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W Garrett Nichols

Publications and source records attributed to W Garrett Nichols.

At least 19 recordsLinked to original sources
PubMed2005

Fatal pulmonary infection associated with a novel organism, "para-streptomyces abscessus".

Actinomycetes are increasingly recognized as pathogenic in the immunocompromised host. We isolated an asporogenous, nonmotile, aerobic gram-positive rod from a transplant recipient with a fatal pulmonary infection. The pathology was similar to that associated with Rhodococcus equi, including intra-histiocytic localization. The organism was relatively inert in standard biochemical tests. 16S rRNA gene sequencing indicated a potentially unique organism most closely related to the genus Streptomyces, for which we propose the name "Para-streptomyces abscessus."

Actinomycetales Infections↗
PubMed2004

Influenza infections after hematopoietic stem cell transplantation: risk factors, mortality, and the effect of antiviral therapy.

BACKGROUND: Community-acquired respiratory viruses, such as influenza virus, are thought to be major causes of morbidity and mortality in patients who had undergone hematopoietic stem cell transplantation (HSCT). Risk factors for acquisition, progression to pneumonia, and the effect of antiviral therapy are unknown. METHODS: We reviewed records from patients with documented influenza over 12 consecutive respiratory-virus infection seasons at a single transplantation center. RESULTS: From 1 September 1989 through 31 March 2002, influenza virus was isolated from 62 of 4797 persons undergoing HSCT (1.3%); 44 patients had upper respiratory tract infections (URIs) alone, and 18 developed pneumonia. Among patients with influenza virus infection, pneumonia developed more commonly among those infected earlier after transplantation (median, 36 vs. 61 days, P=.04) and those with concurrent lymphopenia. Of the 51 cases that were initially diagnosed as URIs, 17 were treated with antivirals, and 34 were not treated. Six untreated patients (18%) developed pneumonia, whereas 1 (13%) of 8 patients treated with rimantadine and 0 of 9 treated with oseltamivir developed pneumonia. The duration of influenza virus shedding was longer in patients treated with steroid doses of >1 mg/kg than among those treated with doses of <1 mg/kg (mean, 15 vs. 9 days); there was a trend towards decreased shedding with oseltamivir therapy (but not rimantadine therapy) after controlling for steroid use (P<.08). The 30-day mortality rate was highest among patients who had progression to pneumonia (5 [28%] of 18 patients); pulmonary copathogens (such as Aspergillus fumigatus) were commonly isolated. CONCLUSIONS: Influenza virus infection is an important cause of mortality early after HSCT. Our nonrandomized data suggest that early antiviral therapy with neuraminidase inhibitors may prevent progression to pneumonia and decrease viral shedding, which may prevent both influenza-related death in index patients and nosocomial transmission to others.

Adolescent↗
PubMed2004

Prolonged outbreak of human parainfluenza virus 3 infection in a stem cell transplant outpatient department: insights from molecular epidemiologic analysis.

Human parainfluenza virus type 3 (hPIV3) infections cause considerable morbidity and mortality after stem cell transplantation, and inpatient nosocomial outbreaks are common. From September 1998 to July 1999, 93 stem cell transplantation recipients at our institution contracted hPIV3, of which 66 (71%) were being followed up in our outpatient department (OPD). The peak incidence was in September and October, when 39 cases were identified; thereafter, hPIV3 incidence decreased to approximately 5 cases per month. Nucleotide sequences (778 nucleotides from variable regions of the hemagglutinin-neuraminidase gene) from 46 patient and 8 community hPIV3 isolates were compared to determine epidemiologic relatedness. Sequence analysis of OPD isolates revealed that 18 of 19 isolates from September and October and 11 of 15 isolates from November 1998 to July 1999 were genetically similar. In contrast, 2 of 3 community isolates from September and October and 0 of 5 from November to July were linked to this cluster. Symptomatic surveillance and isolation were ineffective in terminating the outbreak, suggesting asymptomatic shedding among patients, staff, or visitors or viral persistence on environmental surfaces as possible explanations. The concept of nosocomial transmission should be expanded to include the OPD for immunosuppressed patients.

Cross Infection↗
PubMed2004

Recent advances in the prevention of CMV infection and disease after hematopoietic stem cell transplantation.

Cytomegalovirus (CMV) remains an important pathogen in hematopoietic stem cell transplant (HCT) recipients in the current era of antiviral prophylaxis and preemptive therapy, despite the almost complete elimination of CMV disease during the first 3 months after transplantation. Pretransplant CMV serostatus of the donor and/or recipient remains an important risk factor for poor post-transplant outcome, especially in highly immunodeficient patients (e.g. recipients of ex vivo or in vivo T-cell depletion). Prevention of late CMV disease continues to be a challenge in selected high-risk populations, and indirect immunomodulatory effects of CMV (e.g. invasive bacterial and fungal infections) appear to contribute to the poor outcome. The risk of developing antiviral resistance remains low in most patients; however, in a setting of intense immunosuppression (e.g. after transplantation from a haploidentical donor) the incidence may be as high as 8%. Transfusion-transmitted CMV infection can be reduced by the provision of seronegative or leukocyte-depleted blood products; however, a small risk of 1-2% of CMV disease remains. Surveillance and preemptive therapy is effective in preventing transfusion-related CMV disease. The development of new drugs and immunologic strategies (adoptive transfer of CMV-specific T-cells and donor/recipient vaccination strategies) are important goals for the elimination of the negative impact of CMV in the HCT setting.

Antiviral Agents↗
PubMed2004

Optimization of quantitative detection of cytomegalovirus DNA in plasma by real-time PCR.

Previous studies have shown that detection of cytomegalovirus (CMV) DNA in plasma is less sensitive than the antigenemia assay for CMV surveillance in blood. In 1,983 blood samples, plasma PCR assays with three different primer sets (UL125 alone, UL126 alone, and UL55/UL123-exon 4) were compared to the pp65 antigenemia assay and blood cultures. Plasma PCR detected CMV more frequently in blood specimens than either the antigenemia assay or cultures, but of the three PCR assays, the double-primer assay (UL55/UL123-exon 4) performed best with regard to sensitivity, specificity, and predictive values compared to antigenemia: 122 of 151 antigenemia-positive samples were detected (sensitivity, 80.1%), and there were 122 samples that were PCR positive-antigenemia negative (specificity, 93%). Samples with discrepant results had a low viral load (median, 0.5 cells per slide; 1,150 copies per ml) and were often obtained from patients receiving antiviral therapy. CMV could be detected by other methods in 15 of 29 antigenemia positive-PCR negative samples compared to 121 of 122 PCR positive-antigenemia negative samples (P < 0.001). On a per-subject basis, 21 of 25 patients (antigenemia positive-PCR negative) and all 57 (PCR positive-antigenemia negative) could be confirmed at different time points during follow-up. The higher sensitivity of the double-primer assay resulted in earlier detection compared to antigenemia in a time-to-event analysis of 42 CMV-seropositive stem cell transplant recipients, and two of three patients with CMV disease who were antigenemia negative were detected by plasma PCR prior to the onset of disease. Interassay variability was low, and the dynamic range was >5 log(10). Automated DNA extraction resulted in high reproducibility, accurate CMV quantitation (R = 0.87, P < 0.001), improved sensitivity, and increased speed of sample processing. Thus, primer optimization and improved DNA extraction techniques resulted in a plasma-based PCR assay that is significantly more sensitive than pp65 antigenemia and blood cultures for detection of CMV in blood specimens.

Antigens, Viral↗
PubMed2004

Supportive care.

To optimize treatment outcomes for hematologic malignancies, minimizing the consequences of treatment complications requires as much skill as the choice of the treatment itself. Myelosuppression and immunosuppression are frequent complications and have potentially serious infectious consequences. Invasive fungal infections and infections from respiratory viruses are increasing in frequency and have life-threatening potential. Damage to vital organs, especially the liver, is another important concern. In this chapter, the scope of invasive fungal and respiratory viral infections, recent insights into the pathogenesis of hepatic sinusoidal injury, and recent developments that impact prevention and treatment approaches for these complications are described. In Section I, Dr. John Wingard describes the advantages and disadvantages of various treatment options for invasive infections by the two chief fungal pathogens, Candida and Aspergillus. Adjunctive therapies and practical considerations that clinicians should weigh in choosing one or another of the various agents are discussed. The studies that have evaluated antifungal prophylaxis and empirical treatment strategies are reviewed. Finally, new approaches such as combination therapy, new diagnostics, and efforts to bolster host immunity are considered. In Section II, Dr. W. Garrett Nichols describes the epidemiology of community-acquired respiratory viruses (CRV) in patients with hematologic malignancies. Risk factors, clinical syndromes, and possible indirect effects of CRV infections are discussed. Treatment and prevention options are reviewed. In Section III, Dr. George McDonald describes sinusoidal obstruction syndrome (once known as hepatic veno-occlusive disease). Recent insights into pathogenesis are described. Diagnostic criteria and the advantages and disadvantages of various diagnostic methods are reviewed and prognosis is considered. Prevention and treatment options are discussed.

Aspergillosis↗
PubMed2003

The impact of cytomegalovirus serostatus of donor and recipient before hematopoietic stem cell transplantation in the era of antiviral prophylaxis and preemptive therapy.

In the current era of effective prophylactic and preemptive therapy, cytomegalovirus (CMV) is now a rare cause of early mortality after hematopoietic stem cell transplantation (HSCT). However, the ultimate goal of completely eliminating the impact of CMV on survival remains elusive. Although the direct effects of CMV (ie, CMV pneumonia) have been largely eliminated, several recent cohort studies show that CMV-seropositive transplant recipients and seronegative recipients of a positive graft appear to have a persistent mortality disadvantage when compared with seronegative recipients with a seronegative donor. Recipients of T-cell-depleted allografts and/or transplants from unrelated or HLA-mismatched donors seem to be predominantly affected. Reasons likely include both incomplete prevention of direct and indirect or immunomodulatory effects of CMV as well as consequences of drug toxicities. The effect of donor CMV serostatus on outcome remains controversial. Large multicenter cohort studies are needed to better define the subgroups of seropositive patients that may benefit from intensified prevention strategies and to define the impact of CMV donor serostatus in the era of high-resolution HLA matching. Prevention strategies may require targeting both the direct and indirect effects of CMV infection by immunologic or antiviral drug strategies.

Antiviral Agents↗
PubMed2003

Remission of HHV-8 and HIV-associated multicentric Castleman disease with ganciclovir treatment.

Multicentric Castleman disease (MCD) is a lymphoproliferative disorder associated with human herpesvirus 8 (HHV-8) infection among persons with human immunodeficiency virus (HIV) infection. Treatment often includes chemotherapy, and progression to non-Hodgkin lymphoma frequently occurs. MCD is characterized in part by active HHV-8 replication, and many of the symptoms of MCD may be attributable to viral gene products. We describe the effect of ganciclovir on the clinical and virologic course of MCD in a series of 3 case reports. Two patients experienced a reduction in the frequency of episodic flares of MCD and detectable HHV-8 DNA with intravenous or oral ganciclovir, whereas the third patient recovered from an acute episode of renal and respiratory failure with intravenous ganciclovir therapy. These data provide in vivo evidence for the utility of antiviral agents against HHV-8 in the management of MCD.

Administration, Oral↗
PubMed2003

Itraconazole versus fluconazole for prevention of fungal infections in patients receiving allogeneic stem cell transplants.

Prophylactic fluconazole prevents candidiasis; however, this drug has no activity against molds. We performed a randomized trial to determine whether prophylactic itraconazole prevents invasive mold infections (IMIs). A total of 304 patients receiving allogeneic stem cell transplants (SCT) were randomized to receive fluconazole (400 mg/d) or itraconazole (oral solution 2.5 mg/kg 3 times daily, or intravenous 200 mg daily) for 180 days after SC transplantation, or until 4 weeks after discontinuation of graft-versus-host disease (GVHD) therapy. Proven or probable invasive fungal infections (IFI) were evaluated by intent-to-treat and "on-treatment" analyses. More patients in the itraconazole arm developed hepatotoxicities, and more patients were discontinued from itraconazole because of toxicities or gastrointestinal (GI) intolerance (36% versus 16%, P <.001). Intent-to-treat analysis demonstrated no difference in the incidence of IFI during the intended study period (fluconazole 16% versus itraconazole 13%, P =.46); however, fewer patients in the itraconazole arm developed IFI on treatment (fluconazole 15% versus itraconazole 7%, P =.03). Itraconazole provided better protection against IMI (fluconazole 12% versus itraconazole 5%, P =.03), but similar protection against candidiasis (3% versus 2%, P =.69). There was no difference in overall or fungal-free survival. Itraconazole appears to prevent IMI in the subset of patients who tolerate the drug; however, toxicities and poor tolerability limit its success as prophylactic therapy.

Adult↗
PubMed2003

Conditioning with fludarabine and targeted busulfan for transplantation of allogeneic hematopoietic stem cells.

A regimen of busulfan and cyclophosphamide is standard therapy before transplantation of allogeneic hematopoietic stem cells in patients with chronic myelogenous leukemia (CML) or myelodysplastic syndrome (MDS). The clinical trial reported here was undertaken to test the hypothesis that fludarabine can replace cyclophosphamide in this regimen and facilitate donor engraftment with reduced toxicity. The conditioning regimen consisted of 30 mg/m2 intravenous fludarabine daily from day -9 to day -6, and oral busulfan given at 1 mg/kg 4 times a day every 6 hours from day -5 to day -2, with doses adjusted to target plasma levels of 900 +/- 100 ng/mL at steady state. Cyclosporine and methotrexate were used for prophylaxis for graft-versus-host disease. Enrolled were 42 patients with high-risk CML (n = 4) or MDS (n = 38). The median patient age was 52 years (range, 12-65 years). Mobilized blood stem cells were obtained from HLA-compatible siblings (n = 16) or unrelated donors (n = 26). Engraftment was achieved in all patients, and the day-100 regimen-related mortality was 7%. With a median follow-up of 18 months (range, 13-27 months), the probabilities of overall survival, disease-free survival, and nonrelapse mortality were 42.4%, 34.9%, and 24%, respectively. These data indicate that the combination of fludarabine and targeted busulfan is sufficiently immunosuppressive to facilitate engraftment of blood stem cells from HLA-matched siblings and unrelated donors. Based on these encouraging results, further studies of fludarabine and targeted busulfan are warranted in standard-risk patients.

Adolescent↗
PubMed2003

Airflow obstruction after myeloablative allogeneic hematopoietic stem cell transplantation.

Despite advances in the management of myeloablative allogeneic hematopoietic stem cell transplants, airflow obstruction (AFO) remains a significant complication. We conducted a 12-year study to examine the recent epidemiology of AFO and its associated mortality. Using the rate of percent predicted FEV1 decline after transplant, we defined AFO as a more than 5% per year decline in percent predicted FEV1 with the lowest post-transplant FEV1/FVC ratio less than 0.8. New obstruction was more frequent than previous estimates (26% overall, 32% among patients with chronic graft-versus-host disease [GVHD]) and was significantly associated with older age at transplant, lower pretransplant FEV1/FVC ratio, history of both acute and chronic GVHD, and respiratory viral infection within the first 100 days after transplant. AFO was associated with significant attributable mortality rates of 9% at 3 years, 12% at 5 years, and 18% at 10 years after transplant, which were much higher for the subpopulation of patients with chronic GVHD (22% at 3 years, 27% at 5 years, and 40% at 10 years). These results suggest that the incidence of AFO may have been underestimated previously, and its presence significantly increases the mortality of long-term survivors of myeloablative allogeneic hematopoietic stem cell transplant patients.

Adult↗
PubMed2003

Transferred herpes simplex virus immunity after stem-cell transplantation: clinical implications.

Herpes simplex virus (HSV) commonly reactivates after stem-cell transplantation (SCT), despite acyclovir prophylaxis. Whether HSV-seropositive recipients with HSV-seronegative or type-discordant donors had more frequent and severe HSV infections than those with HSV type-concordant donors was explored. Banked serum samples from HSV-positive SCT recipients and their donors were tested for the presence of HSV antibodies. HSV-1-positive SCT recipients from HSV-1-negative donors had more frequent and longer episodes than HSV-1-positive SCT recipients from HSV-1-positive donors; the proportion of patients receiving antiviral treatment for >10% of follow-up days was 27.4% versus 7.2% (P<.001). Both HSV-1 visceral infection (9.8% vs. 2.2%; P=.001) and acyclovir resistance (5.8% vs. 1.8%; P=.03) were more common in type-discordant than -concordant patients, respectively; these associations were confirmed in multivariable models. Serological testing of donors can identify patients who are at highest risk for HSV-related morbidity, for whom prolonged prophylaxis or donor vaccination (once available) could be considered.

Acyclovir↗
PubMed2003

Transfusion-transmitted cytomegalovirus infection after receipt of leukoreduced blood products.

Leukoreduced blood products are reportedly comparable to cytomegalovirus (CMV)-seronegative products for the prevention of transfusion-transmitted CMV (TT-CMV) infection after stem cell (SC) transplantation. To determine if the incidence of TT-CMV was affected by the increasing use of leukoreduced blood products, we followed a prospective cohort of 807 CMV-seronegative SC transplant (SCT) recipients who underwent weekly surveillance using the pp65 antigenemia assay. The incidence of TT-CMV for 2 time periods was recorded: Period 1 (5/94-11/96), when only CMV-seronegative and/or filtered blood products were provided, and period 2 (12/96-2/00), when leukocyte-reduced platelets obtained by apheresis without filtration were also used. The incidence of TT-CMV was higher during period 2 (18/447, 4%) than period 1 (6/360, 1.7%) (P <.05); this was correlated with higher utilization of both filtered and apheresed products from CMV-positive donors in period 2. Multivariable analysis identified filtered red blood cell (RBC) units (but not apheresis platelet products) from CMV-positive donors as the primary predictor of TT-CMV: each additional filtered RBC unit was associated with a 32% increase in the odds for TT-CMV (95% confidence interval [CI]: 8%-61%, P =.006). Pre-emptive therapy with ganciclovir after detection of antigenemia prevented all but one case of CMV disease prior to day 100. CMV-seronegative products may thus be superior to leukoreduced products (particularly filtered RBCs) for the prevention of TT-CMV. In an era of "universal leukoreduction," the abandonment of CMV-seronegative inventories appears premature, particularly among populations at high risk of CMV disease that do not receive active surveillance.

Blood Component Transfusion↗
PubMed2003

Cytomegalovirus in hematopoietic stem cell transplant recipients: Current status, known challenges, and future strategies.

Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality after hematopoietic stem cell transplantation. Significant progress has been made in the prevention of CMV disease over the past decade, but prevention of late CMV disease continues to be a challenge in selected high-risk populations. The pretransplantation CMV serostatus of the donor and/or recipient remains an important risk factor for posttransplantation outcome despite the use of antiviral prophylaxis and preemptive therapy; CMV-seropositive recipients of T cell-depleted grafts in particular continue to have a survival disadvantage compared with seronegative recipients with seronegative donors. The risk of developing antiviral drug resistance remains low in most patients; however, in a setting of intense immunosuppression (eg, after transplantation from a haploidentical donor), the incidence may be as high as 8%. Primary CMV infection via blood transfusion can be reduced by the provision of seronegative or leukocyte-depleted blood products; however, a small risk of 1% to 2% of CMV disease remains. Surveillance and preemptive therapy are effective in preventing the sequelae of transfusion-related CMV infection. Indirect immunomodulatory effects of CMV are increasingly recognized in hematopoietic stem cell transplant recipients. Strategies currently being investigated include long-term suppression of CMV with valganciclovir for the prevention of late CMV infection and disease, adoptive transfer of CMV-specific T cells, and donor and recipient vaccination strategies.

Acyclovir↗
PubMed2003

Combating infections in hematopoietic stem cell transplant recipients.

Infections with a diverse group of microorganisms remain the leading causes of morbidity and mortality after hematopoietic stem cell transplantation. Importantly, the epidemiology of infectious complications has shifted substantially with changes in antimicrobial prophylaxis, conditioning regimens and graft manipulation, such that invasive mould infections and late viral infections are now the over-riding concerns. New antivirals and antifungals have entered clinical practice and hold considerable promise for improved outcomes.

Bacterial Infections↗
PubMed2003

Immunosuppressive effects of beta-herpesviruses.

Immunomodulatory effects of human beta-herpesviruses have been reported in vitro and in vivo. Clinical studies suggest that beta-herpesvirus infection may increase the risk for other infections, the severity of infection, or the tempo of disease progression. An increased incidence of bacterial and fungal infections, and graft rejection, have been reported in association with cytomegalovirus (CMV), and human herpesviruses type 6 and type 7 infections have been implicated as risk factors for CMV infection and graft rejection. Beta-herpesviruses may also interact with HIV-1 and hepatitis C. To prove a causal relationship between beta-herpesviruses and specific clinical outcomes, randomized trials, with selective suppression of the virus, are required. Such trials have been performed for CMV and showed a reduction in bacterial and fungal infections as well as rejection in selected solid organ transplant recipients. More trials are needed to evaluate whether the effects seen in observational studies are truly related.

Betaherpesvirinae↗