Infectious Disorders - Drug Targets (Formerly Current Drug Targets - Infectious Disorders) - Volume 20, Issue 3, 2020

In this review, Ebolavirus Disease (EVD) outbreaks have been comprehensively reviewed from their beginning until now. It chronologically discusses how each outbreak was tackled, national and international actions taken, diagnostic methods applied, the infection control procedures put in place, and the lessons learnt from each epidemic for the control of subsequent epidemics. Data for this review were obtained from literature published between 1967 and 2016 in key medical databases, the official websites of various governmental organisations, international public health agencies, and regulatory bodies. Despite major developments in the field of EVD, there has been little progress in its specific therapy or prevention. Historically, individuals who recovered from EVD acted as a source of fresh frozen plasma (containing IgG) that has been used to treat other acutely ill patients, however this therapeutic modality has limitations due to the risk of transmission of blood-borne infections. With the use of advanced and efficient purification methods the incidence of unwanted side effects following immune serum therapy has currently been greatly reduced. Creation of a safe plasma pool that covers immunoglobulins against all strains of EVD is now a research priority. Recommendations on how future EVD outbreaks can be better managed have been discussed.

The burden of parasitic infections among children with disability in resource-poor settings has not been summarised through a focused review. Here, we have summarised the key studies reporting the burden of parasitic infections among children without and with a disability. In most instances, among children without disability, Giardia or soil-transmitted helminths dominate the epidemiology, while among disabled individuals, enteric protozoa are the predominant parasites to be reported in both resource-rich and resource-poor countries. Cryptosporidium is generally the leading protozoan to be detected among these populations but all other parasites have been detected in varying frequencies. There is a paucity of data on the precise epidemiology of parasitic infections in children with disability. A large-scale epidemiological study, using modern genomic methodology, is a research priority.

The role of hand hygiene in the prevention of respiratory tract infections in Hajj pilgrims has not been assessed through a focussed systematic review of the literature. Considering this, a systematic review was undertaken to synthesize the up-to-date literature on the compliance and effectiveness of hand hygiene among Hajj attendees. Major databases, including OVID Medline, were searched by using a combination of MeSH terms and text words for potentially relevant articles. Data from identified articles were abstracted, quality assessed and combined into a summary effect. Twelve observational studies containing data of 6,320 pilgrims were included. The compliance of hand washing with non-alcoholic surfactants was 77.7% (ranged from 31.5% to 90.3% in individual studies) and the compliance of hand cleaning with alcoholic products was 44.9% (ranged from 30.7% to 67.4%). Education was a key influencer of hand hygiene practice. Only three of the six studies that assessed the effectiveness of hand hygiene against clinical disease found the practice to be effective, and only one of the two studies that evaluated its effectiveness against a laboratory-confirmed infection found it to be effective. This systematic review suggests that hand hygiene using non-alcoholic products is generally acceptable among Hajj pilgrims but there is no conclusive evidence on its effectiveness.

Background and Objectives: Congenital Rubella Syndrome (CRS) is the leading cause of vaccine-preventable congenital anomalies. Comprehensive country-level data on the burden of CRS in low and middle-income countries, such as Bangladesh, are scarce. This information is essential for assessing the impact of rubella vaccination programs. We aim to systematically review the literature on the epidemiology of CRS and estimate the burden of CRS in Bangladesh. Methods: We conducted a systematic review of existing literature and transmission modelling of seroprevalence studies to estimate the pre-vaccine period burden of CRS in Bangladesh. OVID Medline (1948 – 23 November 2016) and OVID EMBASE (1974 – 23 November 2016) were searched using a combination of the database-specific controlled vocabulary and free text terms. We used an age-stratified deterministic model to estimate the pre-vaccination burden of CRS in Bangladesh. Findings: Ten articles were identified, published between 2000 and 2014, including seven crosssectional studies, two case series and one analytical case-control study. Rubella seropositivity ranged from 47.0% to 86.0% among all age population. Rubella sero–positivity increased with age. Rubella seropositivity among women of childbearing age was 81.0% overall. The estimated incidence of CRS was 0·99 per 1,000 live births, which corresponds to approximately 3,292 CRS cases annually in Bangladesh. Conclusion: The estimated burden of CRS in Bangladesh during the pre-vaccination period was high. This will provide important baseline information to assess the impact and cost-effectiveness of routine rubella immunisation, introduced in 2012 in Bangladesh.

Background: Congenital cytomegalovirus (cCMV) is known to cause childhood deafness, neurodevelopmental disability and death. Simple hygiene precautions are effective in reducing maternal risk of CMV infection. Objective: To review i) awareness of CMV infection and available primary prevention strategies both in the community and amongst health professionals ii) available cCMV information sources in the literature, grey literature and published professional guidelines. Methods: Scoping study to i) identify literature pertaining to cCMV awareness amongst parents and health professionals using MedLine and CINAHL databases via EBSCO ii) review one high income country’s guidelines and recommendations regarding cCMV infection and pregnancy (example country Australia) iii) grey literature for parental information. Results: Worldwide awareness of cCMV and of available prevention strategies amongst women and health professionals are poor. Findings internationally suggest at least half of maternity care health professionals do not routinely provide advice to women regarding simple hygiene precautions that can reduce their risk of infection during pregnancy. Though information resources regarding cCMV are available, they are frequently not included within general healthy pregnancy advice and require individuals to search for ‘congenital cytomegalovirus’. Conclusion: cCMV is a preventable cause of serious congenital disability and death. Prevention opportunities are being missed because most women are not aware of cCMV or how to reduce their risk of infection in pregnancy, in part due to poor health professional awareness. New strategies to disseminate cCMV information to the community and to support health professionals to embed cCMV advice within routine pregnancy counselling is required.

Background: Vaccination is one of the most effective public health tools for the prevention of infectious diseases, morbidity and disability. Little is known about the rate of maternal immunization among mothers of children with Cerebral Palsy (CP), as well as any possible role of maternal immunization in development of CP in the newborns. Objective: To determine the socio-demographic characteristics and self-reported vaccination status of mothers of children with CP and compare vaccination coverage in this cohort with national data on immunization. The study also aims to assess the vaccination status of children with CP. Methods: A subset of the Bangladesh CP Register (BCPR) cohort of women who had children with CP were recruited during April 2017 from a community based early intervention and rehabilitation program going on in Shahjadpur. Socio-demographic characteristics and maternal immunization status were assessed using a semi-structured questionnaire. The vaccination status of the children was also assessed by interviewing mother and observing the BCG marks. All data were compared with the corresponding information among general population using national vaccination coverage survey reports of the Ministry of Health and Family Welfare, Bangladesh. Result: Sixty-eight mothers were interviewed of which 17.6% of mothers reported not receiving any vaccine during pregnancy. Tetanus vaccine was most commonly (82.0%) received during pregnancy. Overall coverage for at least two doses of tetanus toxoid (TT) among mothers of children with CP was significantly lower than the national tetanus coverage (79.4% versus 96.4%, p<0.01). Forty-two (61.7%) mothers with a child with CP reported having not received tetanus vaccine during their pregnancy compared to only twenty (29.4%) mothers with healthy children reported missing tetanus vaccination during their pregnancy. This difference was statistically significant (p<0.01). Hepatitis B and influenza vaccine were received by mothers of children with CP during the antenatal period (2 and 6 respectively). Conclusion: Immunization among mothers of children with CP is significantly poorer than the national coverage. Also, the immunization of the children with CP is poorer than the national EPI coverage. Our findings reflect the necessity for specific strategies to improve the vaccination coverage among mothers of children with disabilities especially CP and the children with CP.

Background: HSV is an important cause of brain infection. Virus entry is often through breeches in the skin. γδT cells play an immunoprotective role in mice after corneal, genital or footpad (subcutaneous) HSV infection. Methods: Here we report that the presence of γδT cells in murine skin is associated with increased severity of herpetic disease, reduced protective cytokine responses and increased viral spread from the skin to the sensory ganglia in the zosteriform model. γδT cell-deficient (TCR δ -/-) mice displayed significantly decreased herpetic lesion severity after flank HSV infection compared to WT C57BL/6 controls at both primary and secondary skin infection sites. Results: Viral titer at the primary skin site was similar to WT mice in γδT cell-deficient mice, but was significantly decreased in the ganglia and secondary skin site. γδT cell-deficient mice showed increased Th1 responses by both T cells and non-T cells at the primary site, and decreased T-cell Th17 responses and immune infiltration at the secondary site. Conclusion: Cytokine responses of epidermal and dermal γδT cells to HSV also differed in WT mice (Th1 in epidermis, and Th17 in the dermis), suggesting a functional dichotomy between these two subsets. Our data suggest that in contrast to other mouse models of HSV infection, skinresident γδT cells promote the pathogenesis of HSV in skin.

Background: Cerebral palsy (CP) is the most common cause of physical disability in childhood, with an estimated 17 million cases worldwide. There is limited data concerning the general health of this population and the immunisation status of children with CP is largely unknown. Objective: We aimed to assess the immunisation status of children with CP in rural Bangladesh and determine the predictors of non-immunisation. Methods: This study is part of the Bangladesh CP Register (BCPR) study; a population based CP register commenced in January 2015 in the Shahjadpur sub-district of Bangladesh. As part of BCPR registration, all children with CP in the catchment area were assessed by a paediatrician and their clinical and immunisation history were collected. Results: Between January and December 2015, 615 children with CP were registered on the BCPR. The median age of the children was 7.5 years, and 38.5% were female. 91.7% of those children had a BCG vaccine scar (as an objective marker for immunisation at birth). However, only 43.2% reported to have received the rubella vaccine during the 2014 national rubella immunisation campaign. Timing of CP diagnosis was found to be an independent predictor for immunisation uptake; those diagnosed before the age of 3 were more likely to have received the rubella vaccine (95% confidence interval [CI] 1.6 - 4.3, odds ratio [OR] 2.6, p <0.0001). Conclusions: To the best of our knowledge, this is the first paper to use a formal CP register to examine the relationship between CP and immunisation status in a low or middle income country like Bangladesh. Our data suggest that more than half of children with CP in rural Bangladesh did not receive immunisation during a recent national campaign.

Objectives: We report the results of the 2007 national serological survey of immunity to diphtheria in Australia to assess the impact of recent schedule changes on diphtheria immunity, and the adequacy of current policy in the context of increased international travel of people and pathogens. Methods: Residual sera (n =1656) collected opportunistically from Australian laboratories in 2007 were tested for diphtheria antibody levels using an enzyme immunoassay, with the protective threshold defined as ≥0.1 IU/mL. About 40% of adults aged ≥30 years are susceptible to diphtheria; following the removal of the 18-month booster and its replacement with a dose in adolescence offered through school-based dTpa vaccination program, 59% of children aged 3 years were susceptible to diphtheria, whilst adolescents demonstrated improved immunity. Results: There is no apparent boosting of diphtheria immunity from meningococcal group C conjugate (MCC) or seven-valent pneumococcal conjugate (7vPCV) vaccines in relevant age groups. Conclusion: Australians who travel to diphtheria-endemic areas should be up-to-date with their vaccinations. Close monitoring of population immunity levels against diphtheria remains important to ensure that immunity does not decline to a level where wide-spread transmission would be possible.

Background: This study evaluates trends in tetanus immunity and epidemiology over the last two decades in Australia, drawing on two national serological surveys and national tetanus morbidity data, to justify current Australian adult tetanus booster recommendations. Methods: We compare tetanus immunity level between two national serosurveys, and examine incidence trends using the most accurate estimation of the true number of cases by correcting for under-ascertainment. Results: Tetanus immunity in people aged <60 years is high, but the elderly, particularly the female elderly, may not be adequately protected. Over the past twenty years older people have regularly accounted for the highest number of tetanus cases, with an increasing proportion of cases. Conclusion: Despite a positive decrease in tetanus incidence, there remains a significant burden in the elderly population of an entirely preventable disease. Supplying a funded booster dose of dTpa at 65 years would be, potentially, an effective strategy to prevent tetanus cases in Australia.

Background: This study assessed the impact of the staged introduction of universal infant and adolescent catch-up hepatitis B vaccination programs on the prevalence of immunity and past hepatitis B virus (HBV) infection in targeted cohorts over almost a decade in Australia. Methods: We compared the prevalence of immunity in relevant cohorts of children and adolescents in repeated national serological surveys conducted in 1998-99, 2002 and 2007. Residual sera (n =2210) collected opportunistically from Australian laboratories in 2007 were tested for antibody to hepatitis B surface antigen (anti-HBs) indicating vaccine-induced immunity; sera from individuals aged 12-29 years with anti-HBs detected (n =386) were then tested for hepatitis B core antibody (anti-HBc) to identify past hepatitis B infection. Results: In 2007, compared with the baseline period of 1998-99, anti-HBs prevalence had increased significantly in all age groups below 24 years, by more than double in target children. Prevalence of anti-HBc was zero in the 12-14 years and reduced by 71% in those aged 15-19 years. The hepatitis B vaccination protected a significant number of targeted adolescents with a modest vaccine uptake (57% to 60% nationally). Conclusion: In a setting without incentives or school entry requirements, adolescent vaccination coverage was significantly higher when delivered by school-based rather than GP-based mechanisms. A cohort of children was growing up in Australia with a high prevalence of vaccineinduced immunity against hepatitis B, providing the best opportunity for controlling HBV infection in Australia.

The number of drugs available for treatment of active tuberculosis is diminishing due to increased multidrug resistance selection in Mycobacterium tuberculosis leading to multiple (MDR) and extensively (XDR) resistant strains. Also, TB is treated with multiple drugs to minimize further resistance development, mandating a sustained effort to identify new lead compounds for treating drug-resistant TB and shortening time to cure for all TB infections. High throughput screening, a well-known approach to discovery of new leads, is conducted in two basic modes 1) using whole cells and screening for inhibition of growth, or whole cell reporter cells that signal when a specific pathway is perturbed, and 2) in vitro non-cell based enzyme or other functional assays for direct ligand-target binding. Combining high throughput screening for inhibitors of growth (to identify and chemically assess inhibitors active on whole cells), followed by target identification abrogates the problem of discovering new leads in non-cell based systems that are inactive on whole cells due to issues with target access (e.g., uptake). High throughput screening of 341,778 compounds by the National Institutes of Health identified 8,950 primary hit, growth inhibitors of M. tuberculosis. Final evaluation based on reproducibility, potency, medicinal chemistry inspection, and cytotoxicity on tissue culture cells identified 1,113 priority compounds. These data were deposited in PubChem, making data available to TB research labs for follow up studies on target identification. This effort led to the identification of compounds targeting Pks13, MmpL3, DprE1, AspS, EthA, GuaB2, nonreplicating cells, and VKOR (Vitamin K epoxide reductase).

Tuberculosis (TB) is a public health problem in developing countries. In recent decades, the incidence of the disease has been gradually reducing in Iran. However, the reducing incidence of the disease has stopped in the country during recent years. It could be due to an increase in immigration, diabetes, HIV/AIDS, and the prevalence of drug-resistant strains. In order to prevent the spread of TB cases and control this disease, it is essential to identify the predisposing factors, which may be related to bacteria, host and environment. The objective of the present systematic review was to investigate the role of potentially effective factors in the increase in TB cases in the country. The epidemiological studies that had considered the risk factors for the development of TB in populations from different regions of Iran were reviewed systematically from the beginning of 2007 to the end of June 2017 in electronic databases. Upon evaluation of the literature, these 7 major risk factors were identified in twenty-five eligible studies, including poor living conditions, drug abuse, HIV/AIDS, multidrug-resistant tuberculosis (MDR-TB), diabetes, migration, and smoking. In conclusion, the increase in predisposing risk factors for catching TB, especially the migration and Beijing strain, shows that in the absence of accurate monitoring, TB cases will increase in the near future in Iran.

Background: Highly active antiretroviral therapy (HAART), especially tenofovir DFcontaining regimens, has been implicated in albuminuria. Objective: We prospectively evaluated the effects of HAART on albumin-to-creatinine ratios (ACRs) in antiretroviral-naïve HIV-infected individuals. Methods: One hundred and two (102) newly diagnosed, antiretroviral-naïve, human immunodeficiency virus (HIV)-infected persons were treated with Tenofovir disoproxil fumarate/ Emtricitabine/Efavirenz (TDF/FTC/EFV), n=33; Zidovudine/Lamivudine/Nevirapine (ZDV/3TC/NVP), n=53; and Zidovudine/Lamivudine/Efavirenz (ZDV/3TC/EFV), n=16. Diabetes mellitus and hypertension were excluded. ACRs and glomerular filtration rates (eGFR) were estimated at baseline, and at 1, 3, 6 and 9 months post-therapy; the prevalence of albuminuria (ACR ≥ 300mg/g), and microalbuminuria (ACR 30-300mg/g) were similarly estimated. HAART effects on normal ACR (0-30mg/g) were also monitored. Results: At baseline, one patient (0.9%) had nephrotic-range albuminuria with ACR of 2450mg/g. Overall, 8 (7.8%) patients had albuminuria; 53 (51.9%) had microalbuminuria; while 41 (40.2%) had normal ACRs, 28 (27.5% of 102) of which had nonalbuminuric renal insufficiency. eGFR and ACRs improved concurrently on HAART (ACR, Wilks’ lambda 0.439, power 0.763, p=0.032); albuminuria improved significantly on all the 3 regimens at 9 months (p=0.006, 0.012 and <0.001 respectively). Microalbuminuria resolved earlier (1 month) with ZDV/3TC/NVP than with TDF/FTC/EFV and ZDV/3TC/EFV (24.31mg/g versus 76.51mg/g and 63.59mg/g; p=0.028, 0.016 respectively). Microalbuminuria relapsed on TDF/FTC/EFV and ZDV/3TC/EFV at 6 months but resolved again at 9 months (66.7 versus 29 mg/g, p=0.006; and 51.2 versus 9.5mg/g, p=0.001 respectively); no relapse on ZDV/3TC/NVP. At 9 months, ZDV/3TC/EFV caused the greatest resolution of microalbuminuria (85.7% decline in ACR from baseline) compared with ZDV/3TC/NVP (72.5% decline) and TDF/FTC/EFV (63.9% decline). In multivariate analyses, predictors of ACR include older age (Odds ratio OR 2.8, p= 0.025); female gender (OR, 3.4, p =0.014); CD4+ (OR 0.99, p=0.002). Conclusion: HIV induces renal impairment. Thus, albuminuria, microalbuminuria and nonalbuminuric renal insufficiency are highly prevalent in antiretroviral-naïve HIV-infected persons but nephrotic-range albuminuria is uncommon. Albuminuria and/microalbuminuria and eGFR improve concurrently on HAART (with/without tenofovir DF). Zidovudine-based HAART (ZDV/3TC/NVP) resolves microalbuminuria earlier, and without relapse, unlike Tenovofir-based regimen and zidovudine with efavirenz (ZDV/3TC/EFV).

Background: Emergence of resistance to some antibiotics in Haemophilus influenzae, a respiratory pathogen is a cause of concern. The aim is to study the antibiotic susceptibility pattern of Haemophilus isolates from respiratory infections with reference to beta-lactam resistance. Methods: This is a laboratory based prospective study done in the department of microbiology in a tertiary care center after institutional ethics committee clearance. Haemophilus influenzae isolates from respiratory tract specimens over a period of one year were subjected to antibiotic susceptibility tests. Beta-lactamase production was detected by nitrocefin disc. hpd gene, blaTEM and blaROB genes were detected by PCR. The data was analysed using SPSS 11.5 version. Results: Of the 162 isolates, 89.5% were from sputum specimens. Ampicillin resistance was seen in 5 (3.09%) isolates. The ampicillin resistant strains were positive for beta-lactamase enzyme and blaTEM gene. BLNAR and isolates with blaROB gene were not found. Conclusion: In case of Haemophilus influenzae respiratory tract infection empirical treatment with amoxicillin clavulanate or third generation cephalosporin may be the drugs of choice in our geographic area.

Background & Aims: Treatment plan of chronic HCV infection has dramatically improved after the introduction of different groups of Direct-Acting Antiviral (DAA) drugs. These drugs have been found to be safe and effective. Sofosbuvir (SOF) plus simeprevir (SMV) regimen has been shown to be tolerable and effective in treatment of patients with HCV genotype 1. The aim of the study was to evaluate the safety and the efficacy of combined sofosbuvir plus simeprevir treatment in genotype 4 chronic HCV patients. Methods: This open-label multicenter prospective study was carried out on 381 Egyptian patients with chronic hepatitis C virus- infection. Treatment experienced and treatment-naive patients were included. Subjects administrated a regimen of sofosbuvir (400 mg/ day) plus semiprevir (150 mg /day) for twelve weeks. Sustained Virological Response (SVR) was confirmed by undetectable HCV RNA by quantitative PCR 3 months after the end of the treatment. Results: 97.6% (372 /381) of patients had SVR. None of the studied clinical and demographic characteristics were associated with the SVR status. However, patients who failed to achieve SVR showed low albumin level and high total leucocyte. The most common side effects of the studied regimen were headache, fatigue, itching, photosensitivity, and cough. Conclusions: Twelve weeks’ regimen of sofosbuvir plus simeprevir was considered to be safe and tolerable in the treatment of HCV genotype 4; also it was associated with high SVR (97.6%).