose was empirically reduced by only 30% on posaconazole initiation. Concurrent sirolimus and posaconazole use seems to be well tolerated with a 33% to 50% empiric sirolimus dose reduction and close monitoring of serum sirolimus trough levels at the time of posaconazole initiation.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 05/2012; 18(9):1462-5. · 3.15 Impact Factor
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ABSTRACT: We report progressive necrotizing fungal cellulitis and myositis in the leg of a patient with glioblastoma multiforme treated with temozolomide and corticosteroids. While the morphologic appearance of the isolate and its ability to grow at temperatures greater than 32°C were suggestive of Mycoleptodiscus indicus, some of the conidia were atypical for this species in that they had single septa and occasional lateral appendages. Furthermore, the isolate was different from M. indicus based on the sequencing analysis of two rDNA regions. This is the first case of Mycoleptodiscus invasive fungal disease in which the causative agent could not be resolved at the species level because of inconsistencies between morphological and molecular data.
Medical mycology: official publication of the International Society for Human and Animal Mycology 02/2012; 50(7):740-5. · 2.13 Impact Factor
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ABSTRACT: We assessed the performance of galactomannan and (1→3)-β-d-glucan in 29 serum samples from patients with multiple myeloma and Waldenstrom's macroglobulinemia without invasive fungal disease to address issues of false positivity and uninterpretable results previously reported among patients with these conditions. Galactomannan and (1→3)-β-d-glucan assays were not falsely elevated in any patient. (1→3)-β-d-glucan assay results were uninterpretable in 24% of patients. Patients with IgG levels of >2,000 mg/dl had higher odds of uninterpretable (1→3)-β-d-glucan results.
Journal of clinical microbiology 12/2011; 50(3):1054-6. · 4.16 Impact Factor
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ABSTRACT: We summarize the history of the clinical drug development of maribavir for its use as prophylaxis in stem-cell transplant recipients. We highlight key aspects in the design and interpretation of the results of the dose escalation phase II maribavir study that may have contributed to the negative findings on the phase III trials. We discuss key aspects of study design that should be considered in the study of new interventions needed to advance the prevention and treatment of CMV in transplant recipients.
Current opinion in virology. 12/2011; 1(6):555-62.
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ABSTRACT: The oral cavity is among the sites in the body most susceptible to infections. In the immunocompetent population these are most frequently localized odontogenic infections caused by bacteria. In severely immunocompromised patients, such as those undergoing allogeneic stem cell transplantation, fungal and viral infections become especially prominent. Infections in this population can present in an unusual fashion, can spread rapidly to other organs in the body, and are more frequently resistant to therapies. This article discusses the current knowledge of the most frequent presentations of infections in this patient population and reviews contemporary approaches to prevention, diagnosis, and management.
Oral and maxillofacial surgery clinics of North America 11/2011; 23(4):579-99, vii.
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ABSTRACT: Parainfluenza virus (PIV) can cause significant morbidity after allogeneic stem cell transplantation (SCT). We report the first use of inhaled DAS181 for PIV in an allogeneic SCT recipient. Symptoms, oxygenation, and pulmonary function tests improved. Nasopharyngeal samples showed a reduction in viral load. DAS181 should be systematically evaluated for severe PIV infection.
Clinical Infectious Diseases 10/2011; 53(7):e77-80. · 9.15 Impact Factor
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Alex F Herrera,
Gabriela Soriano,
Andrew M Bellizzi,
Jason L Hornick,
Vincent T Ho,
Karen K Ballen,
Lindsey R Baden,
Corey S Cutler,
Joseph H Antin,
Robert J Soiffer, Francisco M Marty
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ABSTRACT: Diarrhea is a frequent complication of hematopoietic stem-cell transplantation (HSCT). Important causes of diarrhea after HSCT include acute graft-versus-host disease (GVHD), infections, and medications. After the transplantation and engraftment of hematopoietic stem cells from umbilical-cord blood, we observed a new syndrome of culture-negative, antibiotic-responsive diarrhea not attributable to any known cause.
We conducted a retrospective cohort study of all patients undergoing cord-blood HSCT at our center between March 2003 and March 2010. The cord colitis syndrome was defined as a persistent diarrheal illness in such patients that was not due to acute GVHD, viral or bacterial infection, or another identifiable cause. Clinical and histopathological features of patients meeting the case definition were further analyzed.
Among 104 patients who underwent cord-blood HSCT at our center, the cord colitis syndrome developed in 11 (10.6%). The 1-year Kaplan-Meier cumulative probability of meeting the case definition for the syndrome was 0.16. The median time to onset after transplantation was 131 days (range, 88 to 314). All patients had a response to a 10-to-14-day course of empirical therapy with metronidazole, alone or in combination with a fluoroquinolone. Five of the 11 patients (45%) had recurrent diarrhea shortly after discontinuation of antibiotics, and all patients who had a relapse had a response to reinitiation of antibiotic therapy. On histologic examination, all patients with the cord colitis syndrome had chronic active colitis, with granulomatous inflammation present in 7 of 11 patients (64%).
The cord colitis syndrome is clinically and histopathologically distinct from acute GVHD and other causes of diarrhea in patients who have undergone cord-blood HSCT and is relatively common in this patient population. The syndrome should be considered in such patients who have diarrhea that is not attributable to other causes.
New England Journal of Medicine 09/2011; 365(9):815-24. · 53.30 Impact Factor
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ABSTRACT: Mortality due to mucormycosis is high. We assessed clinical characteristics and mortality among stem cell transplant and hematologic malignancy patients diagnosed with mucormycosis from 2001 to 2009. Thirty patients were diagnosed with probable or proven mucormycosis during the study. Twenty-six were diagnosed premortem, and most were treated with liposomal amphotericin B single-agent antifungal therapy initially. While the initial antifungal and surgical treatment approach remained stable throughout the study period, 6-week mortality significantly declined over time (67% in 2001 to 2003 versus 45% in 2004 to 2006 versus 20% in 2007 to 2009 [P = 0.04]), as did 12-week mortality (78% in 2001 to 2003 versus 55% in 2004 to 2006 versus 20% in 2007 to 2009 [P = 0.01]).
Antimicrobial Agents and Chemotherapy 08/2011; 55(11):5018-21. · 4.84 Impact Factor
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Transplantation 06/2011; 91(12):e80-1. · 4.00 Impact Factor
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ABSTRACT: Mucormycosis is difficult to diagnose. Samples from suspected cases often fail to grow Mucorales in microbiologic cultures. We identified all hematologic malignancy and stem cell transplant patients diagnosed with proven mucormycosis between 2001 and 2009 at Brigham and Women's Hospital/Dana-Farber Cancer Institute. Seminested PCR targeting Mucorales 18S ribosomal DNA and sequencing were performed on formalin-fixed paraffin-embedded tissue samples. Of 29 cases of mucormycosis, 27 had tissue samples available for PCR and sequencing. Mucorales PCR was positive in 22. Among 12 culture-positive cases, 10 were PCR positive and sequencing was concordant with culture results to the genus level in 9. Among 15 culture-negative cases, PCR was positive and sequencing allowed genus identification in 12. Mucorales PCR is useful for confirmation of the diagnosis of mucormycosis and for further characterization of the infection in cases where cultures are negative.
Journal of clinical microbiology 06/2011; 49(6):2151-3. · 4.16 Impact Factor
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JAIDS Journal of Acquired Immune Deficiency Syndromes 04/2011; 56(4):e111-3. · 4.43 Impact Factor
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Francisco M Marty,
Per Ljungman,
Genovefa A Papanicolaou,
Drew J Winston,
Roy F Chemaly,
Lynne Strasfeld,
Jo-Anne H Young,
Tulio Rodriguez,
Johan Maertens,
Michael Schmitt,
Hermann Einsele,
Augustin Ferrant,
Jeffrey H Lipton,
Stephen A Villano,
Hongzi Chen,
Michael Boeckh
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ABSTRACT: Available drugs against cytomegalovirus have adverse effects that compromise their prophylactic use in recipients of allogeneic stem-cell transplants. We assessed the safety, tolerability, and antiviral activity of oral maribavir in such patients.
In this placebo-controlled, randomised, double-blind, multicentre phase 3 study, we enrolled adult patients recipient-seropositive or donor-seropositive for cytomegalovirus who had undergone allogeneic stem-cell transplantation. Patients were recruited from 90 centres in Canada, Europe, and the USA. After engraftment, patients were stratified by recipient cytomegalovirus serostatus and conditioning regimen (myeloablative or reduced-intensity) and assigned (2:1) by masked computer-generated randomisation sequence to receive maribavir 100 mg twice daily or placebo for up to 12 weeks, with weekly blood cytomegalovirus surveillance. If the virus was detected, administration of study drug was stopped and pre-emptive anticytomegalovirus treatment started. The primary endpoint was cytomegalovirus disease within 6 months of transplantation. Analysis was by intention-to-treat. This study is registered with ClinicalTrials.gov, NCT00411645.
Between December, 2006, and May, 2008, 681 patients were enrolled and assigned to receive maribavir (454) or placebo (227). The incidence of cytomegalovirus disease within 6 months was 20 of 454 (4%) for the maribavir group and 11 of 227 (5%) for the placebo group (OR 0.90; 95% CI 0.42-1.92). During the 100 days following transplantation, cytomegalovirus infection rates as measured by pp65 antigenaemia were lower in the maribavir group (26.4%) than in the placebo group (34.8%; OR 0.67; 0.47-0.95), but not when measured by plasma cytomegalovirus DNA PCR (27.8%vs 30.4%; OR 0·88; 0.62-1.25), nor by initiation of treatment against cytomegalovirus (30.6%vs 37.4%; OR 0.73, 0.52-1.03). Maribavir was well tolerated: most adverse events, including incident acute graft-versus-host disease and neutropenia, affected both groups equally, except for taste disturbance (15% maribavir, 6% placebo).
Compared with placebo, maribavir prophylaxis did not prevent cytomegalovirus disease when started after engraftment. Cytomegalovirus disease as a primary endpoint might not be sufficient to show improvements in cytomegalovirus prevention in recipients of allogeneic stem-cell transplants in the setting of pre-emptive antiviral treatment. Clinical and virological composite endpoints should be used in future trials.
ViroPharma Incorporated.
The Lancet Infectious Diseases 03/2011; 11(4):284-92. · 17.39 Impact Factor
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ABSTRACT: The armamentarium of biologic therapies targeting specific elements of the immune system is rapidly expanding. This review describes the spectrum of infectious complications associated to date with each of the immunomodulating biologic therapies approved by the US Food and Drug Administration.
Hematology/oncology clinics of North America 02/2011; 25(1):117-38. · 2.05 Impact Factor
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ABSTRACT: We describe 3 cases of invasive fungal disease in the setting of transplantation-associated immunosuppression, developing months to years after clinically resolved penetrating soft-tissue injuries with wood fragments. Invasive fungal disease resulting from remote inoculation is a distinct syndrome in immunocompromised patients presenting with soft-tissue abnormalities in areas of prior trauma.
Clinical Infectious Diseases 01/2011; 52(1):e7-10. · 9.15 Impact Factor
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ABSTRACT: Gordonia species are aerobic actinomycetes recently recognized as causing human disease, often in the setting of intravascular catheter-related infections. We describe a case of Gordonia bronchialis bacteremia and pleural space infection in the absence of an indwelling intravascular catheter and review the breadth of reported infections with this emerging pathogen.
Journal of clinical microbiology 01/2011; 49(4):1662-6. · 4.16 Impact Factor
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Nicolas C Issa, Francisco M Marty,
Lisa S Gagne,
Sophia Koo,
Kelly A Verrill,
Edwin P Alyea,
Corey S Cutler,
John Koreth,
Philippe Armand,
Vincent T Ho,
Joseph H Antin,
Robert J Soiffer,
Lindsey R Baden
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ABSTRACT: Little data are available regarding the safety and immunologic response to pandemic H1N1 influenza vaccine in recipients of allogeneic hematopoietic stem cell transplantation (HSCT). We measured serum antibody titers against A/California/7/2009 H1N1 using a hemagglutination inhibition assay in 82 allogeneic HSCT recipients who received the 2009 H1N1 vaccine between November 2009 and January 2010 after it became available at our institution. The median time between HSCT and vaccination was 19 months (range, 2.5-94 months), and the median time from vaccination to specimen collection was 56 days (range, 14-140 days). Seroprotective antibody titers (hemagglutination inhibition titer ≥1:40) against 2009 H1N1 influenza A virus were detected in 51% of patients. The presence of chronic graft-versus-host disease and type of conditioning regimen did not affect the rate of detection of seroprotective titers after vaccination. Patients were more likely to have a seroprotective titer the farther away from HSCT they were (adjusted odds ratio, 1.79 per year; 95% confidence interval, 1.12-2.85). Rituximab administration in the year before vaccination was associated with a lack of seroprotective titer (adjusted odds ratio, 0.11; 95% confidence interval, 0.01-0.97). The vaccine was safe and well tolerated. Strategies are needed to improve the influenza vaccine response in this population, especially those receiving immunotherapy.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 10/2010; 17(3):434-8. · 3.15 Impact Factor
