Impact of the COVID-19 pandemic on tuberculosis management in Spain.

BACKGROUND: The impact of COVID-19 on the diagnosis and management of tuberculosis (TB) patients is unknown. METHODS: Participating centres completed a structured web-based survey regarding changes to TB patient management during the COVID-19 pandemic. The study also included data from participating centres on patients aged ≥18 diagnosed with TB in 2 periods: March 15 to June 30, 2020 and March 15 to June 30, 2019. Clinical variables and information about patient household contacts were retrospectively collected. RESULTS: A total of 7 (70%) TB units reported changes in their usual TB team operations. Across both periods of study, 169 patients were diagnosed with active TB (90 in 2019, 79 in 2020). Patients diagnosed in 2020 showed more frequent bilateral lesions in chest X-ray than patients diagnosed in 2019 (P = 0.004). There was a higher percentage of latent TB infection and active TB among children in households of patients diagnosed in 2020, compared with 2019 (P = 0.001). CONCLUSIONS: The COVID-19 pandemic has caused substantial changes in TB care. TB patients diagnosed during the COVID-19 pandemic showed more extended pulmonary forms. The increase in latent TB infection and active TB in children of patient households could reflect increased household transmission due to anti-COVID-19 measures.

Factors Associated with Fatality during the Intensive Phase of Anti-Tuberculosis Treatment.

OBJECTIVE: To determine the case-fatality rate (CFR) at the end of the intensive phase of tuberculosis (TB) treatment, and factors associated with fatality. METHODS: TB patients diagnosed between 2006 and 2013 were followed-up during treatment. We computed the CFR at the end of the intensive phase of TB treatment, and the incidence of death per 100 person-days (pd) of follow-up. We performed survival analysis using the Kaplan-Meier method and Cox regression, and calculate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: A total of 5,182 patients were included, of whom 180 (3.5%) died; 87 of these deaths (48.3%) occurred during the intensive phase of treatment, with a CFR of 1.7%. The incidence of death was 0.028/100 pd. The following factors were associated with death during the intensive phase: being >50 years (HR = 36.9;CI:4.8-283.4); being retired (HR = 2.4;CI:1.1-5.1); having visited the emergency department (HR = 3.1;CI:1.2-7.7); HIV infection (HR = 3.4;CI:1.6-7.2); initial standard treatment with 3 drugs (HR = 2.0;CI:1.2-3.3) or non-standard treatments (HR = 2.68;CI:1.36-5.25); comprehension difficulties (HR = 2.8;CI:1.3-6.1); and smear-positive sputum (HR = 2.3-CI:1.0-4.8). CONCLUSION: There is a non-negligible CFR during the intensive phase of TB, whose reduction should be prioritised. The CFR could be a useful indicator for evaluating TB programs.

Screening for active tuberculosis in high-risk groups.

OBJECTIVE: To evaluate an active case-finding strategy among drug users (DUs), economically disadvantaged individuals and recent immigrants from hyperendemic countries, a population at high risk of developing tuberculosis (TB). METHODS: Retrospective, observational study carried out by the Tuberculosis Unit of the City of Barcelona from September 2009 to December 2012. All participants underwent chest X-ray and were screened for symptoms. RESULTS: Of 5982 participants screened, 30 TB cases were detected (total prevalence 0.5%): 26 were pulmonary, 8 were smear-positive and 2 were resistant to multiple drugs. Directly observed treatment was advised for 19 patients (63%). TB prevalence in the recent immigrants group was significantly greater (1.77%) than in all other groups studied: economically disadvantaged individuals 0.30% (RR 5.9, 95%CI 2.30-15.14); DUs 0.62% (RR 2.05, 95%CI 0.91-4.64), non-recent immigrants 0.41% (RR 4.31, 95%CI 1.68-11.4); and all native-born individuals 0.41% (RR 4.33, 95%CI 1.71-10.92). The rate was much greater than the estimated prevalence for the general population of the city (∼20 cases/100,000 population). CONCLUSIONS: In high-risk groups, active case finding can be used as a public health intervention to detect a large number of TB cases.

Monitoring changes in anti-tuberculosis treatment: associated factors determined at the time of diagnosis.

OBJECTIVES: To determine predictive factors for changes in standard anti-tuberculosis chemotherapy at the time of diagnosis. METHODS: A prospective study was performed among tuberculosis (TB) patients treated at specialised centres during 2008-2009. Treatment outcome was monitored per standard guidelines. Treatment was considered successful if the patient was cured or completed treatment. Factors associated with treatment modification were analysed at the bivariate and multivariate levels using logistic regression. RESULTS: A total of 427 patients were included in the study. The initial standard treatment regimen was retained for 249 patients (58.3%), extended to 9 months for 36 (8.4%) and changed for 142 (33.3%). Factors associated with a change of regimen at the multivariate level were female sex, age ≥ 50 years, human immunodeficiency virus infection, comorbidities, alcoholism, hospitalisation and culture-positive sputum. Drug resistance and toxicity were analysed independently. Treatment outcome was successful in 97.2% of cases without a regimen change and in 87.3% of those with a changed regimen (P < 0.001). CONCLUSION: Factors associated with changes in the initial anti-tuberculosis regimen should be considered for rigorous follow-up. Results obtained through individualised treatment provided by specialists were good despite the complexity of the cases treated.

Rifampicin plus isoniazid for the prevention of tuberculosis in an immigrant population.

OBJECTIVES: To compare the tolerance, adherence and effectiveness of two approaches for the treatment of latent tuberculosis infection (LTBI): 6 months of isoniazid (6H) vs. 3 months of isoniazid plus rifampicin (3RH). POPULATION: Immigrants with LTBI. METHODS: Participants were enrolled in a controlled, randomised clinical trial in Barcelona, Spain, from April 2001 to April 2005. Monthly follow-up was done to assess tolerance, side effects and adherence. Effectiveness was evaluated at 5 years. RESULTS: In the 590 subjects enrolled, the rate of adherence was greater in the 3RH than in the 6H arm (72% vs. 52.4%, P = 0.001). No differences between study arms were observed with respect to hepatotoxicity or side effects. Variables associated with non-adherence were diagnosis by screening (OR 1.88, 95%CI 1.26-2.82, P = 0.001), illegal immigration status (OR 1.48, 95%CI 1.01-2.15, P = 0.03), unemployment (OR 1.91, 95%CI 1.28-2.85, P = 0.0008), illiteracy (OR 1.73, 95%CI 1.04-2.88, P = 0.02), lack of family support (OR 3.7, 95%CI 2.54-5.4, P = 0.001) and the 6-month treatment regimen (OR 2.45, 95%CI 1.68-3.57, P = 0.0001). None of the patients who completed either treatment developed tuberculosis. CONCLUSIONS: The 3RH regimen facilitates adherence to LTBI treatment and offers a safe, well-tolerated and effective alternative.

[Active tuberculosis case finding among immigrants in Barcelona]. / Búsqueda activa de tuberculosis en inmigrantes en Barcelona.

OBJECTIVE: To assess the prevalence of tuberculous infection and disease in recent economic immigrants in Barcelona. SUBJECTS AND METHOD: Examination and testing of immigrants. Tuberculin tests (TTs) were given and the presence of scars from tuberculosis vaccinations were noted. Thresholds of 5 and 15 mm were established for positivity in unvaccinated and vaccinated individuals, respectively. RESULTS: A total of 3651 persons were examined, but only 3151 completed the study. Eighteen were diagnosed with tuberculosis (571.2 per 100,000) and 50.6% were classified as positive TT reactors, 34.4% because of infection and 16.3% possibly because of tuberculosis vaccination. The percentage of reactors was significantly higher in the sample of economic immigrants than in the local population. Age, male sex, place of origin, greater poverty, and higher prevalence of disease in the country of origin were associated with tuberculous infection in the sample. DISCUSSION: Active case finding proved efficient. Interference from tuberculosis vaccination greatly affects the findings, depending on the positivity threshold that is established. We recommend that chest radiographs be used in addition to TTs. Immigration will change the nature of endemic tuberculosis in Spain, and strategies should be specifically designed to deal with the new challenges that will appear.

[Pulmonary symptomatic tuberculosis' diagnostic delay study]. / Estudio del retraso diagnóstico de la tuberculosis pulmonar sintomática.

OBJECTIVE: To study symptomatic pulmonary tuberculosis (PTB) diagnostic delay. PATIENTS AND METHODS: Prospective study of new symptomatic PTB cases (aged > or = 15 years) by structured interview with the patients and their families. The main variables analyzed were patient's delay (PD), doctor's delay (DD), diagnostic process delay (DPD), health care system delay (HCSD) and total delay between the onset of symptoms and start of treatment (TD). Univariate and multivariate statistical analyses were performed for each component of delay. RESULTS: Two hundred eighty-seven patients were studied. The mean delays in days standard deviations were TD 81.8 77.3; PD 43.3 55.7; DD 28.4 59.6; DPD 10.0 17.7, and HCSD 38.5 62.5. CONCLUSIONS: Patients are responsible for 50% of excess delay in diagnosing symptomatic PTB. Patients in the health care system experienced diagnostic delays over 60 days in 18.5% of cases, doctors being responsible for 75% of the diagnostic delay attributable to the system.

Estudio del retraso diagnóstico de la tuberculosis pulmonar sintomática / Pulmonary symptomatic tuberculosis' diagnostic delay study

OBJETIVO: Estudiar el retraso diagnóstico de la tuberculosis pulmonar (TBP) sintomática. PACIENTES Y MÉTODOS: Estudio prospectivo de casos nuevos sintomáticos de TBP (edad 15 años) mediante entrevista estructurada al paciente y su familia. Las variables fundamentales analizadas fueron: retraso del enfermo (RE), retraso atribuible al médico (RM), retraso durante el proceso diagnóstico (RPD), retraso en el sistema sanitario (RSS) y retraso total (RT), esto es, el tiempo transcurrido desde el comienzo de los síntomas hasta el inicio del tratamiento de la TBP. Se realizó un análisis estadístico univariante, así como análisis multivariante para cada uno de los componentes del retraso diagnóstico. RESULTADOS: Se estudió a 287 enfermos. La media en días ñ desviación estándar (DE) fue para el RT y sus distintos componentes de 81,8 ñ 77,3 en el RT, 43,3 ñ 55,7 días en el RE, de 28,4 ñ 59,6 días en el RM; para el RD, de 10,0 ñ 17,7 días y en el RSS de 38,5 ñ 62,5 días. CONCLUSIONES: Dentro del elevado retraso diagnóstico de la TBP los enfermos son responsables del 50 por ciento. En el sistema sanitario el 18,5 por ciento de los enfermos sufrió un retraso diagnóstico mayor de 60 días, siendo los médicos responsables del 75 por ciento de la demora atribuible al sistema (AU)

[Capillary density and respiratory function in the external intercostal muscle]. / Densidad capilar y función respiratoria en el músculo intercostal externo.

UNLABELLED: Changes in lung function have been related to adaptive structural modifications in respiratory muscles. OBJECTIVE: To evaluate the capillary density (Dcap) of the external intercostal muscle in patients with chronic obstructive pulmonary disease (COPD), and its possible relation to respiratory function. METHODS: Forty-two individuals (61 +/- 9 years old) underwent conventional lung function testing and evaluation of respiratory muscles (maximum pressures at rest and a tolerance test using Martyn's technique). The sample included 10 subjects with normal lung function and 32 COPD patients (FEV1 between 13 and 78% of reference), in stable phase and with no respiratory insufficiency (PaO2 > 60 mmHg). A local biopsy of the external intercostal muscle was taken from all subjects at the fifth intercostal space (anterior axillary [correction of axile]) on the non-dominant side. The sample was processed for morphometry and fiber typing with ATPase staining and for quantifying capillarity with Gomori's trichrome staining. RESULTS: The mean diameter was 61 +/- 10 micrograms, with type I fibers predominating (56 +/- 11%). Dcap was 2.8 +/- 0.6 capillaries/fiber (equivalent to 1.02 +/- 0.37 capillaries/mm2 of fibrillary surface). The number of capillaries/fiber was significantly higher in patients with severe COPD (FEV1 < 50% ref) than in controls (3.0 +/- 0.6 versus 2.3 +/- 0.5, p < 0.01) and was inversely related to FEV1 (r = -0.395, p < 0.01). Muscle capillarity was unrelated to other function variables, including markers of respiratory muscle function and gas exchange. CONCLUSION: The structural remodelling of external intercostal muscles in COPD patients also includes an increase in density of interfibrillary capillaries. This increase is proportional to the severity of obstruction and probably reflects an adaptive phenomenon.

[Fiber morphometry of the external intercostal muscle. Comparison of dominant and nondominant sides in patients with severe COPD]. / Morfometría fibrilar del músculo intercostal externo. Comparación entre los lados dominante y no dominante en pacientes con EPOC severa.

The general morphometric characteristics of the external intercostal muscle (EIM) of patients with chronic respiratory disease have been well described. Because this muscle is highly accessible, it can provide an ideal model for longitudinal studies using consecutive biopsies of both sides. Whether or not the EIM fiber phenotype is homogeneous on dominant (D) and non dominant (ND) sides is unknown, however. To evaluate possible structural differences in right and left EIM in patients with COPD, eight patients (63 +/- 7 years of age) were enrolled. Lung function, respiratory muscle power, general muscle power and nutritional state were evaluated. Biopsies of the fifth EIM were taken from both sides. Specimens were processed in parallel manner to determine conventional morphometry (hematoxylin-eosin staining), including minimum diameter (Dm) and fiber area (Ar) in cross sections. Fibers were typed by ATPase (at pH 4.2, 4.6 and 9.4) and NADH-TR staining. Nutrition was normal in all patients. All patients had severe COPD (FEV1 27 +/- 7% of reference, limits 13 to 38% of reference) with air entrapment (RV 163 +/- 36% of reference, limits 181 to 276% of reference). None of the patients showed respiratory insufficiency at rest (PaO2 72 +/- 7 mmHg). Peripheral musculoskeletal power measured by manual dynamometer showed no significant right-left differences: D 29 +/- 2 and ND 28 +/- 3 dynes. Morphometric study of 16 muscle specimens showed no significant differences between fiber size on D and ND sides. DmD was 47 +/- 10 microns and ArD, was 2,595 +/- 1,249 microns2. DmD was 49 +/- 9 microns and ArD was 2,636 +/- 953 microns2. Likewise, no significant differences were found between D and ND fiber types: type ID 51 +/- 4% and type IID 49 +/- 5% versus type IND 52 +/- 4% and type IIND 48 +/- 4%. EIM on N and ND sides is homogeneous at the fifth intercostal space. This finding, along with the scarcely invasive nature of the technique for collecting specimens leads us to suggest that longitudinal studies might be performed on the structural effects of various pharmacological or physical treatments followed by COPD patients

[Cellular homogeneity in diverse portions of the diaphragm]. / Homogeneidad celular en las diversas porciones del diafragma.

The diaphragm is the main inspiratory muscle. It is composed of two parts, the costal and crural, with both anatomical and functional differences. The general morphometric characteristics of the diaphragm have been described in various species but homogeneity throughout the muscle has not been adequately studied. The aim of this study was to evaluate the fiber phenotype of various parts of the diaphragm. The entire diaphragm muscles of five New Zealand rabbits were removed and each was divided into quarters. The specimens were processed for morphometry (hematoxyllineosin stains, NADH-TR and ATPase at pH levels of 4.2, 4.6 and 9.4). For each portion we measured percent and size of fibers, expressing the latter as minimum diameter (Dm), measured area (Ar) and calculated area (Ac). Left and right diaphragm hemispheres (20 portions examined) were similar for fiber percentages and sizes. For left and right halves, respectively 50 +/- 2 and 51 +/- 4% of fibers were type I; type I Dm measurements were 38 +/- 5 and 41 +/- 4 microns; type I Ar values were 1798 +/- 481 and 2030 +/- 390 micron 2; type I Ac values were 1181 +/- 360 and 1321 +/- 382 micron 2; type II Dm values were 46 +/- 4 and 46 +/- 5 microns; type II Ar values were 2466 +/- 388 micron 2 and 2539 +/- 456 micron 2; type II Ac data were 1642 +/- 255 and 1655 +/- 382 micron 2. We likewise found no differences between costal and crural portions of the muscle (n = 20). For costal and crural portions, respectively, 50 +/- 3 and 50 +/- 2% of fibers were type I; type I Dm sizes were 39 +/- 5 and 40 +/- 4 microns; type I Ar measurements were 1859 +/- 521 and 1964 +/- 365 micron 2; type I Ac figures were 1231 +/- 317 and 1266 +/- 288 micron 2; type II Dm were 47 +/- 4 and 44 +/- 3 microns; type II Ar were 2563 +/- 481 and 2430 +/- 331 micron 2; type II Ac were 1729 +/- 373 and 1557 +/- 212 micron 2. Type II fibers, however, were somewhat larger than type I fibers in all portions (p = 0.001). New Zealand rabbit diaphragm muscle has similar percentages of slow and rapid contraction fibers. The size is not different from that observed in other species of mammals of similar size. Fiber type proportions are similar throughout the muscle, with more type II fibers present in all areas. The morphometric characters, therefore, suggest an homogeneous throughout the diaphragm, suggesting homogeneous response of the muscle to usual loads, and also suggesting the possibility of proposing longitudinal morphometric studies using this species as a model.