Journal of Respiration

Background: The primary purpose of introducing the COVID-19 vaccine was to fight the pandemic. However, the vaccine was not well received worldwide. This challenge has threatened the effective implementation and roll-out of COVID-19 immunization campaigns. The challenge of vaccine hesitancy was reported to be more prevalent in rural areas due to various factors such as cultural beliefs, misinformation, poverty, lack of education, and distrust of vaccines. Yet there seems to be a scarcity of studies determining the prevalence of vaccine hesitancy in deep rural areas of Limpopo. Purpose: The study aimed to explore the prevalence of COVID-19 hesitancy among the rural black population in South Africa. Study Methods: A longitudinal quantitative study was conducted with data from the DIMAMO Health and Demographic Surveillance Site (HDSS) database for 2020 to 2022. A non-probability total sampling technique was used to select the respondents. Trained fieldworkers collected data using an electronic data capture questionnaire. A comparison of categorical variables was performed using Chi-Square in SPSS version 26 and the statistical significance was set at p < 0.05, with a 95% confidence interval to analyze the data. Results: The limited availability of vaccination sites in Limpopo Province, South Africa, was associated with a reduced certainty that the vaccine would be accepted, as reported in the current study. The prevalence of visiting traditional healers was significantly higher in non-vaccinated than vaccinated participants among the rural black population, indicating a different cultural belief among the rural black population that existed before and during the COVID-19 pandemic. Conclusion: The present study findings show diverse factors of concern associated with vaccination hesitancy for COVID-19 among rural black people. Lack of education, gender, not being diagnosed with COVID-19, not being a Christian, visiting traditional healers, vaccine mistrust, unknown side effects, and a lack of confidence in the vaccine itself. Conspiracy theories were factors that impacted vaccine acceptance among black people living in rural areas. The prevalence of visiting traditional healers was significantly higher in non-vaccinated than vaccinated participants. Therefore, the present study findings emphasize the need to collectively integrate and utilize the traditional healers in the South African healthcare system. Full article

Thin-section computed tomography (CT) has improved the detection of pericardial recesses and sinuses. Physiologic fluid in the pericardial recesses and sinuses can mimic mediastinal adenopathy. The misinterpretation of pericardial recesses and other benign pericardial entities in the oncologic setting can lead to inappropriate staging and management. Knowledge of the anatomy of the pericardium with emphasis on the imaging of different pericardial recesses on CT is important to avoid misdiagnosis, unnecessary further investigations, and/or biopsy. Full article

On 1 August 2020, South Africa’s Minister of Health announced that more than half of a million coronavirus cases were confirmed in the country. South Africa was by far the hardest-hit country in Africa, accounting for half of all infections reported across the continent. The prevalence of underlying conditions such as fever and blood oxygen saturation (SpO2) has been known known to be a significant determinant in the hospitalisation of COVID-19 patients. Low oxygen saturation on admission was reported as a strong predictor of in-hospital mortality in COVID-19 patients. The study sought to assess the association between body temperature and other clinical risk factors with low SpO2 among COVID-19 inpatient case fatalities. A quantitative retrospective study was carried out in Limpopo Province, employing secondary data from the Limpopo Department of Health (LDoH) on COVID-19 inpatients case fatalities across all districts in the province. The chi-square test and Pearson’s correlation coefficient were used to assess the relationship between body temperature and clinical risk factors with SpO2 levels. The findings of this paper indicated that age (older age), chills, sore throat, anosmia, dysgeusia, myalgia/body aches, diarrhoea and HIV/AIDS were associated with low SpO2 in-hospital mortality in COVID-19 patients. Nasal prongs and a face mask with a reservoir for respiratory support cannula were commonly used patient interfaces to provide supplemental oxygen, with the use of only a high-flow nasal cannula (HFNC) being minimal (7%). The majority of COVID-19 inpatient fatalities had normal body temperature (<38 °C) and SpO2, with no correlation between the two variables. Considering temperature screening as a possible strategy to combat the spread of COVID-19 or suspicious COVID-19 cases appeared, then, to be a pointless exercise. This study aimed to recommend new clinical criteria for detecting COVID-19 cases. Full article

Cystic fibrosis (CF), the most common genetic disease among the Caucasian population, is caused by mutations in the gene encoding for the CF transmembrane conductance regulator (CFTR), a chloride epithelial channel whose dysfunction results in severe airway obstruction and inflammation, eventually leading to respiratory failure. The discovery of the CFTR gene in 1989 provided new insights into the basic genetic defect of CF and allowed the study of potential therapies targeting the aberrant protein. In recent years, the approval of “CFTR modulators”, the first molecules designed to selectively target the underlying molecular defects caused by specific CF-causing mutations, marked the beginning of a new era in CF treatment. These drugs have been demonstrated to significantly improve lung function and ameliorate the quality of life of many patients, especially those bearing the most common CFTR mutatant F508del. However, a substantial portion of CF subjects, accounting for ~20% of the European CF population, carry rare CFTR mutations and are still not eligible for CFTR modulator therapy, partly due to our limited understanding of the molecular defects associated with these genetic alterations. Thus, the implementation of models to study the phenotype of these rare CFTR mutations and their response to currently approved drugs, as well as to compounds under research and clinical development, is of key importance. The purpose of this review is to summarize the current knowledge on the potential of CFTR modulators in rescuing the function of rare CF-causing CFTR variants, focusing on both investigational and clinically approved molecules. Full article

The use of impulse oscillometry (IOS) for lung function testing does not need patient cooperation and has gained increasing popularity among both young and senior populations, as well as in patients with breathing difficulties. However, studies of the IOS sensitivity to regional lung obstructions are limited and have shown mixed results. The objective of this study was to evaluate the performance of an IOS system in 3D-printed lung models with structural abnormalities at different locations and with different severities. Lung trees of two complexity levels were tested, with one extending to the sixth generation (G6) and the other to G12. The IOS responses to varying glottal apertures, carina ridge tumors, and segmental bronchial constrictions were quantified in the G6 lung geometry. Both the G6 and G12 lung casts were prepared using high-resolution 3D printers. Overall, IOS detected the progressive airway obstructions considered in this study. The resonant frequency dropped with increasing obstructions for all three disease phenotypes in the G6 lung models. R20Hz increased with the increase in airway obstructions. Specifically, R20Hz in the airway model with varying glottal apertures agreed reasonably well with complementary measurements using TSI VelociCalc. In contrast to the high-resistance (R) sensitivity to the frequency in G6 lung models, R was nearly independent of frequency in G12 lung models. IOS R20Hz demonstrated adequate sensitivity to the structural remodeling in the central airways. However, the changes of R5Hz and X5Hz vs. airway obstructions were inconclusive in this study, possibly due to the rigid lung casts and the difference of a container–syringe system from human lungs. Full article

Asthma is a respiratory condition often stemming from childhood, characterized by difficulty breathing and/or chest tightness. Current treatment options for both adults and children include beta-2 agonists, inhaled corticosteroids (ICS), and leukotriene modifiers (LTM). Despite recommendations by the Global Initiative for Asthma, a substantial number of patients are unresponsive to treatment and unable to control symptoms. Pharmacogenomics have increasingly become the front line of precision medicine, especially with the recent use of candidate gene and genome- wide association studies (GWAS). Screening patients preemptively could likely decrease adverse events and therapeutic failure. However, research in asthma, specifically in pediatrics, has been low. Although numerous adult trials have evaluated the impact of pharmacogenomics and treatment response, the lack of evidence in children has hindered progress towards clinical application. This review aims to discuss the impact of genetic variability and response to asthmatic medications in the pediatric population. Full article

Background: In chronic obstructive pulmonary disease (COPD), morphological analysis made by computed tomography (CT) is usually correlated with spirometry as the main functional tool. In this study, quantitative CT analysis (QCT) was compared with volumetric capnography (VCap), alongside spirometry and the 6-min walk test (6MWT). Methods: Twenty-seven patients with severe/very severe COPD were included, compared with nineteen control subjects. All participants performed spirometry and chest high resolution CT scans that were analyzed with fully-automated software. The COPD group was also submitted to VCap and 6MWT. Results: COPD patients (65.07 ± 8.25 years) showed an average FEV₁ of 1.2 L (44% of the predicted) and the control group (34.36 ± 8.78 years). VCap × QCT: positive correlations were observed with bronchial wall thickening and negative correlations with diameter and area of the bronchial lumen. Spirometry × QCT: positive correlations were observed between post-BD FVC, FEV₁ and FEF 25–75% and diameter and luminal area of the airways and FVC and lung and vascular volumes (emphysema). Negative correlation was observed between post-BD FVC and FEV₁ when compared with Pi10 (internal perimeter of 10 mm). 6MWT vs. QCT: negative correlations were observed between the distance covered with relative wall thickness (airways) and vascular volume and peripheral vascular volume (vasculature). Conclusion: Relevant correlations between QCT and pulmonary function variables were found, including the VCap, highlighting the importance of structural analysis in conjunction with a multidimensional functional assessment. This is the first study to correlate airway and parenchyma QCT with VCap. Full article

The present study aimed at analyzing the treatment outcomes and risk factors associated with fluoroquinolone drug resistance having mutations in the gyrA and gyrB genes. A total of 258 pulmonary tuberculosis samples with first-line drug-resistant (H, R, or HR) were subjected to GenoType MTBDRsl assay for the molecular detection of mutations. Among the 258 samples, 251 were drug-resistant tuberculosis and seven were sensitive to all first-line TB drugs. Out of 251 DR-TB cases, 42 cases were MDR TB, 200 were INH mono-resistant and nine cases were RIF mono-resistant tuberculosis. Out of 251 DR-TB cases performed with a MTBDRsl assay, 14 had Pre-XDR-FQ, one patient had pre-XDR-SLID, one had extensively drug-resistant tuberculosis (XDR-TB) and 235 cases were sensitive to both FQ and SLID drugs. The study group had a mean average of 42.7 ± 16.4 years. The overall successful treatment outcomes among the MDR, INH mono-resistant, and pre-XRD patients were 70.6%, 82.0%, and 51%, respectively. The percentage of risk for the unfavorable outcomes in the pre-XDR, INH -mono-resistant, and XDR cases were 113.84% increased risk with RR 2.14; 95% CI 0.7821–5.8468. The independent risk factor associated with the unfavorable outcomes to failure was 77.78% increased risk with RR 1.78; 95% CI 0.3375–9.3655. Logistic regression analysis revealed that the percentage relative risk among MDR-TB patients for gender, male (RR: 1.85), age ≥ 61 years (RR: 1.96), and diabetics (RR: 1.05) were 84.62%, 95.83%, and 4.76%, respectively. The independent risk factors associated with INH mono-resistant cases of age 16–60 (RR: 1.86), ≥61 year (RR: 1.18), and treated cases (RR: 5.06). This study presaged the significant risk of INH mono-resistant, pre-XDR, and MDR among males, young adults, diabetics, and patients with previous treatment failure. Timely identification of high-risk patients will give pronounced advantages to control drug resistance tuberculosis diseases. Full article

Acute Respiratory Distress Syndrome is a familiar and destructive clinical condition characterized by progressive, swift and impaired pulmonary state. It leads to mortality if not managed in a timely manner. Recently the role of imbalanced macrophage polarization has been reported in ARDS. Macrophages are known for their heterogeneity and plasticity. Under different microenvironmental stimuli, they (M0) can switch between classically activated macrophage (M1) and alternatively activated (M2) states. This switch is regulated by several signaling pathways and epigenetic changes. In this review, the importance of macrophage M1 and M2 has been discussed in the arena of ARDS citing the phase-wise impact of macrophage polarization. This will provide a further understanding of the molecular mechanism involved in ARDS and will help in developing novel therapeutic targets. Various biomarkers that are currently used concerning this pathophysiological feature have also been summarized. Full article

A granuloma, a pathologic hallmark of tuberculosis (TB), is a complex cellular structure that develops at the site of Mycobacterium tuberculosis (Mtb) infection and is comprised of different immune cell types. Severe pulmonary TB in humans is characterized by the presence of heterogeneous granulomas, ranging from highly cellular to solid/non-necrotic and necrotic lesions, within the lungs. The host-Mtb interactions within the granulomas dictate the containment of Mtb infection or its progression into a necrotic, cavitary disease. However, the immune environment in various granulomas is poorly understood. The myeloid-derived suppressor cells (MDSCs) are key immune cells that regulate the protective versus permissive host responses against Mtb infection. However, their contexture within the lung granulomas remains unclear. In this study, using single and multiplex immunohistochemical staining, we analyzed the distribution of MDSCs, macrophages, CD4+ T cells and their immunometabolic and effector function states in the solid/non-necrotic and necrotic granulomas in patients with active pulmonary TB. We found increased MDSCs with elevated expression of immunosuppressive molecules in the solid/non-necrotic granulomas. In contrast, cells in the solid and necrotic granulomas produced similar levels of IL-6 and IL-10. Our findings suggest that MDSCs are present in solid/non-necrotic granuloma, which may play an essential role in the progression into a necrotic lesion, thus exacerbating disease pathology and transmission. Full article

Cystic fibrosis (CF) is an autosomal recessive multi-organ disease caused by mutations in the CF Transmembrane Conductance Regulator (CFTR) gene, with morbidity and mortality primacy related to the lung disease. The CFTR protein, a chloride/bicarbonate channel, is expressed at the apical side of airway epithelial cells and is mainly involved in appropriate ion and fluid transport across the epithelium. Although many animal and cellular models have been developed to study the pathophysiological consequences of the lack/dysfunction of CFTR, only the three-dimensional (3D) structures termed “spheroids��? and “organoids��? can enable the reconstruction of airway mucosa to model organ development, disease pathophysiology, and drug screening. Airway spheroids and organoids can be derived from different sources, including adult lungs and induced pluripotent stem cells (iPSCs), each with its advantages and limits. Here, we review the major features of airway spheroids and organoids, anticipating that their potential in the CF field has not been fully shown. Further work is mandatory to understand whether they can accomplish better outcomes than other culture conditions of airway epithelial cells for CF personalized therapies and tissue engineering aims. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the latest variant in the coronavirus family, causing COVID-19, has resulted in global pandemic since early 2020 leading to severe public health concern. So far, the pandemic has caused more than 200 million infections and 4 million deaths worldwide. Most of the studies are focused on developing prevention, intervention, and therapeutic strategies. However, underlying pathophysiology of the disease is important as well, which needs further attention. Cell death is one of the major causative mechanisms that leads to severe inflammation, and it is also an a posteriori consequence of the hyperinflammatory storm that renders poor prognosis of the disease. Substantial cell death has been reported in biopsy samples from post mortem patients. Among the distinct cell death pathways, apoptosis, the regulated programmed cell death plays an important role in the pathogenesis of the disease. Understanding the role of SARS-CoV-2 infection in apoptosis is critical to linearize the pathogenesis of the virus as well as the resultant disease, that may uncover novel therapeutic targets in treatment of COVID-19 patients. Here, we review the current progress on the underlying molecular mechanism(s) of SARS-CoV-2-induced apoptosis, not only at the level of the virus but also at its individual proteins. Full article

Introduction: Research into the long-term effects of coronavirus disease 2019 (COVID-19) continues at an unprecedented pace. Many physical long-term symptoms of COVID-19 have been reported and include headache, fatigue, muscle pain and breathlessness, etc. Psychological effects are not dissimilar to survivors of SARS. There is limited qualitative research exploring the mental health impacts and experiences of hospitalized COVID-19 inpatients. Methods: A prospective qualitative study is planned to explore patient experiences post hospital discharge following a diagnosis of COVID-19. The research aims to gain an understanding of how COVID-19 affects quality of life (QoL) and functional abilities. Patients discharged from the hospital will be invited to take part in semi-structured interviews discussing their experiences of hospitalization and the impact of COVID-19 on their QoL. Interviews will be conducted at three and six months following discharge from hospital. This study will provide important qualitative insight and may inform clinical interventions and commissioning decisions. Trial registration: The study has Research Ethics Committee (REC) and Health Research Authority (HRA) approvals obtained from Health and Care Research Wales (HCRW) [IRAS project ID 293196]. Full article

Cystic Fibrosis (CF) is caused by loss of function mutations in the Cystic Fibrosis transmembrane conductance regulator (CFTR). The folding and assembly of CFTR is inefficient. Deletion of F508 in the first nucleotide binding domain (NBD1-ΔF508) further disrupts protein stability leading to endoplasmic reticulum retention and proteasomal degradation. Stabilization and prevention of NBD1-ΔF508 aggregation is critical to rescuing the folding and function of the entire CFTR channel. We report that the phenolic compounds Oleuropein and Hydroxytryosol reduce aggregation of NBD1-ΔF508. The NBD1-ΔF508 aggregate size was smaller in the presence of Hydroxytryosol as determined by dynamic light scattering. Neither phenolic compound increased the thermal stability of NBD1-ΔF508 as measured by differential scanning fluorimetry. Interestingly, Hydroxytyrosol inhibited the stabilizing effect of the indole compound BIA, a known stabilizer, on NBD1-ΔF508. Molecular docking studies predicted that Oleuropein preferred to bind in the F1-type core ATP-binding subdomain in NBD1. In contrast, Hydroxytyrosol preferred to bind in the α4/α5/α6 helical bundle of the ABCα subdomain of NBD1 next to the putative binding site for BIA. This result suggests that Hydroxytyrosol interferes with BIA binding, thus providing an explanation for the antagonistic effect on NBD1 stability upon incubation with both compounds. To our knowledge, these studies are the first to explore the effects of these two phenolic compounds on the aggregation and stability of NBD1-ΔF508 domain of CFTR. Full article

High flow nasal cannula (HFNC) therapy is a non-invasive oxygen delivery mode which is safe and well tolerated by adults and children with respiratory distress. HFNC is increasingly used in children with respiratory distress due to mucus retention, such as bronchiolitis and acute asthma. However, he effectiveness of this therapy in acute asthma has not been well researched. To evaluate HFNC for acute childhood asthma, we designed a randomized prospective crossover trial. In the trial, children aged 6–18 years, with a forced expiratory volume in one second (FEV₁) lability of ≥30% during an exercise challenge test (ECT) are included. The time of fully recovered lung function within 10% of the baseline after peak fall of FEV₁ is compared with and without HFNC therapy. A 50% reduction of recovery time during HFNC therapy compared to recovery time without HFNC is considered clinically relevant, with a power of 80% and a significance level of 5%. Secondly, the pressure used by the HFNC device to deliver the constant present flow is evaluated. A relationship between the measured pressure and the degree of recovery may reveal a working mechanism behind HFNC. Full article

Background: An irreproducibility crisis currently afflicts a wide range of scientific disciplines, including public health and biomedical science. A study was undertaken to assess the reliability of a meta-analysis examining whether air quality components (carbon monoxide, particulate matter 10 µm and 2.5 µm (PM10 and PM2.5), sulfur dioxide, nitrogen dioxide and ozone) are risk factors for asthma exacerbation. Methods: The number of statistical tests and models were counted in 17 randomly selected base papers from 87 used in the meta-analysis. Confidence intervals from all 87 base papers were converted to p-values. p-value plots for each air component were constructed to evaluate the effect heterogeneity of the p-values. Results: The number of statistical tests possible in the 17 selected base papers was large, median = 15,360 (interquartile range = 1536–40,960), in comparison to results presented. Each p-value plot showed a two-component mixture with small p-values < 0.001 while other p-values appeared random (p-values > 0.05). Given potentially large numbers of statistical tests conducted in the 17 selected base papers, p-hacking cannot be ruled out as explanations for small p-values. Conclusions: Our interpretation of the meta-analysis is that random p-values indicating null associations are more plausible and the meta-analysis is unlikely to replicate in the absence of bias. Full article

The association between obstructive lung disease and cardiovascular disease (CVD) has been suggested previously, but few studies have looked at this association in a diabetic cohort, a population highly susceptible to both comorbidities. A total of 1003 subjects in community practice settings were interviewed at home at the time of enrolment into the Vermont Diabetes Information System, a clinical decision support program. Patients self-reported their personal and clinical characteristics, including any obstructive lung disease. Laboratory data were obtained directly from the clinical laboratory. We performed a cross-sectional analysis of the interviewed subjects to assess a possible association between obstructive lung disease and CVD. In a multivariate logistic regression model, obstructive lung disease was significantly associated with CVD, even after correcting for potential confounders, including gender, obesity, low income, cigarette smoking, alcohol problems, and high comorbidity (odds ratio = 1.96; 95% confidence interval 1.37–2.81; p < 0.01). All components of CVD, including coronary artery disease (CAD), congestive heart failure (CHF), peripheral vascular disease (PVD), and cerebrovascular accidents (CVA), were also significantly associated with obstructive lung disease. These data suggest an association between obstructive lung disease and CVD in patients with diabetes. Future studies are needed to identify the mechanism supporting this association Full article

Pathogenic Mycobacterium tuberculosis complex organisms (MTBC) primarily cause pulmonary tuberculosis (PTB); however, MTBC are also capable of causing disease in extrapulmonary (EP) organs, which pose a significant threat to human health worldwide. Extrapulmonary tuberculosis (EPTB) accounts for about 20–30% of all active TB cases and affects mainly children and adults with compromised immune systems. EPTB can occur through hematogenous, lymphatic, or localized bacillary dissemination from a primary source, such as PTB, and affects the brain, eye, mouth, tongue, lymph nodes of neck, spine, bones, muscles, skin, pleura, pericardium, gastrointestinal, peritoneum, and the genitourinary system as primary and/or disseminated disease. EPTB diagnosis involves clinical, radiological, microbiological, histopathological, biochemical/immunological, and molecular methods. However, only culture and molecular techniques are considered confirmatory to differentiate MTBC from any non-tuberculous mycobacteria (NTM) species. While EPTB due to MTBC responds to first-line anti-TB drugs (ATD), drug susceptibility profiling is an essential criterion for addressing drug-resistant EPTB cases (DR-EPTB). Besides antibiotics, adjuvant therapy with corticosteroids has also been used to treat specific EPTB cases. Occasionally, surgical intervention is recommended, mainly when organ damage is debilitating to the patient. Recent epidemiological studies show a striking increase in DR-EPTB cases ranging from 10–15% across various reports. As a neglected disease, significant developments in rapid and accurate diagnosis and better therapeutic interventions are urgently needed to control the emerging EPTB situation globally. In this review, we discuss the recent advances in the clinical diagnosis, treatment, and drug resistance of EPTB. Full article

Introduction: There are no prospective studies looking at complications of pleural procedures. Previous British Thoracic Society Pleural audits and retrospective case series inform current practice. Incidence of any complication is between 1–15%. We sought to add to the existing literature and inform local practice with regards to intercostal drains and thoracocenteses. Methods: Local Caldicott approval was sought for a review of all inpatient adult pleural procedures coded as ‘T122 drainage of pleural cavity’ and ‘T124 insertion of tube drain into pleural cavity’. Those undergoing thoracocentesis (all with a Rocket 6 Fg catheter) and intercostal drain insertion (ICD, all with Rocket 12 Fg drain) were identified. Continuous variables are presented as mean (±range) and categorical variables as percentages where appropriate. Results: 1159 procedures were identified. A total of 199 and 960 were done for pneumothorax and effusions respectively. Mean age was 68.1 years (18–97). There were 280 thoracocenteses and 879 ICDs. Bleeding occurred in 6 (0.5%), all ICDs (clotting and platelets were within normal range; one patient was on aspirin and one on aspirin and clopidogrel). All settled except for one who had intercostal artery rupture needing cardiothoracic intervention (no anti-coagulation). Nine pneumothoraces occurred (0.78%) in seven ICDs and two aspirations). There were three definite pleural space infections (0.3%) with three ICDs. Fall out rates for ICDs were 35 (3%). Nine were not sutured, and out of those, seven inserted in the Accident and Emergency department, out of hours. All others ‘came out’ due to patient factors (previous quoted rates up to 14%). Surgical emphysema occurred in 43 (41 ICDs), 3.7%. Eight were due to fall outs and three required surgical intervention. There was no re-expansion pulmonary oedema nor direct deaths. Conclusions: Complication rates of ICD and thoracocenteses are low. Checklists might help to remind operators of the need for suturing. Limitations of this study are its retrospective nature and reliance on correct hospital coding. We are currently contributing to a prospective observational study on pleural complications. Full article