Seasonal influence on respiratory tract infection severity including COVID-19 quantified through Markov Chain modeling.

Respiratory tract infections (RTIs) are a burden to global health, but their characterization is complicated by the influence of seasonality on incidence and severity. The Re-BCG-CoV-19 trial (NCT04379336) assessed BCG (re)vaccination for protection from coronavirus disease 2019 (COVID-19) and recorded 958 RTIs in 574 individuals followed over 1 year. We characterized the probability of RTI occurrence and severity using a Markov model with health scores (HSs) for four states of symptom severity. Covariate analysis on the transition probability between HSs explored the influence of demographics, medical history, severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), or influenza vaccinations, which became available during the trial, SARS-CoV-2 serology, and epidemiology-informed seasonal influence of infection pressure represented as regional COVID-19 pandemic waves, as well as BCG (re)vaccination. The infection pressure reflecting the pandemic waves increased the risk of RTI symptom development, whereas the presence of SARS-CoV-2 antibodies protected against RTI symptom development and increased the probability of symptom relief. Higher probability of symptom relief was also found in participants with African ethnicity and with male biological gender. SARS-CoV-2 or influenza vaccination reduced the probability of transitioning from mild to healthy symptoms. Model diagnostics over calendar-time indicated that COVID-19 cases were under-reported during the first wave by an estimated 2.76-fold. This trial was performed during the initial phase of the COVID-19 pandemic in South Africa and the results reflect that situation. Using this unique clinical dataset of prospectively studied RTIs over the course of 1 year, our Markov Chain model was able to capture risk factors for RTI development and severity, including epidemiology-informed infection pressure.

Clinical Pharmacokinetics and Pharmacodynamics of Rifampicin in Human Tuberculosis.

The introduction of rifampicin (rifampin) into tuberculosis (TB) treatment five decades ago was critical for shortening the treatment duration for patients with pulmonary TB to 6 months when combined with pyrazinamide in the first 2 months. Resistance or hypersensitivity to rifampicin effectively condemns a patient to prolonged, less effective, more toxic, and expensive regimens. Because of cost and fears of toxicity, rifampicin was introduced at an oral daily dose of 600 mg (8-12 mg/kg body weight). At this dose, clinical trials in 1970s found cure rates of ≥ 95% and relapse rates of < 5%. However, recent papers report lower cure rates that might be the consequence of increased emergence of resistance. Several lines of evidence suggest that higher rifampicin doses, if tolerated and safe, could shorten treatment duration even further. We conducted a narrative review of rifampicin pharmacokinetics and pharmacodynamics in adults across a range of doses and highlight variables that influence its pharmacokinetics/pharmacodynamics. Rifampicin exposure has considerable inter- and intra-individual variability that could be reduced by administration during fasting. Several factors including malnutrition, HIV infection, diabetes mellitus, dose size, pharmacogenetic polymorphisms, hepatic cirrhosis, and substandard medicinal products alter rifampicin exposure and/or efficacy. Renal impairment has no influence on rifampicin pharmacokinetics when dosed at 600 mg. Rifampicin maximum (peak) concentration (Cmax) > 8.2 µg/mL is an independent predictor of sterilizing activity and therapeutic drug monitoring at 2, 4, and 6 h post-dose may aid in optimizing dosing to achieve the recommended rifampicin concentration of ≥ 8 µg/mL. A higher rifampicin Cmax is required for severe forms TB such as TB meningitis, with Cmax ≥ 22 µg/mL and area under the concentration-time curve (AUC) from time zero to 6 h (AUC6) ≥ 70 µg·h/mL associated with reduced mortality. More studies are needed to confirm whether doses achieving exposures higher than the current standard dosage could translate into faster sputum conversion, higher cure rates, lower relapse rates, and less mortality. It is encouraging that daily rifampicin doses up to 35 mg/kg were found to be safe and well-tolerated over a period of 12 weeks. High-dose rifampicin should thus be considered in future studies when constructing potentially shorter regimens. The studies should be adequately powered to determine treatment outcomes and should include surrogate markers of efficacy such as Cmax/MIC (minimum inhibitory concentration) and AUC/MIC.

Image-guided pleural biopsy.

PURPOSE OF REVIEW: The most efficient and cost-effective approach to pleural exudates not diagnosed by means of thoracocentesis remains uncertain. Both closed pleural biopsy and thoracoscopy may be utilized for the acquisition of pleural tissue. This review will focus on the developments in image guidance of closed pleural biopsy. RECENT FINDINGS: Recent studies suggest that computed tomography and ultrasound guidance improve the yield and safety of closed pleural biopsy. Imaging is best suited to reduce the rate of false-negative biopsy in malignant pleural disease by enhanced targeting of localized pleural changes typically situated dorsolaterally close to the diaphragm. Pleural tuberculosis causes effusions with discrete and uniformly distributed pleural thickening, and evidence suggests that the utilization of imaging has little advantage in this setting apart from decreasing the risk associated with blind biopsy. Imaging also facilitates a directed repeat thoracocentesis in the same session. The cumulative yield of image-assisted repeat thoracocentesis and pleural biopsy has been reported to approach that of thoracoscopy, particularly in cases with pleural thickening, nodularity or pleural-based mass lesions. SUMMARY: Image-guided pleural biopsy combined with repeat thoracocentesis is a safe, inexpensive, accessible and sensitive method for further examination of patients with pleural exudates not diagnosed by initial thoracocentesis.

Tuberculosis screening in immigrants from high-prevalence countries: interview first or chest radiograph first? A pro/con debate.

Immigration from high tuberculosis (TB) prevalence countries has a substantial impact on the epidemiology of TB in receiving countries with low TB incidence. Cross-border migration offers an ideal opportunity for active case finding that will result in a lower caseload in the host country and a reduced spread of disease to both the indigenous and migrant populations. Screening strategies can start 'offshore', thereby indirectly assisting and empowering public health systems in the source countries, or be performed at ports of entry with or without long-term engagement of 'onshore' facilities and systems to provide either preventive therapy or surveillance for reactivation of latent TB. The chest radiograph seems to be playing a key role in this process, but questions remain regarding when, where and in whom radiographs are best done for optimal yield and cost-effectiveness, and with what other tests they might best be combined to further increase the usefulness of transborder TB control.

Assessment of the sensitivity and specificity of Xpert MTB/RIF assay as an early sputum biomarker of response to tuberculosis treatment.

BACKGROUND: An accurate biomarker is urgently needed to monitor the response to treatment in patients with pulmonary tuberculosis. The Xpert MTB/RIF assay is a commercially available real-time PCR that can be used to detect Mycobacterium-tuberculosis-specific DNA sequences in sputum samples. We therefore evaluated this assay with serial sputum samples obtained over 26 weeks from patients undergoing treatment for tuberculosis. METHODS: We analysed sputum samples from 221 patients with smear-positive tuberculosis enrolled at two sites (Cape Town, South Africa, and Mbeya, Tanzania) of a multicentre randomised clinical trial REMoxTB of antituberculosis treatment on a weekly basis (weeks 0 to 8), then at weeks 12, 17, 22, and 26 after treatment initiation. The Xpert MTB/RIF results over time were compared with the results of standard smear microscopy and culture methods. FINDINGS: We obtained and analysed 2741 sputum samples from 221 patients. The reduction in positivity rates with Xpert MTB/RIF were slower than those with the standard methods. At week 8, positive results were obtained for 62 (29%) of 212 sputum samples with smear microscopy, 46 (26%) of 175 with solid culture (Löwenstein-Jensen medium), 77 (42%) of 183 with liquid culture (Bactec MGIT960 system), and 174 (84%) of 207 with Xpert MTB/RIF; at 26 weeks, positive results were obtained for ten (5%) of 199, four (3%) of 157, seven (4%) of 169, and 22 (27%) of 83 sputum samples, respectively. The reduction in detection of quantitative M tuberculosis DNA with Xpert MTB/RIF correlated with smear grades (ρ=-0·74; p<0·0001), solid culture grades (ρ=-0·73; p<0·0001), and time to liquid culture positivity (ρ=0·73; p<0·0001). Compared with the combined binary smear and culture results as a reference standard, the Xpert MTB/RIF assay had high sensitivity (97·0%, 95% CI 95·8-97·9), but poor specificity (48·6%, 45·0-52·2). INTERPRETATION: The poor specificity precludes the use of the Xpert MTB/RIF assay as a biomarker for monitoring tuberculosis treatment, and should not replace standard smear microscopy and culture. FUNDING: Global Alliance for TB Drug Development, Bill & Melinda Gates Foundation, UK Medical Research Council, German Ministry of Science and Technology.

Comparison of the quality of smears in transbronchial fine-needle aspirates using two staining methods for rapid on-site evaluation.

Transbronchial needle aspiration (TBNA) via flexible bronchoscopy is a well-established sampling modality for lung masses. The procedure is useful in the diagnosis of neoplastic and non-neoplastic lesions as well as for staging of bronchogenic carcinoma. Rapid on-site evaluation (ROSE) adds value as it has the advantage of triaging material during the procedure so avoiding a battery of investigations. Frequently used rapid stains are the modified Wright-Giemsa water-based stain (WG-ROSE) and the alcohol-based modified Papanicolaou stain (Pap-ROSE). Final review of laboratory-based Giemsa and Pap stains supplemented by ancillary investigations is essential for quality assurance. To investigate whether and how ROSE influenced the quantity and quality of the material submitted to the laboratory we randomized 126 patients to WG-ROSE, requiring only one pathologist on-site, or combined WG- and Pap-ROSE, requiring an additional person on-site to assist with staining. In those patients with positive TBNA we graded the laboratory-based slides of the first pass containing diagnostic material into insufficient, suspicious, adequate and excellent. The first diagnostic pass was found after 3.06 ± 1.94 (SD) passes and 3.13 ± 2.16 passes with WG-ROSE and combined ROSE (P = 0.87), respectively. Following WG-ROSE and combined ROSE 69% and 71.1% (P = 0.509) of slides were diagnostic (adequate or excellent) on laboratory-based Giemsa stains, and 93.3% and 100% (P = 0.134) were scored adequate or excellent on laboratory-based Pap stains. We concluded that the less costly and labour intensive WG-ROSE procedure is adequate for TBNA. This has cost implications especially in resource poor settings.

Why Do We Use 600 mg of Rifampicin in Tuberculosis Treatment?

The 600-mg once daily dose of rifampicin plays a key role in tuberculosis treatment. The evidence underpinning this dose is scant. A review of the historical literature identified 3 strands of reasoning. The first is the pharmacokinetic argument: The 600-mg dose yields serum drug concentrations well above the minimum inhibitory concentration of rifampicin against Mycobacterium tuberculosis. The second is the argument that adverse events may be dose related. The third is the economic argument: Rifampicin was prohibitively expensive at the time of its introduction. Recent in vitro, animal, and early bactericidal activity studies suggest that the 600-mg once daily dose is at the lower end of the dose-response curve, refuting the pharmacokinetic argument. The reduced cost and the lack of evidence of toxicity at higher daily doses remove the other arguments. To optimize tuberculosis treatment, the clinical value of higher doses of rifampicin should be tested in clinical trials.

Management of life-threatening haemoptysis in an area of high tuberculosis incidence.

BACKGROUND: Emergency admissions with life-threatening haemoptysis in an area of high tuberculosis (TB) incidence at the University of Stellenbosch and Tygerberg Academic Hospital, South Africa. It is unclear if lung resection is regularly indicated to prevent recurrence following bronchial artery embolisation (BAE). OBJECTIVE: To prospectively evaluate risk factors for recurrence as selection criteria for surgery following embolisation: lack of complete cessation of haemoptysis, need for blood transfusion, presence of aspergilloma and absence of active TB. DESIGN: Prospective interventional study with 1-year follow-up. RESULTS: Within a 7-month period, 101 consecutive patients were admitted. Seven were excluded and 12 died shortly after admission. Haemoptysis ceased on medical treatment alone within 24 h in 21 of the remaining 82 patients. Their 1-year mortality was 10%. Eleven of 61 patients referred for emergency embolisation died before discharge. Of the 50 patients remaining at risk of recurrence, 38 (76%) were at low risk and 12 (24%) at high risk. Five of these patients (10% of those at risk) underwent surgery. Patients at low risk and operated patients had an uneventful course over 1 year, but two deaths occurred among the seven inoperable patients at high risk. CONCLUSION: Lung resection surgery following successful BAE for life-threatening haemoptysis can safely be avoided in patients at low risk of recurrence.

Stair climbing in the functional assessment of lung resection candidates.

BACKGROUND: Algorithms for the pre-operative evaluation of lung resection candidates with impaired lung function invariably include maximum oxygen uptake (VO(2)MAX) as a critical parameter of functional reserves, with a VO(2)MAX >or=20 ml/kg/min generally considered sufficient for pneumonectomy. Stair climbing is a low-cost alternative to assess exercise capacity. OBJECTIVES: As stair climbing is not standardised, we aimed to compare the altitude reached and the speed of ascent with VO(2)MAX measured by cycle ergometry. METHODS: We prospectively enrolled 44 pulmonary resection candidates (mean age: 47.6 +/- 12.5 years) with an FEV(1) <80%. Patients were asked to climb as high and as fast as they could, to a maximum elevation of 20 m. The altitude reached and the average speed of ascent were compared to VO(2)MAX. RESULTS: Forty-three patients reached a 20-metre elevation. Thirteen of them, as well as the patient who did not reach this height, had a VO(2)MAX <20 ml/kg/min. There was a linear correlation between speed of ascent and VO(2)MAX/kg (R(2) = 0.67), but not between altitude and VO(2)MAX/kg. All 24 patients with a speed >or=15 m/min had a VO(2)MAX >or=20 ml/kg/min. Thirty-nine of 40 patients with a speed >or=12 m/min had a VO(2)MAX >or=15 ml/kg/min. CONCLUSIONS: The average speed of ascent during stair climbing was an accurate semiquantitative predictor of VO(2)MAX/kg, whereas altitude was not. We were able to identify potential cut-off values for lobectomy or pneumonectomy. Pending validation with clinical endpoints, stair climbing may replace formal exercise testing at much lower costs in a large proportion of lung resection candidates.

Utility of rapid on-site evaluation of transbronchial needle aspirates.

BACKGROUND: Rapid on-site evaluation has been proposed as a method to improve the yield of transbronchial needle aspiration. OBJECTIVES: This study investigated whether on-site analysis facilitates routine diagnostic bronchoscopy in terms of sampling, yield and cost. METHODS: Patients with lesions accessible for transbronchial needle aspiration on computed tomography were investigated. A cytopathologist screened the needle aspirates on site for the presence of diagnostic material. The bronchoscopic sampling process was adjusted according to the results. In 90 consecutive patients with neoplastic disease (n=70; 78%), non-neoplastic disease (n=16; 18%) or undiagnosed lesions (n=4; 4%) we aspirated 162 lung tumours or lymph node sites (mediastinal: 7%; tracheobronchial: 68%; other: 25%). In 90 consecutive patients with neoplastic disease (n=70; 78%), non-neoplastic disease (n=16; 18%) or undiagnosed lesions (n=4; 4%) we aspirated 162 lung lesions (paratracheal tumours or lymph nodes: 7%; tracheobronchial lymph nodes: 68%; other: 25%). RESULTS: The diagnostic yield of needle aspiration was 77 and 25% in patients with neoplastic and non-neoplastic lesions, respectively. Sampling could be terminated in 64% of patients after needle aspiration had been performed as the only diagnostic modality, and on-site analysis identified diagnostic material from the first site aspirated in 50% of patients. Only in 2 patients (2%) diagnostic aspirates were not recognized on site. On-site analysis was cost effective due to savings for disposable diagnostic tools, which exceeded the extra expense for the on-site cytology service provided. CONCLUSIONS: Rapid on-site analysis of transbronchial aspirates is a highly useful, accurate and cost-effective addition to routine diagnostic bronchoscopy.

Use of an ultrathin bronchoscope in the assessment of central airway obstruction.

STUDY OBJECTIVE: To assess the utility of an ultrathin bronchoscope (UB) in the assessment of central airway obstruction (CAO). DESIGN: Prospective evaluation SETTING: Tygerberg Hospital, a tertiary teaching hospital. PATIENTS: Consecutive patients referred to the Lung Unit with CAO. INTERVENTIONS: Fiberoptic bronchoscopy (FOB) was performed with a prototype UB (Olympus BF XP40; Olympus Europe; Hamburg, Germany; outer diameter, 2.8 mm; working channel, 1.2 mm). The UB was used whenever a standard bronchoscope (SB) could not pass the obstruction or could not be tolerated by the patient. MEASUREMENTS AND RESULTS: Data relating to indication and performance of FOB, patient demographics, utility in establishing a diagnosis, and planning definitive management were documented. Twenty-four patients (17 men; mean age, 46 years) were studied. Twelve patients (50%) had malignant CAO, 8 patients (33%) had benign tracheal stenosis, 3 patients (12.5%) had stent occlusion, and 1 patient (4%) had bilateral vocal cord paralysis. In 42% of patients, an initial attempt at passing the obstruction with an SB had failed. Vocal cords or trachea were involved in 62% of patients. The mean luminal occlusion was 84% of the total airway lumen (range, 50 to 100%). One complication (desaturation) led to early termination of FOB. In all but three patients with complete obstruction, the UB was able to pass the CAO and allowed assessment of the obstruction and the distal airways (87%). CONCLUSION: UB-FOB was useful and safe in the assessment of patients with CAO from both benign and malignant disease. It aided in establishing a diagnosis and/or planning of definitive management in all patients examined.