Chronic obstructive pulmonary disease – diagnosis and classification of severity

Chronic obstructive pulmonary disease (COPD) is a common, progressive and preventable  non-communicable respiratory disorder. It is often confused with asthma and poorly understood by many lay people. The primary cause of COPD is tobacco smoking, but in the South African (SA) context, biomass fuel exposure/household pollution, tuberculosis, HIV and mining exposure are additional  important causes. There is a very high prevalence of COPD in SA and it is the third leading cause of  mortality globally. The diagnosis of COPD is based predominantly on symptoms, i.e. progressive  shortness of breath and cough in a patient with risk factors – usually smoking. Lung function testing is required to formally make the diagnosis, which places a significant hurdle in correctly identifying COPD in SA, given the limited access to spirometry in many areas. Spirometry is also required to grade the  severity of lung function obstruction. Severity assessment, which is used to plan a management strategy (predominantly bronchodilators with inhaled steroids in severe cases), combines symptoms, lung  function and exacerbations. Based on these 3 factors, a patient can be categorised into 1 of 4 groups and appropriate management instituted. Additional comorbidities, particularly cardiovascular and mental  illness, should also be evaluated. Early identification of COPD, with further avoidance of an aetiological cause such as smoking, is key in preventing disease progression. Appropriate therapy, comprising  non-pharmacological and pharmacological interventions and based on a comprehensive severity assessment, should result in symptom improvement and reduced risk for exacerbation

Challenges for dedicated smoking cessation services in developing countries.

BACKGROUND: South Africa, ranked as the world's second most stressful country to live in, has an estimated 7 million smokers. A dedicated smoking cessation clinic established at Groote Schuur Hospital, Cape Town, provides the only clinical service and training centre in the country. OBJECTIVES: To evaluate the smokers attending the clinic, in order to better understand the requirements of smoking cessation services in resource-limited settings. METHODS: Demographic and smoking-related data were collected prospectively from all clinic attendees since its inception. Nicotine dependence, depression scores and exhaled carbon monoxide levels were formally evaluated. Consent was provided to review the data collected. RESULTS: Ninety-seven smokers were evaluated. Their mean (standard deviation) age was 50.9 (10.7) years, and 59% (57/97) were male. The median age of smoking initiation was 16 years (interquartile range (IQR) 8 - 28), with a current median daily consumption of 12 cigarettes (IQR 7 - 20). Overall, men smoked more than women, with a median of 20 cigarettes per day (IQR 10 - 20) v. 12 (IQR 5 - 20), respectively (p=0.001). The median Fagerström nicotine dependence score was 5 (IQR 3 - 7), with scores of 6 (IQR 4 - 8) for men and 5 (2 - 7) for women (p=0.06); 50% of smokers had a Fagerström score <6 (low to above-average dependence) and 22% a score ≥8 (extreme dependence). The median Patient Health Questionnnaire-9 (PHQ-9) depression score was 8 (IQR 4 - 11), and 49% of smokers had symptoms of at least minor depression (score ≥10). The clinic could not provide pharmacotherapy. The self-reported quit rate was 28% at median follow-up of 22 months (IQR 14 - 39). CONCLUSIONS: In smokers attempting to quit, moderate levels of nicotine dependence coexist with significant depression and anxiety symptoms. These data inform resource allocation and public health strategies, suggesting that in resource-limited smoking cessation services, psychological/behavioural support focusing on depressive symptoms may be a greater priority than simple pharmacotherapy

Comparison of Quantitative Techniques including Xpert MTB/RIF to Evaluate Mycobacterial Burden

Introduction: Accurate quantification of mycobacterial load is important for the evaluation of patient infectiousness, disease severity and monitoring treatment response in human and in-vitro laboratory models of disease. We hypothesized that newer techniques would perform as well as solid media culture to quantify mycobacterial burden in laboratory specimens. Methods: We compared the turn-around-time, detection-threshold, dynamic range, reproducibility, relative discriminative ability, of 4 mycobacterial load determination techniques: automated liquid culture (BACTEC-MGIT-960), [3H]-uracil incorporation assays, luciferase-reporter construct bioluminescence, and quantitative PCR(Xpert -MTB/RIF) using serial dilutions of Mycobacterium bovis and Mycobacterium tuberculosis H37RV. Mycobacterial colony-forming-units(CFU) using 7H10-Middlebrook solid media served as the reference standard. Results: All 4 assays correlated well with the reference standard, however, bioluminescence and uracil assays had a detection threshold ≥1×103 organisms. By contrast, BACTEC-MGIT-960 liquid culture, although only providing results in days, was user-friendly, had the lowest detection threshold (<10 organisms), the greatest discriminative ability (1 vs. 10 organisms; p = 0.02), and the best reproducibility (coefficient of variance of 2% vs. 38% compared to uracil incorporation; p = 0.02). Xpert-MTB/RIF correlated well with mycobacterial load, had a rapid turn-around-time (<2 hours), was user friendly, but had a detection limit of ~100 organisms. Conclusions: Choosing a technique to quantify mycobacterial burden for laboratory or clinical research depends on availability of resources and the question being addressed. Automated liquid culture has good discriminative ability and low detection threshold but results are only obtained in days. Xpert MTB/RIF provides rapid quantification of mycobacterial burden, but has a poorer discrimination and detection threshold

South african thoracic society position statement on post-acute sequelae of SARS-CoV-2 infection

• Post-acute coronavirus disease-19 (COVID-19) respiratory symptoms are common and may be caused by a variety of factors including, among others, cardiac and respiratory dysfunction. • A detailed history and examination with appropriate investigations is imperative to define the exact nature of the dysfunction. • Limited data exist to guide evidence-based approaches to treatment. • Injudicious use of corticosteroids is cautioned against as well as indiscriminate use of off-label drugs

Guidelines for the management of asthma in adults and adolescents: Position statement of the South African Thoracic Society - 2021 update.

Asthma prevalence is increasing worldwide, and surveys indicate that most patients in developed and developing countries, including South Africa, do not receive optimal care and are therefore not well controlled. Standard management guidelines adapted to in-country realities are important to support optimal care. The South African Thoracic Society (SATS) first published a guideline for the management of chronic persistent asthma in 1992, which has subsequently been revised several times. The main aim of the present document was to revise and update SATS' statement on the suggested management of chronic asthma, based on the need to promote optimal care and control of asthma, together with the incorporation of new concepts and drug developments. This revised document reinforces optimal care and incorporates the following primary objectives to achieve the recent advances in asthma care: continued emphasis on the use of inhaled corticosteroids (ICS) as the foundation of asthma treatmentto reduce the reliance on short-acting beta-2 agonist (SABA) monotherapy for asthma symptomsto incorporate the evidence and strategy for the use of the combination of an ICS and formoterol for acute symptom relief (instead of a SABA)to incorporate the evidence and strategy for the use of as-needed ICS-long-acting beta agonists (LABA) for patients with infrequent symptoms or 'mild' asthmato incorporate the evidence and strategy for the use of a long-acting muscarinic antagonist (LAMA) in combination with ICS-LABA; andto incorporate the evidence and strategy for the use of and management with a biologic therapy in severe asthma

Single-inhaler triple therapy fluticasone furoate/umeclidinium/vilanterol versus dual therapy in current and former smokers with COPD: IMPACT trial post hoc analysis.

This is the final version. Available from Elsevier via the DOI in this record. Data sharing: Anonymized individual participant data and study documents can be requested for further research from www.clinicalstudydatarequest.com.BACKGROUND: Smoking is the major risk factor for chronic obstructive pulmonary disease (COPD). In IMPACT, single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy significantly reduced moderate/severe exacerbation rates and improved lung function and health status versus FF/VI or UMEC/VI in COPD patients. This post hoc analysis investigated trial outcomes by smoking status. METHODS: IMPACT was a double-blind, 52-week trial. Patients aged ≥40 years with symptomatic COPD and ≥1 moderate/severe exacerbation in the prior year were randomized 2:2:1 to FF/UMEC/VI 100/62.5/25 μg, FF/VI 100/25 μg, or UMEC/VI 62.5/25 μg. Endpoints assessed by smoking status at screening included rate and risk of moderate/severe exacerbations, change from baseline in trough forced expiratory volume in 1 s, and St George's Respiratory Questionnaire total score at Week 52. Safety was also assessed. RESULTS: Of the 10,355 patients in the intent-to-treat population, 3,587 (35%) were current smokers. FF/UMEC/VI significantly reduced on-treatment moderate/severe exacerbation rates versus FF/VI and UMEC/VI in current (rate ratio 0.85 [95% confidence interval: 0.77-0.95]; P = 0.003 and 0.86 [0.76-0.98]; P = 0.021) and former smokers (0.85 [0.78-0.91]; P < 0.001 and 0.70 [0.64-0.77]; P < 0.001). FF/UMEC/VI significantly reduced time-to-first on-treatment moderate/severe exacerbation versus FF/VI and UMEC/VI in former smokers, and versus FF/VI in current smokers. Similar trends were seen for lung function and health status. Former smokers receiving inhaled corticosteroid-containing therapy had higher pneumonia incidence than current smokers. CONCLUSIONS: FF/UMEC/VI improved clinical outcomes versus dual therapy regardless of smoking status. Benefits of FF/UMEC/VI versus UMEC/VI were greatest in former smokers, potentially due to relative corticosteroid resistance in current smokers. CLINICAL TRIAL REGISTRATION: GSK (CTT116855/NCT02164513).GlaxoSmithKleinGlaxoSmithKlei

Within-Subject Variability of Interferon-g Assay Results for Tuberculosis and Boosting Effect of Tuberculin Skin Testing: A Systematic Review

Background: Variability in interferon-gamma release assays (IGRAs) results for tuberculosis has implications for interpretation of results close to the cut-point, and for defining thresholds for test conversion and reversion. However, little is known about the within-subject variability (reproducibility) of IGRAs. Several national guidelines recommend a twostep testing procedure (tuberculin skin test [TST] followed by IGRA) for the diagnosis of LTBI. However, the effect of a preceding TST on subsequent IGRA results has been reported in studies with apparently conflicting results. Methodology/Findings: We conducted a systematic review to synthesize evidence on within-subject variability of IGRA results and the potential boosting effect of TST. We searched several databases and reviewed citations of previous reviews on IGRAs. We included studies using commercial IGRAs, in addition to non-commercial versions of the ELISPOT assay. Four studies, fulfilling our predefined criteria, examined within-subject variability and 13 studies evaluated TST effects on subsequent IGRA responses. Meta-analysis was not considered appropriate because of heterogeneity in study methods, assays, and populations. Although based on limited data, within-subject variability was present in all studies but the magnitude varied (16-80%) across studies. A TST induced ‘‘boosting’ ’ of IGRA responses was demonstrated in several studies and although more pronounced in IGRA-positive (i.e. sensitized) individuals, also occurred in a smaller but not insignificant proportion of IGRA-negative subjects. The TST appeared to affect IGRA responses only after 3 days and may apparentl

The organisational response of a hospital critical care service to the COVID-19 pandemic: The Groote Schuur Hospital experience.

Background: There are limited data about the coronavirus disease-19 (COVID-19)-related organisational responses and the challenges of expanding a critical care service in a resource-limited setting. Objectives: To describe the ICU organisational response to the pandemic and the main outcomes of the intensive care service of a large state teaching hospital in South Africa. Methods: Data were extracted from administrative records and a prospective patient database with ethical approval. An ICU expansion plan was developed, and resource constraints identified. A triage tool was distributed to referring wards and hospitals. Intensive care was reserved for patients who required invasive mechanical ventilation (IMV). The total number of ICU beds was increased from 25 to 54 at peak periods, with additional non-COVID ICU capacity required during the second wave. The availability of nursing staff was the main factor limiting expansion. A ward-based high flow nasal oxygen (HFNO) service reduced the need for ICU admission of patients who failed conventional oxygen therapy. A team was established to intubate and transfer patients requiring ICU admission but was only available for the first wave. Results: We admitted 461 COVID-19 patients to the ICU over a 13-month period from 5 April 2020 to 5 May 2021 spanning two waves of admissions. The median age was 50 years and duration of ICU stay was 9 days. More than a third of the patients (35%; n=161) survived to hospital discharge. Conclusion: Pre-planning, leadership, teamwork, flexibility and good communication were essential elements for an effective response. A shortage of nurses was the main constraint on ICU expansion. HFNO may have reduced the requirement for ICU admission, but patients intubated after failing HFNO had a poor prognosis. Contributions of the study: We describe the organisational requirements to successfully expand critical care facilities and strategies to reduce the need for invasive mechanical ventilation in COVID-19 pneumonia. We also present the intensive care outcomes of these patients in a resource-constrained environment

Negative Effect of Smoking on the Performance of the QuantiFERON TB Gold in Tube Test.

False negative and indeterminate Interferon Gamma Release Assay (IGRA) results are a well documented problem. Cigarette smoking is known to increase the risk of tuberculosis (TB) and to impair Interferon-gamma (IFN-γ) responses to antigenic challenge, but the impact of smoking on IGRA performance is not known. The aim of this study was to evaluate the effect of smoking on IGRA performance in TB patients in a low and high TB prevalence setting respectively. Patients with confirmed TB from Denmark (DK, n = 34; 20 smokers) and Tanzania (TZ, n = 172; 23 smokers) were tested with the QuantiFERON-TB Gold In tube (QFT). Median IFN-γ level in smokers and non smokers were compared and smoking was analysed as a risk factor for false negative and indeterminate QFT results. Smokers from both DK and TZ had lower IFN-γ antigen responses (median 0.9 vs. 4.2 IU/ml, p = 0.04 and 0.4 vs. 1.6, p < 0.01), less positive (50 vs. 86%, p = 0.03 and 48 vs. 75%, p < 0.01) and more false negative (45 vs. 0%, p < 0.01 and 26 vs. 11%, p = 0.04) QFT results. In Tanzanian patients, logistic regression analysis adjusted for sex, age, HIV and alcohol consumption showed an association of smoking with false negative (OR 17.1, CI: 3.0-99.1, p < 0.01) and indeterminate QFT results (OR 5.1, CI: 1.2-21.3, p = 0.02). Cigarette smoking was associated with false negative and indeterminate IGRA results in both a high and a low TB endemic setting independent of HIV status

Unusual Interferon Gamma Measurements with QuantiFERON-TB Gold and QuantiFERON-TB Gold In-Tube Tests

INTRODUCTION: Interferon gamma (IFN-γ) release assays, such as QuantiFERON®-TB Gold test (QFT-G) and QuantiFERON®-TB Gold In-Tube test (QFT-GIT) are designed to detect M. tuberculosis (Mtb) infection. Recognition of unusual IFN-γ measurements may help indicate inaccurate results. METHODS: We examined QFT-G and QFT-GIT results from subjects who had two or more tests completed. We classified unusual IFN-γ measurements as: 1) High Nil Concentration (HNC) when IFN-γ concentration in plasma from unstimulated blood exceeded 0.7 IU/mL; 2) Low Mitogen Response (LMR) when Mitogen Response was <0.5 IU/mL; 3) Very Low Mitogen Response (VLMR) when Mitogen Response was ≤-0.5 IU/mL; and 4) Very Low Antigen Response (VLAR) when the response to a Mtb antigen was ≤-0.35 IU/mL and ≤-0.5 times the IFN-γ concentration in plasma from unstimulated blood. RESULTS: Among 5,309 results from 1,728 subjects, HNC occurred in 234 (4.4%) tests for 162 subjects, LMR in 108 (2.0%) tests for 85 subjects, VLMR in 22 (0.4%) tests for 21 subjects, and VLAR in 41 (0.8%) tests for 39 subjects. QFT-GIT had fewer HNC, VLMR, and VLAR (p = 0.042, 0.004, and 0.067 respectively); QFT-G had fewer LMR (p = 0.005). Twenty-four (51.6%) of 47 subjects with positive results and HNC were negative or indeterminate by all other tests. Thirteen (61.9%) of 21 subjects with positive results and LMR were negative or indeterminate by all other tests. CONCLUSION: Unusual IFN-γ measurements including HNC, LMR, VLMR, and VLAR were encountered in small numbers, and in most instances were not seen on simultaneously or subsequently performed tests. To avoid erroneous diagnosis of Mtb infection, IGRAs with unusual IFN-γ measurements should be repeated with another blood sample and interpreted with caution if they recur