MenAfriNet: A Network Supporting Case-Based Meningitis Surveillance and Vaccine Evaluation in the Meningitis Belt of Africa.

Meningococcal meningitis remains a significant public health threat, especially in the African meningitis belt where Neisseria meningitidis serogroup A historically caused large-scale epidemics. With the rollout of a novel meningococcal serogroup A conjugate vaccine (MACV) in the belt, the World Health Organization recommended case-based meningitis surveillance to monitor MACV impact and meningitis epidemiology. In 2014, the MenAfriNet consortium was established to support strategic implementation of case-based meningitis surveillance in 5 key countries: Burkina Faso, Chad, Mali, Niger, and Togo. MenAfriNet aimed to develop a high-quality surveillance network using standardized laboratory and data collection protocols, develop sustainable systems for data management and analysis to monitor MACV impact, and leverage the surveillance platform to perform special studies. We describe the MenAfriNet consortium, its history, strategy, implementation, accomplishments, and challenges.

Case-control vaccine effectiveness studies: Data collection, analysis and reporting results.

The case-control methodology is frequently used to evaluate vaccine effectiveness post-licensure. The results of such studies provide important insight into the level of protection afforded by vaccines in a 'real world' context, and are commonly used to guide vaccine policy decisions. However, the potential for bias and confounding are important limitations to this method, and the results of a poorly conducted or incorrectly interpreted case-control study can mislead policies. In 2012, a group of experts met to review recent experience with case-control studies evaluating vaccine effectiveness; we summarize the recommendations of that group regarding best practices for data collection, analysis, and presentation of the results of case-control vaccine effectiveness studies. Vaccination status is the primary exposure of interest, but can be challenging to assess accurately and with minimal bias. Investigators should understand factors associated with vaccination as well as the availability of documented vaccination status in the study context; case-control studies may not be a valid method for evaluating vaccine effectiveness in settings where many children lack a documented immunization history. To avoid bias, it is essential to use the same methods and effort gathering vaccination data from cases and controls. Variables that may confound the association between illness and vaccination are also important to capture as completely as possible, and where relevant, adjust for in the analysis according to the analytic plan. In presenting results from case-control vaccine effectiveness studies, investigators should describe enrollment among eligible cases and controls as well as the proportion with no documented vaccine history. Emphasis should be placed on confidence intervals, rather than point estimates, of vaccine effectiveness. Case-control studies are a useful approach for evaluating vaccine effectiveness; however careful attention must be paid to the collection, analysis and presentation of the data in order to best inform evidence-based vaccine policies.

Case-control vaccine effectiveness studies: Preparation, design, and enrollment of cases and controls.

Case-control studies are commonly used to evaluate effectiveness of licensed vaccines after deployment in public health programs. Such studies can provide policy-relevant data on vaccine performance under 'real world' conditions, contributing to the evidence base to support and sustain introduction of new vaccines. However, case-control studies do not measure the impact of vaccine introduction on disease at a population level, and are subject to bias and confounding, which may lead to inaccurate results that can misinform policy decisions. In 2012, a group of experts met to review recent experience with case-control studies evaluating the effectiveness of several vaccines; here we summarize the recommendations of that group regarding best practices for planning, design and enrollment of cases and controls. Rigorous planning and preparation should focus on understanding the study context including healthcare-seeking and vaccination practices. Case-control vaccine effectiveness studies are best carried out soon after vaccine introduction because high coverage creates strong potential for confounding. Endpoints specific to the vaccine target are preferable to non-specific clinical syndromes since the proportion of non-specific outcomes preventable through vaccination may vary over time and place, leading to potentially confusing results. Controls should be representative of the source population from which cases arise, and are generally recruited from the community or health facilities where cases are enrolled. Matching of controls to cases for potential confounding factors is commonly used, although should be reserved for a limited number of key variables believed to be linked to both vaccination and disease. Case-control vaccine effectiveness studies can provide information useful to guide policy decisions and vaccine development, however rigorous preparation and design is essential.

Bacterial meningitis surveillance in the Eastern Mediterranean region, 2005-2010: successes and challenges of a regional network.

OBJECTIVE: To describe epidemiology of bacterial meningitis in the World Health Organization Eastern Mediterranean Region countries and assist in introduction of new bacterial vaccines. STUDY DESIGN: A laboratory-based sentinel surveillance was established in 2004, and up to 10 countries joined the network until 2010. Personnel at participating hospitals and national public health laboratories received training in surveillance and laboratory methods and used standard clinical and laboratory-confirmed case definitions. RESULTS: Over 22,000 suspected cases of meningitis were reported among children ≤5 years old and >6600 among children >5 years old. In children ≤5 years old, 921 of 13,125 probable cases (7.0%) were culture-confirmed. The most commonly isolated pathogens were S pneumoniae (27% of confirmed cases), N meningitidis (22%), and H influenzae (10%). Among culture-confirmed case-patients with known outcome, case-fatality rate was 7.0% and 12.2% among children ≤5 years old and those >5 years old, respectively. Declining numbers of Haemophilus influenzae type b meningitis cases within 2 years post-Haemophilus influenzae type b conjugate vaccine introduction were observed in Pakistan. CONCLUSIONS: Bacterial meningitis continues to cause significant morbidity and mortality in the Eastern Mediterranean Region. Surveillance networks for bacterial meningitis ensure that all sites are using standardized methodologies. Surveillance data are useful to monitor impact of various interventions including vaccines, but maintaining data quality requires consistent reporting and regular technical support.

Case control study to identify risk factors for acute hepatitis C virus infection in Egypt.

BACKGROUND: Identification of risk factors of acute hepatitis C virus (HCV) infection in Egypt is crucial to develop appropriate prevention strategies. METHODS: We conducted a case-control study, June 2007-September 2008, to investigate risk factors for acute HCV infection in Egypt among 86 patients and 287 age and gender matched controls identified in two infectious disease hospitals in Cairo and Alexandria. Case-patients were defined as: any patient with symptoms of acute hepatitis; lab tested positive for HCV antibodies and negative for HBsAg, HBc IgM, HAV IgM; and 7-fold increase in the upper limit of transaminase levels. Controls were selected from patients' visitors with negative viral hepatitis markers. Subjects were interviewed about previous exposures within six months, including community-acquired and health-care associated practices. RESULTS: Case-patients were more likely than controls to have received injection with a reused syringe (OR=23.1, CI 4.7-153), to have been in prison (OR=21.5, CI 2.5-479.6), to have received IV fluids in a hospital (OR=13.8, CI 5.3-37.2), to have been an IV drug user (OR=12.1, CI 4.6-33.1), to have had minimal surgical procedures (OR=9.7, CI 4.2-22.4), to have received IV fluid as an outpatient (OR=8, CI 4-16.2), or to have been admitted to hospital (OR=7.9, CI 4.2-15) within the last 6 months. Multivariate analysis indicated that unsafe health facility practices are the main risk factors associated with transmission of HCV infection in Egypt. CONCLUSION: In Egypt, focusing acute HCV prevention measures on health-care settings would have a beneficial impact.

International Conference on Emerging Infectious Diseases, 2010.

The seventh International Conference on Emerging Infectious Diseases (ICEID) was held in Atlanta, Georgia, USA, July 11-14, 2010. The conference goal was to bring together public health professionals to encourage exchange of scientific and public health information on global emerging infectious disease issues. The conference was organized by the Centers for Disease Control and Prevention (CDC), American Society for Microbiology, the Council of State and Territorial Epidemiologists, the Association of Public Health Laboratories, and the World Health Organization; additional support was provided by 40 other multidisciplinary public health partners.

Accelerating policy decisions to adopt haemophilus influenzae type B vaccine: a global, multivariable analysis.

BACKGROUND: Adoption of new and underutilized vaccines by national immunization programs is an essential step towards reducing child mortality. Policy decisions to adopt new vaccines in high mortality countries often lag behind decisions in high-income countries. Using the case of Haemophilus influenzae type b (Hib) vaccine, this paper endeavors to explain these delays through the analysis of country-level economic, epidemiological, programmatic and policy-related factors, as well as the role of the Global Alliance for Vaccines and Immunisation (GAVI Alliance). METHODS AND FINDINGS: Data for 147 countries from 1990 to 2007 were analyzed in accelerated failure time models to identify factors that are associated with the time to decision to adopt Hib vaccine. In multivariable models that control for Gross National Income, region, and burden of Hib disease, the receipt of GAVI support speeded the time to decision by a factor of 0.37 (95% CI 0.18-0.76), or 63%. The presence of two or more neighboring country adopters accelerated decisions to adopt by a factor of 0.50 (95% CI 0.33-0.75). For each 1% increase in vaccine price, decisions to adopt are delayed by a factor of 1.02 (95% CI 1.00-1.04). Global recommendations and local studies were not associated with time to decision. CONCLUSIONS: This study substantiates previous findings related to vaccine price and presents new evidence to suggest that GAVI eligibility is associated with accelerated decisions to adopt Hib vaccine. The influence of neighboring country decisions was also highly significant, suggesting that approaches to support the adoption of new vaccines should consider supply- and demand-side factors.

Brucellosis as a cause of acute febrile illness in Egypt.

To develop better estimates of brucellosis incidence, we conducted population-based surveillance for acute febrile illness (AFI) in Fayoum governorate (population 2347249), Egypt during two summer periods (2002 and 2003). All hospitals and a representative sample of community healthcare providers were included. AFI patients without obvious etiology were tested for brucellosis by culture and serology. Incidence estimates were calculated adjusting for sampling methodology and study period. Of 4490 AFI patients enrolled, 321 (7%) met the brucellosis case definition. The estimated annual incidence of brucellosis per 100000 population was 64 and 70 in 2002 and 2003, respectively. The median age of brucellosis patients was 26 years and 70% were male; 53% were initially diagnosed as typhoid fever. Close contact with animals and consumption of unpasteurized milk products were associated with brucellosis. The high incidence of brucellosis in Fayoum highlights its public health importance, and the need to implement prevention strategies in humans and animals.

Population-based surveillance for cryptococcosis in an antiretroviral-naive South African province with a high HIV seroprevalence.

OBJECTIVES: To measure the burden of disease and describe the epidemiology of cryptococcosis in Gauteng Province, South Africa. DESIGN AND METHODS: The study was an active, prospective, laboratory-based, population-based surveillance. An incident case of cryptococcosis was defined as the first isolation by culture of any Cryptococcus species from any clinical specimen, a positive India ink cryptococcal latex agglutination test or a positive histopathology specimen from a Gauteng resident. Cases were identified prospectively at all laboratories in Gauteng. Case report forms were completed using medical record review and patient interview where possible. RESULTS: Between 1 March 2002 and 29 February 2004, 2753 incident cases were identified. The overall incidence rate was 15.6/100 000. Among HIV-infected persons, the rate was 95/100 000, and among persons living with AIDS 14/1000. Males and children under 15 years accounted for 49 and 0.9% of cases, respectively. The median age was 34 years (range, 1 month-74 years). Almost all cases (97%) presented with meningitis. Antifungal therapy was given to 2460 (89%) cases of which 72% received fluconazole only. In-hospital mortality was 27% (749 cases). Recurrences occurred in 263 (9.5%) incident cases. Factors associated with death included altered mental status, coma or wasting; factors associated with survival included employment in the mining industry, visual changes or headache on presentation. CONCLUSIONS: This study demonstrates the high disease burden due to cryptococcosis in an antiretroviral-naive South African population and emphasizes the need to improve early recognition, diagnosis and treatment of the condition.

Cryptococcus gattii infection: characteristics and epidemiology of cases identified in a South African province with high HIV seroprevalence, 2002-2004.

We describe 46 Cryptococcus gattii-infected persons identified by population-based surveillance conducted in South Africa. Most patients with C. gattii infection presented with meningitis. The mortality rate during hospitalization was 36%. We found no significant differences between persons with and persons without C. gattii infection with regard to clinical presentation, acquired immunodeficiency syndrome diagnosis, concomitant conditions, or prior opportunistic infections. C. gattii isolates had low MICs to the tested antifungal drugs.

Rapid enzyme-linked immunosorbent assay for the diagnosis of human brucellosis in surveillance and clinical settings in Egypt.

OBJECTIVE: To optimize and standardize an enzyme-linked immunosorbent assay (ELISA) for rapid diagnosis of human brucellosis in clinical cases identified during a surveillance study for acute febrile illness (AFI). METHODS: Serum samples from patients presenting with AFI at 13 fever hospitals across Egypt between 1999 and 2003 were kept frozen at NAMRU-3 and used in this study. The assay was evaluated in 5 subject groups: brucellosis cases confirmed by blood culture (group I, n=202) 87% positive by standard tube agglutination test (TA), brucellosis cases exclusively confirmed by TA (group II, n=218), blood cultures from AFI cases positive for bacterial species other than Brucella (group III, n=103), AFI cases with unexplained etiologies (group IV, n=654), and healthy volunteers (group V, n=50). All members of groups III-V were negative for brucellosis by TA. RESULTS: Sensitivity and specificity of ELISA for total specific antibodies were >=96% versus 87% for TA as compared to microbial culture, the current gold standard method for Brucella identification. Assessment of Brucella antibody classes by ELISA in random subsets of the 5 groups showed significantly high (p>0.001) levels of anti Brucella IgG (>=81%) and IgM (>=90%) in groups I and II only. CONCLUSION: The obtained sensitivity and specificity results indicate that our ELISA is more suitable for AFI surveillance and clinical settings than blood culture and TA. The developed assay is also cost-effective, easier to use, faster, and the coated plates can be stocked for at least 8 months, providing a potential for field use and automation.

Differentiation of tuberculous meningitis from acute bacterial meningitis using simple clinical and laboratory parameters.

Tuberculous meningitis (TBM) is still a major cause of serious illness in many parts of the world. The newer diagnostic tests and neuroimaging methods are unlikely to be available in many developing countries. We attempt to identify simple parameters for early diagnosis. A retrospective study was performed to compare the clinical and laboratory features of cultured-confirmed, TBM (134) and other bacterial meningitis (709). Features independently predictive of TBM were studied by multivariate logistic regression to develop a diagnostic rule. Six features were found predictive: length of clinical history >5 days, headache, total cerebrospinal fluid (CSF) white blood cell count of <1000/mm3, clear appearance of CSF, lymphocyte proportion of >30%, and protein content of >100 mg/dL. Application of 3 or more parameters revealed 93% sensitivity and 77% specificity. Applying this diagnostic rule can help in the early diagnosis of TBM, in both children and adults.

Evaluation of amphotericin B interpretive breakpoints for Candida bloodstream isolates by correlation with therapeutic outcome.

One hundred seven Candida bloodstream isolates (51 C. albicans, 24 C. glabrata, 13 C. parapsilosis, 13 C. tropicalis, 2 C. dubliniensis, 2 C. krusei, and 2 C. lusitaniae strains) from patients treated with amphotericin B alone underwent in vitro susceptibility testing against amphotericin B using five different methods. Fifty-four isolates were from patients who failed treatment, defined as death 7 to 14 days after the incident candidemia episode, having persistent fever of >or=5 days' duration after the date of the incident candidemia, or the recurrence of fever after two consecutive afebrile days while on antifungal treatment. MICs were determined by using the Clinical Laboratory Standards Institute (formally National Committee for Clinical Laboratory Standards) broth microdilution procedure with two media and by using Etest. Minimum fungicidal concentrations (MFCs) were also measured in two media. Broth microdilution tests with RPMI 1640 medium generated a restricted range of MICs (0.125 to 1 microg/ml); the corresponding MFC values ranged from 0.5 to 4 microg/ml. Broth microdilution tests with antibiotic medium 3 produced a broader distribution of MIC and MFC results (0.015 to 0.25 microg/ml and 0.06 to 2 microg/ml, respectively). Etest produced the widest distribution of MICs (0.094 to 2 microg/ml). However, none of the test formats studied generated results that significantly correlated with therapeutic success or failure.

Excess mortality, hospital stay, and cost due to candidemia: a case-control study using data from population-based candidemia surveillance.

OBJECTIVE: To determine the mortality, hospital stay, and total hospital charges and cost of hospitalization attributable to candidemia by comparing patients with candidemia with control-patients who have otherwise similar illnesses. Prior studies lack broad patient and hospital representation or cost-related information that accurately reflects current medical practices. DESIGN: Our case-control study included case-patients with candidemia and their cost-related data, ascertained from laboratory-based candidemia surveillance conducted among all residents of Connecticut and Baltimore and Baltimore County, Maryland, during 1998 to 2000. Control-patients were matched on age, hospital type, admission year, discharge diagnoses, and duration of hospitalization prior to candidemia onset. RESULTS: We identified 214 and 529 sets of matched case-patients and control-patients from the two locations, respectively. Mortality attributable to candidemia ranged between 19% and 24%. On multivariable analysis, candidemia was associated with mortality (OR, 5.3 for Connecticut and 8.5 for Baltimore and Baltimore County; P < .05), whereas receiving adequate treatment was protective (OR, 0.5 and 0.4 for the two locations, respectively; P < .05). Candidemia itself did not increase the total hospital charges and cost of hospitalization; when treatment status was accounted for, having received adequate treatment for candidemia significantly increased the total hospital charges and cost of hospitalization ($6,000 to $29,000 and $3,000 to $22,000, respectively) and the length of stay (3 to 13 days). CONCLUSION: Our findings underscore the burden of candidemia, particularly regarding the risk of death, length of hospitalization, and cost associated with treatment.

Determining risk factors for candidemia among newborn infants from population-based surveillance: Baltimore, Maryland, 1998-2000.

BACKGROUND: Our objective was to determine risks factors for late onset candidemia, independent of birth weight, in newborn infants. METHODS: We performed a matched case-control study. Cases were identified through active, population-based surveillance for candidemia, conducted in Baltimore City and County during 1998-2000, and were defined as the incident isolation of any Candida species from the bloodstream of an infant 3 months old or younger. Four controls, matched by age, hospital, birth weight category, hospital stay and admission date, were selected for each case. Potential risk factors included clinical, demographic and maternal prenatal data. RESULTS: Of the 35 cases, 19 (54%) infections were with Candida albicans, 9 (26%) were with Candida parapsilosis and 5 (14%) were with Candida glabrata. Cases had a median birth weight of 680 g (range, 430-3200 g); median gestational ages of cases and controls were 25 and 27 weeks, respectively. Compared with controls, cases had significant higher mortality (20% versus 4%; P = 0.004). No maternal factors were associated with increased risk of disease; cases were as likely as controls to be of black race. Multivariable conditional logistic regression analysis revealed that gestational age younger than 26 weeks [adjusted odds ratio, 6.5; 95% confidence interval (95% CI), 1.3-32], vaginal delivery (adjusted odds ratio, 4.3; 95% CI 1.3-14.2) and abdominal surgery (adjusted odds ratio, 10.9; 95% CI 1.9-62) were independently associated with increased risk of candidemia. CONCLUSIONS: Independent of birth weight, infants born at <26 weeks or those who have had abdominal surgery are at a significantly increased risk of candidemia. This study helps define a subgroup of preterm infants at high risk of developing bloodstream infections with Candida species.

An epidemic of coccidioidomycosis in Arizona associated with climatic changes, 1998-2001.

BACKGROUND: Reports of coccidioidomycosis cases in Arizona have increased substantially. We investigated factors associated with the increase. METHODS: We analyzed the National Electronic Telecommunications System for Surveillance (NETSS) data from 1998 to 2001 and used Geographic Information Systems (GIS) to map high-incidence areas in Maricopa County. Poisson regression analysis was performed to assess the effect of climatic and environmental factors on the number of monthly cases; a model was developed and tested to predict outbreaks. RESULTS: The overall incidence in 2001 was 43 cases/100,000 population, a significant (P<.01, test for trend) increase from 1998 (33 cases/100,000 population); the highest age-specific rate was in persons > or =65 years old (79 cases/100,000 population in 2001). Analysis of NETSS data by season indicated high-incidence periods during the winter (November-February). GIS analysis showed that the highest-incidence areas were in the periphery of Phoenix. Multivariable Poisson regression modeling revealed that a combination of certain climatic and environmental factors were highly correlated with seasonal outbreaks (R2=0.75). CONCLUSIONS: Coccidioidomycosis in Arizona has increased. Its incidence is driven by seasonal outbreaks associated with environmental and climatic changes. Our study may allow public-health officials to predict seasonal outbreaks in Arizona and to alert the public and physicians early, so that appropriate preventive measures can be implemented.

A large histoplasmosis outbreak among high school students in Indiana, 2001.

BACKGROUND: A histoplasmosis outbreak occurred in an Indiana high school in November-December 2001. METHODS: To describe the risk factors for this outbreak, we conducted a cohort study of all available students and staff (N = 682) and an environmental investigation. RESULTS: Of the 523 (77%) persons who displayed serologic evidence of recent Histoplasma capsulatum infection, 355 (68%) developed symptoms consistent with acute pulmonary histoplasmosis. Rototilling of soil in a school courtyard known to be a bird roosting site had been performed during school hours on November 12, 2001, 14 days before both the peak of the onset of illness and a rise in student absenteeism. Being a student (odds ratio, 3.3; 95% confidence interval, 2.2-5.0) and being a student in a classroom near the courtyard during the rototilling (odds ratio, 3.1; 95% confidence interval, 1.8-5.2) were independently associated with infection and symptomatic illness. H. capsulatum was isolated from environmental samples, including soil from the courtyard and dust collected from a filter of a heating, ventilating and air-conditioning system. CONCLUSIONS: Soil-disrupting activities within a school courtyard caused the largest outbreak to date of histoplasmosis among adolescents. Improved efforts are needed to educate the community in endemic areas about histoplasmosis to prevent the occurrence of such outbreaks in the future. In addition, increased awareness among health care providers of this disease would facilitate appropriate diagnosis and treatment.

Epidemiologic and molecular characterization of an outbreak of Candida parapsilosis bloodstream infections in a community hospital.

Candida parapsilosis is an important cause of bloodstream infections in the health care setting. We investigated a large C. parapsilosis outbreak occurring in a community hospital and conducted a case-control study to determine the risk factors for infection. We identified 22 cases of bloodstream infection with C. parapsilosis: 15 confirmed and 7 possible. The factors associated with an increased risk of infection included hospitalization in the intensive care unit (adjusted odds ratio, 16.4; 95% confidence interval, 1.8 to 148.1) and receipt of total parenteral nutrition (adjusted odds ratio, 9.2; 95% confidence interval, 0.9 to 98.1). Samples for surveillance cultures were obtained from health care worker hands, central venous catheter insertion sites, and medical devices. Twenty-six percent of the health care workers surveyed demonstrated hand colonization with C. parapsilosis, and one hand isolate was highly related to all case-patient isolates by tests with the DNA probe Cp3-13. Outbreak strain isolates also demonstrated reduced susceptibilities to fluconazole and voriconazole. This largest known reported outbreak of C. parapsilosis bloodstream infections in adults resulted from an interplay of host, environment, and pathogen factors. Recommendations for control measures focused on improving hand hygiene compliance.

Candida parapsilosis characterization in an outbreak setting.

Candida parapsilosis is an important non-albicans species which infects hospitalized patients. No studies have correlated outbreak infections of C. parapsilosis with multiple virulence factors. We used DNA fingerprinting to determine genetic variability among isolates from a C. parapsilosis outbreak and from our clinical database. We compared phenotypic markers of pathogenesis, including adherence, biofilm formation, and protein secretion (secretory aspartic protease [SAP] and phospholipase). Adherence was measured as colony counts on silicone elastomer disks immersed in agar. Biofilms formed on disks were quantified by dry weight. SAP expression was measured by hydrolysis of bovine albumin; a colorimetric assay was used to quantitate phospholipase. DNA fingerprinting indicated that the outbreak isolates were clonal and genetically distinct from our database. Biofilm expression by the outbreak clone was greater than that of sporadic isolates (p < or =0.0005). Adherence and protein secretion did not correlate with strain pathogenicity. These results suggest that biofilm production plays a role in C. parapsilosis outbreaks.