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Introduction A recently published systematic review on the treatment of chronic hepatitis C (CHC) with direct-acting antivirals (DAAs) performed by the Cochrane Collaboration has reached highly controversial conclusions [1,2]. The authors included 138 randomized controlled trials (RCTs) with no restriction on disease stage or type of DAA combination. They concluded that there was no evidence to either confirm or reject the premise that DAAs had any clinical effect, and they also stated that sustained virologic response (SVR) was an unreliable surrogate marker to assess clinical efficacy. We differ on both these counts. These results are in discordance with current international guidelines (https://www.hcvguidelines.org/) [3], the opinion of the of scientific societies for the study of liver diseases in Europe [4] and in America (https://www.aasld.org/about-aasld/press-room/aasld-expresses-concern-cochrane-review-daas), and the endorsement of the World Health Organization, which states that DAAs may eliminate hepatitis C virus (HCV) by 2030 (http://apps.who.int/iris/bitstream/10665/246177/1/WHO-HIV-2016.06-eng.pdf?ua=1; http://www.who.int/hepatitis/news-events/direct-acting-antiviral-cure-hepatitis-c/en/) [5]. The Cochrane Collaboration's results reflect an underestimation of the actual value of observational evidence in the context of the current knowledge of CHC clinical management [6,7].

Summary Despite extensive global efforts in the fight against killer infectious diseases, they still cause one in four deaths worldwide and are important causes of long-term functional disability arising from tissue damage. The continuing epidemics of tuberculosis, HIV, malaria, and influenza, and the emergence of novel zoonotic pathogens represent major clinical management challenges worldwide. Newer approaches to improving treatment outcomes are needed to reduce the high morbidity and mortality caused by infectious diseases. Recent insights into pathogen–host interactions, pathogenesis, inflammatory pathways, and the host's innate and acquired immune responses are leading to identification and development of a wide range of host-directed therapies with different mechanisms of action. Host-directed therapeutic strategies are now becoming viable adjuncts to standard antimicrobial treatment. Host-directed therapies include commonly used drugs for non-communicable diseases with good safety profiles, immunomodulatory agents, biologics (eg monoclonal antibodies), nutritional products, and cellular therapy using the patient's own immune or bone marrow mesenchymal stromal cells. We discuss clinically relevant examples of progress in identifying host-directed therapies as adjunct treatment options for bacterial, viral, and parasitic infectious diseases.

Tuberculosis remains a global emergency causing an estimated 1.5 million deaths annually. For several decades the major focus of tuberculosis treatment has been on antibiotic development targeting Mycobacterium tuberculosis. The lengthy tuberculosis treatment duration and poor treatment outcomes associated with multi-drug resistant tuberculosis (MDR-TB) are of major concern. The sparse new tuberculosis drug pipeline and widespread emergence of MDR-TB signal an urgent need for more innovative interventions to improve treatment outcomes. Building on the historical Pasteur-Bechamp debates on the role of the "microbe" vs the "host internal milieu" in disease causation, we make the case for parallel investments into host-directed therapies (HDTs). A range of potential HDTs are now available which require evaluation in randomized controlled clinical trials as adjunct therapies for shortening the duration of tuberculosis therapy and improving treatment outcomes for drug-susceptible tuberculosis and MDR-TB. Funder initiatives that may enable further research into HDTs are described.

Purpose of review Every year, over 8 million people develop tuberculosis and nearly 1.8 million die from it, despite extensive vaccination and drug treatment programmes. It is increasingly recognized that the diagnosis of tuberculosis, which relies heavily on century-old techniques, is one of the weakest links in the chain of tuberculosis control, hampering not just treatment but also the development of new drugs and vaccines. As a result, recent years have seen the initiation of large-scale studies aiming to identify biomarkers of Mycobacterium tuberculosis infection and disease. This review discusses initial results and future prospects for that work. Recent findings The key finding from recent work has been that no one factor seems able to explain the complex course of Mycobacterium tuberculosis infection. Multifactorial analyses have identified a variety of genes and proteins, mostly involved in bacterial persistence or host responses, that offer promise as biomarkers for different disease stages. Summary The challenge now is to validate the suggested biomarkers being described and then reduce them to clinical practice. If this can be done, it offers the possibility of greatly improved clinical management of tuberculosis, allowing segregation of patients and contacts into appropriate treatment regimens.

During the recent epidemic of Ebola virus disease (EVD) in west Africa,1 several health-care and aid workers infected with EVD were evacuated to Europe and the USA, where local transmission occurred in occupationally exposed health-care workers. Preparation for discharge requires an organised and evidence-based approach to ensure that the patient, health-care workers, family, and community are protected at all times. The risk of infection to others after discharge in the community and of unexpected late clinical events for the patient make discharge policies difficult to formulate.

To the Editor: Extensively drug-resistant tuberculosis (XDR-TB) (defined as TB caused by Mycobacterium tuberculosis strains with in vitro resistance to isoniazid and rifampicin plus any fluoroquinolone and at least one of the second-line injectable drugs, amikacin, capreomycin or kanamycin) on top of being a growing public health concern, represents a nightmare for the clinician [1–4]. The crucial therapeutic issue is the difficulty of identifying at least four available “active” anti-TB drugs, to ensure treatment success as well as to prevent the emergence of additional drug resistance [1–4]. After more than 40 years without new anti-TB drugs appearing on the horizon, new chemical compounds ( i.e. bedaquiline, PA-824 and delamanid) seem promising for these difficult-to-treat cases of TB [4, 5]. While the necessary experimental studies will prove how to use them, more and more interest is currently focused on existing antibacterial drugs with new indications for drug-resistant TB, particularly linezolid, meropenem, clofazimine and cotrimoxazole [6–9]. Based on in vitro and pharmacological data, suggesting that linezolid (an oxazolidinone antibiotic) could be efficacious in treating mycobacterial infections, and on anedoctal evidence of its effectiveness in the smallest groups of patients, it was used off-label, despite its high price, to treat multidrug-resistant (MDR) TB cases in several countries. The little scientific supporting data on the efficacy, safety and tolerability of linezolid came from ad hoc randomised, controlled clinical trials, as well as from large observational studies [7]. The European Respiratory Journal recently published a systematic review and a meta-analysis of individual patients focused on the main published epidemiological observational studies (n=12), describing cohorts of TB patients (n=121) treated with linezolid-containing regimens in 11 countries [7 …

Tuberculosis (TB) is a leading cause of death globally. TB had been considered conquered in Europe but has re-emerged as a significant problem, partly because of poor TB control programs and the link with HIV infection, migrants and other vulnerable populations, but also because a mood of complacency led to declining investment in research and public health infrastructure. In the European Union (EU), efforts initiated by the European Academies Science Advisory Council (EASAC) now assess how research can better inform policy development and indicate the gaps and uncertainties in the scientific evidence base. A growing number of Mycobacterium tuberculosis (Mtb) strains are now resistant to the first-line anti-TB drugs, necessitating use of second-line drugs which are more expensive, less effective and more toxic. The presence of extensively drug-resistant (XDR) TB in the EU illustrates that there are problems with TB management and control. In the EU, the aggregated rate of notified TB is approximately 18 cases per 100,000 population (range 4-120 cases/100,000 in different Member States). The highest rates are found in Eastern European countries. Only about half of EU countries routinely perform drug susceptibility testing linked to notification of TB cases. It is important for the European Commission (EC) to network regional reference laboratories to support molecular epidemiology and exchange of data via creation of interactive international databases of Mtb genotypic and phenotypic information. EU countries should help develop TB laboratory services by investing in training and provision of assistance to maintain quality control in neighbouring Eastern European countries. Improved TB care necessitates research across the spectrum to include fundamental and epidemiological science, research and development (R&D) for new drugs, diagnostics, vaccines, and operational research. Total R&D investment in TB by the EC and Member States is low by comparison with the USA despite Europe being on the frontline of the epidemic. Thus, alternative funding models for targeting TB research priorities by the EU are required. Increasing the visibility of TB as a priority issue for the EU requires the scientific community, with the academies of science, as appropriate, to communicate to politicians, healthcare providers, funders and the public at large about the current threat posed by drug-resistant TB. Any global strategy for TB control must also take into account measures to address the social, environmental and economic issues which are inextricably linked with TB. The academies conclude that, overall, the EU has failed so far to respond sufficiently to the global TB threat but can still draw on considerable strengths in its science. The EU also has a humanitarian responsibility to support TB control in developing countries. It remains very important for the EC that neither biomedical research nor investment in health services should become a casualty of the current economic recession. (C) 2010 Elsevier Ltd. All rights reserved.

It is well recognized that toxins of Staphylococcus aureus and Streptococcus pyogenes are responsible for a wide range of clinical conditions, although their precise mode of action remains unclear. Recently, there has been a resurgence of interest in these toxins, now grouped with superantigens, because they cause profound alterations in the immune system homeostasis. Superantigens are molecules, including endogenous retroviral gene products and microbial toxins, that share a unique set of characteristics. They bind with high affinity to major histocompatibility complex class II at regions distinct from the conventional antigen binding groove and cause prolific activation or anergy of T cells with certain T cell receptor variable-region gene families. Whilst most of the superantigens described to date are products of bacteria or viruses, the presence of superantigens in parasites and their role in disease pathogenesis remain to be defined. It is probable that associations are present between superantigen-induced proliferation or anergy of peripheral blood T cells and clinical manifestations of human infectious diseases. The identification of these may pave the way toward a better understanding of disease pathogenesis and the possible development of newer immunotherapeutic regimes. This review summarizes the current thinking on microbial superantigens, their association with human T cells, and speculations about their significance.

Controlled trials have failed to show an effect of Mycobacterium vaccae immunotherapy on treatment outcome and mortality in patients with tuberculosis (TB); however, several studies have suggested improvement in radiographic clearing and resolution of cavitary disease.To assess the effect of M. vaccae immunotherapy on radiographic healing in pulmonary TB, chest X-rays from three randomized placebo-controlled trials of M. vaccae given as a single injection during the first 2 weeks of treatment were interpreted by a single, masked assessor using a standard scheme. Endpoints were the overall degree of radiographic improvement or deterioration and changes in cavitary disease at the end of antituberculosis treatment and follow-up.Of 1018 patients (478 HIV-infected; 540 HIV-uninfected) with an end of treatment or end of follow-up X-ray analyzed, 496 received M. vaccae and 522 received placebo. There was no difference in radiographic improvement or deterioration or cavitary disease at the end of treatment or follow-up comparing the M. vaccae and placebo groups. Results were similar comparing HIV-infected and HIV-uninfected patients.Adjunctive immunotherapy of drug-susceptible pulmonary TB with M. vaccae during the first 2 weeks of treatment did not improve radiographic responses to treatment or resolution of cavitary disease.

The Chest Clinic and the JICA (Japan International Cooperation Agency) Molecular Laboratories, University Teaching Hospital, Lusaka, Zambia, and the Department of Internal Medicine, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan.To evaluate the polymerase chain reaction (PCR) as a laboratory test for the rapid diagnosis of pulmonary tuberculosis in the African situation by identifying mycobacterial DNA in urine samples using two commonly described molecular methods.Prospective collection and laboratory analysis of urine samples from adult Zambian patients with culture-confirmed pulmonary tuberculosis and healthy controls.Urine was obtained from 63 patients with culture-confirmed active pulmonary tuberculosis and 63 'healthy' control patients with no active tuberculosis. DNA was isolated from urine sediment and subjected to analyses by two well-described PCR-based methods, 'the Sechi method' and 'the Githui method', for the identification of Mycobacterium tuberculosis DNA. The sensitivity and specificity of the two tests were determined.The sensitivity and specificity of the Githui method were 55.6% (35/63) and 98.4% (62/63), respectively. The sensitivity and specificity of the Sechi method were 28.6% (18/63) and 98.4% (62/63), respectively. Of the 63 patients, 50 (79%) were HIV sero-positive and the frequency of positive PCR urines using the Githui method was greater in HIV-positive patients than in HIV-negative patients (32/50 = 64% vs. 3/13 = 23%; P = 0.05).Neither the Githui method nor the Sechi method was sensitive enough to be recommended for routine use in clinical practice. PCR-based assays for the detection of M. tuberculosis DNA in urine will require further refinement before they can be recommended for use in clinical practice in Africa. The presence of mycobacterial DNA in urine samples of patients with pulmonary tuberculosis also requires further study.

University hospital in Lusaka, Zambia.To determine the effects of childhood bacille Calmette-Guerin (BCG) immunization and human immunodeficiency virus (HIV) infection on dual skin test reactions to purified protein derivative (PPD) and Mycobacterium avium sensitin (MAS) in a developing country.Descriptive cross-sectional study.Dual skin testing was performed on 112 adults, 58 HIV-positive and 54 HIV-negative. Forty-seven (42%) of 112 had PPD reactionsor =10 mm and 52 (46%) had MAS reactionsor =10 mm. PPD reactionsor =10 mm were present in 30 (63%) of 48 BCG-positive subjects compared to 17 (27%) of 64 BCG-negative subjects (P0.001). Nineteen (33%) of 58 PPD or MAS skin test positive subjects were PPD dominant, 15 (26%) were MAS dominant, and 24 (41%) were non-dominant. MAS dominant and non-dominant reactions were significantly reduced in HIV-positive subjects, and non-dominant reactions were increased in BCG-positive subjects.Childhood BCG immunization is associated with PPD reactionsor =10 mm among adults. Reduced PPD reaction rates in HIV-positive adults appear to be due to a loss of BCG-induced PPD reactivity. Prior infection with M. avium complex is detectable in a significant proportion of adults in a developing country.

Saliva has been recommended as a safe and effective alternative to serum for enzyme-linked immunosorbent assay (ELISA) for HIV antibodies in surveillance programmes in developing countries. We evaluated the use of saliva specimens for detection of HIV antibodies using three different commercially available ELISAs. Saliva specimens from 107 patients selected at random from HIV high-risk (38), medium-risk (27) and low-risk (42) areas of the hospital were screened with the Wellcozyme HIV1 + 2 GACELISA VK61 (recommended for use with saliva), Wellcozyme HIV1 + 2 VK54/55 and Wellcozyme HIV-1 recombinant VK56/57. Of the 107 patients, 50 were positive and 57 negative for antibodies to HIV on confirmatory Western blot testing. For detection of antibodies to HIV in saliva, the Wellcozyme HIV1 + 2 GACELISA VK61 had a sensitivity and a specificity of 98%, the Wellcozyme HIV-1 recombinant VK56/57 a sensitivity and specificity of 96%, and the Wellcozyme HIV1 + 2 VK54/55 a sensitivity of 94% and a specificity of 95%. For detection of antibodies to HIV in serum, the Wellcozyme HIV-1 recombinant VK56/57 had a sensitivity and a specificity of 100%, the Wellcozyme HIV1 + 2 GACELISA VK61 a sensitivity and a specificity of 98%, and the Wellcozyme HIV1 + 2 VK54/55 a sensitivity and a specificity of 96%. This study illustrates that saliva can be used as an alternative to serum for screening for anti-HIV antibodies in African patients.

Whilst the close relationship between sarcoidosis and tuberculosis has long been recognized, the similarity of sarcoidosis to leprosy has remained in the background. In most of the developing world sarcoidosis has been apparently eclipsed by the high prevalence of these two common mycobacterial diseases. The relevant epidemiological, clinical, immunological and pathological features of leprosy and sarcoidosis are compared and contrasted.

Human monoclonal antibodies (mAb) were produced by hybridomas derived from fusion of the GM4672 lymphoblastoid cell line and peripheral blood mononuclear cells from leprosy patients. Hybridoma supernatants were screened for immunoglobulin (Ig) secretion, binding to Mycobacterium leprae, phenolic glycolipid-I (Phen GL-I), the unique M. leprae glycolipid and single-stranded(ss)DNA by ELISA. On the basis of direct-binding ELISAs, two IgMk mAb (PR4 and TH3) were selected for characterization. PR4 and TH3 bound to M. leprae, Phen GL-I and ssDNA; PR4 also bound to M. avium and M. kansasii and TH3 to M. kansasii. Inhibition assays demonstrated that these antibodies did not bind to the terminal disaccharide of Phen GL-I. In addition, both PR4 and TH3 bound to several autoantigens: ssDNA, double-stranded(ds)DNA and poly(ADP-ribose) but not RNA. PR4 and TH3 were used for preparation of rabbit anti-idiotype antisera. Inhibition studies demonstrated that the affinity purified rabbit anti-idiotype antisera were specific for their respective idiotype and that both Phen GL-I and ssDNA inhibited binding of idiotype to its anti-idiotype. PR4, but not TH3, was found to be similar but not identical to the 16/6 idiotype originally identified on a human monoclonal anti-DNA antibody derived from a patient with systemic lupus erythematosus (SLE).

To review trends in the rates of tuberculosis (TB) case notifications over a 37-year period.A retrospective study of Ministry of Health records on TB notifications between 1 January 1964 and 31 December 2000.Zambia, sub-Saharan Africa.Retrospective analysis of case-notification data for TB of the Zambia Ministry of Health annual returns.Annual TB case-notification rates and trends over the past 37 years.TB case-notification data from 1964 to 2000 show a 12-fold increase over the past two decades, and apparent gains in controlling TB seen in the 1960s and 1970s have been reversed over the past two decades. A stable situation during the period 1964-1984 (case-notification rate remained around 100 per 100,000 population) was followed by an exponential increase since the mid-1980s. The absolute number of new TB cases increased from 8,246 in 1985 (124/100,000) to 38,863 (409/100,000) in 1996 and 52,000 (512/100,000) in 2000. Comparison of case-notification rates over the past 2 decades with neighbouring countries (Zimbabwe, Malawi and Tanzania) show that Zambia has one of the highest case-notification rates in the region.Zambia, like many countries in Africa, is in the midst of a serious TB epidemic and there are no signs that it is abating. This increase was most likely due to the impact of the HIV/AIDS epidemic and subsequent breakdown of TB services. Concerted donor-government efforts should invest appropriately in long-term plans for TB control.

Randomised controlled clinical trial of Mycobacterium vaccae vaccination as an adjunct to anti-tuberculosis treatment in human immunodeficiency virus (HIV) positive patients with smear-positive tuberculosis (TB) in Lusaka, Zambia, and Karonga, Malawi.To explain the difference in mortality between the two trial sites and to identify risk factors for death among HIV-positive patients with TB.Information on demographic, clinical, laboratory and radiographic characteristics was collected. Patients in Lusaka (667) and in Karonga (84) were followed up for an average of 1.56 years. Cox proportional hazard analyses were used to assess differences in survival between the two sites and to determine risk factors associated with mortality during and after anti-tuberculosis treatment.The case fatality rate was 14.7% in Lusaka and 21.4% in Karonga. The hazard ratio for death comparing Karonga to Lusaka was 1.47 (95% confidence interval [CI] 0.9-2.4) during treatment and 1.76 (95%CI 1.0-3.0) after treatment. This difference could be almost entirely explained by age and more advanced HIV disease among patients in Karonga.It is important to understand the reasons for population differences in mortality among patients with TB and HIV and to maximise efforts to reduce mortality.

Four hundred and one consecutive diarrhoea patients and 101 adult patients without diarrhoea were enrolled for this study from a health centre in Lusaka. Campylobacter was isolated from 6% of patients with acute diarrhoea. However, non of these were seen in control group. Further studies are being carried out to determine the importance of Campylobacter species with other bacterial pathogens. It will also be interesting to see its impact and association with human immuno deficiency virus in this region.

The Department of Obstetrics and Gynaecology, University Teaching Hospital, Lusaka, Zambia.To ascertain 1) the non-obstetric causes of maternal mortality, 2) the importance of tuberculosis as a cause of maternal deaths, and 3) the trends in the aetiology of non-obstetric causes of maternal deaths during the past decade in the light of the human immunodeficiency virus epidemic.A 2-year retrospective study of the aetiology of all maternal deaths occurring at the University Teaching Hospital (UTH), Lusaka, Zambia between 1 January 1996 and 31 December 1997. Comparison of these data with available data published between 1974 and 1989.There were 251 maternal deaths recorded during the study period. Of these, 106 (42%) were due to direct (obstetric) causes and 145 (58%) were due to indirect (non-obstetric) causes. Malaria (30%), tuberculosis (25%) and unspecified chronic respiratory tract infections (22%) accounted for 77% of non-obstetric causes of maternal deaths and 44% of all causes of maternal deaths. The diagnosis of AIDS was closely linked with that of tuberculosis (92% of cases), and unspecified chronic respiratory illnesses (97%), but not with malaria (37%). The maternal mortality ratio for UTH was calculated at 921 per 100,000 live births, a significant increase from the 118 noted in 1982 and 667 in 1989.Despite improved obstetric services, the maternal mortality ratios at UTH, Lusaka, have increased eight-fold over the past two decades. This dramatic increase is mainly due to non-obstetric causes of death. Malaria and AIDS-associated tuberculosis and unspecified 'chronic respiratory illnesses' are now major causes of maternal death in Zambia. Greater emphasis is urgently required on early detection, accurate diagnosis, treatment and prevention of malaria and tuberculosis in pregnancy. Further definition of chronic 'unspecified' respiratory illnesses is also required.

TB in HIV-infected individuals is a major cause of morbidity and mortality in developing countries and poses enormous problems to the health services. Despite the availability of curative therapy, the incidence of TB in children and adults is increasing at an alarming rate and poses a grave threat to TB control programmes in developing countries. Prospective studies to define basic clinical, microbiological and epidemiological features of the resurgence of childhood TB in the light of the HIV epidemic are required.

Two closed camps in Hong Kong for Vietnamese refugees.To determine the referral times by clinicians (doctor's delay) of cases of tuberculosis (TB) from refugee camp clinics to the hospital/chest clinic.Retrospective case-note study of 97 Vietnamese patients receiving treatment for tuberculosis.The sites of TB were pulmonary (n = 61), glandular (n = 15), pleural effusion (n = 15), and other (n = 6). The median referral time was 18 days (range 0-417). Median consultations numbered three (range 1-16). Fifty-three (54.6%) patients were prescribed antibiotics. Thirty-nine (40%) patients were referred within 10 days; of these, 18 were referred the same day. These 39 patients were less likely to have received antibiotics (9/39 [23.1%] vs 44/58 [75.9%], relative risk [RR] 0.3 95% confidence interval [CI] 0.17-0.55), but were equally likely to have been physically examined (RR 0.66, 95%CI 0.39-1.1). Sixteen (16.5%) patients were referred after 90 days. They attended the clinic more often (median attendances 6.5 vs 3, P = 0.0002), and were prescribed more antibiotic courses (mean antibiotic prescriptions 1.6 vs 0.7, P = 0.03).Referral times by these clinicians varied widely, with long delays for approximately 60% of patients. Guidelines pertinent to primary care clinicians are needed to heighten their awareness of tuberculosis to prevent referral delays and subsequent TB treatment.