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1.
J Cyst Fibros ; 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38702223

RESUMO

BACKGROUND: Excessive inflammation and recurrent airway infections characterize people with cystic fibrosis (pwCF), a disease with highly heterogeneous clinical outcomes. How the overall immune response is affected in pwCF, its relationships with the lung microbiome, and the source of clinical heterogeneity have not been fully elucidated. METHODS: Peripheral blood and sputum samples were collected from 28 pwCF and an age-matched control group. Systemic immune cell subsets and surface markers were quantified using multiparameter flow cytometry. Lung microbiome composition was reconstructed using metatranscriptomics on sputum samples, and microbial taxa were correlated to circulating immune cells and surface markers expression. RESULTS: In pwCF, we found a specific systemic immune profile characterized by widespread hyperactivation and altered frequencies of several subsets. These included substantial changes in B-cell subsets, enrichment of CD35+/CD49d+ neutrophils, and reduction in dendritic cells. Activation markers and checkpoint molecule expression levels differed from healthy subjects. CTLA-4 expression was increased in Tregs and, together with impaired B-cell subsets, correlated with patients' lung function. Concentrations and frequencies of key immune cells and marker expression correlated with the relative abundance of commensal and pathogenic bacteria in the lungs. CONCLUSION: The CF-specific immune signature, involving hyperactivation, immune dysregulation with alteration in Treg homeostasis, and impaired B-cell function, is a potential source of lung function heterogeneity. The activity of specific microbes contributes to disrupting the balance of the immune response. Our data provide a unique foundation for identifying novel markers and immunomodulatory targets to develop the future of cystic fibrosis treatment and management.

2.
APMIS ; 132(4): 223-235, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38267398

RESUMO

Cystic fibrosis (CF) care in Denmark has been characterized by close monitoring and pre-emptive treatment of lung disease and other CF-related complications. Continuous evaluation through data collection and commitment to clinical research has incrementally improved outcomes. This approach has been in line with best practices set forth by European Standards of Care but has also gone beyond Society standards particularly pertaining to early treatment with high-dose combination antimicrobial therapy. Despite a high prevalence of severe CF variants, lung function has been among the best in Europe. In this review, the Danish approach to management of CF prior to the introduction of new CF modulator treatment is explained and benchmarked. Downsides to the Danish approach are discussed and include increased burden of treatment, risk of antimicrobial resistance, side-effects and costs.


Assuntos
Anti-Infecciosos , Fibrose Cística , Humanos , Fibrose Cística/complicações , Europa (Continente) , Anti-Infecciosos/uso terapêutico , Dinamarca
3.
J Cyst Fibros ; 23(1): 103-108, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37989700

RESUMO

BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (ETI) has improved the clinical status of individuals with cystic fibrosis (CF), however, whether ETI impacts glucose tolerance remains unknown. We aimed to study the change in glycated hemoglobin (HbA1c) and CF related diabetes (CFRD) status after initiation of ETI. METHODS: We included individuals ≥12 years treated with ETI in Denmark in a longitudinal observational study. HbA1c was measured at baseline, 3, 6, 9 and 12 months after treatment initiation. Change in HbA1c was assessed in mixed models adjusted for age, sex, glucose tolerance and prior CFTR modulator treatment. In a sub-population with CFRD, we assessed the change in insulin usage, hypoglycemic events and the 30-day continuous glucose monitoring (CGM) parameters (i.e., average blood glucose, time below (≤3.9 mM) and above (>10.0 mM) normal range, and the variation in glucose) after 12 months of treatment. RESULTS: Among 321 individuals with CF, HbA1c declined by 2.1 mmol/mol [95 % confidence interval (CI): -2.6; -1.5 mmol/mol] after 3 months and by 2.3 mmol/mol [95 %CI: -2.8; -1.9 mmol/mol] after 12 months of ETI treatment. The decline was independent of glucose tolerance status at baseline. In 26 individuals with CFRD at baseline, the mean decline in HbA1c was 3.6 mmol/mol [95 %CI: -6.9; -0.4 mmol/mol] after 12 months, but we did not observe any change in insulin usage, weekly number of hypoglycemic events or CGM parameters. CONCLUSION: In the Danish CF cohort, HbA1c declined over 12 months of ETI treatment, however, among a subset with CFRD, we observed no change in insulin usage and CGM glucose levels.


Assuntos
Glicemia , Fibrose Cística , Indóis , Pirazóis , Piridinas , Pirrolidinas , Quinolonas , Humanos , Automonitorização da Glicemia , Fibrose Cística/tratamento farmacológico , Fibrose Cística/epidemiologia , Hemoglobinas Glicadas , Insulina , Hipoglicemiantes/uso terapêutico , Glucose , Dinamarca/epidemiologia , Regulador de Condutância Transmembrana em Fibrose Cística , Benzodioxóis , Mutação , Aminofenóis/uso terapêutico
4.
Front Endocrinol (Lausanne) ; 14: 1249876, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37720541

RESUMO

Aims: The purpose of the study was to further elucidate the pathophysiology of cystic fibrosis (CF)-related diabetes (CFRD) and potential drivers of hypoglycaemia. Hence, we aimed to describe and compare beta cell function (insulin and proinsulin) and alpha cell function (glucagon) in relation to glucose tolerance in adults with CF and to study whether hypoglycaemia following oral glucose challenge may represent an early sign of islet cell impairment. Methods: Adults with CF (≥18 years) were included in a cross-sectional study using an extended (-10, -1, 10, 20, 30, 45, 60, 90, 120, 150, and 180 min) or a standard (-1, 30, 60, and 120 min) oral glucose tolerance test (OGTT). Participants were classified according to glucose tolerance status and hypoglycaemia was defined as 3-hour glucose <3.9 mmol/L in those with normal glucose tolerance (NGT) and early glucose intolerance (EGI). Results: Among 93 participants, 67 underwent an extended OGTT. In addition to worsening in insulin secretion, the progression to CFRD was associated with signs of beta cell stress, as the fasting proinsulin-to-insulin ratio incrementally increased (p-value for trend=0.013). The maximum proinsulin level (pmol/L) was positively associated with the nadir glucagon, as nadir glucagon increased 6.2% (95% confidence interval: 1.4-11.3%) for each unit increase in proinsulin. Those with hypoglycaemia had higher 60-min glucose, 120-min C-peptide, and 180-min glucagon levels (27.8% [11.3-46.7%], 42.9% [5.9-92.85%], and 80.3% [14.9-182.9%], respectively) and unaltered proinsulin-to-insulin ratio compared to those without hypoglycaemia. Conclusions: The maximum proinsulin concentration was positively associated with nadir glucagon during the OGTT, suggesting that beta cell stress is associated with abnormal alpha cell function in adults with CF. In addition, hypoglycaemia seemed to be explained by a temporal mismatch between glucose and insulin levels rather than by an impaired glucagon response.


Assuntos
Fibrose Cística , Hipoglicemia , Adulto , Humanos , Glucagon , Estudos Transversais , Proinsulina , Fibrose Cística/complicações , Glucose
5.
Pediatr Pulmonol ; 58(9): 2600-2609, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37341613

RESUMO

BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have been shown to have a beneficial effect on pulmonary function and nutritional status in patients with cystic fibrosis (CF), but the extent to which they affect glucose tolerance is not fully understood. In the current study, we evaluated the change in glucose tolerance and insulin secretion after first-generation CFTR modulator treatment in adults with CF. METHODS: We performed a longitudinal observational study with an oral glucose tolerance test performed at baseline and after three and a half years of follow-up. The test comprised glucose, C-peptide and insulin measured at fasting, 1 h, and 2 h, and HbA1c at fasting. We compared changes in parameters of glucose tolerance and insulin secretion from baseline to follow-up. RESULTS: Among 55 participants, 37 (67%) were treated with a first-generation CFTR modulator for a median of 21 months. Glucose levels were unchanged in both the treated and untreated group. In the treated group, C-peptide levels declined, yet no significant differences in glucose, insulin, and C-peptide levels were observed between the groups. HbA1c increased in both groups, while no significant change in the insulin sensitivity indices was detected in either group. However, homeostatic model assessment for insulin resistance tended to decline in the treated group, whilst tending towards an increase in the untreated group. The difference between the groups reached statistical significance (p = 0.040). CONCLUSION: Treatment with first-generation CFTR modulators, mainly tezacaftor/ivacaftor, did not seem to be associated with glucose tolerance nor insulin secretion in adults with CF. However, CFTR modulators may still have a beneficial effect on insulin sensitivity.


Assuntos
Fibrose Cística , Resistência à Insulina , Adulto , Humanos , Fibrose Cística/tratamento farmacológico , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Peptídeo C , Hemoglobinas Glicadas , Insulina , Glucose , Aminofenóis/uso terapêutico , Benzodioxóis , Mutação
6.
Front Immunol ; 13: 934476, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35967433

RESUMO

Background: The antibody response after vaccination is impaired in common variable immunodeficiency (CVID). Objective: We aimed to study the spike receptor-binding domain IgG antibody (anti-S-RBD) levels during a four-dose SARS-CoV-2 vaccination strategy and after monoclonal antibody (mAB) treatment in CVID. Moreover, we assessed the anti-S-RBD levels in immunoglobulin replacement therapy (IgRT) products. Methods: In an observational study, we examined anti-S-RBD levels after the second, third, and fourth dose of mRNA SARS-CoV-2 vaccines. Moreover, we measured anti-S-RBD after treatment with mAB. Finally, anti-S-RBD was assessed in common IgRT products. Antibody non-responders (anti-S-RBD < 7.1) were compared by McNemar's test and anti-S-RBD levels were compared with paired and non-paired Wilcoxon signed rank tests as well as Kruskal-Wallis tests. Results: Among 33 individuals with CVID, anti-S-RBD levels increased after the third vaccine dose (165 BAU/ml [95% confidence interval: 85; 2280 BAU/ml], p = 0.006) and tended to increase after the fourth dose (193 BAU/ml, [-22; 569 BAU/ml], p = 0.080) compared to the previous dose. With increasing number of vaccinations, the proportion of patients who seroconverted (anti-S-RBD ≥ 7.1) increased non-significantly. mAB treatment resulted in a large increase in anti-S-RBD and a higher median level than gained after the fourth dose of vaccine (p = 0.009). IgRT products had varying concentrations of anti-S-RBD (p < 0.001), but none of the products seemed to affect the overall antibody levels (p = 0.460). Conclusion: Multiple SARS-CoV-2 vaccine doses in CVID seem to provide additional protection, as antibody levels increased after the third and fourth vaccine dose. However, anti-S-RBD levels from mAB outperform the levels mounted after vaccination. Clinical Implications: Boosting with SARS-CoV-2 vaccines seems to improve the antibody response in CVID patients. Capsule summary: The third and possibly also the fourth dose of mRNA SARS-CoV-2 vaccine in CVID improve the antibody response as well as stimulate seroconversion in most non-responders.


Assuntos
COVID-19 , Imunodeficiência de Variável Comum , Vacinas Virais , Formação de Anticorpos , COVID-19/prevenção & controle , Vacinas contra COVID-19 , Imunodeficiência de Variável Comum/terapia , Humanos , RNA Mensageiro , SARS-CoV-2
7.
APMIS ; 130(8): 535-539, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35635299

RESUMO

Blood glucose levels exceeding 8 mM are shown to increase glucose levels in airway surface in cystic fibrosis (CF). Moreover, high levels of endobronchial glucose are proposed to increase the growth of common CF bacteria and feed the neutrophil-driven inflammation. In the infected airways, glucose may be metabolized by glycolysis to lactate by both bacteria and neutrophils. Therefore, we aimed to investigate whether increased blood glucose may fuel the glycolytic pathways of the lung inflammation by determining sputum glucose and lactate during an oral glucose tolerance test (OGTT). Sputum from 27 CF patients was collected during an OGTT. Sputum was collected at fasting and one and two hours following the intake of 75 g of glucose. Only participants able to expectorate more than one sputum sample were included. Glucose levels in venous blood and lactate and glucose content in sputum were analyzed using a regular blood gas analyzer. We collected 62 sputum samples: 20 at baseline, 22 after 1 h, and 20 after 2 h. Lactate and glucose were detectable in 30 (48.4%) and 43 (69.4%) sputum samples, respectively. The sputum lactate increased significantly at 2 h in the OGTT (p = 0.024), but sputum glucose was not changed. As expected, plasma glucose level significantly increased during the OGTT (p < 0.001). In CF patients, sputum lactate increased during an OGTT, while the sputum glucose did not reflect the increased plasma glucose. The increase in sputum lactate suggests that glucose spills over from plasma to sputum where glucose may enhance the inflammation by fueling the anaerobic metabolism in neutrophils or bacteria.


Assuntos
Fibrose Cística , Glicemia/metabolismo , Fibrose Cística/microbiologia , Glucose , Teste de Tolerância a Glucose , Humanos , Inflamação , Ácido Láctico , Escarro
8.
Pediatr Pulmonol ; 57(7): 1726-1734, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35478387

RESUMO

BACKGROUND: Inhaled antibiotics are an important part of cystic fibrosis (CF) airway disease management and should be individualized to fit the microorganism and match patient needs. To investigate the implementation of personalized treatment, this study mapped the use of different types of inhaled antibiotics and adherence patterns. METHODS: We performed individual structured interviews in a cross-sectional study at the CF Centre in Copenhagen, Denmark. Patients with CF older than 15 years attending clinical consultations were included. Clinical data were obtained from centralized databases. RESULTS: Among 149 participants, 107 (72%) had indication for treatment with inhaled antibiotics. In this group, 97 (91%) reported the use of inhaled antibiotics within the last 12 months. Change from one inhaled antibiotic to another during that period was reported by 31 (29%), and 17 (25%) with Pseudomonas aeruginosa had used off-label antibiotics. Adherence to a minimum of one daily dose of antibiotic was reported by 78%, while adherence to all daily doses was 28 percentage points lower. Skipping inhalations was due to side effects and doubt about the effect in less than 5% of cases. CONCLUSION: Change of inhaled antibiotics and use of off-label antibiotics for inhalation were common and side effects were a rare cause of nonadherence. This suggests satisfactory implementation of the principle of tailored antibiotic inhalation prescription in the Copenhagen CF population. Adherence to at least one daily inhalation dose was markedly higher than adherence to multiple daily inhalations.


Assuntos
Fibrose Cística , Infecções por Pseudomonas , Infecções Respiratórias , Administração por Inalação , Antibacterianos/uso terapêutico , Estudos Transversais , Fibrose Cística/complicações , Fibrose Cística/tratamento farmacológico , Dinamarca , Humanos , Infecções por Pseudomonas/complicações , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa , Infecções Respiratórias/tratamento farmacológico
9.
IDCases ; 26: e01300, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34692415

RESUMO

Defects in the interleukin-12/interferon-gamma (IFN-γ) pathway and anti-IFN-γ antibodies have been associated with severe nontuberculous mycobacteria (NTM) infections. Consequently, disseminated NTM infections should prompt investigations for immunodeficiency. Herein, we report a case of a treatment refractory and ultimately disseminated and fatal Mycobacterium avium complex infection in a 71-year-old woman of Thai origin. Simultaneously, she had recurrent Salmonella kentucky cultured from stool samples and chronic perianal HSV-2 lesions. Late in the course of disease, anti-IFN-γ autoantibodies were demonstrated. Clinical studies investigating immunomodulating therapy and treatment among patients with anti-IFN-γ autoantibodies are lacking and, in this case, treatment seemed of a more palliative nature.

10.
Clin Med Insights Endocrinol Diabetes ; 14: 11795514211038259, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34413690

RESUMO

BACKGROUND: A frequent comorbidity in cystic fibrosis (CF) is CF related diabetes (CFRD) caused by a gradual decline in insulin secretion. The reduction in the anabolic hormone, insulin, might explain the weight loss that precedes onset of CFRD. We investigated the association between muscle and fat mass in relation to glucose tolerance and insulin function. METHODS: In a cross-sectional study with CF patients (⩾18 years), we conducted an oral glucose tolerance test and dual energy X-ray absorptiometry scan (DXA). Based on plasma glucose, glucose tolerance was defined as normal (NGT): 1-hour <11.1 mmol/L and 2-hour <7.8 mmol/L, impaired (IGT): 2-hour ⩾7.8 and <11.1 mmol/L or CFRD: 2-hour ⩾11.1 mmol/L. Insulin resistance (HOMA-IR) was derived from fasting levels of plasma glucose and plasma insulin, and fat-free and fat mass index (kg/m2) from DXA. Associations were evaluated using linear regression models adjusted for age, sex, and pancreas insufficiency. RESULTS: Among 79 CF patients with exocrine pancreas insufficiency, impairment of glucose tolerance corresponded to reduced insulin secretion. In the IGT group the fat-free mass index (FFMI) was 1.2 kg/m2 (95% CI: [-2.3, -0.03] kg/m2, P = .044) lower compared to the NGT group. FFMI increased insignificantly by 0.4 kg/m2 (95% CI: [-0.6, 1.5] kg/m2, P = .422) among the insulin-treated CFRD group compared to IGT. Fat mass index (FMI) was not different between groups but tended to decrease with glucose tolerance impairment. For each 100 pmol/L increase in fasting insulin FFMI increased by 1.77 kg/m2 (95% CI: [0.21, 3.33] kg/m2/pmol/L/100) and FMI increased by 6.15 kg/m2 (95% CI: [3.87, 8.44] kg/m2/pmol/L/100). In multivariate analyses, HOMA-IR was positively associated with FFMI (ß = 0.5 kg/m2/HOMA-IR, 95% CI: [0.08, 0.92] kg/m2/HOMA-IR, P = .021) and FMI (ß = 1.5 kg/m2/HOMA-IR, 95% CI: [0.87, 2.15] kg/m2/HOMA-IR, P < .001). CONCLUSIONS: Muscle mass was significantly lower among participants with impaired glucose tolerance (IGT), while muscle mass was normalized among those treated with insulin.

11.
PLoS One ; 15(9): e0238524, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32915806

RESUMO

BACKGROUND: Markers of lung inflammation measured directly in expectorated sputum have the potential of improving the timing of antibiotic treatment in cystic fibrosis (CF). L-Lactate might be a marker of inflammation, as it is produced from glucose by polymorphonuclear neutrophils (PMNs) in CF lungs. We aimed to investigate changes in and associations between PMNs, glucose and L-lactate in sputum during antibiotic treatment. In addition, the effect of hemoglobin A1c and plasma glucose on these biomarkers were investigated. METHODS: We sampled non-induced sputum at day 0, 7, 14 and 42 in 27 chronically infected CF patients electively treated with 14 days of intravenous antibiotic. To analyze sputum samples, we used flowcytometry to count PMNs and colorimetric assays to estimate lactate and glucose. RESULTS: No changes in levels of PMNs, glucose and lactate were detected in sputum during the antibiotic treatment. Sputum PMNs were positively associated with both glucose (log coefficient = 0.20, p = 0.01) and L-lactate (log coefficient = 0.34, p<0.001). In multivariate analyses, hemoglobin A1c was negatively associated with sputum PMNs (log coefficient = -1.68, p<0.001) and plasma glucose was negatively associated with sputum glucose (log coefficient = -0.09, p = 0.02). CONCLUSIONS: In CF sputum PMNs, glucose and lactate were unchanged during elective antibiotic treatment. However, sputum PMNs were associated with both sputum glucose and sputum lactate. Surprisingly, hyperglycemia seemed to be associated with less PMNs infiltration and less glucose in CF sputum.


Assuntos
Fibrose Cística/sangue , Glucose/metabolismo , Ácido Láctico/metabolismo , Neutrófilos/metabolismo , Escarro/metabolismo , Adulto , Idoso , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Biomarcadores/metabolismo , Glicemia/metabolismo , Fibrose Cística/fisiopatologia , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Injeções Intravenosas , Contagem de Leucócitos , Masculino , Análise Multivariada , Testes de Função Respiratória , Adulto Jovem
12.
Trop Med Int Health ; 22(7): 846-856, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28464403

RESUMO

OBJECTIVES: In many African countries, child mortality is higher in the rainy season than in the dry season. We investigated the effect of season on child mortality by time periods, sex and age in rural Guinea-Bissau. METHODS: Bandim health project follows children under-five in a health and demographic surveillance system in rural Guinea-Bissau. We compared the mortality in the rainy season (June to November) between 1990 and 2013 with the mortality in the dry season (December to May) in Cox proportional hazards models providing rainy vs. dry season mortality rate ratios (r/d-mrr). Seasonal effects were estimated in strata defined by time periods with different frequency of vaccination campaigns, sex and age (<1 month, 1-11 months, 12-59 months). Verbal autopsies were interpreted using InterVa-4 software. RESULTS: From 1990 to 2013, overall mortality was declined by almost two-thirds among 81 292 children (10 588 deaths). Mortality was 51% (95% ci: 45-58%) higher in the rainy season than in the dry season throughout the study period. The seasonal difference increased significantly with age, the r/d-mrr being 0.94 (0.86-1.03) among neonates, 1.57 (1.46-1.69) in post-neonatal infants and 1.83 (1.72-1.95) in under-five children (P for same effect <0.001). According to the InterVa, malaria deaths were the main reason for the seasonal mortality difference, causing 50% of all deaths in the rainy season, but only if the InterVa included season of death, making the argument self-confirmatory. CONCLUSION: The mortality declined throughout the study, yet rainy season continued to be associated with 51% higher overall mortality.


Assuntos
Mortalidade da Criança , Clima , População Rural/estatística & dados numéricos , Estações do Ano , Fatores Etários , Pré-Escolar , Feminino , Guiné-Bissau , Humanos , Lactente , Recém-Nascido , Masculino , Modelos de Riscos Proporcionais , Fatores Sexuais
13.
Clin Infect Dis ; 61(6): 950-9, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26060293

RESUMO

BACKGROUND: Previous studies have found that BCG vaccination has nonspecific beneficial effects on child survival, especially among children who developed a BCG scar. These studies have mostly been done in settings with a high scar frequency. In rural Guinea-Bissau, many children do not develop a scar; we tested the hypothesis that among BCG-vaccinated children, a vaccination scar was associated with lower mortality and fewer hospital admissions. METHODS: During 2009-2011, children <5 years of age in villages followed by Bandim Health Project's demographic surveillance system had their scar status assessed at semiannual visits. We compared mortality and hospital admission rates of scar-positive and scar-negative BCG-vaccinated children during 6 months of follow-up in Cox proportional hazards models. RESULTS: Among 15 911 BCG-vaccinated children, only 52% had a scar. There were 106 non-injury-related deaths among scar-positive children and 137 among scar-negative children. The mortality rate ratio (MRR) was 0.74 (95% confidence interval [CI], .56-.96) overall; 0.48 (95% CI, .26-.90) in infancy, 0.69 (95% CI, .45-1.05) in the second year of life, and 0.89 (95% CI, .61-1.31) in the third-fifth year of life. The association between scar positivity and lower mortality differed significantly by cause of death and was strongest for respiratory infections (MRR, 0.20 [95% CI, .07-.55]). There were 99 hospital admissions among scar-positive children and 125 admissions among scar-negative children, resulting in an incidence rate ratio of 0.74 (95% CI, .60-.92). CONCLUSIONS: Among BCG-vaccinated children in a setting with low scar prevalence, having a scar is associated with lower mortality and morbidity. BCG scar prevalence may be an important marker of vaccination program quality.


Assuntos
Vacina BCG/administração & dosagem , Vacina BCG/imunologia , Cicatriz/induzido quimicamente , Cicatriz/epidemiologia , Doenças Transmissíveis/mortalidade , Doenças Transmissíveis/patologia , Hospitalização , Vacina BCG/efeitos adversos , Pré-Escolar , Estudos de Coortes , Feminino , Guiné-Bissau/epidemiologia , Humanos , Incidência , Lactente , Masculino , População Rural , Análise de Sobrevida
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