Last data update: Apr 29, 2024. (Total: 46658 publications since 2009)
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Query Trace: Cleveland AA[original query] |
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U.S. women with invasive cervical cancer: Characteristics and potential barriers to prevention
Rosenblum HG , Gargano JW , Cleveland AA , Dahl RM , Park IU , Whitney E , Castilho JL , Sackey E , Niccolai LM , Brackney M , Debess E , Ehlers S , Bennett NM , Kurtz R , Unger ER , Markowitz LE . J Womens Health (Larchmt) 2024 Objectives: Although invasive cervical cancer (ICC) rates have declined since the advent of screening, the annual age-adjusted ICC rate in the United States remains 7.5 per 100,000 women. Failure of recommended screening and management often precedes ICC diagnoses. The study aimed to evaluate characteristics of women with incident ICC, including potential barriers to accessing preventive care. Materials and Methods: We abstracted medical records for patients with ICC identified during 2008-2020 in five U.S. population-based surveillance sites covering 1.5 million women. We identified evidence of adverse social and medical conditions, including uninsured/underinsured, language barrier, substance use disorder, incarceration, serious mental illness, severe obesity, or pregnancy at diagnosis. We calculated descriptive frequencies and compared potential barriers by race/ethnicity, and among women with and without symptoms at diagnosis using chi-square tests. Results: Among 1,606 women with ICC (median age: 49 years; non-White: 47.4%; stage I: 54.7%), the majority (68.8%) presented with symptoms. Forty-six percent of women had at least one identified potential barrier; 15% had multiple barriers. The most common potential barriers among all women were being underinsured/uninsured (17.3%), and language (17.1%). Presence of any potential barrier was more frequent among non-White women and women with than without symptoms (p < 0.05). Conclusions: In this population-based descriptive study of women with ICC, we identified adverse circumstances that might have prevented women from seeking screening and treatment to prevent cancer. Interventions to increase appropriate cervical cancer screening and management are critical for reducing cervical cancer rates. |
Detection of fungal DNA in human body fluids and tissues during a multistate outbreak of fungal meningitis and other infections.
Gade L , Scheel CM , Pham CD , Lindsley MD , Iqbal N , Cleveland AA , Whitney AM , Lockhart SR , Brandt ME , Litvintseva AP . Eukaryot Cell 2013 12 (5) 677-83 Exserohilum rostratum was the major cause of an outbreak of fungal infections linked to injections of contaminated methylprednisolone acetate. Because almost 14,000 persons were exposed to product that was possibly contaminated with multiple fungal pathogens, there was unprecedented need for a rapid throughput diagnostic test that could detect both E. rostratum and other unusual agents of fungal infection. Here we report development of a novel PCR test that allowed for rapid and specific detection of fungal DNA in cerebrospinal fluid (CSF), other body fluids and tissues of infected individuals. The test relied on direct purification of free-circulating fungal DNA from fluids and subsequent PCR amplification and sequencing. Using this method, we detected Exserohilum rostratum DNA in 123 samples from 114 case-patients (28% of 413 case-patients for whom 627 samples were available), and Cladosporium DNA in one sample from one case-patient. PCR with novel Exserohilum-specific ITS-2 region primers detected 25 case-patients with samples that were negative using broad-range ITS primers. Compared to fungal culture, this molecular test was more sensitive: of 139 case-patients with an identical specimen tested by culture and PCR, E. rostratum was recovered in culture from 19 (14%), but detected by PCR in 41 (29%), showing a diagnostic sensitivity of 29% for PCR compared to 14% for culture in this patient group. The ability to rapidly confirm the etiologic role of E. rostratum in these infections provided an important contribution in the public health response to this outbreak. |
HPV type-specific trends in cervical precancers in the United States, 2008-2016
Gargano JW , McClung N , Lewis RM , Park IU , Whitney E , Castilho JL , Pemmaraju M , Niccolai LM , Brackney M , Debess E , Ehlers S , Bennett NM , Scahill M , Cleveland AA , Querec TD , Unger ER , Markowitz LE . Int J Cancer 2022 152 (2) 137-150 Declines in cervical intraepithelial neoplasia grades 2-3 and adenocarcinoma in situ (CIN2+) observed among young women suggest impact from human papillomavirus (HPV) vaccination. To further evaluate vaccine impact including cross-protection and type replacement, we described high-risk (HR)-HPV type-specific cervical precancer incidence rates among women aged 20-39 years, 2008-2016. We analyzed cross-sectional population-based data on 18,344 cases of CIN2+ from a 5-site surveillance system. Diagnostic specimens were tested for individual HPV types, including 14 HR-HPV types (HPV16/18/31/33/35/39/45/51/52/56/58/59/66/68). We estimated age-specific annual HR-HPV type-specific CIN2+ incidence per 100,000 screened women for individual types, vaccine HR-HPV types (HPV16/18) and non-vaccine HR-HPV types (non-HPV16/18). We evaluated trends using average annual percent changes (AAPC) and 95% confidence intervals (CI), and estimated total declines by comparing 2015-2016 to 2008-2009 using incidence rate ratios. Among 20-24-year-olds, HPV16/18-CIN2+ declined from 2008 through 2016 (AAPC: -21.3%, 95% CI: -28.1%, -13.8%), whereas no trend was observed for non-HPV16/18-CIN2+ (AAPC: -1.8%, 95% CI: -8.1%, 4.9%). After 2010, CIN2+ among 20-24-year-olds was more often caused by non-vaccine versus vaccine HR-HPV types. No significant declining trends were observed in older age groups. In 2015-2016 compared to 2008-2009, HPV16-CIN2+ declined 78%, HPV18-CIN2+ 72%, and HPV31-CIN2+ 51% among 20-24-year-olds; no increases were observed in type-specific CIN2+ incidence. Among 25-29-year-olds, HPV16-CIN2+ declined 18%; CIN2+ attributed to seven nonvaccine types increased significantly. No significant declines were observed in older groups. Significant declines in HPV16/18-CIN2+ in 20-24-year-olds and HPV16-CIN2+ in 25-29-year-olds corroborate impact of HPV vaccination. A declining trend in HPV31-CIN2+ is consistent with cross-protection from vaccination. |
Increases in Human Papillomavirus Testing Preceding Diagnosis of Cervical Precancer in 5 US States, 2008-2016
Cleveland AA , Gargano JW , Griffin MR , Park IU , Niccolai LM , Bennett NM , Pemmaraju M , Fink D , Brackney M , Scahill M , Ehlers SJ , Unger ER , Markowitz LE . J Low Genit Tract Dis 2021 25 (3) 192-198 OBJECTIVE: The aim of the study was to describe trends in human papillomavirus (HPV) testing preceding diagnosis of cervical precancer during a time of changing screening recommendations. MATERIALS AND METHODS: We conducted a cross-sectional analysis of data from active, population-based, laboratory surveillance among 1.5 million residents of 5 areas in the United States. We included women aged 21-39 years diagnosed with cervical intraepithelial neoplasia grades 2, 2/3, or 3 or adenocarcinoma in situ (collectively, CIN2+) during 2008-2016, who had a cytology and/or HPV test before diagnosis (n = 16,359). RESULTS: The proportion of women with an HPV test preceding CIN2+ increased from 42.9% in 2008 to 73.3% in 2016 (p < .01); testing increased in all age groups (21-24 y: 35.3% to 47.6%, 25-29 y: 40.9% to 64.1%, 30-39 y: 51.7% to 85.9%, all p < .01). The HPV testing varied by cytology result and was highest among women with atypical squamous cells of unknown significance (n = 4,310/4,629, 93.1%), negative for intraepithelial lesion or malignancy (n = 446/517, 86.3%), and atypical glandular cells (n = 145/257, 56.4%). By 2016, at least half of all cases in every surveillance area had an HPV test before diagnosis. CONCLUSIONS: During 2008-2016, the proportion of women with an HPV test preceding CIN2+ increased significantly for all age groups, cytology results, and surveillance areas. By 2016, most (85.9%) women aged 30-39 years had an HPV test, consistent with recommendations. Increasing utilization of HPV tests, which have demonstrated improved sensitivity for detecting cervical disease, may in part explain increasing rates of cervical precancer among women 30 years and older. |
Trends in high-grade cervical lesions and cervical cancer screening in 5 states, 2008-2015
Gargano JW , Park IU , Griffin MR , Niccolai LM , Powell M , Bennett NM , Johnson Jones ML , Whitney E , Pemmaraju M , Brackney M , Abdullah N , Scahill M , Dahl RM , Cleveland AA , Unger ER , Markowitz LE . Clin Infect Dis 2019 68 (8) 1282-1291 BACKGROUND: We describe changes in rates of cervical intraepithelial neoplasia grades 2, 3 and adenocarcinoma in situ (CIN2+) during a period of human papillomavirus (HPV) vaccine uptake and changing cervical cancer screening recommendations. METHODS: We conducted population-based laboratory surveillance for CIN2+ in catchment areas in 5 states, 2008-2015. We calculated age-specific CIN2+ rates per 100000 women by age groups. We estimated incidence rate ratios (IRR) of CIN2+ for 2-year periods among all women and among screened women to evaluate changes over time. RESULTS: A total of 16572 CIN2+ cases were reported. Among women aged 18-20 and 21-24 years, CIN2+ rates declined in all sites, whereas in women aged 25-29, 30-34, and 35-39 years, trends differed across sites. The percent of women screened annually declined in all sites and age groups. Compared to 2008-2009, rates among screened women were significantly lower for all 3 periods in women aged 18-20 years (2010-2011: IRR 0.82, 95% confidence interval [CI] 0.67-0.99; 2012-2013: IRR 0.63, 95% CI 0.47-0.85; 2014-2015: IRR 0.44, 95% CI 0.28-0.68) and lower for the latter 2 time periods in women aged 21-24 years (2012-2013: IRR 0.86, 95% CI 0.79-0.94; 2014-2015: IRR 0.61, 95% CI 0.55-0.67). CONCLUSIONS: From 2008-2015, both CIN2+ rates and cervical cancer screening declined in women aged 18-24 years. The significant decreases in CIN2+ rates among screened women aged 18-24 years are consistent with a population-level impact of HPV vaccination. |
Trends in human papillomavirus vaccine types 16 and 18 in cervical precancers, 2008-2014
McClung NM , Gargano JW , Bennett NM , Niccolai LM , Abdullah N , Griffin MR , Park IU , Cleveland AA , Querec TD , Unger ER , Markowitz LE . Cancer Epidemiol Biomarkers Prev 2019 28 (3) 602-609 Background: The impact of human papillomavirus (HPV) vaccination has been observed in the United States through declining cervical precancer incidence in young women. To further evaluate vaccine impact, we described trends in HPV vaccine types 16/18 in cervical precancers, 2008-2014.Methods: We analyzed data from a 5-site, population-based surveillance system. Archived specimens from women age 18-39 years diagnosed with cervical intraepithelial neoplasia grades 2-3 or adenocarcinoma in situ (CIN2+) were tested for 37 HPV types. We described the proportion and estimated number of cases of CIN2+ by HPV-type groups over time. Trends in HPV16/18-positive CIN2+ were examined, overall and by vaccination status, age, histologic grade, and race/ethnicity, using Cochrane-Armitage tests.Results: In 10,206 cases, the proportion and estimated number of cases of HPV16/18-positive CIN2+ declined from 52.7% (1,235 cases) in 2008 to 44.1% (819 cases) in 2014 (P < 0.001). Declining trends in the proportion of HPV16/18-positive CIN2+ were observed among vaccinated (55.2%-33.3%, P < 0.001) and unvaccinated (51.0%-47.3%, P = 0.03) women; ages 18-20 (48.7%-18.8%, P = 0.02), 21-24 (53.8%-44.0%, P < 0.001), 25-29 (56.9%-42.4%, P < 0.001), and 30-34 (49.8%-45.8%, P = 0.04) years; CIN2 (40.8%-29.9%, P < 0.001) and CIN2/3 (61.8%-46.2%, P < 0.001); non-Hispanic white (59.5%-47.9%, P < 0.001) and non-Hispanic black (40.7%-26.5%, P < 0.001).Conclusions: From 2008-2014, the proportion of HPV16/18-positive CIN2+ declined, with the greatest declines in vaccinated women; declines in unvaccinated women suggest herd protection.Impact: The declining proportion of HPV16/18-positive CIN2+ provides additional evidence of vaccine impact in the United States. |
Cervical adenocarcinoma in situ: Human papillomavirus types and incidence trends in five states, 2008-2015
Cleveland AA , Gargano JW , Park IU , Griffin MR , Niccolai LM , Powell M , Bennett NM , Saadeh K , Pemmaraju M , Higgins K , Ehlers S , Scahill M , Johnson Jones ML , Querec T , Markowitz LE , Unger ER . Int J Cancer 2019 146 (3) 810-818 Primary prevention through the use of human papillomavirus (HPV) vaccination is expected to impact both cervical intraepithelial neoplasia (CIN) and adenocarcinoma in situ (AIS). While CIN is well described, less is known about the epidemiology of AIS, a rare cervical precancer. We identified AIS and CIN grade 3 (CIN3) cases through population-based surveillance, and analyzed data on HPV types and incidence trends overall, and among women screened for cervical cancer. From 2008-2015, 470 AIS and 6,587 CIN3 cases were identified. The median age of women with AIS was older than those with CIN3 (35 vs 31 years; p<0.01). HPV16 was the most frequently detected type in both AIS and CIN3 (57% in AIS; 58% in CIN3), whereas HPV18 was the second most common type in AIS and less common in CIN3 (38% vs. 5%; p<0.01). AIS lesions were more likely than CIN3 lesions to be positive for high-risk types targeted by the bivalent and quadrivalent vaccines (HPV16/18, 92% vs. 63%; p<0.01), and nonavalent vaccine (HPV16/18/31/33/45/52/58, 95% vs. 87%; p<0.01). AIS incidence rates decreased significantly in the 21-24 year age group (annual percent change [APC] overall: -22.1%, 95% CI: -33.9 to -8.2; APC among screened: -16.1%, 95% CI: -28.8 to -1.2), but did not decrease significantly in any older age group. This report on the largest number of genotyped AIS cases to date suggests an important opportunity for vaccine prevention of AIS, and is the first to document a decline in AIS incidence rates among young women during the vaccine era. This article is protected by copyright. All rights reserved. |
Trends in anogenital wart incidence among Tennessee Medicaid enrollees, 2006-2014: The impact of human papillomavirus vaccination
Shing JZ , Hull PC , Zhu Y , Gargano JW , Markowitz LE , Cleveland AA , Pemmaraju M , Park IU , Whitney E , Mitchel EF , Griffin MR . Papillomavirus Res 2019 7 141-149 INTRODUCTION: Evidence of human papillomavirus (HPV) vaccine impact on anogenital warts (AGWs) by race or urbanicity in the US is lacking. We evaluated HPV vaccine impact in Tennessee by assessing AGW trends among Tennessee Medicaid (TennCare) enrollees aged 15-39 years from 2006-2014. METHODS: Persons with incident AGWs were identified using diagnosis/pharmacy codes from TennCare billing claims. We calculated sex-specific annual AGW incidence by age group, race, and urbanicity; estimated annual percent changes (APCs) using log-linear models; and performed pairwise comparisons by race and urbanicity. RESULTS: AGW incidence decreased among females aged 15-19 (APC=-10.6; P<0.01) and 20-24 years (APC=-3.9; P=0.02). Overall trends were similar between Whites and Blacks, and between those living in metropolitan statistical areas (MSAs) and non-MSAs. Rates among males aged 15-19 years began decreasing after 2010. Among enrollees aged 25-39 years, rates increased or were stable. CONCLUSIONS: Following introduction of the HPV vaccine in 2006, AGWs decreased among age groups most likely to be vaccinated. The change in trend among young males after 2010 suggests early herd effects. Our findings indicate vaccine effects and support the importance of improving adherence to current vaccination recommendations for preventing AGWs and other HPV-related diseases. |
Cytomegalovirus infections in lung and hematopoietic cell transplant recipients in the Organ Transplant Infection Prevention and Detection (OTIP) Study: a multi-year, multi-center prospective cohort study
Avery RK , Silveira FP , Benedict K , Cleveland AA , Kauffman CA , Schuster MG , Dubberke ER , Husain S , Paterson D , Chiller T , Pappas P . Transpl Infect Dis 2018 20 (3) e12877 BACKGROUND: Most studies of post-transplant CMV infection have focused on either solid organ or hematopoietic cell transplant (HCT) recipients. A large prospective cohort study involving both lung and HCT recipients provided an opportunity to compare the epidemiology and outcomes of CMV infections in these two groups. METHODS: Patients were followed for 30 months in a 6-center prospective cohort study. Data on demographics, CMV infections, tissue-invasive disease, recurrences, rejection, and immunosuppression were recorded. RESULTS: The overall incidence of CMV infection was 83/293 (28.3%) in the lung transplant group and 154/444 (34.7%) in the HCT group (p = 0.0706). Tissue-invasive CMV disease occurred in 8/83 (9.6%) of lung and 6/154 (3.9%) of HCT recipients with CMV infection, respectively (p=0.087). Median time to CMV infection was longer in the lung transplant group (236 vs. 40 days, p < 0.0001), likely reflecting the effects of prophylaxis vs. pre-emptive therapy. Total IgG levels of < 350 mg/dl in lung recipients and graft versus host disease (GvHD) in HCT recipients were associated with increased CMV risk. HCT recipients had a higher mean number of CMV episodes (p=0.008), although duration of viremia was not significantly different between the two groups. CMV infection was not associated with reduced overall survival in either group. CONCLUSIONS: Current CMV prevention strategies have resulted in a low incidence of tissue-invasive disease in both lung transplant and HCT, although CMV viremia is still relatively common. Differences between the lung and HCT groups in terms of time to CMV and recurrences of CMV viremia likely reflect differences in underlying host immunobiology and in CMV prevention strategies in the modern era. This article is protected by copyright. All rights reserved. |
Epidemiology and outcomes of Clostridium difficile infection in allogeneic hematopoietic cell and lung transplant recipients
Dubberke ER , Reske KA , Olsen MA , Bommarito K , Cleveland AA , Silveira FP , Schuster MG , Kauffman CA , Avery RK , Pappas PG , Chiller TM . Transpl Infect Dis 2018 20 (2) e12855 BACKGROUND: Clostridium difficile infection (CDI) is a common complication of lung and allogeneic hematopoietic cell (HCT) transplant, but the epidemiology and outcomes of CDI after transplant are poorly described. METHODS: We performed a prospective, multicenter study of CDI within 365 days post-allogeneic HCT or lung transplantation. Data were collected via patient interviews and medical chart review. Participants were followed weekly in the 12 weeks post-transplant and while hospitalized and contacted monthly up to 18 months post-transplantation. RESULTS: Six sites participated in the study with 614 total participants; 4 enrolled allogeneic HCT (385 participants) and 5 enrolled lung transplant recipients (229 participants). 150 CDI cases occurred within one year of transplantation; the incidence among lung transplant recipients was 13.1% and among allogeneic HCTs was 31.2%. Median time to CDI was significantly shorter among allogeneic HCT than lung transplant recipients (27 days vs. 90 days; p=0.037). CDI was associated with significantly higher mortality from 31-180 days post-index date among the allogeneic HCT recipients (Hazard ratio [HR]=1.80; p=0.007). There was a trend towards increased mortality among lung transplant recipients from 120-180 days post-index date (HR=4.7, p=0.09). CONCLUSIONS: The epidemiology and outcomes of CDI vary by transplant population; surveillance for CDI should continue beyond the immediate post-transplant period. This article is protected by copyright. All rights reserved. |
High mortality and coinfection in a prospective cohort of human immunodeficiency virus/acquired immune deficiency syndrome patients with histoplasmosis in Guatemala
Samayoa B , Roy M , Cleveland AA , Medina N , Lau-Bonilla D , Scheel CM , Gomez BL , Chiller T , Arathoon E . Am J Trop Med Hyg 2017 97 (1) 42-48 Histoplasmosis is one of the most common and deadly opportunistic infections among persons living with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome in Latin America, but due to limited diagnostic capacity in this region, few data on the burden and clinical characteristics of this disease exist. Between 2005 and 2009, we enrolled patients ≥ 18 years of age with suspected histoplasmosis at a hospital-based HIV clinic in Guatemala City. A case of suspected histoplasmosis was defined as a person presenting with at least three of five clinical or radiologic criteria. A confirmed case of histoplasmosis was defined as a person with a positive culture or urine antigen test for Histoplasma capsulatum. Demographic and clinical data were also collected and analyzed. Of 263 enrolled as suspected cases of histoplasmosis, 101 (38.4%) were confirmed cases. Median time to diagnosis was 15 days after presentation (interquartile range [IQR] = 5-23). Crude overall mortality was 43.6%; median survival time was 19 days (IQR = 4-69). Mycobacterial infection was diagnosed in 70 (26.6%) cases; 26 (25.7%) histoplasmosis cases were coinfected with mycobacteria. High mortality and short survival time after initial symptoms were observed in patients with histoplasmosis. Mycobacterial coinfection diagnoses were frequent, highlighting the importance of pursuing diagnoses for both diseases. |
Infections in hematopoietic cell transplant recipients: Results from the organ transplant infection project, a multicenter, prospective, cohort study
Schuster MG , Cleveland AA , Dubberke ER , Kauffman CA , Avery RK , Husain S , Paterson DL , Silveira FP , Chiller TM , Benedict K , Murphy K , Pappas PG . Open Forum Infect Dis 2017 4 (2) ofx050 BACKGROUND: Infection is a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Our object was to better define the epidemiology and outcomes of infections after HCT. METHODS: This was a prospective, multicenter cohort study of HCT recipients and conducted from 2006 to 2011. The study included 4 US transplant centers and 444 HCT recipients. Data were prospectively collected for up to 30 months after HCT using a standardized data collection tool. RESULTS: The median age was 53 years, and median follow up was 413 (range, 5-980) days. The most common reason for HCT was hematologic malignancy (87%). The overall crude mortality was 52%. Death was due to underlying disease in 44% cases and infection in 21%. Bacteremia occurred in 231 (52%) cases and occurred early posttransplant (median day 48). Gram-negative bloodstream infections were less frequent than Gram-positive, but it was associated with higher mortality (45% vs 13%, P = .02). Clostridium difficile infection developed in 148 patients (33%) at a median of 27 days post-HCT. There were 53 invasive fungal infections (IFIs) among 48 patients (11%). The median time to IFI was 142 days. Of 155 patients with cytomegalovirus (CMV) infection, 4% had CMV organ involvement. Varicella zoster infection (VZV) occurred in 13 (4%) cases and was disseminated in 2. Infection with respiratory viruses was seen in 49 patients. Pneumocystis jirovecii pneumonia was rare (1%), and there were no documented cases of nocardiosis, toxoplasmosis, endemic mycoses, or mycobacterial infection. This study lacked standardized antifungal and antiviral prophylactic strategies. CONCLUSIONS: Infection remains a significant cause of morbidity and mortality after HCT. Bacteremias and C difficile infection are frequent, particularly in the early posttransplant period. The rate of IFI is approximately 10%. Organ involvement with CMV is infrequent, as are serious infections with VZV and herpes simplex virus, likely reflecting improved prevention strategies. |
Clinical and laboratory profile of persons living with human immunodeficiency virus/acquired immune deficiency syndrome and histoplasmosis from a Colombian hospital
Caceres DH , Tobon AM , Cleveland AA , Scheel CM , Berbesi DY , Ochoa J , Restrepo A , Brandt ME , Chiller T , Gomez BL . Am J Trop Med Hyg 2016 95 (4) 918-924 Histoplasmosis is common among persons living with human immunodeficiency virus/acquired immune deficiency syndrome (PLWHA) in Latin America, but its diagnosis is difficult and often nonspecific. We conducted prospective screening for histoplasmosis among PLWHA with signs or symptoms suggesting progressive disseminated histoplasmosis (PDH) and hospitalized in Hospital La Maria in Medellin, Colombia. The study's aim was to obtain a clinical and laboratory profile of PLWHA with PDH. During 3 years (May 2008 to August 2011), we identified 89 PLWHA hospitalized with symptoms suggestive of PDH, of whom 45 (51%) had histoplasmosis. We observed tuberculosis (TB) coinfection in a large proportion of patients with PDH (35%), so all analyses were performed adjusting for this coinfection and, alternatively, excluding histoplasmosis patients with TB. Results showed that the patients with PDH were more likely to have Karnofsky score ≤ 30 (prevalence ratio [PR] = 1.98, 95% confidence interval [CI] = 0.97-4.06), liver compromised with hepatomegaly and/or splenomegaly (PR = 1.77, CI = 1.03-3.06) and elevation in serum of alanine aminotransferase and aspartate aminotransferase to values > 40 mU/mL (PR = 2.06, CI = 1.09-3.88 and PR = 1.53, CI = 0.99-2.35, respectively). Using multiple correspondence analyses, we identified in patients with PDH a profile characterized by the presence of constitutional symptoms, namely weight loss and Karnofsky classification ≤ 30, gastrointestinal manifestations with alteration of liver enzymes and hepatosplenomegaly and/or splenomegaly, skin lesions, and hematological alterations. Study of the profiles is no substitute for laboratory diagnostics, but identifying clinical and laboratory indicators of PLWHA with PDH should allow development of strategies for reducing the time to diagnosis and thus mortality caused by Histoplasma capsulatum. |
Epidemiology and risk factors for echinocandin nonsusceptible Candida glabrata bloodstream infections: Data from a large multisite population-based candidemia surveillance program, 2008-2014
Vallabhaneni S , Cleveland AA , Farley MM , Harrison LH , Schaffner W , Beldavs ZG , Derado G , Pham CD , Lockhart SR , Smith RM . Open Forum Infect Dis 2015 2 (4) ofv163 Background. Echinocandins are first-line treatment for Candida glabrata candidemia. Echinocandin resistance is concerning due to limited remaining treatment options. We used data from a multisite, population-based surveillance program to describe the epidemiology and risk factors for echinocandin nonsusceptible (NS) C glabrata candidemia. Methods. The Centers for Disease Control and Prevention's Emerging Infections Program conducts population-based laboratory surveillance for candidemia in 4 metropolitan areas (7.9 million persons; 80 hospitals). We identified C glabrata cases occurring during 2008-2014; medical records of cases were reviewed, and C glabrata isolates underwent broth microdilution antifungal susceptibility testing. We defined echinocandin-NS C glabrata (intermediate or resistant) based on 2012 Clinical and Laboratory Standards Institute minimum inhibitory concentration breakpoints. Independent risk factors for NS C glabrata were determined by stepwise logistic regression. Results. Of 1385 C glabrata cases, 83 (6.0%) had NS isolates (19 intermediate and 64 resistant); the proportion of NS isolates rose from 4.2% in 2008 to 7.8% in 2014 (P < .001). The proportion of NS isolates at each hospital ranged from 0% to 25.8%; 3 large, academic hospitals accounted for almost half of all NS isolates. In multivariate analysis, prior echinocandin exposure (adjusted odds ratio [aOR], 5.3; 95% CI, 2.6-1.2), previous candidemia episode (aOR, 2.5; 95% CI, 1.2-5.1), hospitalization in the last 90 days (aOR, 1.9; 95% CI, 1.0-3.5, and fluconazole resistance [aOR, 3.6; 95% CI, 2.0-6.4]) were significantly associated with NS C glabrata. Fifty-nine percent of NS C glabrata cases had no known prior echinocandin exposure. Conclusion. The proportion of NS C glabrata isolates rose significantly during 2008-2014, and NS C glabrata frequency differed across hospitals. In addition to acquired resistance resulting from prior drug exposure, occurrence of NS C glabrata without prior echinocandin exposure suggests possible transmission of resistant organisms. |
Epidemiology and factors associated with candidaemia following Clostridium difficile infection in adults within metropolitan Atlanta, 2009-2013
Vallabhaneni S , Almendares O , Farley MM , Reno J , Smith ZT , Stein B , Magill SS , Smith RM , Cleveland AA , Lessa FC . Epidemiol Infect 2015 144 (7) 1-5 We assessed prevalence of and risk factors for candidaemia following Clostridium difficile infection (CDI) using longitudinal population-based surveillance. Of 13 615 adults with CDI, 113 (0.8%) developed candidaemia in the 120 days following CDI. In a matched case-control analysis, severe CDI and CDI treatment with vancomycin + metronidazole were associated with development of candidaemia following CDI. |
Candida lusitaniae MICs to the echinocandins are elevated but FKS-mediated resistance is rare
Lockhart SR , Pham CD , Kuykendall RJ , Bolden CB , Cleveland AA . Diagn Microbiol Infect Dis 2015 84 (1) 52-54 MIC values were generated for caspofungin, micafungin, and anidulafungin against 106 isolates of C. lusitaniae, and these values were compared to established epidemiologic cutoff values. The majority of isolates were wild type both by MIC value as well as by FKS1 hotspot sequencing. Although C. lusitaniae isolates have MIC values to the echinocandins that are elevated compared to other common species, with regard to known mechanisms of resistance to the echinocandins, isolates with MIC values at or below the epidemiological cutoff values of 0.5 and 1mug/mL for micafungin and anidulafungin, respectively, should be considered wild type. |
Emerging Infections Program as surveillance for antimicrobial drug resistance
Fridkin SK , Cleveland AA , See I , Lynfield R . Emerg Infect Dis 2015 21 (9) 1578-81 Across the United States, antimicrobial drug-resistant infections affect a diverse population, and effective interventions require concerted efforts across various public health and clinical programs. Since its onset in 1994, the Centers for Disease Control and Prevention Emerging Infections Program has provided robust and timely data on antimicrobial drug-resistant infections that have been used to inform public health action across a spectrum of partners with regard to many highly visible antimicrobial drug-resistance threats. These data span several activities within the Program, including respiratory bacterial infections, health care-associated infections, and some aspects of foodborne diseases. These data have contributed to estimates of national burden, identified populations at risk, and determined microbiological causes of infection and their outcomes, all of which have been used to inform national policy and guidelines to prevent antimicrobial drug-resistant infections. |
Declining incidence of candidemia and the shifting epidemiology of Candida resistance in two US netropolitan areas, 2008-2013: results from population-based surveillance
Cleveland AA , Harrison LH , Farley MM , Hollick R , Stein B , Chiller TM , Lockhart SR , Park BJ . PLoS One 2015 10 (3) e0120452 BACKGROUND: Recent reports have demonstrated a decline in bacterial bloodstream infections (BSIs) following adherence to central line insertion practices; however, declines have been less evident for BSIs due to Candida species. METHODS: We conducted active, population-based laboratory surveillance for candidemia in metropolitan Atlanta, GA and Baltimore, MD over a 5-year period. We calculated annual candidemia incidence and antifungal drug resistance rates. RESULTS: We identified 3,848 candidemia cases from 2008-2013. Compared with 2008, candidemia incidence per 100,000 person-years decreased significantly by 2013 in both locations (GA: 14.1 to 9.5, p<0.001; MD: 30.9 to 14.4, p<0.001). A total of 3,255 cases (85%) had a central venous catheter (CVC) in place within 2 days before the BSI culture date. In both locations, the number of CVC-associated cases declined (GA: 473 to 294; MD: 384 to 151). Candida albicans (CA, 36%) and Candida glabrata (CG, 27%) were the most common species recovered. In both locations, the proportion of cases with fluconazole resistance decreased (GA: 8.0% to 7.1%, -10%; MD: 6.6% to 4.9%, -25%), while the proportion of cases with an isolate resistant to an echinocandin increased (GA: 1.2% to 2.9%, +147%; MD: 2.0% to 3.5%, +77%). Most (74%) echinocandin-resistant isolates were CG; 17 (<1%) isolates were resistant to both drug categories (multidrug resistant [MDR], 16/17 were CG). The proportion of CG cases with MDR Candida increased from 1.8% to 2.6%. CONCLUSIONS: We observed a significant decline in the incidence of candidemia over a five-year period, and increases in echinocandin-resistant and MDR Candida. Efforts to strengthen infection control practices may be preventing candidemia among high-risk patients. Further surveillance for resistant Candida is warranted. |
Molecular mechanisms of fluconazole resistance in Candida parapsilosis isolates from a U.S. surveillance system.
Grossman NT , Pham CD , Cleveland AA , Lockhart SR . Antimicrob Agents Chemother 2014 59 (2) 1030-7 Candida parapsilosis is the second or third most common cause of candidemia in many countries. The Infectious Disease Society of America recommends fluconazole as primary therapy for C. parapsilosis candidemia. Although fluconazole resistance among C. parapsilosis isolates is low in most US institutions, the resistance rate can be as high as 7.5%. This study was designed to assess the mechanisms of fluconazole resistance in 706 incident bloodstream isolates from US hospitals. We sequenced the ERG11 and MRR1 genes of 122 C. parapsilosis isolates with resistant (30 isolates; 4.2%), susceptible dose-dependent (37 isolates; 5.2%) and susceptible (55 isolates) fluconazole MIC values, and used RT-PCR on RNA from 17 isolates to investigate the regulation of MDR1. By comparing these isolates to fully fluconazole susceptible isolates we detected at least two mechanisms of fluconazole resistance: an amino acid substitution in the 14-alpha-demethylase gene ERG11, and overexpression of the efflux pump MDR1, possibly due to point mutations in the MRR1 transcription factor that regulates MDR1. The ERG11 single nucleotide polymorphism (snp) was found in 57% of the fluconazole resistant isolates and in no susceptible isolates. The MRR1 snps were more difficult to characterize, as not all resulted in overexpression of MDR1 and not all MDR1 overexpression was associated with a snp in MRR1. Further work to characterize the MRR1 snps and search for overexpression of other efflux pumps is needed. |
Epidemiology of invasive mold infections in lung transplant recipients
Doligalski CT , Benedict K , Cleveland AA , Park B , Derado G , Pappas PG , Baddley JW , Zaas DW , Harris MT , Alexander BD . Am J Transplant 2014 14 (6) 1328-33 Invasive mold infections (IMIs) are a major source of morbidity and mortality among lung transplant recipients (LTRs), yet information regarding the epidemiology of IMI in this population is limited. From 2001 to 2006, multicenter prospective surveillance for IMIs among LTR was conducted by the Transplant-Associated Infection Surveillance Network. The epidemiology of IMI among all LTRs in the cohort is reported. Twelve percent (143/1173) of LTRs under surveillance at 15 US centers developed IMI infections. The 12-month cumulative incidence of IMIs was 5.5%; 3-month all-cause mortality was 21.7%. Aspergillus caused the majority (72.7%)of IMIs; non-Aspergillus infections (39, 27.3%) included Scedosporium (5, 3.5%), mucormycosis (3, 2.1%) and "unspecified" or "other" mold infections (31, 21.7%). Late-onset IMI was common: 52% occurred within 1 year posttransplant (median 11 months, range 0-162 months). IMIs are common late-onset complications with substantial mortality in LTRs. LTRs should be monitored for late-onset IMIs and prophylactic agents should be optimized based on likely pathogen. |
The role of FKS mutations in C. glabrata: MIC values, echinocandin resistance and multidrug resistance
Pham CD , Iqbal N , Bolden CB , Kuykendall RJ , Harrison LH , Farley MM , Schaffner W , Beldavs ZG , Chiller TM , Park BJ , Cleveland AA , Lockhart SR . Antimicrob Agents Chemother 2014 58 (8) 4690-6 Candida glabrata is the second leading cause of candidemia in US hospitals. Current guidelines suggest that an echinocandin be used as primary therapy for C. glabrata due to the high rate of resistance to fluconazole. Recent case reports indicate that C. glabrata resistance to echinocandins may be increasing. We performed susceptibility testing on 1380 isolates of C. glabrata collected between 2008 and 2013 from four US cities, Atlanta, Baltimore, Knoxville and Portland. Our analysis showed that 3.1%, 3.3%, and 3.6% of the isolates were resistant to anidulafungin, caspofungin and micafungin, respectively. We screened 1032 of these isolates, including all 77 that had either a resistant or intermediate MIC value to one or more echinocandin, for mutations in the hotspot regions of FKS1 and FKS2, the major mechanism of echinocandin resistance. Fifty-one isolates were identified with hotspot mutations, 16 in FKS1 and 35 in FKS2. All but one of the isolates with an FKS mutation were resistant to one or more echinocandin by susceptibility testing. Of the isolates resistant to one or more echinocandin, 36% were also resistant to fluconazole. Echinocandin resistance among US C. glabrata isolates is a concern especially in light of the fact that a third of those isolates may be multidrug resistant. Further monitoring of US C. glabrata isolates for echinocandin resistance is warranted. |
Preliminary laboratory report of fungal infections associated with contaminated methylprednisolone injections
Lockhart SR , Pham CD , Gade L , Iqbal N , Scheel CM , Cleveland AA , Whitney AM , Noble-Wang J , Chiller TM , Park BJ , Litvintseva AP , Brandt ME . J Clin Microbiol 2013 51 (8) 2654-61 In September 2012, the Centers for Disease Control and Prevention (CDC) initiated an outbreak investigation of fungal infections linked to injection of contaminated methylprednisolone acetate (MPA). Between 2 October 2012 and 14 February 2013, the CDC laboratory received 799 fungal isolates or human specimens, including cerebrospinal fluid (CSF), synovial fluid, and abscess tissue, from 469 case patients in 19 states. A novel broad-range PCR assay and DNA sequencing were used to evaluate these specimens. Although Aspergillus fumigatus was recovered from the index case, Exserohilum rostratum was the primary pathogen in this outbreak and was also confirmed from unopened MPA vials. Exserohilum rostratum was detected or confirmed in 191 specimens or isolates from 150 case patients, primarily from Michigan (n = 67 patients), Tennessee (n = 26), Virginia (n = 20), and Indiana (n = 16). Positive specimens from Michigan were primarily abscess tissues, while positive specimens from Tennessee, Virginia, and Indiana were primarily CSF. E. rostratum antifungal susceptibility MIC50 and MIC90 values were determined for voriconazole (1 and 2 mug/ml, respectively), itraconazole (0.5 and 1 mug/ml), posaconazole (0.5 and 1 mug/ml), isavuconazole (4 and 4 mug/ml), and amphotericin B (0.25 and 0.5 mug/ml). Thirteen other mold species were identified among case patients, and four other fungal genera were isolated from the implicated MPA vials. The clinical significance of these other fungal species remains under investigation. The laboratory response provided significant support to case confirmation, enabled linkage between clinical isolates and injected vials of MPA, and described significant features of the fungal agents involved in this large multistate outbreak. |
Fungal infections associated with contaminated methylprednisolone injections - preliminary report
Smith RM , Schaefer MK , Kainer MA , Wise M , Finks J , Duwve J , Fontaine E , Chu A , Carothers B , Reilly A , Fiedler J , Wiese AD , Feaster C , Gibson L , Griese S , Purfield A , Cleveland AA , Benedict K , Harris JR , Brandt ME , Blau D , Jernigan J , Weber JT , Park BJ . N Engl J Med 2012 369 (17) 1598-609 BACKGROUND: Fungal infections are rare complications of injections for treatment of chronic pain. In September 2012, we initiated an investigation into fungal infections associated with injections of preservative-free methylprednisolone acetate that was purchased from a single compounding pharmacy. METHODS: Three lots of methylprednisolone acetate were recalled by the pharmacy; examination of unopened vials later revealed fungus. Notification of all persons potentially exposed to implicated methylprednisolone acetate was conducted by federal, state, and local public health officials and by staff at clinical facilities that administered the drug. We collected clinical data on standardized case-report forms, and we tested for the presence of fungi in isolates and specimens by examining cultures and performing polymerase-chain-reaction assays and histopathological and immunohistochemical testing. RESULTS: As of October 19, 2012, more than 99% of 13,534 potentially exposed persons had been contacted. As of December 10, there were 590 reported cases of infection in 19 states, with 37 deaths (6%). As of November 26, laboratory evidence of Exserohilum rostratum was present in specimens from 100 case patients (17%). Additional data were available for 386 case patients (65%); 300 of these patients (78%) had meningitis. Case patients had received a median of 1 injection (range, 1 to 6) of implicated methylprednisolone acetate. The median age of the patients was 64 years (range, 16 to 92), and the median incubation period was 20 days (range, 0 to 120); 33 patients (9%) had a stroke. CONCLUSIONS: Analysis of preliminary data from a large multistate outbreak of fungal infections showed substantial morbidity and mortality. The infections were associated with injection of a contaminated glucocorticoid medication from a single compounding pharmacy. Rapid public health actions included prompt recall of the implicated product, notification of exposed persons, and early outreach to clinicians. |
Changes in incidence and antifungal drug resistance in candidemia: results from population-based laboratory surveillance in Atlanta and Baltimore, 2008-2011
Cleveland AA , Farley MM , Harrison LH , Stein B , Hollick R , Lockhart SR , Magill SS , Derado G , Park BJ , Chiller TM . Clin Infect Dis 2012 55 (10) 1352-61 BACKGROUND: Candidemia is common and associated with high morbidity and mortality; changes in population-based incidence rates have not been reported. METHODS: We conducted active, population-based surveillance in metropolitan Atlanta, Georgia, and Baltimore City/ County, Maryland (combined population 5.2 million), during 2008-2011. We calculated candidemia incidence and antifungal drug resistance compared to prior surveillance (Atlanta: 1992-1993; Baltimore: 1998-2000). RESULTS: We identified 2,675 cases of candidemia with 2,329 isolates during 3 years of surveillance. Mean annual crude incidence per 100,000 person-years was 13.3 in Atlanta, and 26.2 in Baltimore. Rates were highest among adults aged ≥65 years (Atlanta, 59.1; Baltimore, 72.4), and infants (aged <1 year) (Atlanta, 34.3; Baltimore, 46.2). In both locations compared to prior surveillance, adjusted incidence significantly declined for infants of both black and white race (Atlanta, black risk ratio (RR): 0.26, 95% confidence interval [CI]: [0.17-0.38]; white RR: 0.19, 95% CI: [0.12-0.29]; Baltimore, black RR: 0.38, 95% CI: [0.22-0.64], white RR: 0.51, 95% CI: [0.29-0.90]). Prevalence of fluconazole resistance (7%) was unchanged compared to prior surveillance; 32 (1%) isolates were echinocandin-resistant, and nine (eight C. glabrata) were multi-drug resistant to both fluconazole and an echinocandin. CONCLUSIONS: We describe marked shifts in candidemia epidemiology over the past two decades. Adults aged ≥ 65 years replaced infants as the highest incidence group; adjusted incidence has declined significantly in infants. Use of antifungal prophylaxis, improvements in infection control, or changes in catheter insertion practices may be contributing to these declines. Further surveillance for antifungal resistance and efforts to determine effective prevention strategies are needed. |
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