Drugs for treating infections caused by non-tubercular mycobacteria: a narrative review from the study group on mycobacteria of the Italian Society of Infectious Diseases and Tropical Medicine.

BACKGROUND: Non-tuberculous mycobacteria (NTM) are generally free-living organism, widely distributed in the environment, with sporadic potential to infect. In recent years, there has been a significant increase in the global incidence of NTM-related disease, spanning across all continents and an increased mortality after the diagnosis has been reported. The decisions on whether to treat or not and which drugs to use are complex and require a multidisciplinary approach as well as patients' involvement in the decision process. METHODS AND RESULTS: This review aims at describing the drugs used for treating NTM-associated diseases emphasizing the efficacy, tolerability, optimization strategies as well as possible drugs that might be used in case of intolerance or resistance. We also reviewed data on newer compounds highlighting the lack of randomised clinical trials for many drugs but also encouraging preliminary data for others. We also focused on non-pharmacological interventions that need to be adopted during care of individuals with NTM-associated diseases CONCLUSIONS: Despite insufficient efficacy and poor tolerability this review emphasizes the improvement in patients' care and the needs for future studies in the field of anti-NTM treatments.

Recommendations for the diagnosis of pediatric tuberculosis.

Tuberculosis (TB) is still the world's second most frequent cause of death due to infectious diseases after HIV infection, and this has aroused greater interest in identifying and managing exposed subjects, whether they are simply infected or have developed one of the clinical variants of the disease. Unfortunately, not even the latest laboratory techniques are always successful in identifying affected children because they are more likely to have negative cultures and tuberculin skin test results, equivocal chest X-ray findings, and atypical clinical manifestations than adults. Furthermore, they are at greater risk of progressing from infection to active disease, particularly if they are very young. Consequently, pediatricians have to use different diagnostic strategies that specifically address the needs of children. This document describes the recommendations of a group of scientific societies concerning the signs and symptoms suggesting pediatric TB, and the diagnostic approach towards children with suspected disease.

Policy and programmatic directions for the Lesotho tuberculosis programme: Findings of the national tuberculosis prevalence survey, 2019.

INTRODUCTION: The Kingdom of Lesotho has one of the highest burdens of tuberculosis (TB) in the world. A national TB prevalence survey was conducted to estimate the prevalence of bacteriologically confirmed pulmonary TB disease among those ≥15 years of age in 2019. METHOD: A multistage cluster-based cross-sectional survey where residents ≥15 years in 54 clusters sampled from across the country were eligible to participate. Survey participants were screened using a symptom screen questionnaire and digital chest X-ray (CXR). Respondents who acknowledged cough of any duration, fever, weight loss, night sweats and/or had any CXR abnormality in the lungs were asked to provide two spot sputum specimens. All sputum testing was conducted at the National TB Reference Laboratory (NTRL), where samples underwent Xpert MTB/RIF Ultra (1st sample) and MGIT culture (2nd sample). HIV counselling and testing was offered to all survey participants. TB cases were those with Mycobacterium tuberculosis complex-positive samples with culture; and where culture was not positive, Xpert MTB/RIF Ultra (Xpert Ultra) was positive with a CXR suggestive of active TB and no current or prior history of TB. RESULT: A total of 39,902 individuals were enumerated, and of these, 26,857 (67.3%) were eligible to participate; 21,719 (80.9%) participated in the survey of which 8,599 (40%) were males and 13,120 (60%) were females. All 21,719 (100%) survey participants underwent symptom screening and a total of 21,344 participants (98.3%) had a CXR. Of the 7,584 (34.9%) participants who were eligible for sputum examination, 4,190 (55.2%) were eligible by CXR only, 1,455 (19.2%) by symptom screening, 1,630 by both, and 309 by CXR exemption. A total of 6,780 (89.4%) submitted two sputum specimens, and 311 (4.1%) submitted one sample only. From the 21,719 survey participants, HIV counseling and testing was offered to 17,048, and 3,915 (23.0%) were documented as HIV-positive. The survey identified 132 participants with bacteriologically confirmed pulmonary TB thus providing an estimated prevalence of 581 per 100,000 population (95% CI 466-696) for those ≥15 years in 2019. Using the survey results, TB incidence was re-estimated to be 654 per 100,000 (95% CI 406-959), which was comparable to the 2018 TB incidence rate of 611 per 100,000 (95% CI 395-872) reported by the World Health Organization (WHO). The highest TB burden was found in those ≥55 years and among men. The ratio of prevalence to case notification was estimated at 1.22. TB/HIV coinfection was identified in 39 (29.6%) participants. Out of the 1,825 participants who reported a cough, 50% of these participants, mostly men, did not seek care. Those who sought care predominantly went to the public health facilities. CONCLUSION: The TB prevalence survey results confirmed that burden of TB and TB/HIV coinfection remains very high in Lesotho. Given that TB prevalence remains high, and there is a significant proportion of participants with confirmed TB that did not report TB suggestive symptoms. The National TB Programme will need to update its TB screening and treatment algorithms to achieve the End TB targets. A major focus will need to be placed on finding the "missing cases" i.e., undiagnosed or under-reported TB cases, or ensuring that not only TB symptomatic but also those who do not present with typical TB symptoms are promptly identified to reduce further onward transmission.

Vaccination in post-tuberculosis lung disease management: A review of the evidence.

INTRODUCTION AND OBJECTIVES: Post-tuberculosis lung disease (PTLD), as other chronic respiratory disorders, may have infectious complications; some of them can be prevented with vaccinations. So far, no document has discussed the potential role of vaccination in PTLD. Therefore, the objective of this review was to describe vaccination recommendations to prevent infections potentially capable of complicating PTLD. MATERIALS AND METHODS: A non-systematic review of the literature was conducted. The following keywords were used: tuberculosis, vaccination, vaccines and PTLD. PubMed/MEDLINE and Embase were used as the search engine, focusing on English-language literature only. RESULTS: We identified 9 vaccines potentially useful in PTLD. Influenza, pneumococcal and anti-COVID-19 vaccinations should be recommended. Patients with PTLD can also benefit from vaccination against shingles. Vaccination against pertussis is mainly relevant during childhood. Diphtheria, tetanus and measles vaccination are recommended for general population and should be considered in patients with PTLD not previously vaccinated. Tdap (Tetanus, diphtheria, and pertussis) booster should be repeated in every adult every ten years. Vaccination against BCG retains its importance during early childhood in countries where TB is endemic. CONCLUSIONS: Vaccination deserves to be considered among the strategies to prevent and/or mitigate PTLD complications. Further evidence is necessary to better understand which vaccines have the greatest impact and cost-benefit.

Clinical standards for the dosing and management of TB drugs.

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.

Clinical standards for drug-susceptible pulmonary TB.

BACKGROUND: The aim of these clinical standards is to provide guidance on 'best practice´ for diagnosis, treatment and management of drug-susceptible pulmonary TB (PTB).METHODS: A panel of 54 global experts in the field of TB care, public health, microbiology, and pharmacology were identified; 46 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 46 participants.RESULTS: Seven clinical standards were defined: Standard 1, all patients (adult or child) who have symptoms and signs compatible with PTB should undergo investigations to reach a diagnosis; Standard 2, adequate bacteriological tests should be conducted to exclude drug-resistant TB; Standard 3, an appropriate regimen recommended by WHO and national guidelines for the treatment of PTB should be identified; Standard 4, health education and counselling should be provided for each patient starting treatment; Standard 5, treatment monitoring should be conducted to assess adherence, follow patient progress, identify and manage adverse events, and detect development of resistance; Standard 6, a recommended series of patient examinations should be performed at the end of treatment; Standard 7, necessary public health actions should be conducted for each patient. We also identified priorities for future research into PTB.CONCLUSION: These consensus-based clinical standards will help to improve patient care by guiding clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment for PTB.

Spinal tuberculosis: proposed spinal infection multidisciplinary management project (SIMP) flow chart revision.

OBJECTIVE: We propose a revised flow chart of spinal infection multidisciplinary management project (SIMP) aimed to standardize the diagnostic process and management of spinal tuberculosis (TB). MATERIALS AND METHODS: We reviewed data from all TB cases with osteoarticular involvement treated at a large tertiary teaching hospital in Bologna, Northern Italy, from January 2013 to December 2017. We cross-linked notified osteoarticular TB cases with SIMP database and we analysed clinical, diagnostic, and treatment data of all cases managed by SIMP. RESULTS: Osteoarticular TB accounted for the 7.8% (n=40) of all TB cases notified between 2013 and 2017 (N=513). Among the identified cases, 52% (n=21/40) had spine involvement: all were enrolled and evaluated by SIMP multidisciplinary group. Females accounted for 57% (12/21) of patients, the median age was 52 years (range 24-82). In the 67% (n=14/21) of cases, the major clinical symptom of spinal TB was back pain reported for a median of 4.5 months (range 1-12 months) before hospital admission. The interferon gamma release assay was positive in 75% (n=16/21) of patients. All patients performed MRI with gadolinium, which indicated spondylodiscitis in 90%. 18F-FDG-PET/CT revealed average maximum standardized uptake value (SUV max) of 12.54 (range 5.3-22) in 17/19 (89.5%). Bacteriological confirmation of TB was obtained in 86% of cases (n=18/21). One-third of patients (7/21) underwent surgery and 95% successfully completed the anti-TB treatment. CONCLUSIONS: Our data reveal that a multidisciplinary approach to spine tuberculosis facilitates early and accurate diagnosis and can improve medical and surgical management of this disease.

National population-based tuberculosis prevalence survey in Ghana, 2013.

BACKGROUND: The prevalence of tuberculosis (TB) disease is one of the three main indicators used to assess the epidemiological burden of TB and the impact change of TB control; the other two are incidence and mortality.OBJECTIVE: To estimate the prevalence of TB disease among adults in Ghana.METHODS: A nationally representative cross-sectional survey was conducted. Participants were screened for TB using interview and chest X-ray (CXR). For those participants with cough ≥2 weeks and/or abnormal CXR, spot and morning sputum specimens were collected and examined by smear microscopy and culture.RESULTS: The study revealed that the prevalence of smear-positive TB among adults (age ≥15 years) was 111 (95%CI 76-145) and that of bacteriologically confirmed TB was 356 (95%CI 288-425) per 100 000 population. Males and older people had a higher prevalence than their counterparts. The majority of TB cases were smear-negative and had an abnormal CXR without reported chronic cough.CONCLUSION: The survey revealed much higher TB disease burden than previously estimated. This implies that the programme needs more effort and resources to find undiagnosed and unreported cases. The higher proportion of smear-negative and asymptomatic TB cases suggests the need to revise the existing screening and diagnostic algorithms.

Tuberculosis, COVID-19 and migrants: Preliminary analysis of deaths occurring in 69 patients from two cohorts.

Little is known about the relationship between the COVID-19 and tuberculosis (TB). The aim of this study is to describe a group of patients who died with TB (active disease or sequelae) and COVID-19 in two cohorts. Data from 49 consecutive cases in 8 countries (cohort A) and 20 hospitalised patients with TB and COVID-19 (cohort B) were analysed and patients who died were described. Demographic and clinical variables were retrospectively collected, including co-morbidities and risk factors for TB and COVID-19 mortality. Overall, 8 out of 69 (11.6%) patients died, 7 from cohort A (14.3%) and one from cohort B (5%). Out of 69 patients 43 were migrants, 26/49 (53.1%) in cohort A and 17/20 (85.0%) in cohort B. Migrants: (1) were younger than natives; in cohort A the median (IQR) age was 40 (27-49) VS. 66 (46-70) years, whereas in cohort B 37 (27-46) VS. 48 (47-60) years; (2) had a lower mortality rate than natives (1/43, 2.3% versus 7/26, 26.9%; p-value: 0.002); (3) had fewer co-morbidities than natives (23/43, 53.5% versus 5/26-19.2%) natives; p-value: 0.005). The study findings show that: (1) mortality is likely to occur in elderly patients with co-morbidities; (2) TB might not be a major determinant of mortality and (3) migrants had lower mortality, probably because of their younger age and lower number of co-morbidities. However, in settings where advanced forms of TB frequently occur and are caused by drug-resistant strains of M. tuberculosis, higher mortality rates can be expected in young individuals.

Team approach to manage difficult-to-treat TB cases: Experiences in Europe and beyond.

As recommended by the World Health Organization (WHO), optimal management of MDR-TB cases can be ensured by a multi-speciality consultation body known as 'TB Consilium'. This body usually includes different medical specialities, competences and perspectives (e.g., clinical expertise both for adults and children; surgical, radiological and public health expertise; psychological background and nursing experience, among others), thus lowering the risk of making mistakes - or managing the patients inappropriately, in order to improve their clinical outcomes. At present, several high MDR-TB burden countries in the different WHO regions (and beyond) have introduced TB Consilium-like bodies at the national or subnational level to reach consensus on the best treatment approach for their patients affected by TB. In addition, in countries/settings where a formal system of consultation does not exist, specialized staff from MDR-TB reference centres or international organizations usually spend a considerable amount of their working time responding to phone or e-mail clinical queries on how to manage M/XDR-TB cases. The aim of this manuscript is to describe the different experiences with the TB Consilia both at the international level (European Respiratory Society - ERS/WHO TB Consilium) and in some of the countries where this experience operates successfully in Europe and beyond. The Consilium experiences are described around the following topics: (1) history, aims and focus; (2) management and funding; (3) technical functioning and structure; (4) results achieved. In addition a comparative analysis of the TB Consilia in the different countries has been performed.

Perforins in human cytolytic cells: the effect of age.

The ageing process is associated with a progressive increase in the number of circulating NK cells, together with a decreased lytic activity per cell. A similar decrease in activity was also found for CD8 lymphocytes. Cytotoxic T- and NK cells express cytoplasm granules containing cytolytic effector molecules (as perforins, studied here) which can recognize and destroy damaged, infected and/or mutated target cells. To investigate whether an altered distribution of perforins in cytolytic cells or a reduced number of cytolytic cells producing perforins underlies decreased cytolytic activity with advancing age, perforin expression was assessed at the single cell level in T- (CD4 and CD8) and NK (CD16) peripheral blood lymphocytes from elderly subjects by flow cytometry. Perforin distribution at the cellular level in CD8+ and CD16+ cell cytoplasm suggested a similar distribution during ageing and a similar number of cells producing perforins. In addition, perforin utilization was maintained in the generation of cytolytic activity against K562 target cells and perforin synthesis in culture following activation was unabated. These data stress the importance of other factors, such as defective signal transduction for granule exocytosis, that may account for the different pattern of lytic activity found in aged people.

Silent oophoritis due to cytomegalovirus in a patient with advanced HIV disease.

A case of isolated necrotizing cytomegalovirus (CMV) oophoritis disclosed only by necropsy studies in a patient with AIDS, is described. This unusual case report is discussed with a review of the literature dealing with CMV involvement of genital organs in the immunocompromised host, and in patients with HIV infection and AIDS.

Metabolic complications of HIV-1 antiretroviral therapy: the lipodystrophy syndrome.

The lipodystrophy syndrome is one of the complications reported with increased frequency in patients with HIV-1 infection receiving antiretroviral therapy. The wide range of prevalence estimates may be due to differing definitions, methods and patient populations. We described the various pathogenic theories and the morphological and metabolic alterations associated with this syndrome. Even if no effective treatment exists, a correct lifestyle, adequate diet and physical exercise seem to be very important. Moreover drug therapies should be used with care to avoid potentially harmful interactions with antiretroviral agents. Ideally, the future effort to define the mechanism of lipodystrophy would be multidisciplinary and would involve not only experts in AIDS research but also nutritionists, endocrinologists and cardiologists.

A comparison of immunocomplex-dissociated serum HIV-1 p24 antigenemia and plasma HIV-1 viral load: assessment of 3,129 paired assays.

In order to compare HIV-1 p24 antigenemia and plasma HIV-1 RNA levels as markers of viral replication, 3,129 paired determinations of alkaline immunocomplex-dissociated serum HIV-1 p24 antigenemia (performed with an immunoenzymatic assay), and plasma HIV-1 RNA levels (carried out with a branched DNA method, a reverse transcriptase-coupled polymerase chain reaction, and a nucleic acid sequence-based assay) were assessed over a two-year-period. When excluding samples with undetectable plasma HIV-1 RNA levels (which tested negative or borderline positive at serum p24 antigen assay in 97.9% of cases), immunocomplex-dissociated p24 antigenemia proved significantly less sensitive than viral load at all considered HIV-1 RNA reference levels, although the profile of positive serum p24 antigen assays (values above 10 pg/ml) paralleled the trend of plasma HIV-1 viral load, especially at higher levels. However, serum HIV-1 p24 antigenemia (even after immunocomplex dissociation) can be longer suggested as a the sole virological tool in the laboratory management of HIV-1 infection, due to its significantly lower sensitivity levels compared with viral load assessment.

[The diagnosis of new cases of HIV infection: a reversal of the trend?]. / Diagnosi di nuovi casi di infezione da HIV: un'inversione di tendenza?

In order to assess the trend of new cases of HIV infection, spontaneous requests of HIV counseling and testing made at our outpatient Center since 1993 were retrospectively evaluated. During the considered 6-year period, 7,492 subjects had voluntary HIV testing, and 225 proved HIV-positive (3.0%). While the overall number of spontaneous requests of HIV serology did not show remarkable variations over time, a tendency towards a significant increase of newly diagnosed HIV disease was observed during the past two years (1997 and 1998). In particular, among the 57 subjects with HIV infection disclosed in 1998, a predominance of young adults and a relatively elevated frequency of females compared with males was demonstrated, while heterosexual (38 cases) and homo-bisexual contacts (18 cases) accounted for the great majority of newly identified retroviral infections, and 66.1% out of the 56 patients who acquired HIV infection by sexual route were stable partners of individuals with known HIV disease. Although epidemiological estimates foresaw a progressive reduction of cases of HIV infection since 1990, a surprising increase of newly diagnosed HIV disease among patients who spontaneously asked for HIV testing was observed in our experience. The apparent temporal coincidence of this phenomenon with the remarkable advances obtained in both diagnostic and therapeutic strategies of HIV disease just since 1996, could not be a fortuitous event. The non-decline of newly diagnosed cases of HIV infection should re-orient strategies of communication and prophylaxis dealing with HIV disease, and involving the general population and people with persisting high-risk behavior.