Alimuddin Zumla

Human Zika infection induces a reduction of IFN-γ producing CD4 T-cells and a parallel expansion of effector Vδ2 T-cells

The definition of the immunological response to Zika (ZIKV) infection in humans represents a key issue to identify protective profile useful for vaccine development and for pathogenesis studies. No data are available on the cellular immune response in the acute phase of human ZIKV infection, and its role in the protection and/or pathogenesis needs to be clarified. We studied and compared the phenotype and functionality of T-cells in patients with acute ZIKV and Dengue viral (DENV) infections. A significant activation of T-cells was observed during both ZIKV and DENV infections. ZIKV infection was characterized by a CD4 T cell differentiation toward effector cells and by a lower frequency of IFN-γ producing CD4 T cells. Moreover, a substantial expansion of CD3+CD4−CD8− T-cell subset expressing Vδ2u2009TCR was specifically observed in ZIKV patients. Vδ2 T cells presented a terminally differentiated profile, expressed granzyme B and maintained their ability to produce IFN-γ. These findings provide new knowledge on the immune response profile during self-limited infection that may help in vaccine efficacy definition, and in identifying possible immuno-pathogenetic mechanisms of severe infection.

Predominance of one T-cell antigen receptor BV haplotype in African populations.

Abstractu2002The human T-cell antigen receptor (TCR) is the counter-receptor for the HLA/peptide complex displayed on the surface of antigen-presenting cells. It confers antigen specificity on T lymphocytes and therefore plays a central role in pathogen recognition and host response. The most frequently used form of the TCR is a heterodimer composed of variable α and β chains. We investigated allele frequencies for four variable-region gene segments of the β chain (2S1, 3S1, 8S3, and 15S1) in 146 Caucasians and 165 Africans. The results reveal significant unexpected differences between the two populations for allele frequencies, phenotypes, genotypes, and haplotypes. Among Caucasians, there are 43 phenotypes, whereas there are 31 among the Africans studied. There are 17 haplotypes in the Caucasian sample but only 10 in Africans. This loss of diversity is largely due to the high frequency of one haplotype in the African sample which represents 65% of the informative chromosomes. At least one copy of this haplotype is present in 90% of informative individuals. As a result, 29% of Africans are homozygous for the common haplotype. Less genetic diversity at TCRBV is unexpected, since Africans usually show greater genetic diversity than other ethnic groups. For example, there are approximately twice as many HLA haplotypes in Africans compared to Caucasians. Homozygosity is also unexpected because it reduces the number of TCR variants available to recognize HLA pathogen-derived peptide complexes.

A large ongoing outbreak of hepatitis A predominantly affecting young males in Lazio, Italy; August 2016 - March 2017

The hepatitis A virus (HAV) is mainly transmitted through the faecal-oral route. In industrialized countries HAV infection generally occurs as either sporadic cases in travelers from endemic areas, local outbreak within closed/semi-closed population and as foodborne community outbreak. Recently, an increasing number of HAV infection clusters have been reported among young men-who-have-sex-with-men (MSM). The Lazio Regional Service for the epidemiology and control for infectious diseases (SeRESMI) has noticed an increase of acute hepatitis A (AHA) since September 2016. Temporal analysis carried out with a discrete Poisson model using surveillance data between January 2016 and March 2017 evidenced an ongoing outbreak of AHA that started at the end of August. Molecular investigation carried out on 130 out of 513 cases AHA reported until March 2017 suggests that this outbreak is mainly supported by an HAV variant which is currently spreading within MSM communities across Europe (VRD_521_2016). The report confirms that AHA is an emerging issue among MSM. In addition through the integration of standard (case based) surveillance with molecular investigation we could discriminate, temporally concomitant but epidemiologically unrelated, clusters due to different HAV variants. As suggested by the WHO, in countries with low HAV circulation, vaccination programmes should be tailored on the local epidemiological patterns to prevent outbreaks among high risk groups and eventual spillover of the infection in the general population.

Relationship Between Viremia and Specific Organ Damage in Ebola Patients: A Cohort Study

BackgroundnPathogenesis of Ebola virus disease remains poorly understood. We used concomitant determination of routine laboratory biomarkers and Ebola viremia to explore the potential role of viral replication in specific organ damage.nnnMethodsnWe recruited patients with detectable Ebola viremia admitted to the EMERGENCY Organizzazione Non Governativa Organizzazione Non Lucrativa di Utilità Sociale (ONG ONLUS) Ebola Treatment Center in Sierra Leone. Repeated measure of Ebola viremia, alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, creatine phosphokinase (CPK), lactate dehydrogenase (LDH), activated prothrombin time (aPTT), international normalized ratio (INR), creatinine, and blood urea nitrogen (BUN) were recorded. Patients were followed up from admission until death or discharge.nnnResultsnOne hundred patients (49 survivors and 51 nonsurvivors) were included in the analysis. Unadjusted analysis to compare survivors and nonsurvivors provided evidence that all biomarkers were significantly above the normal range and that the extent of these abnormalities was generally higher in nonsurvivors than in survivors. Multivariable mixed-effects models provided strong evidence for a biological gradient (suggestive of a direct role in organ damage) between the viremia levels and either ALT, AST, CPK LDH, aPTT, and INR. In contrast, no direct linear association was found between viremia and either creatinine, BUN, or bilirubin.nnnConclusionsnThis study provides evidence to support that Ebola virus may have a direct role in muscular damage and imbalance of the coagulation system. We did not find strong evidence suggestive of a direct role of Ebola virus in kidney damage. The role of the virus in liver damage remains unclear, but our evidence suggests that acute severe liver injury is not a typical feature of Ebola virus disease.

Aiming for zero tuberculosis transmission in low-burden countries

Published Online October 12, 2017 http://dx.doi.org/10.1016/ S2213-2600(17)30382-X The End TB Strategy, approved by the World Health Assembly in May 2014, proposes ambitious targets to reduce the global burden of tuberculosis (TB). The strategy calls for all governments to show high-level political commitment, including those of high-income countries with a low burden of disease. The framework for TB elimination in low-incidence countries, launched at the World TB Conference in 2015, challenged low-burden countries to aim for TB elimination (defined as <1 incident case of TB per million population) by 2035 or earlier. In low-incidence settings, most cases of TB occur among foreign-born individuals; thus, to achieve a substantial reduction in case numbers, meticulous premigration screening and an emphasis on the identification of active cases among often hard-to-reach populations, with treatment of both active and latent TB infection, is necessary. Consideration will need to be given to risk–benefit analyses and the cost-effectiveness of these approaches, which might not always be feasible or ethically acceptable. Despite these efforts, it seems unlikely that lowincidence countries will achieve TB elimination according to the current definition. As long as uncontrolled Mycobacterium tuberculosis transmission persists in large parts of the world, cross-border importation of infection and disease is an inevitable result of high population mobility. In addition to unprecedented levels of migration, frequent international travel (eg, for business and leisure) provides opportunities for new infections or reinfections to occur, which will hamper efforts to eliminate TB, and could lead to political fatigue caused by chasing a seemingly unrealistic public health target. An alternative means to achieve and sustain highlevel political commitment in low-incidence countries is to introduce zero TB transmission as an interim and measurable target, and credit countries with TB transmission-free status, akin to WHO’s Roll Back Polio campaign. Zero TB transmission could be defined as no more than one bacteriologically confirmed case of locally acquired TB among people born in the country of interest per million population. Whole genome sequencing (WGS) is the biggest advance in diagnostic microbiology since culture techniques enabled pathogen identification and Robert Koch showed the cause of TB to be M tuberculosis. WGS allows locally transmitted TB to be monitored with accuracy unattainable with previous molecular methods. For all incident cases to be traced with WGS, all bacteriologically confirmed cases of TB would need to be routinely submitted for WGS to allow genome comparisons with previously sequenced strains, with reconstruction of probable transmission pathways. WGS data can also assist in individual patient management by predicting drug resistance with minimal lag time and at no additional cost. The detection of laboratory cross-contamination using WGS—a problem that occurs in all settings, but is rarely discussed—provides important patient and programmatic benefit because it limits false-positive diagnoses with unnecessary treatment, and improves the accuracy of laboratory results. The introduction of routine WGS to track TB transmission and drugresistance profiles in settings in which incidence of TB is low would make TB control services leaders in the exciting public health revolution facilitated by advances in genomics. Some might argue that the implementation of routine WGS for accurate tracking of TB transmission in countries with a low incidence of TB could detract from efforts to improve TB control in high-incidence settings by diverting financial and academic resources away from the everyday challenges faced in resource-limited settings. However, such implementation of routine WGS might instead ensure the sustained engagement of low-incidence countries in global TB control challenges, with more support provided to resourcelimited settings. The refinement of novel technological advances will also provide crucial insight for and direct benefit to high-incidence settings, once these technologies are sufficiently mature and cost-efficient. Additionally, constant vigilance will be required for countries to maintain their TB transmission-free status, if all low-incidence countries are requested to report the number of locally transmitted TB cases to WHO on an annual basis and if TB transmission-free status can be revoked when set criteria are no longer met. This will discourage disinvestment in TB control services as the incidence of TB declines, which is a constant challenge Aiming for zero tuberculosis transmission in low-burden countries

Undiagnosed Active Pulmonary Tuberculosis among Pilgrims during the 2015 Hajj Mass Gathering: A Prospective Cross-sectional Study

Mass gatherings pose a risk for tuberculosis (TB) transmission and reactivation of latent TB infection. The annual Hajj pilgrimage attracts 2 million pilgrims many from high TB-endemic countries. We evaluated the burden of undiagnosed active pulmonary TB in pilgrims attending the 2015 Hajj mass gathering. We conducted a prospective cross-sectional study in Mecca, Kingdom of Saudi Arabia, for nonhospitalized adult pilgrims from five high TB-endemic countries. Enrollment criteria were the presence of a cough and the ability to produce a sputum sample. Sputum samples were processed using the Xpert MTB-RIF assay. Data were analyzed for drug-resistant TB, risk factors, and comorbidities by the country of origin. Of 1,164 consenting pilgrims enrolled from five countries: Afghanistan (316), Bangladesh (222), Nigeria (176), Pakistan (302), and South Africa (148), laboratory results were available for 1,063 (91.3%). The mean age of pilgrims was 54.5 (range = 18-94 years) with a male to female ratio of 2.6:1; 27.7% had an underlying comorbidity, with hypertension and diabetes being the most common, 20% were smokers, and 2.8% gave a history of previous TB treatment. Fifteen pilgrims (1.4%) had active previously undiagnosed drug-sensitive pulmonary TB (Afghanistan [12; 80%], Pakistan [2; 13.3%], and Nigeria [1; 6.7%]). No multidrug-resistant TB cases were detected. Pilgrims from high TB-endemic Asian and African countries with undiagnosed active pulmonary TB pose a risk to other pilgrims from over 180 countries. Further studies are required to define the scale of the TB problem during the Hajj mass gathering and the development of proactive screening, treatment and prevention guidelines.

Unique TCR β-subunit variable gene haplotypes in Africans

Abstract. This study investigated polymorphisms of genes in two regions of the T-cell antigen receptor β-subunit (TCRB) locus, including BV9S2P, and BV6S7 in a 5′ linkage group, and BV8S3, BV24S1, BV25S1, BV18S1, BV2S1, BV15S1 and BV3S1 in a 3′ linkage group. These loci have been genotyped in individuals from five regions in Africa, including The Gambia, Nigeria, Cameroon, Tanzania, and Zambia, and in individuals from northern Britain, northern India, and Papua New Guinea (PNG). In the 3′ linkage group, 11 unique haplotypes were identified in the combined African populations; two equally frequent haplotypes represent the majority of African chromosomes. One haplotype was found in all four regions studied. This is the most frequent haplotype in the northern British, northern Indian and PNG populations. Although present, it is infrequent in the African populations. A North-South gradient in the frequency of a common African haplotype was observed. The distribution did not represent that of a known disease. Evidence suggests that malaria is not responsible for selection of these haplotypes. Overall, this study highlights large differences in the genetic constitution of the TCRB locus between Africans and other populations.

Ending the Global Tuberculosis Epidemic by 2030 — The Moscow Declaration and achieving a Major Translational Change in Delivery of TB Healthcare

According to the latest WHO Annual Global TB Report (WHO, 2017a), Tuberculosis (TB) remains the world’s top infectious diseases cause of death, being responsible for an estimated 1.674.000 deaths worldwide in 2016. Alarmingly, there were 600.000 cases of rifampicin-resistant TB of which 490.000 had multidrug-resistant TB (MDR-TB). Less than 50% of these patients survive after receiving currently recommended WHO treatment regimens, illustrating the dire state of current global TB control efforts. The first WHO Global Ministerial Conference “Ending Tuberculosis in the Sustainable Development Era: A Multisectoral Response”, was held in Moscow, the Russian Federation, on 17th November 2017. Ministers from 75 countries agreed on the “Moscow Declaration” (WHO, 2017d) committing to urgent action to fulfill the WHO “End Tuberculosis” strategy by 2030 (WHO, 2017b). It also commits to increasing multisectoral action, tracking progress, and ensuring accountability. The Moscow declaration will inform the first UN General Assembly High-Level Meeting on TB to be held in New York in September 2018 to generate further commitments from member states. Key sentences in the declaration read: “Universal health coverage, sustainable financing for multisectoral action, rapid scale up of innovative approaches and tools, and discovery of new and better tools for prevention, diagnosis and treatment of TB will be fundamental to transform the fight. We also recognize the urgent need for committing immediate, intensified, innovative and multisectoral actions to rapidly accelerate progress in both research and implementation”.

Outcomes of multidrug-resistant tuberculosis in Zambia: a cohort analysis

PurposeThe purpose of this study was to establish a baseline for measuring the impact of the programmatic management of drug-resistant TB program by following up on outcomes of all patients diagnosed with multidrug-resistant tuberculosis in Zambia between 2012 and 2014.MethodsA cohort study of all the MDR-TB patients diagnosed at the national TB reference laboratory from across Zambia. MDR-TB was diagnosed by culture and DST, whereas outcome data were collected in 2015 by patient record checks and home visits.ResultsThe total number of patients diagnosed was 258. Of those, 110 (42.6%) patients were traceable for this study. There were 67 survivor participants (60.9%); 43 (39.1%) were deceased. Out of the 110 patients who were traced, only 71 (64.5%) were started on second-line treatment. Twenty-nine (40.8%) patients were declared cured and 16.9% were still on treatment; 8.4% had failed treatment. The survival rate was 20.2 per 100 person-years of follow-up. Taking ARVs was associated with a decreased risk of dying (hazard ratio 0.12, pxa0=xa00.002). Sex, age, marital status and treatment category were not important predictors of survival in MDR-TB patients.ConclusionsMore than half of the patients diagnosed with MDR-TB were lost to follow-up before second-line treatment was initiated.

Tuberculosis among older adults in Zambia: burden and characteristics among a neglected group

BackgroundThe 2010 Global Burden of Disease estimates show that 57% of all TB deaths globally occurred among adults older than 50xa0years of age. Few studies document the TB burden among older adults in Southern Africa. We focused on adults older than 55xa0years to assess the relative TB burden and associated demographic factors.MethodsA cross sectional nationally representative TB prevalence survey conducted of Zambian residents aged 15xa0years and above from 66 clusters across all the 10 provinces of Zambia. Evaluation included testing for TB as well as an in-depth questionnaire. We compared survey data for those aged 55 and older to those aged 15–54xa0years. Survey results were also compared with 2013 routinely collected programmatic notification data to generate future hypotheses regarding active and passive case finding.ResultsAmong older adults with TB, 30/ 54 (55.6%) were male, 3/27 (11.1%) were HIV infected and 35/54 (64.8%) lived in rural areas. TB prevalence was higher in those aged ≥55 (0.7%) than in the 15–54 age group (0.5%). Males had higher rates of TB across both age groups with 0.7% (15–54) and 1.0% (≥55) compared with females 0.4% (15–54) and 0.6% (≥55). In rural areas, the prevalence of TB was significantly higher among older than younger adults (0.7% vs 0.3%), while the HIV infection rate was among TB patients was lower (11.1% vs 30.8%). The prevalence survey detected TB in 54/7484 (0.7%) of older adults compared to 3619/723,000 (0.5%) reported in 2013 programmatic data.ConclusionHigh TB rates among older adults in TB endemic areas justify consideration of active TB case finding and prevention strategies.