Background. Active case finding (ACF) for tuberculosis (TB) is a key strategy to reduce diagnostic delays, expedite treatment, and prevent transmission. Objective. Our objective was to identify the populations, settings, screening and diagnostic approaches that optimize coverage (proportion of those targeted who were screened) and yield (proportion of those screened who had active TB) in ACF programs. Methods. We performed a comprehensive search to identify studies published from 1980-2016 that reported the coverage and yield of different ACF approaches. For each outcome, we conducted meta-analyses of single proportions to produce estimates across studies, followed by meta-regression to identify predictors. Findings. Of 3,972 publications identified, 224 met criteria after full-text review. Most individuals who were targeted successfully completed screening, for a pooled coverage estimate of 93.5%. The pooled yield of active TB across studies was 3.2%. Settings with the highest yield were internally-displaced persons camps (15.6%) and healthcare facilities (6.9%). When compared to symptom screening as the reference standard, studies that screened individuals regardless of symptoms using microscopy, culture, or GeneXpert®MTB/RIF (Xpert) had 3.7% higher case yield. In particular, microbiological screening (usually microscopy) as the initial test, followed by culture or Xpert for diagnosis had 3.6% higher yield than symptom screening followed by microscopy for diagnosis. In a model adjusted for use of Xpert testing, approaches targeting persons living with HIV (PLWH) had a 4.9% higher yield than those targeting the general population. In all models, studies targeting children had higher yield (4.8%-5.7%) than those targeting adults. Conclusion. ACF activities can be implemented successfully in various populations and settings. Screening yield was highest in internally-displaced person and healthcare settings, and among PLWH and children. In high-prevalence settings, ACF approaches that screen individuals with laboratory tests regardless of symptoms have higher yield than approaches focused on symptomatic individuals.
Introduction Pulmonary tuberculosis (TB) is an important risk factor for chronic respiratory disease due to residual lung damage. Yet, the WHO End TB strategy does not mention post-TB chronic lung disorders (PTBLDs) and programmatic interventions to address PTBLD are lacking. This study assessed the scope of current guidelines and evidence on PTBLD to inform policy and research action. Methods A systematic literature search was conducted following Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. Eight databases (TRIP, International Guideline Library, MEDLINE/PubMed, EMBASE, Web of Science, Global Health, Cochrane Library) were searched for records on PTBLD published between 1 January 1990 and 1 December 2017. Non-English records, case series, conference abstracts and letters to editors were excluded. Data were extracted and charted on publication year, location, PTBLD condition(s) and main study outcome. Results A total of 212 guidelines and 3661 articles were retrieved. After screening, only three international TB guidelines mentioned TB sequelae, but none described how to identify or manage the condition. A total of 156 articles addressed PTBLD: 54 (35%) mentioned unspecified TB sequelae; 47 (30%) specific post-TB conditions including aspergillosis, bronchial stenosis or bronchiectasis; 52 (33%) post-TB obstructive disorders or lung function impairment; and 20 (13%) post-TB respiratory symptoms or chest X-ray abnormalities. The first two groups mostly assessed surgery or ventilation techniques for patient management, while the last two groups typically assessed prevalence or predictors of disease. Conclusion This is the first review to provide a comprehensive overview of the current literature on PTBLD. The scope of evidence around the burden of PTBLD warrants inclusion and recognition of the problem in international TB guidelines. Research is now needed on early detection of PTBLD and patient management options that are suitable for high-burden TB countries.
BACKGROUND: Optimal drug dosing is important to ensure adequate response to treatment, prevent development of drug resistance and reduce drug toxicity. The aim of these clinical standards is to provide guidance on 'best practice´ for dosing and management of TB drugs.METHODS: A panel of 57 global experts in the fields of microbiology, pharmacology and TB care were identified; 51 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all participants.RESULTS: Six clinical standards were defined: Standard 1, defining the most appropriate initial dose for TB treatment; Standard 2, identifying patients who may be at risk of sub-optimal drug exposure; Standard 3, identifying patients at risk of developing drug-related toxicity and how best to manage this risk; Standard 4, identifying patients who can benefit from therapeutic drug monitoring (TDM); Standard 5, highlighting education and counselling that should be provided to people initiating TB treatment; and Standard 6, providing essential education for healthcare professionals. In addition, consensus research priorities were identified.CONCLUSION: This is the first consensus-based Clinical Standards for the dosing and management of TB drugs to guide clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment to improve patient care.
Although the efficacy of isoniazid in the prevention of tuberculosis in HIV-infected persons with a positive tuberculin skin test is proven, several feasibility issues remain unanswered. In resource poor settings where a chest radiograph may not be readily available, the question of whether cough alone is an adequate screening tool needs to be considered. We analysed screening data collected as part of an isoniazid efficacy study. Although the study was not designed specifically to answer this question, the data suggests that cough alone may be inadequate for screening patients for potential tuberculosis preventive therapy, and that a chest radiograph may be necessary. Feasibility studies are needed.
World TB Day falls on March 24th each year, and it commemorates the day in 1882 when Dr Robert Koch announced that he had discovered the microbial cause of tuberculosis, Mycobacterium tuberculosis (WHO, 2020aWHO World tuberculosis day.2020https://www.who.int/news-room/events/detail/2020/03/24/default-calendar/world-tuberculosis-day-2020Google Scholar, WHO, 2020bWHO End TB strategy. https://www.who.int/tb/post2015_strategy/en/. [Accessed 3 February 2020].Google Scholar, WHO, 2020cWHO Europe. Drug resistant strains could become the dominant form of TB in Europe: it's time to end TB. http://www.euro.who.int/en/health-topics/communicable-diseases/tuberculosis/news/news/2019/3/drug-resistant-strains-could-become-the-dominant-form-of-tb-in-europe-its-time-to-end-tb.Google Scholar). At the time of Professor Koch's announcement in Berlin, TB was an endemic in Europe and the Americas, and caused the death of one in every seven people (Wallstedt and Maeurer, 2015Wallstedt H. Maeurer M. The history of tuberculosis management in Sweden.Int J Infect Dis. 2015; 32: 179-182Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar. Koch's discovery opened the way towards diagnosing, treating and curing patients with TB. One hundred and twenty eight years later, according to the WHO Annual TB Report, an estimated 10 million people fell ill with TB and 1.5 million died of it. Tuberculosis remains the top infectious disease killer worldwide (WHO, 2019WHO Global tuberculosis report.2019https://www.who.int/tb/publications/global_report/en/Google Scholar). The theme of World TB Day 2020 is the same as last year - 'IT'S TIME'. This places emphasis on the urgency to act on the commitments made by global leaders at the September 2018 UNGA-HLM (WHO, 2020aWHO World tuberculosis day.2020https://www.who.int/news-room/events/detail/2020/03/24/default-calendar/world-tuberculosis-day-2020Google Scholar, WHO, 2020bWHO End TB strategy. https://www.who.int/tb/post2015_strategy/en/. [Accessed 3 February 2020].Google Scholar, WHO, 2020cWHO Europe. Drug resistant strains could become the dominant form of TB in Europe: it's time to end TB. http://www.euro.who.int/en/health-topics/communicable-diseases/tuberculosis/news/news/2019/3/drug-resistant-strains-could-become-the-dominant-form-of-tb-in-europe-its-time-to-end-tb.Google Scholar) to: scale up access to prevention and treatment; build a multisectorial accountability; ensure sufficient and sustainable financing including research; promote an end to stigma and discrimination, and promote an equitable, rights-based and people-centered TB response. World TB day gives all TB stakeholders time to reflect and raise political, public and donor awareness about the devastating health, social and economic consequences of TB, and to step up efforts to end the global TB epidemic. The End TB Strategy (WHO, 2015) has set ambitious targets to reduce TB incidence and mortality by 90% and 95% respectively by 2035 compared with 2015. Each day, over 4000 people lose their lives to TB and close to 30,000 people fall ill with this preventable and curable disease. This is nearly 3 decades after tuberculosis was declared a global emergency by the WHO. For a disease where effective treatment has been available for over 60 years, this status quo is unacceptable. Observance of World TB Day 2020 provides yet another opportunity to raise awareness about commitments made by the United Nations and to take forward solutions needed to find, treat, and prevent this devastating disease. In support of World TB Day 2020, The IJID is publishing this TB theme volume of 17 focused articles, which cover a range of topics: The review by Alffenaar et al., 2020Alffenaar J.-W. Akkerman O. Kim H.Y. Tiberi S. Migliori G.B. Precision and personalized medicine and anti-TB treatment: is TDM feasible for programmatic use?.Int J Infect Dis. 2020; 92S: S5-S9Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar highlights the importance of therapeutic drug monitoring (TDM), an important tool in the era of precision medicine recently recommended by the ATS/CDC/ERS/IDSA multidrug-resistant guidelines (Nahid et al., 2019Nahid P. Mase S.R. Migliori G.B. Sotgiu G. Bothamley G.H. Brozek J.L. et al.Treatment of drug-resistant tuberculosis. Treatment of drug-resistant tuberculosis. An official ATS/CDC/ERS/IDSA clinical practice guideline.Am J Respir Crit Care Med. 2019; 200: e93-e142Crossref PubMed Scopus (124) Google Scholar). TDM is only useful for dose optimization if a patient is on an appropriate regimen guided by drug susceptibility testing. Expanding PK/PD research followed by clinical trials including both clinical outcome as well as cost-effectiveness will increase the level of evidence supporting TDM. TDM will also help preventing the development of resistance by ensuring adequate drug levels while reducing adverse events. The challenge is the availability of the techniques to monitors drugs concentrations. Simpler methods like saliva or urine testing are urgently needed. Akkerman et al., 2020Akkerman O.W. ter Beek L. Centis R. Maeurer M. Visca D. Muñoz-Torrico M. et al.Rehabilitation, optimized nutritional care, and boosting host internal milieu to improve long-term treatment outcomes in tuberculosis patients.Int J Infect Dis. 2020; 92S: S10-S14Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar highlight that there is still no guidance for assessing lung function in patients completing their treatment to assess quality of life and need for pulmonary rehabilitation. These patients are often also malnourished which lead to further deterioration of the lung function. Migliori et al., 2020Migliori G.B. Tiberi S. Zumla A. Petersen E. Chakaya J.M. Wejse C. et al.MDR/XDR-TB management of patients and contacts: challenges facing the new decade. The 2020 clinical update by the Global Tuberculosis Network.Int J Infect Dis. 2020; 92S: S15-S25Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar discuss the current management of multi-drug resistant (MDR) TB. The core published documents and guidelines have been reviewed including the recently published MDR-TB WHO rapid advice and ATS/CDC/ERS/IDSA guidelines (Sterling et al., 2020Sterling T.R. Njie G. Zenner D. Cohn D.L. Reves R. Ahmed A. et al.Guidelines for the treatment of latent tuberculosis infection: recommendations from the national tuberculosis controllers association and CDC, 2020.MMWR Recomm Rep. 2020; 69: 1-11Crossref PubMed Scopus (81) Google Scholar). The document, resulting from a Consensus among GTN (Global Tuberculosis Network) experts, represents a comprehensive and complete clinical guidance on this important issue. Two papers discuss important clinical and public health priorities in core settings around the globe, with special focus on LTBI detection and treatment. The Russian Federation has implemented an annual screening program for LTBI in children. As a result, the annual incidence in Russian children decreased from 19.1 per 100,000 in 2001 to 8.3 per 100,000 population in 2018 (Aksenova et al., 2020Aksenova V.S. Vasilyeva I.A. Kasaeva T.C. Samoilova A.G. Pshenichnaya N. Tyulkova T.E. Latent tuberculosis infection in children and adolescents in Russia.Int J Infect Dis. 2020; 92S: S26-S30Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar). In China, the development of active TB from LTBI in the general rural population was 0.87 per 100 person-years in the first 2 years among individuals who newly converted IGRA positive. The large trials conducted more than 50 years ago were reviewed to describe the historical background for current guidelines on LTBI and to demonstrate similarities with current high-burden populations where there is limited use of Tuberculosis Preventive Therapy (TPT). The trials demonstrated a 27–95% reduction in incidence of active TB among the treated compared with placebo (Mølhave and Wejse, 2020Mølhave M. Wejse C. Historical review of studies on the effect of treating latent tuberculosis.Int J Infect Dis. 2020; 92S: S31-S36Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar). A 3-month regimen with twice-weekly rifapentine plus isoniazid (3H2P2, both with a maximum dose of 600 mg) has been practiced for LTBI treatment in China for years (Cui et al., 2020Cui X. Gao L. Cao B. Management of latent tuberculosis infection in China: exploring solutions suitable for high-burden countries.Int J Infect Dis. 2020; 92S: S37-S40Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar). Respiratory clinic follow-up after TB treatment may be useful in the monitoring and management of post-TB infections especially in patients with residual cavitation and/or bronchiectasis as further infectious insults can be prevented or mitigated (Hsu et al., 2020Hsu D. Irfan M. Jabeen K. Iqbal N. Hasan R. Migliori G.B. et al.Post tuberculosis treatment infectious complications.Int J Infect Dis. 2020; 92S: S41-S45Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar). Clinicians should also be aware of the possibility, and associated higher mortality, of NTM-Aspergillus co-infection (Jhun et al., 2017Jhun B.W. Jung W.J. Hwang N.Y. Park H.Y. Jeon K. Kang E.S. et al.Risk factors for the development of chronic pulmonary aspergillosis in patients with nontuberculous mycobacterial lung disease.PLoS One. 2017; 12e0188716Crossref PubMed Scopus (27) Google Scholar, Naito et al., 2018Naito M. Kurahara Y. Yoshida S. Ikegami N. Kobayashi T. Minomo S. et al.Prognosis of chronic pulmonary aspergillosis in patients with pulmonary non-tuberculous mycobacterial disease.Respir Investig. 2018; 56: 326-331Crossref PubMed Scopus (12) Google Scholar). The incidence of NTM infections is rising owing to a growing population of immuno-compromised and vulnerable individuals, complex medical and surgical procedures as well as increased awareness and diagnostic capabilities. Improved and rapid detection of TB cases in high burden countries has however also brought NTM infections into limelight and identified a need for research efforts towards rapid diagnostic tests, and identification of biomarkers to monitor treatment response in patients with NTM infections (Ahmed et al., 2020Ahmed I. Tiberi S. Farooqi J. Jabeen K. Yeboah-Manu D. Migliori G.B. et al.Non-tuberculous mycobacterial infections—A neglected and emerging problem.Int J Infect Dis. 2020; 92S: S46-S50Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar). The development and deployment of new tools will certainly accelerate progress towards ending TB, however, the end of TB is only realizable if sustained efforts to actively find TB cases, that cover a large proportion of the population, are adopted even with currently available tools (Chakaya et al., 2020Chakaya J.M. Harries A.D. Marks G.B. Ending tuberculosis by 2030—Pipe dream or reality?.Int J Infect Dis. 2020; 92S: S51-S54Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar). Contact investigation is the search for secondary cases of tuberculosis (TB) or tuberculosis infection (LTBI) among contacts of patients with a transmissible form of TB. The implementation of preventive therapy for persons with the highest risk of developing TB, that is the reduction of the pool of future cases of TB, is now considered as one of the activities able to support the decline in the prevalence of TB. This implies that the search for Mtb- infected contacts and the prevention of TB should be performed in parallel to the diagnostic and curative activities (Zellweger, 2020Zellweger J.P. Is the EU model for contact investigation applicable to high TB burden settings?.Int J Infect Dis. 2020; 92S: S55-S59Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar). In countries with a high proportion of migrants from high endemic countries, screening for LTBI has a high priority. Molecular typing and development of public private partnerships are needed (Al Abri et al., 2020aAl Abri S. Kasaeva T. Migliori G.B. Goletti D. Zenner D. Denholm J. et al.Tools to implement the World Health Organization End TB Strategy: Addressing common challenges in high and low endemic countries.Int J Infect Dis. 2020; 92S: S60-S68Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar). Accurate data on the prevalence of LTBI due to MDR Mtb strains are unavailable, since the strains cannot be isolated for resistance testing. The interferon-gamma release assays (IGRA) assays are not ideal due to issues of sensitivity, specificity, inability to distinguish infection with MDR-Mtb strains and the high costs. The development of new diagnostic tests which are better than currently available LTBI tests at predicting who is at risk of progression to active TB disease are urgently needed. Mwaba et al., 2020Mwaba P. Chakaya J.M. Petersen E. Wejse C. Zumla A. Kapata N. Advancing new diagnostic tests for latent tuberculosis infection due to multidrug-resistant strains of Mycobacterium tuberculosis — End of the road?.Int J Infect Dis. 2020; 92S: S69-S71Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar) reflect on the challenges of developing new diagnostic tests for Latent TB infection due multi-drug resistant strains of Mycobacterium tuberculosis. A Markov model was used to estimate cost of screening using an Interferon-gamma release assay (IGRA) or tuberculin skin test (TST), applied to all migrants from high TB endemic countries, followed by preventive TB treatment. The model compared seven different scenarios comparing the direct cost and the quality of life years, QALYs, saved. IGRA testing followed by three months preventive treatment with rifapentine/isoniazid, 3HP was the most cost-effective intervention (Al Abri et al., 2020bAl Abri S. Kowada A. Yaqoubi F. Al Khalili S. Ndunda N. Petersen E. Cost-effectiveness of IGRA/QFT-1 Plus for TB screening of migrants in Oman.Int J Infect Dis. 2020; 92S: S72-S77Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar). The TB prevalence among newly enrolled HIV-infected patients during the study period was 13.4% (22/164) in Guinea Bissau (Aunsborg et al., 2020Aunsborg J.W. Hønge B.L. Jespersen S. Rudolf F. Medina C. Correia F.G. et al.A clinical score has utility in tuberculosis case-finding among patients with HIV: a feasibility study from Bissau.Int J Infect Dis. 2020; 92S: S78-S84Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar). Using the TBscore and a diagnostic algorithm it was possible to bring the proportion of patients started on TB treatment from 2.7% (10/367) the year before the study to 10.4% (17/164) during the study period (Aunsborg et al., 2020Aunsborg J.W. Hønge B.L. Jespersen S. Rudolf F. Medina C. Correia F.G. et al.A clinical score has utility in tuberculosis case-finding among patients with HIV: a feasibility study from Bissau.Int J Infect Dis. 2020; 92S: S78-S84Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar). FDG PET/CT imaging has high sensitivity in active TB, complementing conventional radiologic imaging (X-ray, CT, MRI) in the diagnosis of primary pulmonary, extrapulmonary and post-primary or miliary TB. FDG PET/CT has low specificity when it is used for solitary pulmonary nodule characterization and its ability to differentiate TB from malignancy is limited in this setting (Priftakis et al., 2020Priftakis D. Riaz S. Zumla A. Bomanji J. Towards more accurate 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) imaging in active and latent tuberculosis.Int J Infect Dis. 2020; 92S: S85-S90Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar). The main recommendations and contraindications of sanatorium therapies (i.e., bed rest, fresh air, sunlight) and pulmonary collapse techniques are reviewed, evaluating their physiological basis and their impact on patients' outcomes. Studies describing new interventional pulmonology and surgical techniques, as well as we assess new perspectives based on old medical and surgical treatments, whose potential implementation could help complicated patients were reviewed (Mondoni et al., 2020Mondoni M. Centanni S. Sotgiu G. New perspectives on difficult-to-treat tuberculosis based on old therapeutic approaches.Int J Infect Dis. 2020; 92S: S91-S99Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar). Keeping up to date on the latest developments of TB epidemiology, diagnostics, treatment regimens is vital for continuing medical education (CME) and continuing professional development (CPD). For achieve this, update courses with the latest developments are important, especially. The Queen Mary University of London (QMUL) Certificate in Tuberculosis (TBCert) course provides a unique opportunity for CME/CPD for a global healthcare worker fraternity to receive the latest information from various international experts. It can be accessed remotely from any corner of the globe since it is a distance-based learning course, which was launched in 2019. The course is open to doctors, nurses and public health workers who wish to sub-specialize in tuberculosis (Tiberi et al., 2020Tiberi S. Zumla A. Raviglione M. Lipman M. Kon O.M. Griffiths C. et al.A postgraduate qualification in tuberculosis—Message in a bottle.Int J Infect Dis. 2020; 92S: S100-S102Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar). The papers in this World TB Day 2020 IJID theme series volume not only highlights the many challenges and gaps in meeting the WHO goals to end TB by 2035, but they also show several innovations in the diagnosis and management of this continuing global scourge of TB. More investments and commitments from national governments and donors is needed to bridge the widening implementation gap and to achieve the goals of the UN General Assembly resolution for the UN High-Level Meeting on TB, for ending the TB epidemic by 2035. All authors have a specialist interest in TB. Authors declare no other conflicts of interest. Prof Giuseppe Ippolito, Dr Nathan Kapata and Sir Prof Alimuddin Zumla are members of the Pan-African Network on Emerging and Re-emerging Infections (PANDORA-ID-NET), funded by the European & Developing Countries Clinical Trials Partnership, supported under Horizon 2020. Sir Zumla is in receipt of a National Institutes of Health Research senior investigator award. Prof Maeurer acknowledges support from and is funded by the Champalimaud Foundation . Prof Ippolito acknowledges support from the I talian Ministry of Health (Ricerca Corrente Linea 1). This article is part of a supplement entitled Commemorating World Tuberculosis Day March 24th, 2020: "IT'S TIME TO FIND, TREAT ALL and END TUBERCULOSIS!" published with support from an unrestricted educational grant from QIAGEN Sciences Inc.
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.
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