Outcome definitions for multidrug-resistant tuberculosis treated with shorter treatment regimens.

To assess whether the revised 2013 World Health Organization (WHO) definitions for multidrug-resistant tuberculosis (MDR-TB) treatment outcomes apply to shorter treatment regimens in low- and middle-income countries and to propose modified criteria. Criteria for 'failure' and 'cure' outcomes were assessed using data on 1006 patients enrolled in an observational study on the standardised 9-11 month shorter MDR-TB regimen in Africa. Absence of conversion in the intensive phase, a WHO criteria for failure, was the worst performing criterion; reversion had low sensitivity and other criteria provided limited added value. Based on our study results, we propose new definitions for 'treatment failure' as treatment termination or the permanent discontinuation of 2 anti-tuberculosis drugs due to 1) positive culture after 6 months of treatment (except for one isolated positive culture) or 2) at least two consecutive grade 2+ positive sputum smears after 6 months of treatment if culture is not available; and for 'cure' as treatment completion without proof of failure AND two consecutive negative cultures taken 30 days apart, one of which should be after 6 months of treatment. The proposed new definitions are applicable to shorter regimens in low- and middle-income countries, and should also work for the newly recommended longer regimens. .

Challenges and opportunities to prevent tuberculosis in people living with HIV in low-income countries.

People living with the human immunodeficiency virus (HIV) (PLHIV) are at high risk for tuberculosis (TB), and TB is a major cause of death in PLHIV. Preventing TB in PLHIV is therefore a key priority. Early initiation of antiretroviral therapy (ART) in asymptomatic PLHIV has a potent TB preventive effect, with even more benefits in those with advanced immunodeficiency. Applying the most recent World Health Organization recommendations that all PLHIV initiate ART regardless of clinical stage or CD4 cell count could provide a considerable TB preventive benefit at the population level in high HIV prevalence settings. Preventive therapy can treat tuberculous infection and prevent new infections during the course of treatment. It is now established that isoniazid preventive therapy (IPT) combined with ART among PLHIV significantly reduces the risk of TB and mortality compared with ART alone, and therefore has huge potential benefits for millions of sufferers. However, despite the evidence, this intervention is not implemented in most low-income countries with high burdens of HIV-associated TB. HIV and TB programme commitment, integration of services, appropriate screening procedures for excluding active TB, reliable drug supplies, patient-centred support to ensure adherence and well-organised follow-up and monitoring that includes drug safety are needed for successful implementation of IPT, and these features would also be needed for future shorter preventive regimens. A holistic approach to TB prevention in PLHIV should also include other important preventive measures, such as the detection and treatment of active TB, particularly among contacts of PLHIV, and control measures for tuberculous infection in health facilities, the homes of index patients and congregate settings.

High effectiveness of a 12-month regimen for MDR-TB patients in Cameroon.

SETTING: Two specialised multidrug-resistant tuberculosis (MDR-TB) treatment units in Cameroon. OBJECTIVE: To assess outcome and adverse drug events with a standardised 12-month regimen for MDR-TB among second-line drug naïve patients. DESIGN: Prospective observational study of MDR-TB patients treated with a standardised 12-month regimen including gatifloxacin, clofazimine, prothionamide, ethambutol and pyrazinamide throughout, supplemented by kanamycin and isoniazid during an intensive phase of a minimum of 4 months. Progress was monitored monthly until treatment completion and twice over one year after treatment cessation. RESULTS: Eighty-seven potentially eligible patients were lost and never treated due to delayed availability of test results. Among the 150/236 eligible and treated patients, 134 (89%) successfully completed treatment, 10 died, 5 were lost, 1 failed and none relapsed. The patients' mean age was 33.7 years (range 17-68), 73 (49%) were females, 120 (80%) had failed on previous treatment, 30 (20%) were human immunodeficiency virus seropositive, 62 (43%) had a body mass index <18.5 kg/m(2) and 41 (27%) had radiographic involvement of five or six of the six lung zones. The most important adverse drug event was hearing impairment, which occurred in 46 of 106 (43%) patients. CONCLUSIONS: These results add further evidence for the usefulness of shorter, standardised regimens among patients without second-line drug resistance.

Management of asthma in resource-limited settings: role of low-cost corticosteroid/ß-agonist combination inhaler.

The management of asthma requires medicines that are effective in relaxing airway smooth muscles and in reducing airway inflammation. Rapid-acting ß2 agonist is a bronchodilator that provides quick symptom relief in patients with asthma. However, it does not effectively address the underlying problem of airway inflammation. Excess use of inhaled bronchodilators alone for symptom relief may result in delay in seeking health care, which in turn may result in delayed use of anti-inflammatory agents. Inhaled corticosteroid (ICS) is critical in the treatment of airway inflammation; it reduces the risk of life-threatening asthma attacks and the need for hospitalisation. ICS is underused, however, and a substantial proportion of patients with persistent asthma in resource-limited settings have no access to affordable ICS for long-term treatment. International guidelines recommend the use of rapid-acting ß-agonists as needed as rescue treatment when symptoms occur. Studies have shown that the use of both ICS and rapid-acting ß-agonist as needed for symptom relief might be a better option. The combination of ICS and rapid-acting bronchodilator in a single inhaler is currently too expensive and is not affordable for the poor. Although ICS and short-acting ß2 agonist (SABA) for rescue treatment can be obtained to a certain extent by using separate ICS and SABA inhalers, the first step is to ensure access to affordable, quality-assured essential asthma medicine in resource-limited settings.

Gaps in using bronchodilators, inhaled corticosteroids and influenza vaccine among 23 high- and low-income sites.

BACKGROUND: Increasing access to essential respiratory medicines and influenza vaccination has been a priority for over three decades. Their use remains low in low- and middle-income countries (LMICs), where little is known about factors influencing use, or about the use of influenza vaccination for preventing respiratory exacerbations. METHODS: We estimated rates of regular use of bronchodilators, inhaled corticosteroids and influenza vaccine, and predictors for use among 19 000 adults in 23 high-income countries (HICs) and LMIC sites. RESULTS: Bronchodilators, inhaled corticosteroids and influenza vaccine were used significantly more in HICs than in LMICs, after adjusting for similar clinical needs. Although they are used more commonly by people with symptomatic or severe respiratory disease, the gap between HICs and LMICs is not explained by the prevalence of chronic obstructive pulmonary disease or doctor-diagnosed asthma. Site-specific factors are likely to influence use differently. The gross national income per capita for the country is a strong predictor for use of these treatments, suggesting that economics influence under-treatment. CONCLUSION: We still need a better understanding of determinants for the low use of essential respiratory medicines and influenza vaccine in low-income settings. Identifying and addressing these more systematically could improve the access and use of effective treatments.

Siblings, asthma, rhinoconjunctivitis and eczema: a worldwide perspective from the International Study of Asthma and Allergies in Childhood.

BACKGROUND: Associations of larger families with lower prevalences of hay fever, eczema and objective markers of allergic sensitization have been found fairly consistently in affluent countries, but little is known about these relationships in less affluent countries. METHODS: Questionnaire data for 210,200 children aged 6-7 years from 31 countries, and 337,226 children aged 13-14 years from 52 countries, were collected by Phase Three of the International Study of Asthma and Allergies in Childhood (ISAAC). Associations of disease symptoms and labels of asthma, rhinoconjunctivitis and eczema were analysed by numbers of total, older and younger siblings, using mixed (multi-level) logistic regression models to adjust for individual covariates and at the centre level for region, language and national affluence. RESULTS: In both age groups, inverse trends (P < 0.0001) were observed for reported 'hay fever ever' and 'eczema ever' with increasing numbers of total siblings, and more specifically older siblings. These inverse associations were significantly (P < 0.005) stronger in more affluent countries. In contrast, symptoms of severe asthma and severe eczema were positively associated (P < 0.0001) with total sibship size in both age groups. These associations with disease severity were largely independent of position within the sibship and national GNI per capita. CONCLUSIONS: These global findings on sibship size and childhood asthma, rhinoconjunctivitis and eczema suggest at least two distinct trends. Inverse associations with older siblings (observations which prompted the 'hygiene hypothesis' for allergic disease) are mainly a phenomenon of more affluent countries, whereas greater severity of symptoms in larger families is globally more widespread.

Management of asthma in Benin: the challenge of loss to follow-up.

SETTING: An asthma pilot project in Benin. OBJECTIVE: To assess the implementation of standard case management of asthma at three referral centres and three primary care centres. METHODS: The project began with local adaptation of international asthma guidelines, followed by situation analysis, pre-intervention, training and intervention. The initial dosage of inhaled beclometasone was determined by asthma severity. Outcome of treatment was assessed annually, starting from one year after enrolment. RESULTS: Of 103 asthma patients identified during situation analysis, only 11 (11%) were prescribed inhaled corticosteroids. After health worker training, a total of 430 asthma patients were identified in 2008, of whom 273 (63.5%) returned after initial management with 7-day oral prednisolone. Of the 273 patients, 261 (95.6%) had persistent asthma, 231 (86.2%) had peak flow measurement variability of ≥20%, and 155 (56.8%) had had one or more unplanned visits to health facilities in the previous year. Outcome at one year evaluation was as follows: 63 (24.1%) had improved, 48 (18.4%) remained stable, 14 (5.4%) were worse and 136 (52.4%) were lost to follow-up. CONCLUSION: It is feasible to train health workers to manage asthma patients in a standardised manner. However, a high proportion of patients were lost to follow-up during treatment.

Allergic Rhinitis and its Impact on Asthma (ARIA): achievements in 10 years and future needs.

Allergic rhinitis (AR) and asthma represent global health problems for all age groups. Asthma and rhinitis frequently coexist in the same subjects. Allergic Rhinitis and its Impact on Asthma (ARIA) was initiated during a World Health Organization workshop in 1999 (published in 2001). ARIA has reclassified AR as mild/moderate-severe and intermittent/persistent. This classification closely reflects patients' needs and underlines the close relationship between rhinitis and asthma. Patients, clinicians, and other health care professionals are confronted with various treatment choices for the management of AR. This contributes to considerable variation in clinical practice, and worldwide, patients, clinicians, and other health care professionals are faced with uncertainty about the relative merits and downsides of the various treatment options. In its 2010 Revision, ARIA developed clinical practice guidelines for the management of AR and asthma comorbidities based on the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) system. ARIA is disseminated and implemented in more than 50 countries of the world. Ten years after the publication of the ARIA World Health Organization workshop report, it is important to make a summary of its achievements and identify the still unmet clinical, research, and implementation needs to strengthen the 2011 European Union Priority on allergy and asthma in children.

International consensus on (ICON) pediatric asthma.

Asthma is the most common chronic lower respiratory disease in childhood throughout the world. Several guidelines and/or consensus documents are available to support medical decisions on pediatric asthma. Although there is no doubt that the use of common systematic approaches for management can considerably improve outcomes, dissemination and implementation of these are still major challenges. Consequently, the International Collaboration in Asthma, Allergy and Immunology (iCAALL), recently formed by the EAACI, AAAAI, ACAAI, and WAO, has decided to propose an International Consensus on (ICON) Pediatric Asthma. The purpose of this document is to highlight the key messages that are common to many of the existing guidelines, while critically reviewing and commenting on any differences, thus providing a concise reference. The principles of pediatric asthma management are generally accepted. Overall, the treatment goal is disease control. To achieve this, patients and their parents should be educated to optimally manage the disease, in collaboration with healthcare professionals. Identification and avoidance of triggers is also of significant importance. Assessment and monitoring should be performed regularly to re-evaluate and fine-tune treatment. Pharmacotherapy is the cornerstone of treatment. The optimal use of medication can, in most cases, help patients control symptoms and reduce the risk for future morbidity. The management of exacerbations is a major consideration, independent of chronic treatment. There is a trend toward considering phenotype-specific treatment choices; however, this goal has not yet been achieved.

The challenges of replicating the methodology between Phases I and III of the ISAAC programme.

BACKGROUND: The International Study of Asthma and Allergies in Childhood (ISAAC) used standardised methods to examine symptom prevalence of asthma, rhinitis and eczema in adolescents and children between Phases I and III. Centres followed essential rules to ensure comparability of methodology, examined by a centralised data centre. METHODS: Centre reports (CRs) were compared for both phases and age groups. Methodological differences were categorised under major deviations (centres excluded), minor deviations (deviations identified in published tables) and very minor deviations (deviations not identified). RESULTS: There were 112 CRs for adolescents and 70 for children. Six centres for adolescents and four for children had major deviations and were excluded. Minor deviations (35 for adolescents and 20 for children) were identified in the publications. Very minor deviations (92 for adolescents and 51 for children) were not identified. The odds ratios for having any differences in methodology between phases with a change in Principal Investigator were 0.80 (95%CI 0.36-1.81) for adolescents and 0.91 (95%CI 0.32-2.62) for children. CONCLUSION: The majority of the centres replicated the ISAAC methodology to a high standard. Careful documentation of methodology using standardised tools with careful checks allows the full potential of studies such as ISAAC to be realised.

Asthma as a hidden disease in rural China: opportunities and challenges of standard case management.

OBJECTIVE: To assess the implementation of standard case management of asthma in Huaiyuan County, Anhui Province, China, in 2008. DESIGN: The study project began with the local adaptation of international asthma guidelines, followed by a situation analysis, pre-intervention study, training and intervention. Inhaled beclomethasone (US$15 for a 200-puff [250 µg/puff] inhaler) was prescribed for patients with persistent asthma. Treatment outcome was assessed at 1 year after enrolment. RESULTS: Asthma was never diagnosed in the participating facilities before the project was introduced. Of the 95 patients diagnosed with persistent asthma, 72 (75.8%) were prescribed inhaled beclomethasone, and 23 (24.2%) were not, because they either refused to use inhaled beclomethasone or did not return after the initial visit. At 1 year evaluation, of the 72 patients with persistent asthma treated with inhaled corticosteroids, 12 (16.7%) improved, 7 (9.7%) remained stable, none were worse, 1 (1.4%) had died, and 52 (72.2%) were lost to follow-up. Of the 52 patients lost to follow-up, 25 (48%) were found to be alive but had stopped using inhaled beclomethasone. CONCLUSION: Asthma is more frequently disabling and costly than had been recognised earlier. Asthma patients can be provided the care that they require, but affordable access to inhaled corticosteroids remains a challenge.

Global analysis of breast feeding and risk of symptoms of asthma, rhinoconjunctivitis and eczema in 6–7 year old children: ISAAC Phase Three

Background: In Phase Three of the International Study of Asthma and Allergies in Childhood (ISAAC), we investigated the relationship between breast feeding in infancy and symptoms of asthma, rhinoconjunctivitis and eczema in 6–7 year old children. Methods: Parents or guardians of 6–7 year old children completed written questionnaires on current symptoms of asthma, rhinoconjunctivitis and eczema, and on a range of possible asthma risk factors including a history of breast feeding ever. Prevalence odds ratios were estimated using logistic regression, adjusted for gender, region of the world, language, per capita gross national income, and other risk factors. Results: In all 206,453 children from 72 centres in 31 countries participated in the study. Reported breast feeding ever was not associated with current wheeze, with an odds ratio (adjusted for gender, region of the world, language, per capita gross national income, and factors encountered in infancy) of 0.99 (95% CI 0.92–1.05), current rhinoconjunctivitis (OR 1.00, 95% CI 0.93–1.08), current eczema (OR 1.05, 95% CI 0.97–1.12), or symptoms of severe asthma (OR 0.95, 95% CI 0.87–1.05). Breast feeding was however associated with a reduced risk of severe rhinoconjunctivitis (OR 0.74, 95% CI 0.59–0.94) and severe eczema (OR 0.79, 95% CI 0.66–0.95). Conclusions: There was no consistent association between breast feeding use in the first year of life and either a history or current symptoms of wheezing, rhinoconjunctivitis or eczema in 6–7 year old children, but possibly an effect on severe symptoms of the latter two conditions (AU)

Global analysis of breast feeding and risk of symptoms of asthma, rhinoconjunctivitis and eczema in 6-7 year old children: ISAAC Phase Three.

BACKGROUND: In Phase Three of the International Study of Asthma and Allergies in Childhood (ISAAC), we investigated the relationship between breast feeding in infancy and symptoms of asthma, rhinoconjunctivitis and eczema in 6-7 year old children. METHODS: Parents or guardians of 6-7 year old children completed written questionnaires on current symptoms of asthma, rhinoconjunctivitis and eczema, and on a range of possible asthma risk factors including a history of breast feeding ever. Prevalence odds ratios were estimated using logistic regression, adjusted for gender, region of the world, language, per capita gross national income, and other risk factors. RESULTS: In all 206,453 children from 72 centres in 31 countries participated in the study. Reported breast feeding ever was not associated with current wheeze, with an odds ratio (adjusted for gender, region of the world, language, per capita gross national income, and factors encountered in infancy) of 0.99 (95% CI 0.92-1.05), current rhinoconjunctivitis (OR 1.00, 95% CI 0.93-1.08), current eczema (OR 1.05, 95% CI 0.97-1.12), or symptoms of severe asthma (OR 0.95, 95% CI 0.87-1.05). Breast feeding was however associated with a reduced risk of severe rhinoconjunctivitis (OR 0.74, 95% CI 0.59-0.94) and severe eczema (OR 0.79, 95% CI 0.66-0.95). CONCLUSIONS: There was no consistent association between breast feeding use in the first year of life and either a history or current symptoms of wheezing, rhinoconjunctivitis or eczema in 6-7 year old children, but possibly an effect on severe symptoms of the latter two conditions.

Exposure to combustion of solid fuel and tuberculosis: a matched case-control study.

The present study was conducted in Benin to ascertain the association between exposure to combustion of solid fuel (coal and biomass) and tuberculosis. Cases were consecutive, sputum smear-positive tuberculosis patients never previously treated for tuberculosis for as long as 1 month. Two controls were selected from the neighbourhood of each case, matched by age and sex by a predefined procedure. A total of 200 new smear-positive cases and 400 neighbourhood controls were enrolled. In univariate analysis, using solid fuel for cooking (OR 1.7, 95% CI 1.1-2.8), ever smoking (OR 5.5, 95% CI 3.1-9.8), male sex (OR 10.5, 95% CI 1.6-71.1), daily use of alcoholic beverages (OR 2.3, 95% CI 1.2-4.2) and having a family member with tuberculosis in the previous 5 yrs (OR 30.5, 95% CI 10.8-85.8) were all significantly associated with tuberculosis cases. When all significant variables were entered into a multivariate conditional logistic regression model, the association between using solid fuel for cooking and tuberculosis cases was no longer statistically significant (adjusted OR 1.4, 95% CI 0.7-2.7). In conclusion, the association between exposure to combustion of solid fuel and tuberculosis was relatively weak and not statistically significant.

Prioritised research agenda for prevention and control of chronic respiratory diseases.

The 2008-2013 World Health Organization (WHO) action plan on noncommunicable diseases (NCDs) includes chronic respiratory diseases as one of its four priorities. Major chronic respiratory diseases (CRDs) include asthma and rhinitis, chronic obstructive pulmonary disease, occupational lung diseases, sleep-disordered breathing, pulmonary hypertension, bronchiectiasis and pulmonary interstitial diseases. A billion people suffer from chronic respiratory diseases, the majority being in developing countries. CRDs have major adverse effects on the life and disability of patients. Effective intervention plans can prevent and control CRDs, thus reducing morbidity and mortality. A prioritised research agenda should encapsulate all of these considerations in the frame of the global fight against NCDs. This requires both CRD-targeted interventions and transverse NCD programmes which include CRDs, with emphasis on health promotion and disease prevention.

Assessing allergic rhinitis in developing countries.

BACKGROUND: Allergic rhinitis (AR) affects 5% to 40% of the general population. In developing countries, AR is poorly documented and tracked due to a lack of appropriate diagnostic tools. OBJECTIVE: 1) To validate a questionnaire standardised in industrialised countries to ascertain AR, the Score For Allergic Rhinitis (SFAR), in developing countries; 2) to better understand AR prevalence previously reported from developing countries by comparing results from the SFAR and the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaires. METHODS: Six African countries were selected for their climates. In each country, 70 individuals with and 30 without nasal symptoms filled out the SFAR and the ISAAC questionnaires. Skin prick tests (SPTs) for allergens were performed by the physician if necessary. RESULTS: The SFAR presented a close match with the gold standard (the physician's diagnosis of AR backed up by SPT where necessary) in terms of various performance parameters. In particular, it showed high sensitivity (0.84) and specificity (0.81). Compared to the ISAAC questionnaire, the SFAR had greater sensitivity and equal specificity. CONCLUSIONS: In the absence of a medical visit, the SFAR is a useful standardised screening instrument for the collection of information needed for the identification of AR in developing countries.

Isoniazid preventive therapy for people living with HIV: public health challenges and implementation issues.

Isoniazid preventive therapy (IPT) is recognised as an important component of collaborative tuberculosis (TB) and human immunodeficiency virus (HIV) activities to reduce the burden of TB in people living with HIV (PLHIV). However, there has been little in the way of IPT implementation at country level. This failure has resulted in a recent call to arms under the banner title of the 'Three I's' (infection control to prevent nosocomial transmission of TB in health care settings, intensified TB case finding and IPT). In this paper, we review the background of IPT. We then discuss the important challenges of IPT in PLHIV, namely responsibility and accountability for the implementation, identification of latent TB infection, exclusion of active TB and prevention of isoniazid resistance, length of treatment and duration of protective efficacy. We also highlight several research questions that currently remain unanswered. We finally offer practical suggestions about how to scale up IPT in the field, including the need to integrate IPT into a package of care for PLHIV, the setting up of operational projects with the philosophy of 'learning while doing', the development of flow charts for eligibility for IPT, the development and implementation of care prior to antiretroviral treatment, and finally issues around procurement, distribution, monitoring and evaluation. We support the implementation of IPT, but only if it is done in a safe and structured way. There is a definite risk that 'sloppy' IPT will be inefficient and, worse, could lead to the development of multidrug-resistant TB, and this must be avoided at all costs.