Pablo Cruz-Hervert

Partial protection of seasonal trivalent inactivated vaccine against novel pandemic influenza A/H1N1 2009: case-control study in Mexico City

Objective To evaluate the association of 2008-9 seasonal trivalent inactivated vaccine with cases of influenza A/H1N1 during the epidemic in Mexico. Design Frequency matched case-control study. Setting Specialty hospital in Mexico City, March to May 2009. Participants 60 patients with laboratory confirmed influenza A/H1N1 and 180 controls with other diseases (not influenza-like illness or pneumonia) living in Mexico City or the State of Mexico and matched for age and socioeconomic status. Main outcome measures Odds ratio and effectiveness of trivalent inactivated vaccine against influenza A/H1N1. Results Cases were more likely than controls to be admitted to hospital, undergo invasive mechanical ventilation, and die. Controls were more likely than cases to have chronic conditions that conferred a higher risk of influenza related complications. In the multivariate model, influenza A/H1N1 was independently associated with trivalent inactivated vaccine (odds ratio 0.27, 95% confidence interval 0.11 to 0.66) and underlying conditions (0.15, 0.08 to 0.30). Vaccine effectiveness was 73% (95% confidence interval 34% to 89%). None of the eight vaccinated cases died. Conclusions Preliminary evidence suggests some protection from the 2008-9 trivalent inactivated vaccine against pandemic influenza A/H1N1 2009, particularly severe forms of the disease, diagnosed in a specialty hospital during the influenza epidemic in Mexico City.

Association of Pulmonary Tuberculosis and Diabetes in Mexico: Analysis of the National Tuberculosis Registry 2000-2012

Background Tuberculosis (TB) remains a public health problem in Mexico while the incidence of diabetes mellitus type 2 (DM) has increased rapidly in recent years. Objective To describe the trends of incidence rates of pulmonary TB associated with DM and not associated with DM and to compare the results of treatment outcomes in patients with and without DM. Materials and Methods We analysed the National Tuberculosis Registry from 2000 to 2012 including patients with pulmonary TB among individuals older than 20 years of age. The association between DM and treatment failure was analysed using logistic regression, accounting for clustering due to regional distribution. Results In Mexico from 2000 to 2012, the incidence rates of pulmonary TB associated to DM increased by 82.64%, (p <0.001) in contrast to rates of pulmonary TB rate without DM, which decreased by 26.77%, (p <0.001). Patients with a prior diagnosis of DM had a greater likelihood of failing treatment (adjusted odds ratio, 1.34 (1.11–1.61) p <0.002) compared with patients who did not have DM. There was statistical evidence of interaction between DM and sex. The odds of treatment failure were increased in both sexes. Conclusion Our data suggest that the growing DM epidemic has an impact on the rates of pulmonary TB. In addition, patients who suffer from both diseases have a greater probability of treatment failure.

Results of the Implementation of a Pilot Model for the Bidirectional Screening and Joint Management of Patients with Pulmonary Tuberculosis and Diabetes Mellitus in Mexico

Background Recently, the World Health Organisation and the International Union Against Tuberculosis and Lung Disease published a Collaborative Framework for the Care and Control of Tuberculosis (TB) and Diabetes (DM) (CFTB/DM) proposing bidirectional screening and joint management. Objective To evaluate the feasibility and effectiveness of the CFTB/DM in Mexico. Design. Prospective observational cohort. Setting. 15 primary care units in 5 states in Mexico. Participants: Patients aged ≥20 years diagnosed with DM or pulmonary TB who sought care at participating clinics. Intervention: The WHO/Union CFTB/DM was adapted and implemented according to official Mexican guidelines. We recruited participants from July 2012 to April 2013 and followed up until March 2014. Bidirectional screening was performed. Patients diagnosed with TB and DM were invited to receive TB treatment under joint management. Main outcome measures. Diagnoses of TB among DM, of DM among TB, and treatment outcomes among patients with DM and TB. Results Of 783 DM patients, 11 (1.4%) were unaware of their TB. Of 361 TB patients, 16 (4.4%) were unaware of their DM. 95 TB/DM patients accepted to be treated under joint management, of whom 85 (89.5%) successfully completed treatment. Multiple linear regression analysis with change in HbA1c and random capillary glucose as dependent variables revealed significant decrease with time (regression coefficients (β)  = −0.660, (95% confidence interval (CI), −0.96 to −0.35); and β = −1.889 (95% CI, −2.77 to −1.01, respectively)) adjusting by sex, age and having been treated for a previous TB episode. Patients treated under joint management were more likely to experience treatment success than patients treated under routine DM and TB programs as compared to historical (adjusted OR (aOR), 2.8, 95%CI 1.28–6.13) and same period (aOR 2.37, 95% CI 1.13–4.96) comparison groups. Conclusions Joint management of TB and DM is feasible and appears to improve clinical outcomes.

Using high-throughput sequencing to leverage surveillance of genetic diversity and oseltamivir resistance: a pilot study during the 2009 influenza A(H1N1) pandemic.

Background Influenza viruses display a high mutation rate and complex evolutionary patterns. Next-generation sequencing (NGS) has been widely used for qualitative and semi-quantitative assessment of genetic diversity in complex biological samples. The “deep sequencing” approach, enabled by the enormous throughput of current NGS platforms, allows the identification of rare genetic viral variants in targeted genetic regions, but is usually limited to a small number of samples. Methodology and Principal Findings We designed a proof-of-principle study to test whether redistributing sequencing throughput from a high depth-small sample number towards a low depth-large sample number approach is feasible and contributes to influenza epidemiological surveillance. Using 454-Roche sequencing, we sequenced at a rather low depth, a 307 bp amplicon of the neuraminidase gene of the Influenza A(H1N1) pandemic (A(H1N1)pdm) virus from cDNA amplicons pooled in 48 barcoded libraries obtained from nasal swab samples of infected patients (n  =  299) taken from May to November, 2009 pandemic period in Mexico. This approach revealed that during the transition from the first (May-July) to second wave (September-November) of the pandemic, the initial genetic variants were replaced by the N248D mutation in the NA gene, and enabled the establishment of temporal and geographic associations with genetic diversity and the identification of mutations associated with oseltamivir resistance. Conclusions NGS sequencing of a short amplicon from the NA gene at low sequencing depth allowed genetic screening of a large number of samples, providing insights to viral genetic diversity dynamics and the identification of genetic variants associated with oseltamivir resistance. Further research is needed to explain the observed replacement of the genetic variants seen during the second wave. As sequencing throughput rises and library multiplexing and automation improves, we foresee that the approach presented here can be scaled up for global genetic surveillance of influenza and other infectious diseases.

Effect of isoniazid on antigen-specific interferon-γ secretion in latent tuberculosis

Treatment of persons with latent tuberculosis (TB) infection at greatest risk of reactivation is an important component of TB control and elimination strategies. Biomarkers evaluating the effectiveness of treatment of latent TB infection have not yet been identified. This information would enhance control efforts and assist the evaluation of new treatment regimes. We designed a two-group, two-arm, randomised clinical study of tuberculin skin test-positive participants: 26 with documented contact with TB patients and 34 with non-documented contact. Participants in each group were randomly assigned to the immediate- or deferred-isoniazid treatment arms. Assays of in vitro interferon (IFN)-γ secretion in response to recombinant Rv1737 and overlapping synthetic peptide pools from various groups of immunodominant proteins were performed. During isoniazid therapy, a significant increase from baseline in the proportion of IFN-γ responders to the 10-kDa culture filtrate protein, Rv2031, Rv0849, Rv1986, Rv2659c, Rv2693c and the recombinant Rv1737 protein was observed (p⩽0.05). The peptide pool of Rv0849 and Rv1737 recombinant proteins induced the highest percentage of IFN-γ responders after isoniazid therapy. The in vitro IFN-γ responses to these proteins might represent useful markers to evaluate changes associated with treatment of latent TB infection. Peptide pool of Rv0849 and recombinant protein Rv1737 may be useful to test the efficacy of treatment of latent TB http://ow.ly/Catld

Association between Highly Active Antiretroviral Therapy and Type of Infectious Respiratory Disease and All-Cause In-Hospital Mortality in Patients with HIV/AIDS: A Case Series.

Background Respiratory manifestations of HIV disease differ globally due to differences in current availability of effective highly active antiretroviral therapy (HAART) programs and epidemiology of infectious diseases. Objective To describe the association between HAART and discharge diagnosis and all-cause in-hospital mortality among hospitalized patients with infectious respiratory disease and HIV/AIDS. Material and Methods We retrospectively reviewed the records of patients hospitalized at a specialty hospital for respiratory diseases in Mexico City between January 1st, 2010 and December 31st, 2011. We included patients whose discharge diagnosis included HIV or AIDS and at least one infectious respiratory diagnosis. The information source was the clinical chart. We analyzed the association between HAART for 180 days or more and type of respiratory disease using polytomous logistic regression and all-cause hospital mortality by multiple logistic regressions. Results We studied 308 patients, of whom 206 (66.9%) had been diagnosed with HIV infection before admission to the hospital. The CD4+ lymphocyte median count was 68 cells/mm3 [interquartile range (IQR): 30–150]. Seventy-five (24.4%) cases had received HAART for more than 180 days. Pneumocystis jirovecii pneumonia (PJP) (n = 142), tuberculosis (n = 63), and bacterial community-acquired pneumonia (n = 60) were the most frequent discharge diagnoses. Receiving HAART for more than 180 days was associated with a lower probability of PJP [Adjusted odd ratio (aOR): 0.245, 95% Confidence Interval (CI): 0.08–0.8, p = 0.02], adjusted for sociodemographic and clinical covariates. HAART was independently associated with reduced odds (aOR 0.214, 95% CI 0.06–0.75) of all-cause in-hospital mortality, adjusting for HIV diagnosis previous to hospitalization, age, access to social security, low socioeconomic level, CD4 cell count, viral load, and discharge diagnoses. Conclusions HAART for 180 days or more was associated with 79% decrease in all-cause in-hospital mortality and lower frequency of PJP as discharge diagnosis. The prevalence of poorly controlled HIV was high, regardless of whether HIV was diagnosed before or during admission. HIV diagnosis and treatment resources should be improved, and strengthening of HAART program needs to be promoted.

Molecular clustering of patients with diabetes and pulmonary tuberculosis: A systematic review and meta-analysis

Introduction Many studies have explored the relationship between diabetes mellitus (DM) and tuberculosis (TB) demonstrating increased risk of TB among patients with DM and poor prognosis of patients suffering from the association of DM/TB. Owing to a paucity of studies addressing this question, it remains unclear whether patients with DM and TB are more likely than TB patients without DM to be grouped into molecular clusters defined according to the genotype of the infecting Mycobacterium tuberculosis bacillus. That is, whether there is convincing molecular epidemiological evidence for TB transmission among DM patients. Objective: We performed a systematic review and meta-analysis to quantitatively evaluate the propensity for patients with DM and pulmonary TB (PTB) to cluster according to the genotype of the infecting M. tuberculosis bacillus. Materials and methods We conducted a systematic search in MEDLINE and LILACS from 1990 to June, 2016 with the following combinations of key words “tuberculosis AND transmission” OR “tuberculosis diabetes mellitus” OR “Mycobacterium tuberculosis molecular epidemiology” OR “RFLP-IS6110” OR “Spoligotyping” OR “MIRU-VNTR”. Studies were included if they met the following criteria: (i) studies based on populations from defined geographical areas; (ii) use of genotyping by IS6110- restriction fragment length polymorphism (RFLP) analysis and spoligotyping or mycobacterial interspersed repetitive unit-variable number of tandem repeats (MIRU-VNTR) or other amplification methods to identify molecular clustering; (iii) genotyping and analysis of 50 or more cases of PTB; (iv) study duration of 11 months or more; (v) identification of quantitative risk factors for molecular clustering including DM; (vi) > 60% coverage of the study population; and (vii) patients with PTB confirmed bacteriologically. The exclusion criteria were: (i) Extrapulmonary TB; (ii) TB caused by nontuberculous mycobacteria; (iii) patients with PTB and HIV; (iv) pediatric PTB patients; (v) TB in closed environments (e.g. prisons, elderly homes, etc.); (vi) diabetes insipidus and (vii) outbreak reports. Hartung-Knapp-Sidik-Jonkman method was used to estimate the odds ratio (OR) of the association between DM with molecular clustering of cases with TB. In order to evaluate the degree of heterogeneity a statistical Q test was done. The publication bias was examined with Begg and Egger tests. Review Manager 5.3.5 CMA v.3 and Biostat and Software package R were used. Results Selection criteria were met by six articles which included 4076 patients with PTB of which 13% had DM. Twenty seven percent of the cases were clustered. The majority of cases (48%) were reported in a study in China with 31% clustering. The highest incidence of TB occurred in two studies from China. The global OR for molecular clustering was 0.84 (IC 95% 0.40–1.72). The heterogeneity between studies was moderate (I2 = 55%, p = 0.05), although there was no publication bias (Beggs test p = 0.353 and Eggers p = 0.429). Conclusion There were very few studies meeting our selection criteria. The wide confidence interval indicates that there is not enough evidence to draw conclusions about the association. Clustering of patients with DM in TB transmission chains should be investigated in areas where both diseases are prevalent and focus on specific contexts.

Surveillance of nosocomial infections in a Mexican community hospital: how are we doing?

OBJECTIVE To compare the nosocomial infection (NI) rate obtained from a retrospective review of clinical charts with that from the routine nosocomial infection surveillance system in a community hospital. MATERIAL AND METHODS Retrospective review of a randomized sample of clinical charts.Results were compared to standard surveillance using crude and adjusted analyses. RESULTS A total of 440 discharges were reviewed, there were 27 episodes of NIs among 22 patients. Cumulated incidence was 6.13 NI per 100 discharges. Diarrhea, pneumonia and peritonitis were the most common infections. Predictors of NI by Cox regression analysis included pleural catheter (HR 16.38), entry through the emergency ward, hospitalization in the intensive care unit (HR 7.19), and placement of orotracheal tube (HR 5.54). CONCLUSIONS Frequency of NIs in this community hospital was high and underestimated. We identified urgent needs in the areas of training and monitoring.

Hepatitis A seroprevalence in adolescents and young adults in Mexico: A 2012 National Health and Nutrition Survey analysis

To describe hepatitis A virus (HAV) seroprevalence and associated factors in adolescents (10-19 years) and young adults (20-25 years) in different Mexican regions, using 2012 National Health and Nutrition Survey data. A random selection of 1581 serum samples was analyzed. Weighted HAV seroprevalence with 95% confidence intervals (95%CI) and its association with sociodemographic factors were estimated. Mean weighted HAV seroprevalence was 69.3% (95%CI: 64.8-73.4) overall, with 58.8% (95%CI: 53.4-64.1) in adolescents and 83.0% (95%CI: 75.3-88.7) in young adults. By age of 10, 46.7% (95%CI: 33.9-60.0) were seropositive and by age of 15, 52.8% (95%CI: 36.5-68.5), corresponding to intermediate endemicity nationally. Factors associated with HAV seropositivity (adjusted odds ratio, aOR) included: lower socioeconomic status (SES) (aOR = 4.09 for low and aOR = 2.31 for medium versus high SES), older age (aOR = 0.29 for adolescents versus young adults), living in the South (aOR = 2.12 versus Central Mexico) or in rural areas (aOR = 2.25 versus urban areas). Regional differences and increased seroprevalence of HAV in marginalized populations present an important public health issue, as a relatively large proportion of young adults are susceptible to infection. The burden of symptomatic disease must be addressed further to support specific programs of continued sanitation and education improvement, and the possibility of vaccination in more susceptible regions.

Genotyping and spatial analysis of pulmonary tuberculosis and diabetes cases in the state of Veracruz, Mexico

Background Genotyping and georeferencing in tuberculosis (TB) have been used to characterize the distribution of the disease and occurrence of transmission within specific groups and communities. Objective The objective of this study was to test the hypothesis that diabetes mellitus (DM) and pulmonary TB may occur in spatial and molecular aggregations. Material and methods Retrospective cohort study of patients with pulmonary TB. The study area included 12 municipalities in the Sanitary Jurisdiction of Orizaba, Veracruz, México. Patients with acid-fast bacilli in sputum smears and/or Mycobacterium tuberculosis in sputum cultures were recruited from 1995 to 2010. Clinical (standardized questionnaire, physical examination, chest X-ray, blood glucose test and HIV test), microbiological, epidemiological, and molecular evaluations were carried out. Patients were considered “genotype-clustered” if two or more isolates from different patients were identified within 12 months of each other and had six or more IS6110 bands in an identical pattern, or < 6 bands with identical IS6110 RFLP patterns and spoligotype with the same spacer oligonucleotides. Residential and health care centers addresses were georeferenced. We used a Jeep hand GPS. The coordinates were transferred from the GPS files to ArcGIS using ArcMap 9.3. We evaluated global spatial aggregation of patients in IS6110-RFLP/ spoligotype clusters using global Moran´s I. Since global distribution was not random, we evaluated “hotspots” using Getis-Ord Gi* statistic. Using bivariate and multivariate analysis we analyzed sociodemographic, behavioral, clinic and bacteriological conditions associated with “hotspots”. We used STATA® v13.1 for all statistical analysis. Results From 1995 to 2010, 1,370 patients >20 years were diagnosed with pulmonary TB; 33% had DM. The proportion of isolates that were genotyped was 80.7% (n = 1105), of which 31% (n = 342) were grouped in 91 genotype clusters with 2 to 23 patients each; 65.9% of total clusters were small (2 members) involving 35.08% of patients. Twenty three (22.7) percent of cases were classified as recent transmission. Moran`s I indicated that distribution of patients in IS6110-RFLP/spoligotype clusters was not random (Moran`s I = 0.035468, Z value = 7.0, p = 0.00). Local spatial analysis showed statistically significant spatial aggregation of patients in IS6110-RFLP/spoligotype clusters identifying “hotspots” and “coldspots”. GI* statistic showed that the hotspot for spatial clustering was located in Camerino Z. Mendoza municipality; 14.6% (50/342) of patients in genotype clusters were located in a hotspot; of these, 60% (30/50) lived with DM. Using logistic regression the statistically significant variables associated with hotspots were: DM [adjusted Odds Ratio (aOR) 7.04, 95% Confidence interval (CI) 3.03–16.38] and attending the health center in Camerino Z. Mendoza (aOR18.04, 95% CI 7.35–44.28). Conclusions The combination of molecular and epidemiological information with geospatial data allowed us to identify the concurrence of molecular clustering and spatial aggregation of patients with DM and TB. This information may be highly useful for TB control programs.