Tom Chiller

Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS.

Objective:Cryptococcal meningitis is one of the most important HIV-related opportunistic infections, especially in the developing world. In order to help develop global strategies and priorities for prevention and treatment, it is important to estimate the burden of cryptococcal meningitis. Design:Global burden of disease estimation using published studies. Methods:We used the median incidence rate of available studies in a geographic region to estimate the region-specific cryptococcal meningitis incidence; this was multiplied by the 2007 United Nations Programme on HIV/AIDS HIV population estimate for each region to estimate cryptococcal meningitis cases. To estimate deaths, we assumed a 9% 3-month case-fatality rate among high-income regions, a 55% rate among low-income and middle-income regions, and a 70% rate in sub-Saharan Africa, based on studies published in these areas and expert opinion. Results:Published incidence ranged from 0.04 to 12% per year among persons with HIV. Sub-Saharan Africa had the highest yearly burden estimate (median incidence 3.2%, 720 000 cases; range, 144 000–1.3 million). Median incidence was lowest in Western and Central Europe and Oceania (≤0.1% each). Globally, approximately 957 900 cases (range, 371 700–1 544 000) of cryptococcal meningitis occur each year, resulting in 624 700 deaths (range, 125 000–1 124 900) by 3 months after infection. Conclusion:This study, the first attempt to estimate the global burden of cryptococcal meningitis, finds the number of cases and deaths to be very high, with most occurring in sub-Saharan Africa. Further work is needed to better define the scope of the problem and track the epidemiology of this infection, in order to prioritize prevention, diagnosis, and treatment strategies.

Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective.

In the past decade, modifications in HCT management and supportive care have resulted in changes in recommendations for the prevention of infection in HCT patients. These changes are fuelled by new antimicrobial agents, increased knowledge of immune reconstitution, and expanded conditioning regimens and patient populations eligible for HCT. Despite these advances, infection is reported as the primary cause of death in 8% of autologous HCT patients and 17 – 20% of allogeneic HCT recipients [3]. The major changes in this document, including changes in recommendation ratings, are summarized here. The organization of this document is similar to the previous guidelines. Specifically, the prevention of exposure and disease among pediatric and adult autologous and allogeneic HCT recipients is discussed. The current recommendations consider myeloablative and reduced intensity conditioning for allogeneic HCT similarly since data on infectious complications following reduced intensity conditioning compared to myeloablative conditioning are sparse [4–7]. However, increased information regarding post-transplant immune recovery highlighting differences between myeloablative and reduced intensity HCT are included. The sections of the document have been re-arranged in an attempt to follow the time course of potential infectious risks for patients receiving HCT. Following the background section, information on hematopoietic cell product safety is provided. The subsequent sections discuss prevention of infection by specific micro-organisms. Following organism-specific information, the sections then discuss means of preventing nosocomial infections as well as “do’s and don’ts” for patients following discharge post-transplant. Finally, information on vaccinations is provided. This will hopefully allow the reader to follow the prevention practices needed from the time a donor is selected until the patient regains immune competence. Several topics are new or expanded from the prior document (Table 2). These include information on multiple organisms which were previously not discussed but have seemingly become more clinically relevant in HCT patients over the past decade. Data, and where possible, recommendations are provided regarding the following organisms that were not included in the previous document: Bordetella pertussis; the polyomaviruses BK and JC; hepatitis A, B, and C viruses; human herpesviruses 6, 7, and 8; human metapneumovirus; human immunodeficiency virus; tuberculosis; nocardiosis; malaria; and leishmaniasis. In recognition of our global society, several organisms are discussed that may be limited to certain regions of the world. Included in that section are also those infections that may be ubiquitous but occur infrequently, such as Pneumocystis jiroveci and Nocardia. Table 2 Summary of Changes compared to the Guidelines published in 2000 [1]. Several other changes should be noted. For bacterial infections, these guidelines now recommend quinolone prophylaxis for patients wth neutropenia expected to last as least 7 days (BI). Additionally, the recommendations for contact precautions (AIII), vaccination (BI), and prophylaxis patients with GVHD (AIII) against Streptococcus pneumoniae have been strengthened. The subsection on central line associated blood stream infections is now in the bacterial section. The vaccination section has been dramatically expanded. Changes include the recommendations for PCV rather than PPSV-23 for pneumococcal vaccination, starting some vaccinations earlier post-transplant, and the addition of recommendations for Varivax, HPV vaccine, and (the non-use of) Zostavax vaccine are included. Two additional appendices were added to provide information on desensitization to sulfa drugs and visitor screening questionnaires. Finally, the dosing appendix has merged both adult and pediatric dosing and provides recommendations for several newer antimicrobial agents that were not previously available. In summary, the changes and expansion to this document reflect the growing body of literature detailing infectious complications in HCT patients.

Prospective Surveillance for Invasive Fungal Infections in Hematopoietic Stem Cell Transplant Recipients, 2001–2006: Overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database

BACKGROUND The incidence and epidemiology of invasive fungal infections (IFIs), a leading cause of death among hematopoeitic stem cell transplant (HSCT) recipients, are derived mainly from single-institution retrospective studies. METHODS The Transplant Associated Infections Surveillance Network, a network of 23 US transplant centers, prospectively enrolled HSCT recipients with proven and probable IFIs occurring between March 2001 and March 2006. We collected denominator data on all HSCTs preformed at each site and clinical, diagnostic, and outcome information for each IFI case. To estimate trends in IFI, we calculated the 12-month cumulative incidence among 9 sequential subcohorts. RESULTS We identified 983 IFIs among 875 HSCT recipients. The median age of the patients was 49 years; 60% were male. Invasive aspergillosis (43%), invasive candidiasis (28%), and zygomycosis (8%) were the most common IFIs. Fifty-nine percent and 61% of IFIs were recognized within 60 days of neutropenia and graft-versus-host disease, respectively. Median onset of candidiasis and aspergillosis after HSCT was 61 days and 99 days, respectively. Within a cohort of 16,200 HSCT recipients who received their first transplants between March 2001 and September 2005 and were followed up through March 2006, we identified 718 IFIs in 639 persons. Twelve-month cumulative incidences, based on the first IFI, were 7.7 cases per 100 transplants for matched unrelated allogeneic, 8.1 cases per 100 transplants for mismatched-related allogeneic, 5.8 cases per 100 transplants for matched-related allogeneic, and 1.2 cases per 100 transplants for autologous HSCT. CONCLUSIONS In this national prospective surveillance study of IFIs in HSCT recipients, the cumulative incidence was highest for aspergillosis, followed by candidiasis. Understanding the epidemiologic trends and burden of IFIs may lead to improved management strategies and study design.

Invasive fungal infections among organ transplant recipients: results of the transplant-associated infection surveillance network (Transnet)

BACKGROUND Invasive fungal infections (IFIs) are a major cause of morbidity and mortality among organ transplant recipients. Multicenter prospective surveillance data to determine disease burden and secular trends are lacking. METHODS The Transplant-Associated Infection Surveillance Network (TRANSNET) is a consortium of 23 US transplant centers, including 15 that contributed to the organ transplant recipient dataset. We prospectively identified IFIs among organ transplant recipients from March, 2001 through March, 2006 at these sites. To explore trends, we calculated the 12-month cumulative incidence among 9 sequential cohorts. RESULTS During the surveillance period, 1208 IFIs were identified among 1063 organ transplant recipients. The most common IFIs were invasive candidiasis (53%), invasive aspergillosis (19%), cryptococcosis (8%), non-Aspergillus molds (8%), endemic fungi (5%), and zygomycosis (2%). Median time to onset of candidiasis, aspergillosis, and cryptococcosis was 103, 184, and 575 days, respectively. Among a cohort of 16,808 patients who underwent transplantation between March 2001 and September 2005 and were followed through March 2006, a total of 729 IFIs were reported among 633 persons. One-year cumulative incidences of the first IFI were 11.6%, 8.6%, 4.7%, 4.0%, 3.4%, and 1.3% for small bowel, lung, liver, heart, pancreas, and kidney transplant recipients, respectively. One-year incidence was highest for invasive candidiasis (1.95%) and aspergillosis (0.65%). Trend analysis showed a slight increase in cumulative incidence from 2002 to 2005. CONCLUSIONS We detected a slight increase in IFIs during the surveillance period. These data provide important insights into the timing and incidence of IFIs among organ transplant recipients, which can help to focus effective prevention and treatment strategies.

Fluoroquinolone-Resistant Campylobacter Species and the Withdrawal of Fluoroquinolones from Use in Poultry: A Public Health Success Story

Campylobacter species cause 1.4 million infections each year in the United States. Fluoroquinolones (e.g., ciprofloxacin) are commonly used in adults with Campylobacter infection and other infections. Fluoroquinolones (e.g., enrofloxacin) are also used in veterinary medicine. Human infections with fluoroquinolone-resistant Campylobacter species have become increasingly common and are associated with consumption of poultry. These findings, along with other data, prompted the US Food and Drug Administration to propose the withdrawal of fluoroquinolone use in poultry in 2000. A lengthy legal hearing concluded with an order to withdraw enrofloxacin from use in poultry (effective in September 2005). Clinicians are likely to continue to encounter patients with fluoroquinolone-resistant Campylobacter infection and other enteric infection because of the continued circulation of fluoroquinolone-resistant Campylobacter species in poultry flocks and in persons returning from foreign travel who have acquired a fluoroquinolone-resistant enteric infection while abroad. Judicious use of fluoroquinolones and other antimicrobial agents in human and veterinary medicine is essential to preserve the efficacy of these important chemotherapeutic agents.

Plasmid-Mediated Quinolone Resistance in Non-Typhi Serotypes of Salmonella enterica

BACKGROUND Serious infections with Salmonella species are often treated with fluoroquinolones or extended-spectrum beta-lactams. Increasingly recognized in Enterobacteriaceae, plasmid-mediated quinolone resistance is encoded by qnr genes. Here, we report the presence of qnr variants in human isolates of non-Typhi serotypes of Salmonella enterica (hereafter referred to as non-Typhi Salmonella) from the United States National Antimicrobial Resistance Monitoring System for Enteric Bacteria. METHODS All non-Typhi Salmonella specimens from the United States National Antimicrobial Resistance Monitoring System for Enteric Bacteria collected from 1996 to 2003 with ciprofloxacin minimum inhibitory concentrations > or = 0.06 microg/mL (233 specimens) and a subset with minimum inhibitory concentrations < or = 0.03 microg/mL (102 specimens) were screened for all known qnr genes (A, B, and S) by polymerase chain reaction. For isolates with positive results, qnr and quinolone resistance-determining region sequences were determined. Plasmids containing qnr genes were characterized by conjugation or transformation. RESULTS Conjugative plasmids harboring qnrB variants were detected in 7 Salmonella enterica serotype Berta isolates and 1 Salmonella enterica serotype Mbandaka isolate. The S. Mbandaka plasmid also had an extended-spectrum beta -lactamase. Variants of qnrS on nonconjugative plasmids were detected in isolates of Salmonella enterica serotype Anatum and Salmonella enterica serotype Bovismorbificans. CONCLUSIONS Plasmid-mediated quinolone resistance appears to be widely distributed, though it is still uncommon in non-Typhi Salmonella isolates from the United States, including strains that are quinolone susceptible by the criteria of the Clinical and Laboratory Standards Institute (formerly the National Committee for Clinical Laboratory Standards). The presence of this gene in non-Typhi Salmonella that causes infection in humans suggests potential for spread through the food supply, which is a public health concern.

Factors Associated with Mortality in Transplant Patients with Invasive Aspergillosis

BACKGROUND Invasive aspergillosis (IA) is an important cause of morbidity and mortality in hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) recipients. The purpose of this study was to evaluate factors associated with mortality in transplant patients with IA. METHODS Transplant patients from 23 US centers were enrolled from March 2001 to October 2005 as part of the Transplant Associated Infection Surveillance Network. IA cases were identified prospectively in this cohort through March 2006, and data were collected. Factors associated with 12-week all-cause mortality were determined by logistic regression analysis and Cox proportional hazards regression. RESULTS Six-hundred forty-two cases of proven or probable IA were evaluated, of which 317 (49.4%) died by the study endpoint. All-cause mortality was greater in HSCT patients (239 [57.5%] of 415) than in SOT patients (78 [34.4%] of 227; P<.001). Independent poor prognostic factors in HSCT patients were neutropenia, renal insufficiency, hepatic insufficiency, early-onset IA, proven IA, and methylprednisolone use. In contrast, white race was associated with decreased risk of death. Among SOT patients, hepatic insufficiency, malnutrition, and central nervous system disease were poor prognostic indicators, whereas prednisone use was associated with decreased risk of death. Among HSCT or SOT patients who received antifungal therapy, use of an amphotericin B preparation as part of initial therapy was associated with increased risk of death. CONCLUSIONS There are multiple variables associated with survival in transplant patients with IA. Understanding these prognostic factors may assist in the development of treatment algorithms and clinical trials.

Changes in Incidence and Antifungal Drug Resistance in Candidemia: Results From Population-Based Laboratory Surveillance in Atlanta and Baltimore, 2008–2011

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 with prior surveillance (Atlanta, 1992-1993; Baltimore, 1998-2000). RESULTS We identified 2675 cases of candidemia with 2329 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 with 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}, .17-.38]; white RR: 0.19 [95% CI, .12-.29]; Baltimore: black RR, 0.38 [95% CI, .22-.64]; white RR: 0.51 [95% CI: .29-.90]). Prevalence of fluconazole resistance (7%) was unchanged compared with prior surveillance; 32 (1%) isolates were echinocandin-resistant, and 9 (8 Candida glabrata) were multidrug resistant to both fluconazole and an echinocandin. CONCLUSIONS We describe marked shifts in candidemia epidemiology over the past 2 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.

Guidelines for preventing infectious complications among hematopoietic cell transplant recipients: a global perspective.

Guidelines for preventing infectious complications among hematopoietic cell transplant recipients: a global perspective

Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis

BACKGROUND Cryptococcus is the most common cause of meningitis in adults living with HIV in sub-Saharan Africa. Global burden estimates are crucial to guide prevention strategies and to determine treatment needs, and we aimed to provide an updated estimate of global incidence of HIV-associated cryptococcal disease. METHODS We used 2014 Joint UN Programme on HIV and AIDS estimates of adults (aged >15 years) with HIV and antiretroviral therapy (ART) coverage. Estimates of CD4 less than 100 cells per μL, virological failure incidence, and loss to follow-up were from published multinational cohorts in low-income and middle-income countries. We calculated those at risk for cryptococcal infection, specifically those with CD4 less than 100 cells/μL not on ART, and those with CD4 less than 100 cells per μL on ART but lost to follow-up or with virological failure. Cryptococcal antigenaemia prevalence by country was derived from 46 studies globally. Based on cryptococcal antigenaemia prevalence in each country and region, we estimated the annual numbers of people who are developing and dying from cryptococcal meningitis. FINDINGS We estimated an average global cryptococcal antigenaemia prevalence of 6·0% (95% CI 5·8-6·2) among people with a CD4 cell count of less than 100 cells per μL, with 278 000 (95% CI 195 500-340 600) people positive for cryptococcal antigen globally and 223 100 (95% CI 150 600-282 400) incident cases of cryptococcal meningitis globally in 2014. Sub-Saharan Africa accounted for 73% of the estimated cryptococcal meningitis cases in 2014 (162 500 cases [95% CI 113 600-193 900]). Annual global deaths from cryptococcal meningitis were estimated at 181 100 (95% CI 119 400-234 300), with 135 900 (75%; [95% CI 93 900-163 900]) deaths in sub-Saharan Africa. Globally, cryptococcal meningitis was responsible for 15% of AIDS-related deaths (95% CI 10-19). INTERPRETATION Our analysis highlights the substantial ongoing burden of HIV-associated cryptococcal disease, primarily in sub-Saharan Africa. Cryptococcal meningitis is a metric of HIV treatment programme failure; timely HIV testing and rapid linkage to care remain an urgent priority. FUNDING None.