[Show abstract][Hide abstract] ABSTRACT: Invasive pulmonary aspergillosis (IPA) is an opportunistic fungal infection in patients undergoing chemotherapy for hematological malignancy, hematopoietic stem cell transplant, or other forms of immunosuppression. In this group, Aspergillus infections account for the majority of deaths due to mold pathogens. Although early detection is associated with improved outcomes, current diagnostic regimens lack sensitivity and specificity. Patients undergoing chemotherapy, stem cell transplantation and lung transplantation were enrolled in a multi-site prospective observational trial. Proven and probable IPA cases and matched controls were subjected to discovery proteomics analyses using a biofluid analysis platform, fractionating plasma into reproducible protein and peptide pools. From 556 spots identified by 2D gel electrophoresis, 66 differentially expressed post-translationally modified plasma proteins were identified in the leukemic subgroup only. This protein group was rich in complement components, acute-phase reactants and coagulation factors. Low molecular weight peptides corresponding to abundant plasma proteins were identified. A candidate marker panel of host response (9 plasma proteins, 4 peptides), fungal polysaccharides (galactomannan), and cell wall components (β-D glucan) were selected by statistical filtering for patients with leukemia as a primary underlying diagnosis. Quantitative measurements were developed to qualify the differential expression of the candidate host response proteins using selective reaction monitoring mass spectrometry assays, and then applied to a separate cohort of 57 patients with leukemia. In this verification cohort, a machine learning ensemble-based algorithm, generalized pathseeker (GPS) produced a greater case classification accuracy than galactomannan (GM) or host proteins alone. In conclusion, Integration of host response proteins with GM improves the diagnostic detection of probable IPA in patients undergoing treatment for hematologic malignancy. Upon further validation, early detection of probable IPA in leukemia treatment will provide opportunities for earlier interventions and interventional clinical trials.
[Show abstract][Hide abstract] ABSTRACT: While antibody titers and neutralization are considered the gold standard for the selection of successful vaccines, these parameters are often inadequate predictors of protective immunity. As antibodies mediate an array of extra-neutralizing Fc functions, when neutralization fails to predict protection, investigating Fc-mediated activity may help identify immunological correlates and mechanism(s) of humoral protection. Here, we used an integrative approach termed Systems Serology to analyze relationships among humoral responses elicited in four HIV vaccine trials. Each vaccine regimen induced a unique humoral "Fc fingerprint." Moreover, analysis of case:control data from the first moderately protective HIV vaccine trial, RV144, pointed to mechanistic insights into immune complex composition that may underlie protective immunity to HIV. Thus, multi-dimensional relational comparisons of vaccine humoral fingerprints offer a unique approach for the evaluation and design of novel vaccines against pathogens for which correlates of protection remain elusive.
[Show abstract][Hide abstract] ABSTRACT: Among 302 first candidemia episodes, 210 (69.6%) were initially treated with an echinocandin or polyene (E/P) antifungal drug. In 137 (72.5%) patients with fluconazole-susceptible isolates, treatment was changed to fluconazole based on disk diffusion susceptibility testing. Clinical outcomes were not compromised in patients receiving E/P who were de-escalated to fluconazole for treatment of candidemia based on disk diffusion results.
No preview · Article · Nov 2015 · Diagnostic microbiology and infectious disease
[Show abstract][Hide abstract] ABSTRACT: Background:
Increasing the breadth of HIV vaccine-elicited immune responses or targeting conserved regions may improve coverage of circulating strains. HVTN 083 tested whether cellular immune responses with these features are induced by prime-boost strategies employing heterologous vectors, heterologous inserts, or a combination of both.
180 participants were randomized to combinations of adenovirus vectors (Ad5 or Ad35) and HIV-1 envelope (Env) gene inserts (clade A or B) in a prime-boost regimen.
T cell responses to heterologous and homologous insert regimens targeted a similar number of epitopes (ratio of means=1.0, 95%CI=[0.6, 1.6], p=0.91), however heterologous insert regimens induced significantly more epitopes that were shared between EnvA and EnvB than homologous insert regimens (ratio of means=2.7, 95%CI=[1.2, 5.7], p=0.01). Participants in the heterologous versus homologous insert groups had T cell responses that targeted epitopes with greater evolutionary conservation (entropy 0.32±0.1 bits, p=0.003) and epitopes recognized by responders provided higher coverage (49%, p=0.035). Heterologous vector regimens had higher numbers of total, EnvA, and EnvB epitopes than homologous vector regimens (p=0.02, 0.044, 0.045 respectively).
These data demonstrate that vaccination with heterologous insert prime-boosting increased T cell responses to shared epitopes while heterologous vector prime-boosting increased the number of T cell epitopes recognized.
No preview · Article · Oct 2015 · The Journal of Infectious Diseases
[Show abstract][Hide abstract] ABSTRACT: Opportunistic infection with Pneumocystis jiroveci pneumonia (PCP) has not been recognized as a significant complication of early-stage breast cancer treatment. However, we have observed an increase in PCP incidence among patients receiving chemotherapy for early-stage breast cancer. Herein we identify risk factors for and calculate incidence of PCP in this population. We identified all cases of PCP at Dana-Farber Cancer Institute/Brigham and Women's Hospital (DFCI/BWH) from 1/1/2000 to 12/31/2013 in patients with stage I-III breast cancer treated with an adriamycin/cyclophosphamide (AC)-containing regimen. Nineteen cases of PCP in non-metastatic breast cancer patients were identified. All patients with PCP were diagnosed after receipt of either three or four cycles of AC chemotherapy on a dose-dense schedule. Patients who developed PCP were treated with median 16.4 mg prednisone equivalents/day as nausea prophylaxis for a median 64 days. The overall incidence of PCP among 2057 patients treated with neoadjuvant or adjuvant dose-dense AC for three or more cycles was 0.6 % (95 % confidence interval 0.3-1.0 %). No PCP was diagnosed in 1001 patients treated with non-dose-dense AC. There was one death from PCP. Women receiving dose-dense AC chemotherapy for early-stage breast cancer are at risk for PCP. Administering the same chemotherapy and corticosteroid dose over an 8-week versus 12-week non-dose-dense schedule appears to have created a novel infectious vulnerability. Replacing dexamethasone with alternative anti-emetics may mitigate this risk.
No preview · Article · Sep 2015 · Breast Cancer Research and Treatment
[Show abstract][Hide abstract] ABSTRACT: An HIV-1 DNA prime vaccine, with a recombinant adenovirus type 5 (rAd5) boost, failed to protect from HIV-1 acquisition. We
studied the nature of the vaccine-induced antibody (Ab) response to HIV-1 envelope (Env). HIV-1–reactive plasma Ab titers
were higher to Env gp41 than to gp120, and repertoire analysis demonstrated that 93% of HIV-1–reactive Abs from memory B cells
responded to Env gp41. Vaccine-induced gp41-reactive monoclonal antibodies were non-neutralizing and frequently polyreactive
with host and environmental antigens, including intestinal microbiota (IM). Next-generation sequencing of an immunoglobulin
heavy chain variable region repertoire before vaccination revealed an Env-IM cross-reactive Ab that was clonally related to
a subsequent vaccine-induced gp41-reactive Ab. Thus, HIV-1 Env DNA-rAd5 vaccine induced a dominant IM-polyreactive, non-neutralizing
gp41-reactive Ab repertoire response that was associated with no vaccine efficacy.
[Show abstract][Hide abstract] ABSTRACT: It has been a year since the first case associated with the current Ebola virus outbreak in West Africa was identified and just over 8 months since we first started reporting on the outbreaks that stemmed from that patient in Guinea.(1) Today's posts at NEJM.org include an anniversary update on the fight against Ebola virus disease (EVD).(2) It is painfully clear that the world's initial handling of this dangerous outbreak was far from optimal, but we now appear to be making progress in the battle. This headway is evidenced by the observations that the rate of appearance of new cases . . .
Preview · Article · Dec 2014 · New England Journal of Medicine
[Show abstract][Hide abstract] ABSTRACT: Although the Ebola virus was recognized in 1976,(1) until now Ebola virus disease (EVD) had been confined to remote areas in Africa, occurring in discrete outbreaks. Even with the thousands of cases in the current outbreak, most cases occur in areas where tragically few resources are available to care for affected patients - in Guinea, Liberia, and Sierra Leone. However, a small number of patients have been transferred to hospitals with modern technology. In addition, in-country transmission has led to new cases of Ebola in Nigeria, Spain, and the United States. This is a troubling development, but it affords us . . .
Preview · Article · Nov 2014 · New England Journal of Medicine
[Show abstract][Hide abstract] ABSTRACT: The governors of a number of states, including New York and New Jersey, recently imposed 21-day quarantines on health care workers returning to the United States from regions of the world where they may have cared for patients with Ebola virus disease. We understand their motivation for this policy - to protect the citizens of their states from contracting this often-fatal illness. This approach, however, is not scientifically based, is unfair and unwise, and will impede essential efforts to stop these awful outbreaks of Ebola disease at their source, which is the only satisfactory goal. The governors' action is like . . .
Preview · Article · Oct 2014 · New England Journal of Medicine
[Show abstract][Hide abstract] ABSTRACT: Background:
Invasive aspergillosis (IA) remains a leading cause of mortality in immunocompromised patients, in part due to the difficulty of diagnosing this infection.
Using thermal desorption-gas chromatography/mass spectrometry, we characterized the in vitro volatile metabolite profile of Aspergillus fumigatus, the most common cause of IA, and other pathogenic aspergilli. We prospectively collected breath samples from patients with suspected invasive fungal pneumonia from 2011 to 2013, and assessed whether we could discriminate patients with proven or probable IA from patients without aspergillosis, as determined by European Organization for Research and Treatment of Cancer/Mycoses Study Group consensus definitions, by direct detection of fungal volatile metabolites in these breath samples.
The monoterpenes camphene, α- and β-pinene, and limonene, and the sesquiterpene compounds α- and β-trans-bergamotene were distinctive volatile metabolites of A. fumigatus in vitro, distinguishing it from other pathogenic aspergilli. Of 64 patients with suspected invasive fungal pneumonia based on host risk factors, clinical symptoms, and radiologic findings, 34 were diagnosed with IA, whereas 30 were ultimately diagnosed with other causes of pneumonia, including other invasive mycoses. Detection of α-trans-bergamotene, β-trans-bergamotene, a β-vatirenene-like sesquiterpene, or trans-geranylacetone identified IA patients with 94% sensitivity (95% confidence interval [CI], 81%-98%) and 93% specificity (95% CI, 79%-98%).
In patients with suspected fungal pneumonia, an Aspergillus secondary metabolite signature in breath can identify individuals with IA. These results provide proof-of-concept that direct detection of exogenous fungal metabolites in breath can be used as a novel, noninvasive, pathogen-specific approach to identifying the precise microbial cause of pneumonia.
Preview · Article · Oct 2014 · Clinical Infectious Diseases
[Show abstract][Hide abstract] ABSTRACT: Finding an effective human immunodeficiency virus type 1 (HIV-1) vaccine remains a major global health priority. In a phase I/II, placebo-controlled trial, healthy, HIV-1-negative adults were randomized to receive one of 5 vaccine regimens: LIPO-5 (combination of 5 lipopeptides) alone (250 mu g), ALVAC-HIV (vCP1452) alone, or 3 groups of ALVAC-HIV (vCP1452) followed by ALVAC-HIV (vCP1452) plus LIPO-5 (250, 750, and 2,500 mu g). Only 73/174 participants (42%) received all four vaccinations due to a study halt related to myelitis. There were no significant differences in systemic reactions between groups or in local reactogenicity between groups receiving ALVAC-HIV (vCP1452). Significant differences in local reactogenicity occurred between groups receiving LIPO-5 (P <= 0.05). Gag and Env antibodies were undetectable by ELISA 2 weeks after the fourth vaccination for all but one recipient. Antibodies to Gag and Env were present in 32% and 24% of recipients of ALVAC-HIV (vCP1452) alone and in 47% and 35% of ALVAC-HIV (vCP1452) + LIPO recipients, respectively. Coadministration of LIPO-5 did not significantly increase the response rate compared to ALVAC-HIV (vCP1452) alone, nor was there a significant relationship between dose and antibody responses among ALVAC-HIV (vCP1452) + LIPO groups. Over 90% of study participants had no positive gamma interferon (IFN-gamma) enzyme-linked immunosorbent spot assay (ELISpot) responses to any peptide pool at any time point. The study was halted due to a case of myelitis possibly related to the LIPO-5 vaccine; this case of myelitis remains an isolated event. In general, there was no appreciable cell-mediated immunity detected in response to the vaccines used in this study, and antibody responses were limited.
[Show abstract][Hide abstract] ABSTRACT: In March 2014, an outbreak of a febrile illness associated with a high case fatality rate was identified in the Guéckédou region of Guinea-Conakry, a remote part of West Africa. An international field investigation was initiated. On April 16, the Journal published a preliminary report identifying the outbreak as due to Ebola virus.(1) The initial sequence data showed that the outbreak strain was Zaire ebolavirus, but a strain distinct from those identified in prior outbreaks, such as those in the Democratic Republic of Congo (DRC) and Gabon. In Guinea there appeared to be ongoing human-to-human transmission. Over the next 4 . . .
Preview · Article · Sep 2014 · New England Journal of Medicine
[Show abstract][Hide abstract] ABSTRACT: Background Defining mucosal immune responses and inflammation to candidate human immunodeficiency virus type 1 (HIV-1) vaccines represents a current research priority for the HIV-1 vaccine field. In particular, it is unclear whether intramuscular immunization can elicit immune responses at mucosal surfaces in humans. Methods In this double-blind, randomized, placebo-controlled clinical trial, we evaluated systemic and mucosal immune responses to a candidate adenovirus serotype 26 (Ad26) vectored HIV-1 envelop (Env) vaccine in baseline Ad26-seronegative and Ad26-seropositive healthy volunteers. Systematic mucosal sampling with rectal Weck-Cel sponges and rectal biopsies were performed. Results Intramuscular immunization elicited both systemic and mucosal Env-specific humoral and cellular immune responses in the majority of subjects. Individuals with preexisting Ad26-specific neutralizing antibodies had vaccine-elicited immune responses comparable to those of subjects who were Ad26 seronegative. We also observed no increase in activated total or vector-specific mucosal CD4+ T lymphocytes following vaccination by either histopathology or flow cytometry. Conclusions These data demonstrate that a single intramuscular administration of this Ad26-vectored HIV-1 Env vaccine elicited both systemic and mucosal immune responses in humans. Induction of antigen-specific humoral and cellular mucosal immunity was not accompanied by a detectable increase in mucosal inflammation. Clinical Trials Registration NCT01103687.
No preview · Article · Aug 2014 · The Journal of Infectious Diseases
[Show abstract][Hide abstract] ABSTRACT: Background:
Comprehensive data that address current HIV nonoccupational postexposure prophylaxis (nPEP) practices in the emergency care of sexual assault patients are limited. The U.S. Centers for Disease Control and Prevention released HIV nPEP guidelines in 2005 and updated guidelines for Sexually Transmitted Disease Treatment in 2006 and 2010, each of which support providing nPEP to sexual assault patients. This study examined the offer, acceptance, and adherence rates of nPEP among sexual assault patients treated at an emergency department (ED).
We conducted a retrospective review between January 1, 2008, and December 31, 2011, of women, aged 16 years and older, treated for sexual assault in an academic ED that participates in the sexual assault nurse examiner program.
One hundred seventy-one female patients were treated in the ED for 179 sexual assault events. nPEP was not indicated in 19 cases and was offered to all 138 of patients for whom nPEP was appropriate. Five patient cases that exceeded the 72-hour exposure window were offered nPEP. Of the 143 patient cases offered nPEP, 124 (86.7%) initiated nPEP. Of the 124 who accepted PEP, 34 (27.4%) had documented completion of the 28-day course.
nPEP was offered in all 138 cases where patients were eligible for treatment. Of patients who accepted nPEP, a minority are documented to have completed a course of treatment. Systems to improve postassault follow-up care should be considered.
No preview · Article · Jul 2014 · Women s Health Issues
[Show abstract][Hide abstract] ABSTRACT: Optimal hepatitis B (HBV) vaccination strategies for lung transplantation (LT) candidates are not well established.
LT candidates with negative anti-HBs and anti-HBc antibody titers at baseline who received standard-dose HBV vaccination (Recombivax-HB 10 mcg/mL or Engerix-B 20 mcg/mL) administered at months 0, 1, and 6 or an accelerated vaccination schedule on days 0, 7 to 14, and 21 to 28 between June 1988 and October 2012 were studied. Patients who were more likely to undergo LT within 6 months of evaluation received the accelerated vaccination schedule starting in August 2009.
Ninety-six HBV-seronegative patients who completed the vaccination series and had postvaccination anti-HBs titers available were identified. Median age was 60 years; 55.2% were female, and 92.7% were white. Underlying lung diseases included COPD (44.8%), idiopathic pulmonary fibrosis (22.9%), interstitial lung disease (15.6%), and cystic fibrosis (8.3%). The overall anti-HBs response rate was 54.2%. There was no significant difference in vaccine responses between accelerated and standard vaccination schedules (54.2% vs. 54.1%; P=1.0). Patients who received steroids or other immunosuppressants before transplantation had lower response rates compared with those who did not (38.9% vs. 63.3%; P=0.03).
Better vaccination strategies to improve response rate are needed in this population. The accelerated HBV vaccination schedule elicited similar anti-HBs responses as the standard schedule and could be advantageous in this population, given current organ allocation practices, and it could allow repeat vaccination series for initial nonresponders before transplantation.