Loss of control in preschoolers with asthma is a risk factor for disease persistency.

AIM: To describe the relationship between loss of control events in preschoolers with asthma and persistence of disease. METHODS: We reviewed medical records of children <6 years diagnosed with asthma in 2018 to assess loss of control events during three years of follow-up. Asthma persistency was defined by redeem of short-acting ß2-agonist or asthma controllers within one year after the end of follow-up. Logistic regression models were applied to analyse the association between loss of control events and persistence of asthma. RESULTS: We included 172 patients (median age 1.8 years), whereof 126 (73.3%) experienced a loss of control event and 87 (50.6%) had asthma one year after the end of follow-up. Any loss of control event was associated with persistence of asthma adjusted for controller treatment at inclusion, prior exacerbations, atopic comorbidity and caesarean section: aOR, 10.9 (95% CI, 3.9-34.6), p < 0.001. This was also significant restricted to events in the first year of follow-up: 3.52 (1.50-8.67), p < 0.01 and among children only experiencing one event: 6.4 (1.7-27.3), p = 0.01. CONCLUSION: Loss of control events during a 3-year period among preschoolers with asthma are closely related to disease persistency, which may aid clinicians to assess risk of persistent asthma in young children.

Objective confirmation of asthma diagnosis, treatment adherence and patient outcomes in children and adolescents.

AIM: The aim of this study was to investigate the diagnostic workup in children with asthma hypothesising that objective confirmation of the diagnosis is associated with improved treatment adherence and patient outcomes. METHODS: We reviewed medical records of children aged 5-18 years diagnosed with asthma at the Department of Paediatric and Adolescent Medicine, Herlev-Gentofte Hospital, Denmark, in 2018. Objective confirmation of the diagnosis was based on either (1) lung function, (2) bronchodilator response, (3) bronchial hyperresponsiveness and/or (4) elevated FeNO and was associated with treatment adherence (proportion of days covered, PDC), lung function development and exacerbations during a two-year follow-up period. RESULTS: A total of 88 children were included. Asthma was objectively confirmed in 67 (76%). Children with objective confirmation of the diagnosis were more likely to redeem short-acting beta-2-agonist prescriptions: at least once, aOR = 1.3 (95% CI, 1.1-13.1), p = 0.036, and were more adherent to inhaled corticosteroid treatment: PDC>80%, aOR = 10.4 (1.8-201.1), p = 0.033. Further, objective confirmation was associated with improved lung function and reduced bronchodilator response, but not with exacerbations. CONCLUSION: Objective confirmation of the asthma diagnosis in children is associated with an increased treatment adherence and improved lung function, which underlines the importance of conducting objective tests in the diagnostic workup in paediatric asthma management.

Risk Factors for Non-Adherence to Inhaled Corticosteroids in Preschool Children with Asthma.

Non-adherence to asthma controllers increases morbidity among school-aged children. This study aimed to determine non-adherence risk factors in preschool children with asthma. We investigated 172 children <6 years diagnosed with asthma in 2018 and analyzed baseline characteristics and loss of control events extracted from the medical records for four years following diagnosis. At end of follow-up, 79 children had a prescription of inhaled corticosteroids (ICS) and were included in the analyses. Adherence was assessed in a two-year period through pharmacy claims using percentage of days covered (PDC) analyzed dichotomously with non-adherence defined as PDC < 80% and using adherence ratio (AR) defined as days with medical supply divided by days without. Of the 79 children, 59 (74.7%) were classified as non-adherent. In analyses adjusted for sex, age and exacerbations prior to inclusion, adherence was positively associated with having had a loss of control event requiring a step-up in asthma controller (aAR:2.34 [1.10;4.98], p = 0.03), oral corticosteroids (aAR:2.45 [1.13;5.34], p = 0.026) or redeeming a short-acting b2-agonist prescription (aAR:2.91 [1.26;6.74], p = 0.015). Further, atopic comorbidity was associated with increased adherence (aAR:1.18 [1.01;1.37], p = 0.039), whereas having a first degree relative with asthma was associated with worse adherence (aAR:0.44 [0.23;0.84], p = 0.015). This study found poor adherence to ICS among three quarters of preschool children with asthma. Increasing adherence was associated with atopic comorbidity and loss of control events, whereas lower adherence was associated with atopic predisposition. These findings should be considered to improve adherence in preschool children with asthma.

Simultaneous quantification of isoniazid, rifampicin, ethambutol and pyrazinamide by liquid chromatography/tandem mass spectrometry.

A remediable cause of poor treatment response in drug-susceptible tuberculosis (TB) patients may be low plasma levels of one or more of the first-line anti-TB drugs. The aim of this work was to develop an accurate and precise LC-MS/MS method for simultaneous quantification of all four first-line anti-TB drugs in plasma suitable for therapeutic drug monitoring (TDM). To adjust for degradation and losses during sample preparation, isotopically labeled compounds were used as internal standards. Plasma samples spiked with internal standards were extracted using protein precipitation with methanol and acetonitrile. Simultaneous separation of all four drugs was accomplished with a Chromolith Reversed-Phase column and mobile phases consisting of water, methanol, ammonium acetate and formic acid with subsequent mass spectrometric quantification. The linear range of the calibration curve for isoniazid was 0.5-10 mg/L, for rifampicin 0.75-30 mg/L, for ethambutol 0.25-10 mg/L and for pyrazinamide 4-80 mg/L. The lower limit of quantification was 0.5 mg/L, 0.75 mg/L, 0.25 mg/L and 4.0 mg/L, respectively. Precision estimated by the coefficient of variation was <15% for all four drugs. The LC-MS/MS method can readily be used for simultaneous quantification of first-line anti-TB drugs in plasma and is well suited for TDM.

Clinical significance of 2 h plasma concentrations of first-line anti-tuberculosis drugs: a prospective observational study.

OBJECTIVES: To study 2 h plasma concentrations of the first-line tuberculosis drugs isoniazid, rifampicin, ethambutol and pyrazinamide in a cohort of patients with tuberculosis in Denmark and to determine the relationship between the concentrations and the clinical outcome. METHODS: After 6-207 days of treatment (median 34 days) 2 h blood samples were collected from 32 patients with active tuberculosis and from three patients receiving prophylactic treatment. Plasma concentrations were determined using LC-MS/MS. Normal ranges were obtained from the literature. Clinical charts were reviewed for baseline characteristics and clinical status at 2, 4 and 6 months after the initiation of treatment. At a 1 year follow-up, therapy failure was defined as death or a relapse of tuberculosis. RESULTS: Plasma concentrations below the normal ranges were frequently observed: isoniazid in 71%, rifampicin in 58%, ethambutol in 46%, pyrazinamide in 10% and both isoniazid and rifampicin in 45% of the patients. The plasma concentrations of isoniazid correlated inversely with the C-reactive protein level at the time of sampling (P = 0.001). During 1 year of follow-up, therapy failure occurred in five patients. Therapy failure occurred more frequently when the concentrations of isoniazid and rifampicin were both below the normal ranges (P = 0.013) and even more frequently when they were below the median 2 h drug concentrations obtained in the study (P = 0.005). CONCLUSIONS: At 2 h, plasma concentrations of isoniazid and rifampicin below the normal ranges were frequently observed. The inverse correlation between the plasma concentrations of isoniazid and C-reactive protein indicate a suboptimal treatment effect at standard dosing regimens. Dichotomization based on median 2 h drug concentrations was more predictive of outcome than dichotomization based on normal ranges.

A review of paediatric tuberculosis in Denmark: 10-year trend, 2000-2009.

Paediatric tuberculosis (TB) is a key indicator for recent transmission and presents a reservoir for the disease. We describe trends in epidemiology, microbiological characteristics and treatment outcome in Denmark between 2000 and 2009. Data were retrieved from the national TB surveillance system and the International Reference Laboratory of Mycobacteriology. In total, 323 TB cases were reported in children aged <15 years, accounting for 7.6% of all notified cases in Denmark. The overall incidence rate of childhood TB declined from 4.1 per 100,000 to 1.9 per 100,000 in the study period. Immigrant children comprised 79.6% of all cases, with the highest incidence rate of 94.1 per 100,000 children in 2001. In contrast to immigrant children, the majority of Danish children were aged <5 years and had a known exposure to TB. Pulmonary TB was the commonest presentation. Only half of the cases were culture confirmed. We observed an overall decreasing trend in the child to adult notification ratio, but a slight increase in the ratio when calculated specifically for ethnic Danes. Childhood TB needs continuous attention with a special focus on risk groups. Emphasis on improving early TB case detection, contact tracing and further implementation of preventive treatment is necessary.

Diabetes, glycemic control, and risk of tuberculosis: a population-based case-control study.

OBJECTIVE: To examine the association between diabetes, glycemic control, and risk of tuberculosis (TB). RESEARCH DESIGN AND METHODS: We conducted a population-based case-control study in Northern Denmark. Cases of active TB were all individuals with a first-time principal hospital diagnosis of TB between 1980 and 2008. Each case subject was matched with up to five population control subjects with similar age, sex, place and length of residence in Denmark, and country of emigration. We computed odds ratios (ORs) for a first-time TB diagnosis among people with and without diabetes using regression to control for other comorbidities, alcoholism, immunosuppressive medications, and socioeconomic markers. RESULTS: We identified 2,950 patients, including 156 diabetic individuals (5.3%), with active TB, and 14,274 population control subjects, of which 539 had diabetes (3.8%). The adjusted OR for active TB among subjects with diabetes was 1.18 (95% CI 0.96-1.45) compared with nondiabetic individuals. We found a similar risk increase from diabetes in the 843 (29%) TB case subjects who were immigrants; adjusted OR = 1.23 (95% CI 0.78-1.93). In a subset with laboratory data, diabetic individuals with an HbA(1c) <7.0, 7-7.9, and ≥8.0% had ORs of 0.91 (0.51-1.63), 1.05 (0.41-2.66), and 1.19 (CI 0.61-2.30), respectively, compared with individuals without diabetes. CONCLUSIONS: In the low TB-burden country of Denmark, the TB risk increase associated with diabetes is substantially lower than previously suggested. We found no evidence for any association between TB and dysglycemia.

[Strengthening of laboratories is a new component in the global strategy for tuberculosis control]. / Styrkelse af laboratorier er et nyt element i den globale tuberkulosekontrolstrategi.

Although old techniques remain important, new techniques offer new possibilities. Mutations conferring resistance to rifampin and isoniazid can be detected in primary specimens from infectious pulmonary cases. Infections can be detected with interferon-gamma release assays, and chains of transmission can be detected by mycobacteria interspersed repetitive units. Centralized diagnostics makes it possible to apply results of routine analyses in national and international surveillance.

[Treatment and diagnostics of tuberculosis: moving slowly forward]. / Behandling og diagnostik af tuberkulose: fremad med små skridt.

Development of new drugs for the treatment of drug sensitive and drug resistant tuberculosis is badly needed. Substantial progress has been made in the field and presently six new drug components are in clinical phase I and II trials. Drugs approved for other indications e.g. newer fluoroquinolones and oxazolidinones are also being assessed in human phase II and III trials. Efforts are made to develop easy-to-handle diagnostic tools that will allow early detection of potential MDR or XDR cases. The Xpert RIF/MTB is a prototype of such an invention. At long last the field is moving slowly forward.

Diabetic ketoacidosis in Denmark Incidence and mortality estimated from public health registries.

The aims of this study were to estimate incidence of diabetic ketoacidosis and mortality from diabetic ketoacidosis using data from public health registries. Four thousand eight hundred and seven admissions in the period 1996-2002 and 137 deaths in the period 1996-2000 with a diagnosis of diabetic ketoacidosis were identified from the Danish National Patient Registry and Danish Cause of Death Registry, respectively. Annual incidence of diabetic ketoacidosis in the general population was estimated to 12.9 per 100,000, being higher in males than in females (14.4 versus 11.4 per 100,000, p<0.0001). Twelve percent of all patients were classified as Type 2 diabetes, predominantly in patients >50 years. Overall mortality was 4%, being higher in patients >70 years than in patients < or =70 years (15% versus 2%, p<0.0001). One or more additional somatic diagnoses were stated on 77% of the death certificates, most often a diagnosis of cardiovascular (47%) or infectious (30%) diseases. Compared to previous studies, the incidence in the general population seems to have remained unaltered the past 25 years, but may have decreased in younger patients. Older patients with diabetic ketoacidosis differed from younger patients in having a higher mortality and a larger proportion of patients classified as Type 2 diabetes.

Treatment of diabetic ketoacidosis in adults in Denmark: a national survey.

The aims of this study were to investigate management routines of diabetic ketoacidosis (DKA) in adult patients in departments of internal medicine in Denmark and to relate current routines of treatment to available evidence. A questionnaire requesting information on management routines of DKA was sent to all departments of internal medicine in Denmark responsible of managing DKA. Fifty-nine departments (88%) returned the questionnaire and/or a copy of their management protocol. At 19 departments (32%), all patients with DKA were managed in an intensive care unit (ICU). Twenty-four different insulin regimens and 21 fluid protocols were identified. Routines of insulin therapy varied in terms of doses and routes of administration. Fifty-eight departments (97%) used isotonic saline for hydration. Potassium supplements were administered as a separate infusion of either isotonic potassium-sodium-chloride (83%) or isotonic potassium-chloride (10%). Recommended volumes to be administered during the first 8h of treatment varied significantly (median 4800ml, range 3750-7700ml). Use of bicarbonate was endorsed by 80%. This study shows significant variations in management routines of DKA in Denmark. In many cases, the treatment routines employed are not supported by evidence from clinical trials. We recommend implementation of national and/or European guidelines for management of DKA in adult patients.