SARJ Vol 23, No 4 (2017)

South African

Respiratory Journal VOLUME 23

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NUMBER 4

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DECEMBER 2017

OFFICIAL JOURNAL OF THE S.A. THORACIC SOCIETY ISSN 2304-0017

S4

S4

SOUTH AFRICAN

RESPIRATORY JOURNAL VOLUME 23 | NUMBER 4 | DECEMBER 2017

CONTENTS EDITORIAL 94

96

Recurrent active tuberculosis in HIV-infected persons: Throwing out the baby with the bathwater!

A Esmail, K Dheda Identifying the magnitude of the problem is the first step R van Zyl-Smit

CASE REPORT 97

Suspected mushroom worker’s lung – a case report from South Africa D Fakey, M Suleman

REVIEW 100 A review of pulmonary sarcoidosis M Mitha

ORIGINAL RESEARCH 106 Predictors and short-term outcomes of recurrent pulmonary tuberculosis in Kampala, Uganda: A cohort study N Kalema, C Lindan, D Glidden, A Katamba, A Alfred, W Katagira, P Byanyima, E Musisi, S Ingvar, J Zawedde, C Yoon, I Ayakaka, J L Davis, L Huang, W Worodria, A Cattamanchi 113 Knowledge of the health consequences of tobacco smoking among Nigerian smokers: A secondary analysis of the Global Tobacco Survey B O Adeniyi, O S Ilesanmi, O M Babasola, B I Awokola, A O Kareem, D Obaseki, G E Erhabor 122

BREATH-TAKING NEWS

124

PRODUCT NEWS

127

SATS NEWS CITATION

130 Professor Abolade Ajani Awotedu P O Oluboyo

The Editor The South African Respiratory Journal PO Box 13725, Mowbray, 7705 Tel. 021 650 3050 | Fax: 021 650 2610 | Email: sarj@iafrica.com The views expressed in individual articles and advertising material are the personal views of the authors and are not necessarily shared by the editors, the advertisers or the publishers. No articles may be reproduced without the written consent of the publishers.

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EDITORIAL

Recurrent active tuberculosis in HIV-infected persons: Throwing out the baby with the bathwater!

Of the infectious diseases, tuberculosis (TB) is now the biggest killer worldwide. In 2015, more than 10 million individuals were estimated to have contracted active TB globally.[1] Not surprisingly, Africa bears a substantial TB burden given that HIV co-infection, poverty and overcrowding, malnutrition, indoor air pollution, and smoking are common.[2,3] TB is now the most common cause of death in South Africa (SA), which has the highest incidence of TB among the 22 highburden countries.[1] In HIV-uninfected persons, it is estimated that the risk of active TB increases twofold following an initial episode of active TB.[4] Furthermore, data from SA have shown that the incidence of recurrent TB (active TB in those previously treated for active TB) was 4 times higher than in those with newly diagnosed active TB (no previous treatment for active TB).[5,6] This risk is extraordinarily higher in HIV-infected individuals, where a recurrence rate of 24 per 100 person-years has been reported, compared with the rate of 4.7 per 100 person-years in their HIV-uninfected counterparts.[4] In this issue of the journal, Kalema et al.[7] highlight the strikingly high prevalence of recurrent active TB in HIV-infected individuals (defined as active TB presenting more than 2 years after the previous episode, thus likely excluding cases of relapse).[5] The prevalence of recurrent TB described in this study is considerably higher than in previous studies from sub-Saharan Africa (35% v. ~20%, respectively).[4-6] Given this high burden of disease in a large at-risk population, and the considerable associated morbidity and mortality, the question arises: what can be done to prevent recurrent TB? The high prevalence of recurrent TB in this study likely reflects high levels of TB transmission. Therefore, interruption of TB transmission is central to addressing the issues highlighted by Kalema et al.[7] A good starting point would be to ensure adherence to anti-TB treatment, as rates of TB treatment completion in Africa remain low.[8] Failure to complete treatment is associated with high rates of recurrent disease, which perpetuates transmission, especially when there is HIV coinfection.[9] Furthermore, it is estimated that >40% of TB in Africa remains unreported or undiagnosed in the community – these cases are sentinels for transmission.[8] This ‘diagnostic gap’ may be due to inaccessibility to healthcare facilities, absence of TB symptoms that are severe enough to require medical attention, paucibacilliary disease, psychosocial factors, and the flawed public health strategy of passive case-finding. This deficiency could be addressed through costeffective community-based active case-finding strategies. We recently published the first randomised controlled trial (RCT) evaluating the role of new molecular tools (GeneXpert MTB/RIF) for active case finding – the findings indicated that active case-finding was feasible using a mobile van and almost doubled the proportion of patients initiating treatment compared with smear microscopy. [10] There is also an urgent need to develop a low-cost, non-sputum-based, accurate, field-friendly point-of-care diagnostic tool for TB detection. This would facilitate community-based active finding, thereby finding ‘open’ cases early and interrupting transmission. Another aspect that requires targeting is pre-treatment loss to follow-up. These are

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microbiologically proven cases that never return to initiate treatment – they make up 20 - 40% of diagnosed cases in some settings.[11,12] These patients are diagnosed with TB but never return to seek treatment, which aids further transmission.

Botha et al.[11] and Squire et al. [12] also raised an important question about the utility and efficacy of secondary prophylaxis in patients with previous active TB residing in areas with a high force of infection, especially if they are HIV-infected. There are scanty data about the efficacy and risk-benefit ratio of secondary prophylaxis in HIV-uninfected persons, i.e. prophylaxis given to individuals who have completed treatment for active TB. However, in HIV-infected persons, a recent systematic review demonstrated a substantial reduction of ~60% in the incidence of recurrent TB when using isoniazid as preventive therapy.[13] Therefore, for the majority of the patients included in this study (HIV co-infection rate of ~70%), secondary prevention for TB could have been beneficial. Current WHO guidelines recommend TB preventive therapy for all patients infected with HIV irrespective of the CD4 counts, and in whom active TB has been excluded.[13,14] HIV-infected patients who were previously treated for active TB are likely to derive an even greater benefit from TB preventive therapy compared with patients receiving primary prevention for TB.[6,13] Despite the high recurrence risk in HIV-uninfected patients,[4] these patients do not currently receive TB preventive therapy in routine care, as the evidence base for this intervention is weak. Hence, there is a need for additional studies in this area to quantify the benefit-to-harm ratio. The study by Kalema et al.[7] highlights this important deficiency.

TB preventive therapy rates (whether for primary or secondary prophylaxis) in HIV-infected individuals in Uganda, and indeed in the rest of the African continent, remain low overall.[15,16] The reasons for the low uptake of TB preventive therapy include the perception of short-term efficacy of isoniazid preventive therapy (IPT), lack of infrastructure to support tuberculin skin testing (TST) required for risk stratification (although not expressly mandated by the guidelines), and the erroneous perception of healthcare workers that patients with advanced HIV, such as those included in the current study (median CD4 count of 20 cells/µL), are less likely to benefit from IPT. Furthermore, the optimal duration for TB preventive therapy in high-transmission settings is currently unclear, and should probably also be individualised.[9,15,18-20] Therefore, provision of secondary IPT in a high-burden setting, such as the setting described by Kalema et al.,[7] should be individualised considering CD4 count, risk of hepatotoxicity, likely adherence to treatment, drug-drug interactions, and potential benefit v. harm.

In conclusion, Kalema et al.[7] have highlighted the high prevalence of recurrent TB in Kampala, Uganda. Addressing this important but neglected entity will require strengthening of healthcare systems to ensure high TB treatment completion rates. TB preventive therapy in HIV co-infected persons should be implemented as recommended in the WHO guidelines. [14] In general, the utility of pulsed preventive

EDITORIAL therapy is currently under study and may have higher efficacy with better compliance. It is currently unclear whether HIV-uninfected patients from high-burden settings would benefit from secondary prophylaxis, what the optimal duration of therapy should be, and what regimens should be used. In the meanwhile, we suggest that treatment of these individuals should be individualised. The search for the elusive holy grail of mycobacterial diagnostics, i.e. a low-cost, non-sputumbased, field-friendly test for TB, continues. Omitting targeted health interventions and follow-up, including secondary prophylaxis, in HIVinfected patients after they have completed TB treatment is counterintuitive (especially in patients with advanced-stage HIV), erroneously dismissive, and akin to ‘throwing out the baby with the bath water’.

Aliasgar Esmail, Keertan Dheda Lung Infection and Immunity Unit, Department of Medicine, Division of Pulmonology and UCT Lung Institute, University of Cape Town and Groote Schuur Hospital, Observatory, Cape Town, South Africa a.esmail@uct.ac.za

1. World Health Organization. Global Tuberculosis Report 2016. Geneva: WHO, 2016. http://apps.who.int/medicinedocs/documents/s23098en/s23098en.pdf (accessed 20 October 2017).

2. Dheda K, Barry CE, Maartens G. Tuberculosis. Lancet 2016;387(10024):1211-1126. https://doi.org/10.1016/s0140-6736(15)00151-8 3. Dheda K, Gumbo T, Maartens G, et al. The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis. Lancet Respir Med 2017;5(4):321-338. https://doi.org/10.1016/ s2213-2600(14)70031-1 4. Wood R, Lawn SD, Caldwell J, Kaplan R, Middelkoop K, Bekker LG. Burden of new and recurrent tuberculosis in a major South African city stratified by age and HIVstatus. PLoS One 2011;6(10):e25098. https://doi.org/10.1371/journal.pone.0025098 5. Glynn JR, Murray J, Bester A, Nelson G, Shearer S, Sonnenberg P. High rates of recurrence in HIV-infected and HIV-uninfected patients with tuberculosis. J Infect Dis 2010;201(5):704-711. https://doi.org/10.1086/650529 6. Verver S, Warren RM, Beyers N, et al. Rate of reinfection tuberculosis after successful treatment is higher than rate of new tuberculosis. Am J Respir Crit Care Med 2005;171(12):1430-1435. https://doi.org/10.1164/rccm.200409-1200oc 7. Kalema N, Lindan C, Glidden D, et al. Predictors and short-term outcomes of recurrent pulmonary tuberculosis, Uganda: A cohort study. S Afr Respir J 2017; 23(4):106-112. https://doi.org/10.7196/SARJ.2017.v23i4.173

8. WHO. Global Tuberculosis Report. Geneva: WHO, 2015.

9. Golub JE, Durovni B, King BS, et al. Recurrent tuberculosis in HIV-infected patients in Rio de Janeiro, Brazil. AIDS 2008;22(18):2527-2533. https://doi.org/10.1097/ QAD.0b013e328311ac4e 10. Calligaro GL, Zijenah LS, Peter JG, et al. Effect of new tuberculosis diagnostic technologies on community-based intensified case finding: A multicentre randomised controlled trial. Lancet Infect Dis 2017;17(4):441-450. https://doi.org/10.1016/s14733099(16)30384-x 11. Botha E, Den Boon S, Verver S, et al. Initial default from tuberculosis treatment: How often does it happen and what are the reasons? Int J Tuberculosis Lung Dis 2008;12(7):820-823.

12. Squire SB, Belaye AK, Kashoti A, et al. 'Lost' smear-positive pulmonary tuberculosis cases: Where are they and why did we lose them? Int J Tuberc Lung Dis 2005;9(1):25-31.

13. Bruins WS, van Leth F. Effect of secondary preventive therapy on recurrence of tuberculosis in HIV-infected individuals: A systematic review. Infect Dis 2017;49(3):161-169. https://doi.org/10.1080/23744235.2016.1262059 14. World Health Organization. Guidelines for intensified tuberculosis case finding and isoniazid preventive therapy for people living with HIV in resource constrained settings. Geneva: WHO, 2012.

15. Group TAS, Danel C, Moh R, et al. A trial of early antiretrovirals and isoniazid preventive therapy in Africa. N Engl J Med 2015;373(9):808-822. https://doi/ org/10.1056/NEJMoa1507198 16. Mindachew M, Deribew A, Memiah P, Biadgilign S. Perceived barriers to the implementation of isoniazid preventive therapy for people living with HIV in resource constrained settings: A qualitative study. Pan Afr Med J 2014;17:26. https://doi. org/10.11604/pamj.2014.17.26.2641 17. Teklay G, Teklu T, Legesse B, Tedla K, Klinkenberg E. Barriers in the implementation of isoniazid preventive therapy for people living with HIV in Northern Ethiopia: A mixed quantitative and qualitative study. BMC Public Health 2016;16(1):840. https:// doi.org/10.1186/s12889-016-3525-8 18. Semu M, Fenta TG, Medhin G, Assefa D. Effectiveness of isoniazid preventative therapy in reducing incidence of active tuberculosis among people living with HIV/ AIDS in public health facilities of Addis Ababa, Ethiopia: A historical cohort study.

BMC Infect Dis 2017;17(1):5. https://doi.org/10.1186/s12879-016-2109-7 19. Churchyard GJ, Fielding K, Charalambous S, et al. Efficacy of secondary isoniazid preventive therapy among HIV-infected Southern Africans: Time to change policy?

AIDS 2003;17(14):2063-2070. https://doi.org/10.1097/00002030-200309260-00007 20. Fitzgerald DW, Desvarieux M, Severe P, Joseph P, Johnson WD Jr, Pape JW. Effect of post-treatment isoniazid on prevention of recurrent tuberculosis in HIV-1-infected individuals: A randomised trial. Lancet 2000;356(9240):1470-1474. https://doi. org/10.1016/s0140-6736(00)02870-1

S Afr Respir J 2017;23(4):94-95. DOI:10.7196/SARJ.2017.v23i4.194

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EDITORIAL

Identifying the magnitude of the problem is the first step There is an aphorism in clinical trials: ‘if it is not documented it did not happen’. In clinical practice this translates into ‘if you don’t know about a problem there is nothing you can do about it’. In this edition of the SARJ, Adeniyi et al.[1] report on a secondary analysis of the Global Adult Tobacco Survey data regarding smoking in Nigeria.

In this small sample of adult smokers, some important issues were identified. Smoking, as expected in a developing country, showed a male predominance and, given the high rural sample smoking rates, were low (<5%). What came out clearly in this analysis, was the low awareness of the harms of smoking; for example, only one-third of participants knew that smoking could cause mouth, bladder or stomach cancer. Another striking finding was that only 48% of rural dwellers knew that smoking caused lung cancer compared with 71.6% of urban dwellers.

In a country like South Africa (SA), we would assume that all smokers would know about the harms of smoking, given the extensive anti-smoking campaigns and basic health education provided at schools. The challenge is thus not one of educating about the risks, but of emphasising the benefits of quitting using the standard 5A’s approach as outlined in the SA Thoracic Society’s smoking cessation guidelines.[2] The other key consideration in SA is the wide variance in smoking rates across the country. The recent SA Demographic and Health Survey 2016[3] reported overall smoking prevalence rates of 6% and 37% for women and men, respectively. In the Western Cape, however, 25% of women and 43% of men smoke compared with Limpopo Province, where only 1.3% of women and 26% of men smoke. Thus, if a targeted smoking cessation intervention were to be planned, the highest potential returns would be in the Western Cape rather than Limpopo.

In Nigeria, it would appear that a large amount of basic tobacco education is required to first inform smokers of the health risks of tobacco smoking before any attempts at a smoking cessation intervention should be undertaken. Remarkably, this is not unique to Nigeria, as in a country such as China, although 73% knew smoking caused lung cancer, only 20% knew smoking could cause stroke.[4] The path to successfully giving up smoking always starts

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with the knowledge that it is bad for you. The chemical ‘grip’ of the nicotine addiction, which is accompanied by withdrawal symptoms on smoking cessation, frequently requires a mental fight and a firm resolution to put the benefits of quitting ahead of the relief a ‘quick puff ’ would bring.

The first step towards tackling a major modifiable risk factor like smoking is to quantify the prevalence of and contributing factors to ongoing smoking. Subsequently, a targeted, locally appropriate approach to cessation is required. A tailored strategy that is cognisant of the socioeconomic demographics, level of education and basic awareness/acceptance of the harms of smoking is essential if we wish to have the greatest impact in any given community. Understanding the scale of smoking habits and attitudes of smokers is not a guarantee for success, but not knowing is highly likely to result in failed or misguided interventions, however well-meaning they may be.

Richard van Zyl-Smit Head: Lung Clinical Research Unit, University of Cape Town Lung Institute, Division of Pulmonology and Department of Medicine, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa richard.vanzyl-smit@uct.ac.za

1. Adeniyi BO, Ilasanmi OS, Babasola OM, et al. Health consequences of tobacco smoking among Nigerian smokers: A national survey. S Afr Respir J 2017;23(4):113119. https://doi.org/10.7196/sarj.178 2. Van Zyl-Smit RN, Allwood B, Stickells D, et al. South African tobacco smoking cessation clinical practice guideline. S Afr Med J 2013;103(11):869-876. https://doi. org/10.7196/samj.7484 3. Statistics South Africa (SSA). South African Demographic and Health Survery 2016 Key indicators report. Pretoria: SSA, 2017.

4. Yang J, Hammond D, Driezen P, Fong GT, Jiang Y. Health knowledge and perception of risks among Chinese smokers and non-smokers: Findings from the Wave 1 ITC China Survey. Tob Control 2010;19(Suppl 2):i18-i23. https://doi.org/10.1136/ tc.2009.029710

S Afr Respir J 2017;23(4):96. DOI:10.7196/SARJ.2017.v23i4.186

CASE REPORT

Suspected mushroom worker’s lung – a case report from South Africa D Fakey, MB ChB, FCP; M Suleman, MD, FCCP Department of Pulmonology and Critical Care, Inkosi Albert Luthuli Hospital, Nelson R Mandela School of Medicine, College of Health Sciences, Durban, University of KwaZulu-Natal, South Africa Corresponding author: D Fakey (dilshaadf@gmail.com)

Mushroom worker’s lung (MWL) has been described in workers exposed to mushroom spores or to inhaled antigens (thermophilic actinomycetes) from compost. South Africa is listed as one of the biggest exporters of mushrooms worldwide, yet the incidence of MWL locally has not been documented. We highlight a case of a delayed presentation of suspected MWL owing to non-recognition of the condition and the subsequent improvement in symptoms upon avoidance of the offending antigen. A high index of suspicion is required to ensure that MWL, associated with significant morbidity, is not missed.

S Afr Respir J 2017;23(4):97-99. DOI:10.7196/SARJ.2017.v23i4.167

Occupational hypersensitivity pneumonitis (OHP) is a non-IgEmediated allergic reaction to a host of organic materials or lowmolecular-weight agents inhaled at the workplace. There are more than 200 antigens known to cause this condition, which can be categorised into bacteria, fungi, enzymes and animal/insect proteins, plant proteins, low-molecular-weight chemicals or metals.[1] Patients presenting with respiratory symptoms are commonly questioned about a farming history or exposure to birds to assess occupational or other allergenic exposure, but exposure to other agents, such as mushrooms, is often not enquired about.

Mushroom worker's lung (MWL) has been described in workers exposed to mushroom spores or to inhaled antigens (thermophilic actinomycetes) from compost.

Mushrooms propagate by disseminating millions of microscopic spores that form in the gills or underneath the mushroom's cap.

These spores are either spread by the wind or by animal feeding.[2] Case reports have been published attributing the aetiology of MWL more commonly to the inhalation of spores of the shiitake mushroom (Lentinus edodes),[3] bunashimeji (Hypsizigus marmoreus),[4] Pholiota nameko mushrooms[5] and oyster mushrooms (Pleurotus osteatus).[6] Compared with oyster mushrooms and shiitake mushrooms, button mushrooms (Agaricus bisporus) are less likely to release spores as harvesting occurs before the caps open, a process that is associated with spore release.[6,7] Mushrooms are produced commercially in Europe, the British Isles, the Far East, North America, Australia and South Africa (SA).

In 2009, SA was listed as one of the top eleven mushroom exporters worldwide,[8] and yet, to our knowledge, this is the first case report describing MWL in SA. We present a case of an unusually late presentation of MWL owing to a diagnostic delay of several years prior to the patient’s referral.

Case report

A 29-year-old man, who had been employed at a local mushroom farm since 2008, was referred to our pulmonology unit with a history

of progressive dyspnoea and a chronic productive cough for the past 3 years. His duties at work included planting and harvesting button mushrooms within an enclosed area, as well as making and packing mushroom compost. Although protective respiratory equipment was available to him, he did not use this consistently. Prior to his referral, the management of his symptoms had included the prescription of multiple courses of antibiotics, empirical treatment for tuberculosis (TB) in 2014, and commencement of inhaler therapy for asthma with intermittent salbutamol via a metered dose inhaler (MDI), as well as fluticasone/salmeterol via an MDI twice daily. None of these interventions had alleviated his symptoms of dyspnoea or cough.

He also complained of weight loss over the 3 years but was unable to quantify his total weight loss. There was no history of fever or night sweats. He was a non-smoker and had tested negative for HIV previously.

Clinically, he had clubbing of his fingers and toes, and was plethoric.

He appeared comfortable with a respiratory rate of 18 breaths per minute, although his oxygen saturation measured by pulse oximetry was 88% on room air. His lung fields were clear and the pulmonary component of the second heart sound was accentuated. He had no features of decompensated cardiac failure. His haemoglobin (Hb) on admission was 19 g/dL with a haematocrit of 59% and a red cell count of 6.3 x 109/L, correcting to an Hb of 15.3 g/dL after venesection.

He had a normal white cell count of 4.43 × 109/L, normal eosinophil count, and normal inflammatory markers with a procalcitonin value of <0.5 μg/L. Serum precipitins to Aspergillus fumigatus and other thermophilic actinomycetes were not available at our facility.

His chest radiograph showed a normal cardiothoracic ratio with increased reticular shadowing bilaterally, ill-defined air space opacification of both lung fields, and a prominent pulmonary conus (Fig. 1). Pulmonary function testing showed an obstructive picture with a forced vital capacity (FVC) of 3.1 L (65% of the predicted value) and a forced expiratory volume in 1 second (FEV1) of 1.58 L (39% of the predicted value), with an FEV1/FVC of 50.9%. Reversibility of 240 mL and 15% was noted post bronchodilator use. The patient’s

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CASE REPORT

Fig. 2. High-resolution computed tomography chest scan (axial view) showing mosaic attenuation.

Fig. 1. Admission chest radiograph showing increased reticular shadowing and bilateral ill-defined opacities. diffusing capacity for carbon monoxide was reduced at 37% of the predicted value when corrected for alveolar volume. Whole-body plethysmography showed a residual volume of 203% with a total lung capacity (TLC) of 104% predicted, which was suggestive of air trapping.

A high-resolution computed tomography (HRCT) scan of his chest showed bilateral upper-lobe fibrotic changes, diffuse groundglass opacities bilaterally with mosaic attenuation in keeping with air trapping. There were bilateral upper-lobe, subpleural, subcentimetre, perilymphatic, non-calcified nodules as well as interlobular septal thickening and intralobular interstitial thickening noted diffusely (Fig. 2). An echocardiogram was ordered which showed a dilated right atrium (47 mm) and right ventricle (48 mm) with an elevated pulmonary artery systolic pressure of 45 mmHg. His ejection fraction was also moderately impaired at 45%.

He underwent an uneventful flexible bronchoscopy with transbronchial biopsy. Both the sputum and bronchoalveolar lavage (BAL) specimens were negative for infective pathogens. Differential cell counts on BAL samples are not available at our facility. His histology results were pending and the patient was discharged with a prescription for domiciliary oxygen and a follow-up date within 2 weeks to review the results, after which a decision regarding medical therapy would be considered. At the time of discharge, he noted improvement in his symptoms and his oxygen saturation measured by pulse oximetry had improved to 92% on room air. He was advised to avoid returning to work until he had been reviewed.

At his follow-up visit, the patient noted worsening in his symptoms with recurrence of dyspnoea and a cough. He had returned to work despite our recommendation and had effectively conducted an unintentional provocation test. His oxygen saturation measured by pulse oximetry had declined to 78% at that visit, with fine crackles noted posteriorly. The bronchoscopic biopsy results were reviewed, which showed alveolar septal walls expanded by fibrosis and

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interstitial inflammation composed of lymphocytes, histiocytes and plasma cells. There were no eosinophils, foreign body giant cells or granulomas. These were nonspecific features of interstitial pneumonia and fibrosis and although these were not sufficient to confirm hypersensitivity pneumonitis (HP), they were consistent with the overall picture. His clinical improvement while away from work and subsequent worsening on return to the farm was also highly suggestive of OHP. He was commenced on oral prednisone at a dose of 30 mg once daily (0.5 mg/kg) and strongly advised not to return to work.

On subsequent review he had shown further improvement in his symptoms with an oxygen saturation measured by pulse oximetry of 95% on room air one month later. Pulmonary function testing has shown an improvement in his FVC to 4.26 L (90% of the predicted value) and FEV1 2.28 (57% of the predicted value). At the time of submission, his steroids were being tapered over a period of 3 to 6 months and his case was referred to occupational health for intervention.

Discussion

A review of this case highlighted a few key learning points. This patient was symptomatic for a prolonged period, with chronic hypoxia and resultant secondary polycythaemia, which put him at a greater risk for thrombotic events and possible morbidity. He had been initiated empirically on anti-tuberculosis therapy without microbiological evidence, which was reasonable in the endemic TB region that we live in. However, his failure to respond to therapy should have prompted a search for an alternative cause of his symptoms.

Similarly, the lack of response to asthma treatment and absence of other features to support the diagnosis makes it more likely that his airflow obstruction was a feature of HP rather than a true manifestation of asthma. Approximately 20 - 40% of patients with HP may have nonspecific airway hyper-reactivity, with 5 - 10% of these patients diagnosed with concomitant asthma. The bronchial hyper-reactivity seen in patients with HP may be secondary to bronchiolitis.[1,2] Furthermore, the delay in recognising the condition allowed him to have repetitive exposure to the offending antigen. The chronicity of his symptoms with features of fibrosis evident on his HRCT chest scan suggested longstanding exposure.

CASE REPORT This case draws attention to the diagnostic challenges associated with this condition. There have been many proposed diagnostic criteria for HP. The most commonly utilised criteria, published by Schuyler and Cormier[9] have not been validated. These criteria include the presence of compatible symptoms, evidence of exposure to the offending antigen, symptoms correlating with recurrent antigen exposure, consistent findings on chest imaging, a lymphocyte predominance on BAL fluid and compatible histopathological features.

Inhalational challenges have been utilised in the appropriate setting when alternative procedures have failed to identify the diagnosis of hypersensitivity or causal exposure with accuracy, or when the suspected precipitating agent has not been described as causing OHP. [10] We postulate that the lack of documentation of cases of MWL in SA is due to this condition being under-recognised or under-reported and further steps should be taken to assess all workers at mushroomcultivating farms for respiratory symptoms. Farm managers should also ensure that protective respiratory equipment is available and consistently utilised. Ultimately, a high index of suspicion is required and a thorough occupational and exposure history should be obtained in any patient with dyspnoea of unknown cause to ensure that a treatable condition associated with significant morbidity is not overlooked.

Acknowledgements. None.

Author contributions. Both authors wrote the manuscript and approved the final version.

Funding. None.

Conflicts of interest. None.

1. Kurup VP, Zacharisen MC, Fink JN. Hypersensitivity pneumonitis. Indian J Chest Dis Allied Sci 2006;48(2):115.

2. Steinman HA. f212 Mushroom (Champignon). http://www.phadia.com/en/products/ allergy-testing-products/immunocap-allergen-information/food-of-plant-origin/ miscellaneous/mushroom-champignon (accessed 14 May 2017).

3. Murakami M, Kawabe K, Hojo S, et al. Decreased pulmonary perfusion in hypersensitivity pneumonitis caused by Shiitake mushroom spores. J Intern Med 1997;241(1):85-88. https://doi.org/10.1046/j.1365-2796.1997.83103000.x 4. Tanaka H, Sugawara H, Saikai T, Tsunematsu K, Takahashi H, Abe S. Mushroom workerâ&#x20AC;&#x2122;s lung caused by spores of Hypsizigus marmoreus (Bunashimeji): Elevated serum surfactant protein D levels. Chest 2000;118(5):1506-1509. https://doi. org/10.1378/chest.118.5.1506 5. Ishii M, Kikuchi A, Kudoh K, et al. Hypersensitivity pneumonitis induced by inhalation of mushroom (Pholiota nameko) spores. Intern Med 1994;33(11):683-685. https://doi.org/10.2169/internalmedicine.33.683 6. Mori S, Nakagawa-Yoshida K, Tsuchihashi H, et al. Mushroom worker's lung resulting from indoor cultivation of Pleurotus osteatus. Occup Med 1998;48(7):465-468. https:// doi.org/10.1093/occmed/48.7.465 7. Helbling A, Brander KA, Horner WE, et al. Allergy to Basidiomycetes. In: Breitenbach M, Crameri R, Lehrer SB, eds. Fungal Allergy and Pathogenicity. Basel: Karger, 2002;81:31-37.

8. Department of Agriculture, Forestry and Fisheries (SA). International Tradeprobe No. 32, March 2011. Arcadia: National Agriculture Marketing Council. http://www.namc. co.za/upload/trade_probe/NAMC-DAFF%20TradeProbe%20(No%2032-March%20 11).pdf (accessed 14 May 2017).

9. Schuyler M, Cormier Y. The diagnosis of hypersensitivity pneumonitis. Chest 1997;111(3):534-536. https://doi.org/10.1378/chest.111.3.534 10. Quirce S, Vandenplas O, Campo P, et al. Occupational hypersensitivity pneumonitis: An EAACI position paper. Allergy 2016;71(6):765-779. https://doi.org/10.1111/ all.12866

Accepted 8 August 2017.

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REVIEW

A review of pulmonary sarcoidosis M Mitha, MB ChB, Dip HIV Man (SA), FCP (SA), MSc (Epi) Department of Pulmonology and Critical Care, Inkosi Albert Luthuli Central Hospital, Durban, South Africa Corresponding author: M Mitha (mohmitha@gmail.com)

Sarcoidosis is an inflammatory disease of unknown aetiology that affects multiple organs, with a predilection for the respiratory system.

The defining characteristic is the presence of non-caseating granulomas on histopathology. It is a disease that can mimic several infectious and non-infectious disorders, and implementation of treatment is often delayed if the diagnosis is not suspected.

S Afr Respir J 2017;23(4):100-104. DOI:10.7196/SARJ.2017.v23i4.168

History and evolution

Jonathan Hutchinson initially described sarcoidosis as ‘Mortimers malady’ in 1869, and thought it to be a dermatological condition after reviewing two patients who had multiple plaques on their body, which differed from tuberculosis (TB) and systemic lupus erythematosus.

A French dermatologist, Besnier, then coined the term ‘lupus pernio’ several years later after describing a patient with purplish swellings on the nose, ears and fingers. At the turn of the 20th century the term ‘sarcoid’ was conceived after the Norwegian dermatologist, Caesar Boeck, thought the lesions resembled benign sarcoma. He was the first physician to demonstrate the granulomas on histology as well as highlight the multisystem nature of the disease. The disease’s multisystem nature became more apparent with the classification of two distinct syndromes: Heerfordt syndrome, which was characterised by cutaneous lesions, uveitis, parotid and submaxillary salivary gland enlargement and cranial nerve palsies; and Löfgren syndrome, which was characterised by fever, bilateral hilar lymphadenopathy, polyarthritis and erythema nodosum.[1] The disease was then proven by a test developed by Angsar Kveim that was improved by Louis Siltzbach and is therefore known as the Kveim-Siltzbach test.[1,2] It involves injecting crude pieces of sarcoid tissue intradermally which results in papules several weeks later in patients with sarcoidosis, but not in controls.[2]

Epidemiology

The incidence of the disease in the northern hemisphere is 5 - 40 per 100 000. The disease is almost 4-fold more likely to affect African Americans compared with white Americans. The disease also tends to affect females in a 2:1 ratio compared with males.[3,4] It occurs in the 2nd and 3rd decade of life, however, studies in Scandinavia have demonstrated a bimodal peak with the disease also occurring in the 4th to 6th decade.[5] It has also been demonstrated that African Americans have a later age of onset, being affected in the 4th decade.[4] A few studies have been conducted in South Africa (SA), albeit on a small series and have demonstrated similar findings with predominance in Africans.

However, Benatar et al.[6] reported conflicting data from a study in Cape Town, which showed a 1:1 female to male ratio in black

100 SARJ VOL. 23 NO. 4 2017

Africans; however, it should be noted that they had a total of 25 black African patients in the study. A study conducted in Johannesburg by Smith et al.[7] showed a ratio of 1:1 in the white population. Morar et al.[8] showed a preponderance among Africans by race and among females by gender.

Aetiology and pathogenesis

The aetiology of the disease is ever-evolving and still not well understood. It is an interplay of genetic, environmental, host immunological and, possibly, infectious factors. The hypothesis on the development of the granuloma is that it is due to an exaggerated inflammatory response to a partially soluble or insoluble antigen which walls off the agent resulting in granuloma formation. This probably occurs to prevent injury to the surrounding tissue.[9] The granulomas are composed of tissue macrophages, activated monocytes, T and B lymphocytes, fibroblasts, and other matrix-associated cells.

There is a 5-fold increased risk of sarcoidosis among first-degree relatives and it was also shown that there is a higher concordance rate among monozygotic compared with dizygotic twins.[10,11] There are also certain major histocompatibilty complexes associated with specific phenotypes with different human leukocyte antigen genes between acute, chronic active, remitting and extra pulmonary sarcoidosis.[12,13] Sarcoidosis has shown seasonal clustering, with more incident cases in the latter part of winter and the beginning of spring in both the northern and southern hemispheres.[14] The disease is more prevalent in certain occupations, with a higher incidence in military and agricultural workers.[15] It was noted that there was a higher incidence of sarcoidosis among first responders to the 2001 World Trade Centre attacks in New York City.[16] It is intriguing to note that smoking is a protective factor against sarcoidosis.[17] The role of infection is not as well understood in the pathogenesis and aetiology. A study in Japan had revealed the presence of Propionobacterium acnes in a small proportion of patients with lung and lymph node biopsies, but it is now thought to be a latent organism.[18] There is no overt link between Mycobacterium tuberculosis and sarcoidosis, however, Mycobacterium genes, such as protein mycobacterial catalase-peroxidase (mKatG), have been found in sarcoid samples which had identical physicochemical

REVIEW properties to the Kveim-Siltzbach reagent and which induced a similar T cell response.[19]

Table 1. Scadding staging based on CXR Stage

CXR

Pulmonary sarcoidosis

0

Normal

1

Bilateral hilar lymphadenopathy

60 - 90

2

Bilateral hilar lymphadenopathy with pulmonary disease

40 - 70

3

Pulmonary disease without bilateral hilar lymphadenopathy

10 - 20

4

Lung fibrosis

0

The lung is the most commonly affected organ in sarcoidosis, with ~90 - 95% of cases having pulmonary involvement; in 50% of cases the index manifestations are pulmonary in nature.[20,21] The presentation is protean and varies from asymptomatic to cough, dyspnoea, fatigue and wheezing.[15,21,22] The presence of wheezing is generally due to bronchial hyper-reactivity and it becomes difficult to differentiate it from asthma, hence sarcoid may be misclassified as asthma or bronchitis.[23] Clinical examination also depends on the stage of the disease, and ranges from normal to features of chronic lung disease at the end stages. Crepitations are evident in 4% of cases in early sarcoid and in 25% of cases who have end-stage disease.[24,25] Clubbing is uncommon; however, it may be present in those patients who develop bronchiectasis. Haemoptysis is also an uncommon symptom and if present, the exclusion of concomitant infections, malignancies and mycetomas is mandatory.[26] Pulmonary hypertension can occur in sarcoidosis for several reasons, including hypoxia, invasion of the pulmonary vasculature by granulomas, fibrocystic lung disease causing traction of the vessels, and pulmonary venous hypertension due to cardiomyopathy.[27] Pleural effusions and pneumothorax are rare presentations of sarcoid.[28] Sarcoidosis tends to affect the upper lobes but can occur throughout the entire lung. Lesions can occur in the sub-pleural area and along the bronchial tree. The granuloma lesions have a predilection for the bronchovascular bundles and perilymphatic areas. [29-31] Diagnosis is often delayed when there are only pulmonary symptoms present and generally requires assessment by multiple physicians before the diagnosis is made. In general, the diagnosis is made 3 months after the initial symptoms are noted and in 25% of patients it takes approximately 6 months before a diagnosis is established.[21,23] Diagnosis of sarcoid is based on clinical, radiological and histological features â&#x20AC;&#x201C; histology is required to clinch the diagnosis based on the finding of the non-necrotising granulomas.[32,33] The only occasions when a biopsy is not required is for Heerfordt syndrome and LĂśfgrenâ&#x20AC;&#x2122;s syndrome.[34] However, there are several conditions which can produce granulomas; hence the combination of clinical and radiological testing is required to establish the diagnosis. It is essential to exclude tuberculosis, which can mimic sarcoid and hence delay the diagnosis especially in the SA setting.

Radiological evaluation is still based on the chest X-ray (CXR) classification developed by Scadding in the 1960s, which categorises changes from stages 0 - 4 (Table 1).[35] This classification is very useful for staging patients and providing prognostic information, lower stages having a better prognosis compared to those in the higher category.

High resolution computed tomography (HRCT) of the chest is superior to CXR in detecting parenchymal disease and for evaluation of the mediastinum. It is useful for assessing if there is any other concomitant lung disease as well as assessing if there is disease reversibility.[36,37] The HRCT also assists in identifying the most suitable area for biopsy if it is indicated.[37,38] The indication for an HRCT is when there is a high index of suspicion but the CXR is atypical or discordant with the clinical findings. There are several features which

Resolution, %

CXR = chest X-ray.

are suggestive of sarcoidosis but not pathognomonic of the disease.

These features include: beading along the fissures and pleura; lymph node calcifications; paraseptal nodules in the upper lobe; traction bronchiectasis; honeycombing; air trapping on expiratory phase; and relative sparing of the lower lobes.[29,30] [18F]-Fluorodeoxyglucose positron emission tomography (18FDGPET) is a useful test in ascertaining disease activity. It is useful for identifying organ involvement as well as areas of maximal disease activity. This is specifically helpful in identifying areas for biopsy for histological diagnosis as biopsies from lesions that are more metabolically active produce a far greater diagnostic yield compared with inactive lesions. The 18FDG-PET also aids the diagnosis in cases with persistent symptoms where the conventional biomarkers are not supportive, as it may demonstrate ongoing disease activity. A drawback of the 18FDG-PET is the cost, high radiation exposure and the time taken to conduct the test.[22,34,39,40] Magnetic resonance imaging is not useful for pulmonary disease. Its main role is for the detection of cardiac and neurological disease.[22,23] Gallium scanning has also fallen away in recent years owing to the development of more specialised diagnostic tools. It has a low specifity and is not easily reproducible.[38,39] There is no clear-cut definition of what constitutes the amount of abnormal signal needed to determine active disease.

Bronchoscopy is a useful tool in the diagnosis of sarcoid as it allows for visual inspection, bronchoalveolar lavage (BAL) and biopsy. On inspection, cobblestoning of the endobronchial mucosa can be noted owing to the presence of multiple waxy nodules. There can also be mucosal thickening, which results in the loss of normal contours of the spurs at the level of bifurcation of the bronchi. Bronchial stenosis can occur although it is extremely rare and it may be confused with a malignancy.[21] BAL fluid cytology can assist in the diagnosis of sarcoid; however, it is not routinely used in the SA setting. There is usually a lymphocytic predominance with a normal eosinophil and neutrophil count.[41] A lymphocyte count of >25% after the exclusion of infection is highly suggestive of sarcoidosis.[21] There was a suggestion to use the CD4/CD8 ratio; however, it remains controversial as it has a very low sensitivity and high specificity when the ratio is above 3.5.[42] Endobronchial and transbronchial needle aspiration, with or without endobronchial ultrasound, is very useful for histological confirmation of sarcoid. The yield of granulomas detected on endobronchial biopsy is higher if there is an abnormal macroscopic appearance (90%) compared with a normal appearance (40%).[34]

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REVIEW Transbronchial biopsy yields ~40 - 90%; however, it carries a higher risk of pneumothorax and the risk of sampling the incorrect area.[34] Endobronchial ultrasound fine-needle aspiration and transbronchial needle aspiration is very useful in patients who have mediastinal adenopathy with a yield rate of 70 - 90%. It has now virtually replaced mediastinoscopy for lymph-node evaluation.[34,43,44] Several biomarkers have been developed to assist in the diagnosis and response to treatment for sarcoidosis; however, the most widely used in our setting still remains the serum angiotensin-converting enzyme (sACE) that is produced by the cells surrounding the granuloma. It has a sensitivity of 60% and a specificity of 70% and is elevated in 40 - 80% of patients with sarcoidosis.[45] It has a high false-positive rate and is elevated in other granulomatous and nongranulomatous diseases.[46] It is reliable for monitoring disease activity and response to treatment but not for establishing the diagnosis.[33] At present, even with the newer biomarkers, there is no single biomarker that can be reliably used to diagnose, monitor disease activity or make treatment decisions.

Pulmonary function testing (PFT) is useful for monitoring the response to treatment in patients with pulmonary sarcoidosis. The majority of patients have a restrictive pattern on spirometry; however, a significant proportion of patients have an obstructive pattern.[15,38] The obstructive pattern may be due to narrowing from fibrosis, granuloma infiltration, small-airway disease or compression by mediastinal lymph nodes.[21] Obstructive PFT is more common in those with progressive parenchymal disease.[47] The greater the disease progression, the more likelihood of having an impaired PFT.[34] The most common finding is a reduced lung volume with a reduction of the forced vital capacity (FVC).[21] It is also the most simple and accurate parameter to reflect the impact of pulmonary disease, hence making it a good parameter for follow-up and treatment response.[21] There is also a reduction in the membrane component of the diffusion capacity for carbon monoxide which is a very sensitive test.[34] The 6-minute walk test is only helpful in assessing the functional status of patients with sarcoid and is typically reduced. It is further reduced in those with concomitant pulmonary hypertension.[48] It is mandatory to perform other baseline tests as sarcoid is a multisystem disease. A screening electrocardiogram for cardiac sarcoidosis, an ophthalmological exam for eye involvement, a liver function test for hepatic disease, urea and electrolytes, as well as serum and urinary calcium, are all necessary, as sarcoid is a known to cause hypercalcaemia and the complications that arise from it.

Sarcoidosis treatment requires immunosuppressive therapy with the aim of preventing organ damage, improving symptomatology as well as quality of life and to induce remission.[49] Many patients will resolve spontaneously without treatment although a relapse may occur. Therapy is indicated in those who are symptomatic, have parenchymal disease, progressive disease and those with marked disease activity.[49,50] The choice of immunosuppressive agent is influenced by several factors. Glucorticoids are favoured in patients who would respond well, have no comorbidities such as diabetes mellitus and hypertension, and acute onset disease.[49] Steroid-sparing agents are used in those who are resistant to glucocorticoids, have comorbidities and who have extrapulmonary involvement, such as concomitant cardiac and neurosarcoidosis.[49,50]

102 SARJ VOL. 23 NO. 4 2017

Glucocorticoids have been the mainstay of treatment as they are readily available, reliable, effective, easily titrated and are cheap relative to the steroid-sparing agents. There is marked improvement in radiological and PFT parameters in patients who receive steroids. There is no data to determine the starting dose, nor is there any evidence of when and how to start weaning the steroids as well as the ideal treatment duration.

[15,22,49,50] Expert opinion suggests a starting dose of 20 - 40 mg/day for 1 - 3 months, then to taper down over the next 3 months to 10 - 15 mg/ day, or the lowest effective dose, and maintain that dose for a further 9 12 months, with the total treatment duration being between 12 and 18 months.[28] Tapering should not be too rapid as this may cause relapse.

Intravenous glucocorticoids have been used and their only benefit has been shown to be quicker remission, however, the clinical status at 1 year has been the same as in those who received oral treatment.[50] Cytotoxic agents are used in those who fail to respond adequately to glucocorticoids and in those in whom glucocorticoids are contraindicated. The most commonly used second-line agent is methotrexate.[49,50] It is administered orally or via a transdermal patch at a weekly dose of 10 - 20 mg. It tends to have a long response time and it may take up to 6 months to see tangible results.[51] There has been limited case series reporting the use of azathioprine as a second-line agent for sarcoid. It is administered at a daily dose of 1.5 - 2.5 mg/kg. It has a higher risk of infections as well as greater side effects when compared with methotrexate[49] and can be considered in those in whom fertility is required.

Leflunomide is another drug of choice as a steroid-sparing agent, however, there are minimal data on its use. It is administered at a daily dose of 10 - 20 mg and has less pulmonary toxicity compared with methotrexate.[50] Mycophenolate mofetil can also be used for the treatment of sarcoidosis but the available data are limited to case reports. The dose is 500 - 1 500mg daily and it has a side-effect profile which can be very limiting.[49,50,52] In patients with very severe sarcoidosis in whom there is minimal or no response with the anti-metabolite agents mentioned above, the use of monoclonal antibodies can be considered; however, the evidence to support their use is based on case reports of small numbers of patients and limited series data â&#x20AC;&#x201C; infliximab is an exception as it has undergone randomised control trials and has shown some benefits in the treatment of pulmonary sarcoid.[49,50,53,54] The assessment of the response to treatment is based on several factors, i.e. improvement in symptoms, radiological improvement, and an improvement of Ë&#x192;10% in the FVC on PFT. Poorer responses have been noted in cases with involvement of â&#x2030;Ľ3 organ systems, advanced respiratory disease and in African Americans.[49,50] Sarcoidosis and HIV can coexist and this is important in the SA setting. Studies in Europe have revealed that patients who are severely immunosuppressed do not develop sarcoidosis but those patients who commence highly active antiretroviral therapy and who achieved viral suppression, were more likely to develop sarcoidosis. This has given rise to the postulation that it may develop due to an immune reconstitution inflammatory syndrome.[55,56]

Conclusion

Pulmonary sarcoidosis remains a challenge for physicians to diagnose and treat optimally as it can mimic several other diseases. The

REVIEW management guidelines are based merely on expert opinion. Owing to the high burden of HIV and TB, and its impact on pulmonary sarcoid, as well as the fact that we have a multiracial population, further research is required in the SA setting to better ascertain the epidemiology of the disease.

Acknowledgements. None.

Author contributions. Sole author.

Funding. None.

Conflicts of interest. None.

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31. Judson MA. The clinical features of sarcoidosis: A comprehensive review. Clin Rev Allergy Immunol 2015;49(1):63-78. https://doi.org/10.1007/s12016-014-8450-y 32. American Thoracic Society. Statement on sarcoidosis. Am J Respir Crit Care Med 1999;160(2):736-755. https://doi.org/10.1164/ajrccm.160.2.ats4-99 33. Baughman RP, Lower EE, du Bois RM. Sarcoidosis. Lancet 2003;361(9363):1111-1118. https://doi.org/10.1016/s0140-6736(03)12888-7 34. Wessendorf TE, Bonella F, Costabel U. Diagnosis of sarcoidosis. Clin Rev Allergy Immunol 2015;49(1):54-62. https://doi.org/10.1007/s12016-015-8475-x 35. Scadding JG. Prognosis of intrathoracic sarcoidosis in England. A review of 136 cases after five years' observation. BMJ 1961;2(5261):1165-1172. https://doi.org/10.1136/ bmj.2.5261.1165 36. Brauner MW, Lenoir S, Grenier P, Cluzel P, Battesti JP, Valeyre D. Pulmonary sarcoidosis: CT assessment of lesion reversibility. Radiology 1992;182(2):349-354. https://doi.org/10.1148/radiology.182.2.1732948 37. Greco FG, Spagnolo P, Muri M, et al. The value of chest radiograph and computed tomography in pulmonary sarcoidosis. Sarcoidosis Vasc Diff Lung Dis 2014;31(2):108116.

38. Keir G, Wells AU. Assessing pulmonary disease and response to therapy: Which test? Semin Respir Crit Care Med 2010;31(4):409-418. https://doi. org/10.1055/s-0030-1262209 39. Silva M, Nunes H, Valeyre D, Sverzellati N. Imaging of sarcoidosis. Clin Rev Allergy Immunol 2015;49(1):45-53. https://doi.org/10.1007/s12016-015-8478-7 40. Teirstein AS, Machac J, Almeida O, Lu P, Padilla ML, Iannuzzi MC. Results of 188 whole-body fluorodeoxyglucose positron emission tomography scans in 137 patients with sarcoidosis. Chest 2007;132(6):1949-1953. https://doi.org/10.1378/chest.07-1178 41. Bonella F, Ohshimo S, Bauer P, Guzman J, U. Costabel U. Bronchoalveolar lavage. Eur Respir Mon; 2010;48:59-72. https://doi.org/10.1183/1025448x.ERM4810 42. Costabel U, Bonella F, Ohshimo S, Guzman J. Diagnostic modalities in sarcoidosis: BAL, EBUS, and PET. Semin Respir Crit Care Med 2010;31(4):404-408. https://doi. org/10.1055/s-0030-1262207 43. Garwood S, Judson MA, Silvestri G, Hoda R, Fraig M, Doelken P. Endobronchial ultrasound for the diagnosis of pulmonary sarcoidosis. Chest 2007;132(4):1298-1304. https://doi.org/10.1378/chest.07-0998 44. Tremblay A, Stather DR, Maceachern P, Khalil M, Field SK. A randomized controlled trial of standard vs endobronchial ultrasonography-guided transbronchial needle aspiration in patients with suspected sarcoidosis. Chest 2009;136(2):340-346. https:// doi.org/10.1378/chest.08-2768 45. Studdy PR, Lapworth R, Bird R. Angiotensin-converting enzyme and its clinical significance – a review. J Clin Pathol 1983;36(8):938-947. https://doi.org/10.1136/ jcp.36.8.938 46. Lieberman J, Nosal A, Schlessner A, Sastre-Foken A. Serum angiotensin-converting enzyme for diagnosis and therapeutic evaluation of sarcoidosis. Am Rev Respir Dis 1979;120(2):329-335. https://doi/abs/10.1164/arrd.1979.120.2.329 47. Handa T, Nagai S, Fushimi Y, et al. Clinical and radiographic indices associated with airflow limitation in patients with sarcoidosis. Chest 2006;130(6):1851-1856. https:// doi.org/10.1378/chest.130.6.1851 48. Baughman RP, Sparkman BK, Lower EE. Six-minute walk test and health status assessment in sarcoidosis. Chest 2007;132(1):207-213. https://doi.org/10.1378/ chest.06-2822 49. Wijsenbeek MS, Culver DA. Treatment of sarcoidosis. Clin Chest Med 2015;36(4):751767. https://doi.org/10.1016/j.ccm.2015.08.015 50. Baughman RP, Lower EE. Treatment of sarcoidosis. Clin Rev Allergy Immunol 2015;49(1):79-92. https://doi.org/10.1007/s12016-015-8492-9

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REVIEW 51. Valeyre D, Prasse A, Nunes H, Uzunhan Y, Brillet P-Y, MĂźller-Quernheim J. Sarcoidosis. Lancet 383(9923):1155-1167. https://doi.org/10.1016/s01406736(13)60680-7 52. Hamzeh N, Voelker A, ForssĂŠn A, et al. Efficacy of mycophenolate mofetil in sarcoidosis. Respir Med 2014;108(11):1663-1669. https://doi.org/10.1016/j. rmed.2014.09.013 53. Baughman RP, Drent M, Kavuru M, et al. Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement. Am J Respir Crit Care Med 2006;174(7):795802. https://doi.org/10.1164/rccm.200603-402oc 54. Rossman MD, Newman LS, Baughman RP, et al. A double-blinded, randomized, placebo-controlled trial of infliximab in subjects with active pulmonary sarcoidosis.

Sarcoidosis Vasc Diff Lung Dis 2006;23(3):201-208.

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55. Foulon G, Wislez M, Naccache J-M, et al. Sarcoidosis in HIV-infected patients in the era of highly active antiretroviral therapy. Clin Infect Dis 2004;38(3):418-425. https:// doi.org/10.1086/381094 56. Trevenzoli M, Cattelan AM, Marino F, Marchioro U, Cadrobbi P. Sarcoidosis and HIV infection: A case report and a review of the literature. Postgrad Med J 2003;79(935):535-538. https://doi.org/10.1136/pmj.79.935.535

Accepted 21 September 2017.

ORIGINAL RESEARCH

Predictors and short-term outcomes of recurrent pulmonary tuberculosis in Kampala, Uganda: A cohort study N Kalema,1,2 MB ChB, MMed, MAS; C Lindan,3 MD, MS; D Glidden,3 PhD; S D Yoo,1,4 MD; A Katamba,2 MB ChB, PhD; A Alfred,1 MSc; W Katagira,1 MB ChB, MMed; P Byanyima,1 DMLT, BIS; E Musisi,1 MSc; S Kaswabuli,1 BS/B; S Ingvar,1 BSN, MPH; J Zawedde,1 BSN; C Yoon,1,5 MD, MPH; I Ayakaka,1 MB ChB, MPH; J L Davis,7,8 MD, MAS; L Huang,1,5,6 MD, MAS; W Worodria,1,2 MB ChB, MMed, PhD; A Cattamanchi,1,3,5 MD, MAS Infectious Diseases Research Collaboration, Kampala, Uganda Department of Medicine, Mulago Hospital, Makerere University, Kampala, Uganda 3 Department of Epidemiology and Biostatistics and Global Health Sciences, University of California San Francisco, San Francisco, California, USA 4 Department of Internal Medicine, Jimma University, Jimma, Ethiopia 5 Division of Pulmonary and Critical Care Medicine, Zuckerberg San Francisco General Hospital, University of California San Francisco, San Francisco, CA 6 HIV, Infectious Diseases, and Global Medicine Division, Zuckerberg San Francisco General Hospital, University of California San Francisco, San Francisco, CA 7 Yale School of Public Health, New Haven, Connecticut, USA 8 Pulmonary, Critical Care, and Sleep Medicine Section, Yale School of Medicine, New Haven, Connecticut, USA 1 2

Corresponding author: N Kalema (kalemanelson@gmail.com)

Background. Recurrent tuberculosis (TB) occurring >2 years after completing treatment for a prior TB episode is most often due to reinfection with a new strain of Mycobacterium tuberculosis.

Objectives. We determined the prevalence and outcome of late recurrent TB among hospitalised patients in Kampala, Uganda.

Methods. We conducted a retrospective analysis of patients admitted to Mulago Hospital, who had a cough of >2 weeks’ duration and completed TB treatment >2 years prior to admission. All patients had mycobacterial culture performed on two sputum specimens and vital status ascertained 2 months post enrolment. We performed logistic regression and Cox proportional hazards modelling to identify predictors of recurrent TB and of survival, respectively.

Results. Among 234 patients, 36% (n=84) had recurrent TB. Independent predictors included younger age (adjusted odds ratio (aOR) 0.64, 95% confidence interval (CI) 0.42 - 0.97; p=0.04), chest pain >2 weeks (aOR=3.32; 95% CI 1.38 - 8.02; p=0.007), severe weight loss of ≥5 kg (aOR 4.88; 95% CI 1.66 - 14.29; p=0.004) and the presence of ≥1 WHO danger sign of severe illness (aOR=3.55; 95% CI 1.36 - 9.29; p=0.01). Two-month mortality was 17.8% (95% CI 10.5 - 29.2), and was higher among patients who were not initiated on TB treatment (aHR 16.67; 95% CI 1.18 - 200; p=0.04), those who were HIV-positive and not on antiretroviral treatment (aHR 16.99; 95% CI 1.17 - 246.47; p=0.04) and those with a history of smoking (aHR 1.20; 95% CI 1.03 - 1.40; p=0.02).

Conclusion. The high prevalence of late recurrent TB likely reflects high levels of TB transmission in Kampala. Increased use of empiric TB treatment and early ART treatment initiation if HIV-positive should be considered in patients with a prior history of TB, particularly if they are young, with weight loss ≥5 kg, chest pain >2 weeks or ≥1 WHO danger sign of severe illness.

S Afr Respir J 2017;23(4):106-112. DOI:10.7196/SARJ.2017.v23i4.173

Recurrence of tuberculosis (TB) following completion of treatment is an important but understudied problem in high-burden countries.[1-3] Recurrent TB can result from relapse of the original Mycobacterium tuberculosis strain or from reinfection with a new strain.[4] Relapse usually occurs because of inadequate treatment, whereas reinfection reflects high rates of ongoing TB transmission in at-risk populations.[3,5] Data show that the risk of recurrent TB owing to reinfection is higher among HIV-positive than HIVnegative persons.[6] Thus, assessing the burden of recurrent TB and its causes in high TB-HIV incidence settings can help TB control programmes to determine whether limited additional resources should be focused on enhanced treatment monitoring and adherence to reduce relapse, or on TB case-finding and treatment to interrupt transmission.

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Molecular genotyping is the gold standard for assessing whether recurrent TB is due to relapse versus reinfection. Unfortunately, only a few studies in high-TB-burden settings have described the burden of recurrent pulmonary TB using molecular genotyping. These studies indicate that the length of time between completion of treatment and recurrence is indicative of whether recurrent disease is a result of reinfection or relapse. A study in southern India found that among patients who developed recurrent pulmonary TB 1 to 2 years following completion of treatment, the recurrence was due to relapse in 91% of HIV-uninfected patients, and was due to reinfection in 88% of HIVinfected patients.[7] In Uganda, relapse was found to be the cause of recurrence in 82% (n=80/98) of patients presenting with another episode of TB 1 - 2 years following treatment of prior disease.[8] In contrast, among patients who developed recurrent TB >2 years

ORIGINAL RESEARCH after completion of treatment, molecular genotyping studies have shown reinfection to be the predominant cause.[9] In Cape Town, South Africa (SA), a study in a predominantly HIV-uninfected population found that reinfection accounted for 12/16 (75%) cases of recurrent TB.[10] Similarly, another study from SA found that reinfection accounted for 34% (n=23/66) recurrent TB episodes among patients who completed treatment within the prior 2 years but for 65% (n=43/66) of recurrent TB episodes among patients who had completed treatment >2 years earlier.[11] Studies from low-burden settings where reinfection is less likely to occur, have found that >90% of relapses develop within 2 years of completion of treatment, which is a key reason why phase 3 trials of novel anti-TB drugs or regimens limit follow-up to 2 years.[12] Thus, assessing TB recurrence among patients who completed treatment for an episode of TB more than 2 years earlier can serve as a proxy for reinfection.

Few studies have assessed the burden and outcome of reinfection in East Africa. Therefore, we assessed the prevalence of late recurrent pulmonary TB among hospitalised patients in Kampala, Uganda. In addition, we identified the predictors and short-term mortality of late recurrent TB.

Methods

Study design We performed a secondary analysis of data collected on a cohort of patients who were admitted with presumed pneumonia to Mulago Hospital in Kampala, Uganda, from October 2008 to December 2013.

The parent study, called the International HIV-associated Opportunistic Infections (IHOP) study, has been described in detail previously.[13-15] Briefly, IHOP was a prospective study of consecutive adults ≥18 years of age admitted to Mulago Hospital with a history of unexplained cough of 2 weeks’ to 6 months’ duration. Patients who had been on TB treatment within the last 2 years or had evidence of heart failure were excluded. At the time of enrolment, patients completed a questionnaire on demographics and clinical history. HIV testing was performed using the Ugandan Ministry of Health-approved sequential HIV-antibody testing algorithm that incorporates three rapid enzyme immunoassay kits, and CD4 cell counts were measured among those who were HIV-seropositive. Smear microscopy and Lowenstein-Jensen culture were performed on two sputum samples (spot and early morning) for detection of TB. In addition, Xpert MTB/RIF testing was performed on sputum samples of patients enrolled after August 2009, and on banked sputum sediment for study participants enrolled between October 2008 and August 2009, before Xpert MTB/RIF testing was available.

Test results were provided to ward clinicians who made all treatment decisions. Study staff scheduled patients for in-person follow-up at 2 weeks, 1 month and 2 months after enrolment to ascertain vital status, and to determine whether anti-TB and/or antiretroviral treatment (ART) had been initiated. Study staff contacted patients or their nominated next of kin by phone to ascertain TB treatment and vital status if a follow-up visit was missed.

The parent study was approved by the institutional review boards of the University of California, San Francisco, Makerere University School of Medicine (ref. no. 2006-017 SOMREC), and Mulago Hospital, as well as by the Uganda National Council for Science and Technology (ref. no. HS259). All participants provided informed written consent.

For this study, we evaluated data on all patients who reported completing treatment for drug-susceptible TB >2 years prior to study enrolment. We also re-contacted patients or their next of kin to ascertain their vital status at 60 days, if this information was missing.

Outcome definitions The primary study outcome was culture-confirmed late recurrent pulmonary TB. Patients were considered to have late recurrent TB if one or more sputum culture results were positive and confirmed to be M. tuberculosis by speciation testing. Patients who had contaminated or missing cultures were excluded from the analysis (Fig. 1). The secondary study outcome was mortality at 60 days after enrolment.

Statistical analyses We compared baseline demographic and clinical characteristics between patients with and without late recurrent TB using the χ2 test for dichotomous variables and the Mann-Whitney rank sum test for continuous variables. We performed univariate logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association of baseline patient characteristics with late recurrent TB; variables associated with the outcome at a p-value <0.1 were considered for inclusion in a multivariate model. [2,16-18] Likelihood ratio testing (LRT) was used for model building and the goodness-of-fit test was used to assess the model fit. To determine the cumulative 2-month mortality, we performed Kaplan-Meier survival analysis and log-rank tests of equality across strata for categorical predictors.

Cox proportional hazards modelling was used to identify clinical factors associated with 2-month mortality. We included a priori known risk factors for TB-related mortality, including age, gender, history of smoking, World Health Organization (WHO) danger signs of severe illness (temperature >39°C, a respiratory rate of >30 breaths per minute, a heart rate of >120 beats per minute, and being nonambulatory because of illness),[19] HIV infection, ART and anti-TB treatment.[20-24] LRT was used for model building and the goodnessof-fit test to assess model fit. Cox proportional hazards assumptions were tested using the method of Schoenfeld residuals and determined to meet assumptions (p>0.05). The c-statistic was calculated as a standard summary measure of model performance.[25] Presumed pneumonia (N=2 650) No prior TB (N=2 390) Prior TB history (N=260) Excluded Contamination (n=24) Missing cultures (n=2) Study population (N=234)

M. tb. confirmed (n=84, 36%)

No M. tb. detected (n=150, 64%)

Fig. 1. Study population flow chart.

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ORIGINAL RESEARCH

Results

Study population A total of 2 650 patients were enrolled into the parent IHOP study, of whom 260 had a previous history of TB and had completed treatment >2 years previously; 26 patients were excluded from the study owing to contaminated cultures (n=24) or lack of culture results (n=2). Thus, we present data on 234 patients (Fig. 1). The median (interquartile range (IQR)) age was 36.9 (30.8 - 44.2) years and 58.6% were male (Table 1).

The majority of the participants (68.8%) were HIV-seropositive with a median (IQR) CD4 cell count of 119 (22 - 304) cells/uL; 46.6% were on ART at enrolment into the study. More than half (61.6%) had ≥1 WHO severe illness danger signs.

Prevalence and diagnosis of late recurrent TB Overall, 35.9% of patients (n=84) had culture-confirmed late recurrent TB. Smear microscopy results were available for 96.6% (n=226/234) and Xpert MTB/RIF results for 95.7% (n=224/234) patients. Using culture results as the gold standard, Xpert MTB/ RIF had higher sensitivity (78.6%; 95% CI 68.3 - 86.8 v. 65.8%; 95% CI 54.3 - 76.1; McNemar’s χ 2 test p=0.0124) but similar specificifity (96.4%; 95% CI 91.9 - 98.8 v. 95.9%; 95% CI 91.3 - 98.5; McNemar’s χ2 exact test; p=1.000) when compared with sputum smear microscopy. Xpert MTB/RIF identified rifampicin resistance in 3.6% (n=3/84) of patients with culture-confirmed late recurrent TB.

Demographic and clinical predictors of late recurrent TB Compared with patients without late recurrent TB, patients with culture-confirmed late recurrent pulmonary TB were more likely to report severe weight loss of ≥5 kg (75.3% v. 55.7%; p=0.004), have chest pain ≥2 weeks (77.2% v. 46.0%; p<0.001), have a lower CD4 cell count if HIV-positive (70 v. 132 cells/µL; p=0.039), be non-ambulatory (56.9% v. 35.7%; p=0.004), have tachycardia (28.6% v. 9.3%; p<0.001) and have ≥1 WHO danger signs of severe illness (70.8% v. 56.4%; p=0.044) (Table 1). In multivariate analysis, only younger age (aOR 0.64; 95% CI 0.42 - 0.97; p=0.04), chest pain >2 weeks (aOR 3.32; 95% CI 1.38 - 8.02; p=0.007), severe weight loss of ≥5 kg (aOR 4.88; 95% CI 1.66 - 14.29; p=0.004) and presence of ≥1 WHO severe illness danger sign (aOR 3.55; 95% CI 1.36 - 9.29; p=0.010) remained independently associated with late recurrent TB. Inclusion of HIV infection, stratified or not by CD4 cell count, in the model did not alter the final effect estimates (Table 2).

Treatment of late recurrent TB Among the 84 patients with culture-confirmed late recurrent TB, 85.7% (n=72) were initiated on anti-TB treatment; 79.8% (n=67) were initiated before hospital discharge based on smear or Xpert MTB/RIF testing (52 were on the category I treatment regimen – rifampicin, isoniazid, ethambutol and pyrazinamide – and 15 were on the category II treatment regimen – streptomycin plus category I regimen). [26] Five (5.9%) confirmed treatment initiation after

Table 1. Baseline characteristics of the study population and association with recurrent pulmonary TB, Uganda (2008 - 2013) All

No recurrent TB

Recurrent TB

Characteristics

(N=234), n (%)*

(N=150), n (%)*

(N=84), n (%)*

Age (years), median (IQR)

36.9 (30.8 - 44.2)

38.1 (31.9 - 46.2)

34.4 (29.5 - 39.9)

0.083

Male

137 (58.6)

85 (56.7)

52 (61.9)

0.435

Smoking† (≥100 cigarettes, lifetime)

77 (32.9)

48 (32.0)

29 (34.5)

0.693

Ever smoked (pack yrs), median (IQR)

3.9 (1.5 - 8.4)

4.1 (1.5 - 8.4)

3.8 (1.2 - 6.4)

0.660

HIV-seropositive

161 (68.8)

102 (68.0)

59 (70.2)

0.723

CD4 cell count (cells/uL), median (IQR)

119 (22 - 304)

132 (23 - 308)

70 (20 - 295)

0.039

On ART at admission (N=161)

75 (46.6)

50 (49.0)

25 (42.4)

0.415

Years on ART, median (IQR)

3.2 (0.8 - 5.1)

3.7 (0.9 - 5.7)

1.7 (0.5 - 4.3)

0.191

134 (63.2)

73 (55.7)

61 (75.3)

0.004

96 (56.5)

52 (46.0)

44 (77.2)

<0.001

Non-ambulatory (N=198)‡

86 (43.4)

45 (35.7)

41 (56.9)

0.004

Temperature >39 °C

9 (3.9)

4 (2.7)

5 (6.0)

0.210

Respiratory rate >30 breaths/min

100 (42.7)

63 (42.0)

37 (44.1)

0.761

Heart rate >120 bpm

38 (16.2)

14 (9.3)

24 (28.6)

<0.001

N=198

N=140

N=76

0

76 (38.4)

55 (43.7)

21 (29.2)

≥1

122 (61.6)

71 (56.4)

51 (70.8)

Weight loss ≥5 kg (N=212)

‡

Chest pain >2 weeks (N=170)

‡

p-value

WHO danger signs

WHO danger signs

TB = tuberculosis; IQR = interquartile range, ART = antiretroviral therapy. *Unless otherwise specified. † Persons who reported smoking at least 100 cigarettes or more in a lifetime at the time of enrolment. ‡ Missing data.

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0.044

ORIGINAL RESEARCH hospital discharge but were uncertain of the regimen. For unknown reasons, 14.3% (n=12) of patients did not initiate treatment at 2 months following diagnosis.

Discussion

We found that among Ugandan patients who were hospitalised with symptoms of pneumonia and who had completed TB treatment at least 2 years earlier, 36% had culture-confirmed late recurrent TB. Xpert testing was ~10% more sensitive than smear microscopy but missed ~20% of patients with culture-confirmed late recurrent TB. Patients with late recurrent TB had high short-term mortality (17.8%); the mortality rate was increased among those who had not initiated anti-TB treatment and, if HIV-infected, were not on

0.75 0.00

0.00

0 Number at risk No TB treatment Initiated TB treatment

On ART Not on ART

0.25

No TB treatment Initiated TB treatment

Log rank test: p=0.016

0.50

Survival, %

0.50

Log rank test: p=0.0614

0.25

Survival, %

0.75

1.00

1.00

Mortality of patients with late recurrent TB Of the 84 patients with culture-confirmed late recurrent TB, 66% (n=56) were alive, 18% (n=15) were lost to follow-up and 16% (n=13) had died 60 days after enrolment. Among the 69 patients for whom vital status could be confirmed, the cumulative incidence of 2-month mortality was 17.8% (95% CI 10.5 - 29.2). Among the 13 patients who died, 69% (n=9) had initiated anti-TB treatment – 5 on category I, 3 on category II re-treatment , 1 on an unknown TB treatment regimen – and 4 received antibiotics but no anti-TB treatment.

In addition, 69% (n=9/13) of patients who died were HIV-seropositive and had a median (IQR) CD4 cell count of 20 (9 - 47) cells/uL, only 22% (n=2/9) were on ART at study enrolment.

In multivariate analysis, the 2-month hazard of mortality was increased among patients who had not initiated TB treatment (aHR

16.67, 95% CI 1.18 - 200; p=0.04), HIV co-infected patients who were not on ART (aHR 16.99; 95% CI 1.17 - 246.47; p=0.04) and patients with 1 pack-year history of smoking (aHR 1.20, 95% CI 1.03 - 1.40; p=0.02) (Table 3). Early anti-TB treatment and ART improved survival (Figs 2 and 3). Patients with ≥1 WHO severe illness danger signs (aHR 5.92; 95% CI 0.73 - 48.03; p=0.096) also had increased 2-month mortality, although this did not reach pre-specified statistical significance.

10

20

30

40

50

11 57

9 54

8 52

8 50

8 50

8 49

0

60

Time (days) 8 45

Fig. 2. Kaplan Meier log-rank survival curve by TB treatment initiation.

Number at risk On ART Not on ART

10

20

30

40

50

60

27 15

27 14

25 13

Time (days) 28 21

28 19

27 17

27 15

Fig. 3. Kaplan Meier log-rank survival curve by ART initiation.

Table 2. Predictors of recurrent pulmonary TB among patients admitted with suspected pneumonia Characteristics

OR (95% CI), (N=234)

p-value

aOR (95% CI), (N=133)

p-value

Age, decades

0.70 (0.54 - 0.92)

0.011

0.64 (0.42 - 0.97)

0.035

HIV-seropositive

1.11 (0.62 - 1.98)

0.723

Chest pain >2 weeks (N=170)*

3.97 (1.93 - 8.16)

<0.001

3.32 (1.38 - 8.02)

0.007

Weight loss ≥5 kg (N=212)*

2.42 (1.31 - 4.47)

0.005

4.88 (1.66 - 14.3)

0.004

Non-ambulatory (N=198)*

2.38 (1.32 - 4.30)

0.004

Temperature >39 °C

2.31 (0.60 - 8.85)

0.222

Respiratory rate >30 breaths/min

1.09 (0.63 - 1.86)

0.761

Heart rate >120 bpm

3.89 (1.88 - 8.03)

<0.001

WHO danger signs

WHO danger signs 0

Ref

≥1

1.88 (1.01 - 3.49)

Ref 0.045

3.55

(1.36 - 9.29)

0.010

TB = tuberculosis; OR = odds ratio; aOR = adjusted odds ratio; WHO = World Health Organization; bpm = beats per minute; Ref = 1. *Missing data.

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ORIGINAL RESEARCH ART. These findings highlight the high transmission rate of TB and support empirical TB treatment initiation (and early ART, if HIVpositive) in patients with a remote history of prior TB and recurrent TB symptoms.

Our findings are similar to previous cohort studies from East Africa assessing the prevalence of late recurrent TB. In a large populationbased cohort study of TB patients who were actively followed up between 1996 and 2010 in northern rural Malawi, recurrent TB developed in 42% (n=41/98) of participants who had completed TB treatment >2 years earlier.[9] In a phase 3 vaccine trial that enrolled and prospectively followed up HIV-infected adults in Tanzania for >5 years, TB (defined as one or more positive smear or culture results) was diagnosed in 13.8% (n=11/80) of participants at a median of 108.3 months after prior active TB.[27] A molecular genotyping study attributed 76% of recurrent episodes to reinfection.[28] As other studies have shown that the majority of recurrent TB occurring ≥2 years after prior treatment completion is due to reinfection,[4,9] we can assume that the majority of cases in our study were a result of acquiring a new M. tuberculosis strain, even though molecular genotyping was not performed. The recent National Tuberculosis Prevalence Survey, which found that TB prevalence was nearly twofold higher than previously reported, indicates that TB transmission remains high in Uganda.[29] Thus, our findings support the recently revised Uganda National Strategic Plan’s emphasis on enhancing case detection, through systematic screening of high-risk groups, improved utilisation of current diagnostic tools, addressing key barriers in health-seeking behaviour, enhanced involvement of the private sector, and stepping up community engagement.[30] More accurate diagnostics are essential to enhanced case-finding.

Xpert had higher sensitivity than smear microscopy, i.e. 78.6% (95% CI 68.3 - 86.8) v. 65.8% (95% CI 54.3 - 76.1), respectively. However, of the 66 patients who received Xpert testing in real-time and had

positive results, initiation of same-day treatment was missed for 11% (n=7); 6% (n=4) initiated TB treatment after hospital discharge and 5% (n=3) did not initiate treatment during the 2-month follow-up period. Xpert specificity (96.5%) in this study was lower than that reported in a large meta-analysis by Steingart et al.[31] but is consistent with more recent studies of Xpert testing in populations with a prior history of TB.[32] Nonetheless, the positive predictive value was high (93.0%; 95% CI 84.3 - 97.7) given the high prevalence of recurrent TB in our population. Only 3% of our patients had RIF resistance identified by Xpert testing, which further supports reinfection, rather than relapse, as the reason for recurrent TB in the majority of patients.

Our data support the increased use of empirical treatment among hospitalised patients with a remote history of TB and symptoms suggesting recurrent TB disease, particularly when they are HIVpositive and diagnostics such as Xpert are not available. To help clinicians prioritise which patients should be treated empirically, we explored clinical characteristics associated with culture-confirmed late recurrent TB. We found that patients who had severe weight loss, chest pain for ≥2 weeks, and at least one of the WHO severe illness danger signs were more likely to have late recurrent disease.

It was noteworthy that these findings were consistent with a WHO recommendation regarding empirical TB treatment in patients with ≥1 WHO severe illness danger signs. Increased use of empirical treatment is particularly important given our finding that mortality was high in hospitalised patients with late recurrent TB, and that earlier initiation of TB treatment appeared to reduce mortality.

Study strengths and limitations A key strength of our study is that recurrent TB diagnosis was based on culture results rather than smear microscopy or Xpert MTB/RIF, which are both known to yield false-positive results owing to identification of dead bacilli. Our study also had several

Table 3. Factors associated with 2-month mortality among patients with recurrent pulmonary TB* Characteristics

HR (95% CI) (N=68)

p-value

Age, decades

0.99 (0.58 - 1.70)

0.982

Male

1.91 (0.52 - 7.04)

0.334

Pack-years

1.03 (0.94 - 1.12)

0.576

Chest pain >2 weeks (N=45)

2.13 (0.27 - 16.86)

0.472

Weight loss ≥5 kg (N=65)

1.46 (0.32 - 6.67)

0.624

aHR (95% CI) (N=57)

p-value

1.20 (1.03 - 1.40)

0.018

WHO danger sign category (N=57) 0

Ref

Ref

≥1 - 4

5.10 (0.64 - 39.95)

0.124

5.92 (0.73 - 48.03)

0.096

Missed TB treatment initiation

2.94 (0.89 - 10.00)

0.076

16.67 (1.18 - 200)

0.037

ART initiated HIV-uninfected

Ref

HIV-infected, on ART

0.41 (0.07 - 2.45)

0.327

Ref 0.25 (0.02 - 3.75)

0.319

HIV-infected, no ART

2.22 (0.57 - 8.57)

0.249

16.99 (1.17 - 246.47)

0.038

TB = tuberculosis; HR = unadjusted hazard ratio; CI = confidence interval; aHR = adjusted hazard ratio; WHO = World Health Organization; Ref = 1; ART = antiretroviral therapy. *Table shows the conditional total effect of TB treatment initiation (main exposure of interest) on 60-day mortality (outcome), and the adjusted direct effect estimates of of smoking, HIV infection (on ART v. not on ART), and the presence of WHO danger signs of severe illness.

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ORIGINAL RESEARCH potential limitations. Prevalence estimates from patients who were hospitalised at a referral facility are always likely to be higher than in the general population. Even so, our findings are similar to those reported from cohort studies in Malawi and Tanzania.[9,27] Because our study was based on a secondary data analysis, we were limited to the data that had already been collected. As a result, we did not have information on factors that have been shown to predict recurrence, such as residual cavitary lesions, or information on drug adherence or anti-TB regimen taken during the prior disease episode.

Conclusions and implications

Late recurrent TB was common among hospitalised patients in Uganda but was often missed by currently available rapid diagnostics. Shortterm mortality was high, but reduced among those who initiated antiTB treatment promptly, or who started ART if they were HIV-infected.

These data support early empirical treatment when Xpert testing is not available or is negative, particularly in HIV-infected patients with severe weight loss (>5 kg), chest pain for >2 weeks and ≥1 WHO severe illness danger signs. Future studies should compare outcomes of patients with presumed recurrent TB when empirical treatment is provided based on the algorithm proposed here v. routine care.

Acknowledgements.We would like to thank the Mulago Hospital administration, healthcare providers, and patients for their support and participation in the study. We also would like to thank the staff and administration of the Infectious Diseases Research Collaboration and the Uganda National TB Reference Laboratory for making this study possible. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author contributions. Conceived and designed the experiments: NK, WW, AK, AI, JLD, SDY, LH, AC. Performed the experiments: SK, EM, PB, AA. Analysed the data: NK, DG, AC, JLD, LH. Contributed reagents, materials, and analysis tools: LH, AC, JLD. Wrote the manuscript: NK, DG, KL, SDY, LH, JLD, WW, AC. Enroled and cared for the patients included in this study: KW, NK, ZJ, SI. Funding. The research was supported by the Training in Clinical Research programme at the University of California San Francisco, that was made possible by the Fogarty International Center of the National Institutes of Health under the Award Number D43 TW010037 as well as NIH K24HL087713 (LH), R01HL090335 (LH), K23HL094141 (AC), K23AI080147 (JLD), R21AI101714 (JLD), K12 HL090147-04 (NDW), and U2RTW0006879 (COHRE).

Conflicts of interest. None.

1. Zignol M, Wright A, Jaramillo E, Nunn P, Raviglione MC. Patients with previously treated tuberculosis no longer neglected. Clin Infect Dis 2007;44(1):61-64. https:// doi.org/10.1086/509328.

2. Panjabi R, Comstock G, Golub J. Recurrent tuberculosis and its risk factors: adequately treated patients are still at high risk. Int J Tuberculosis Lung Dis 2007;11(8):828837. http://www.ingentaconnect.com/content/iuatld/ijtld/2007/00000011/00000008/ art00002 3. Lambert ML, Hasker E, Van Deun A, Roberfroid D, Boelaert M, Van der Stuyft P. Recurrence in tuberculosis: Relapse or reinfection? Lancet Infect Dis 2003;3(5):282287. https://doi.org/10.1016/S1473-3099(03)00607-8.

4. Chaisson RE, Churchyard GJ. Recurrent tuberculosis: Relapse, reinfection, and HIV. J Infect Dis 2010;201(5):653-655. https://doi.org/10.1086/650531.

5. Weis SE, Slocum PC, Blais FX, et al. The effect of directly observed therapy on the rates of drug resistance and relapse in tuberculosis. N Engl J Med 1994;330(17):1179-1184. https://doi.org/10.1056/nejm199404283301702.

6. Glynn JR, Murray J, Bester A, Nelson G, Shearer S, Sonnenberg P. High rates of recurrence in HIV-infected and HIV-uninfected patients with tuberculosis. J Infect Dis. 2010;201(5):704-711. https://doi.org/10.1086/650529 7. Narayanan S, Swaminathan S, Supply P, et al. Impact of HIV infection on the recurrence of tuberculosis in South India. J Infect Dis 2010;201(5):691-703. https:// doi.org/10.1086/650528.

8. Luzze H, Johnson DF, Dickman K, et al. Relapse more common than reinfection in recurrent tuberculosis 1 - 2 years post treatment in urban Uganda. Int J Tuberculosis Lung Dis 2013;17(3):361-367. https://doi.org/10.5588/ijtld.11.0692 9. Guerra-Assunção JA, Houben RMGJ, Crampin AC, et al. Recurrence due to relapse or reinfection with Mycobacterium tuberculosis: A whole-genome sequencing approach in a large, population-based cohort with a high HIV infection prevalence and active follow-up. J Infect Dis 2015;211(7):1154-1163. https://doi.org/10.7554/elife.05166.

10. Van Rie A, Warren R, Richardson M, et al. Exogenous reinfection as a cause of recurrent tuberculosis after curative treatment. N Engl J Med 1999;341(16):11741179. https://doi.org/10.1056/NEJM199910143411602 11. Marx FM, Dunbar R, Enarson DA, et al. The temporal dynamics of relapse and reinfection tuberculosis after successful treatment: A retrospective cohort study. Clin Infect Dis 2014;58(12):1676-1683. https://doi.org/10.1093/cid/ciu186 12. Bark CM, Furin JJ, Johnson JL. Approaches to clinical trials of new anti-TB drugs. Clin Investigation 2012;2(4):359-370. https://doi.org/10.4155/cli.12.22 13. Kyeyune R, den Boon S, Cattamanchi A, et al. Causes of early mortality in HIVinfected TB suspects in an East African referral hospital. J AIDS 2010;55(4):446-450 https://doi.org/10.1097/qai.0b013e3181eb611a 14. Cattamanchi A, Huang L, Worodria W, et al. Integrated strategies to optimize sputum smear microscopy. Am J Respir Crit Care Med 2011;183(4):547-551. https://doi. org/10.1164/rccm.201008-1207oc 15. Yoon C, Cattamanchi A, Davis JL, et al. Impact of Xpert MTB/RIF testing on tuberculosis management and outcomes in hospitalized patients in Uganda. PLoS One 2012;7(11):e48599. https://doi.org/10.1371%2Fjournal.pone.0048599.

16. Bates MN, Khalakdina A, Madhukar P, et al. Risk of tuberculosis from exposure to tobacco smoke. JAMA 2007;167(4):335-342. https://doi.org/10.1001/ archinte.167.4.335 17. Picon PD, Bassanesi SL, Caramori ML, Ferreira RL, Jarczewski CA, Vieira PR. Risk factors for recurrence of tuberculosis. J Bras Pneumol 2007;33(5):572-578. https://doi. org/10.1590/S1806-37132007000500013 18. Yen YF, Yen MY, Lin YS, et al. Smoking increases risk of recurrence after successful anti-tuberculosis treatment: A population-based study. Int J Tuberculosis Lung Dis 2014;18(4):492-498. https://doi.org/10.5588/ijtld.13.0694 19. World Health Organization. Improving the Diagnosis and Treatment of SmearNegative Pulmonary and Extra-Pulmonary Tuberculosis among Adults and Adolescents. Recommendations for HIV-Prevalent and Resource-Constrained Settings: WHO/HTM/2007.379 & WHO/HIV/2007.1. Geneva: WHO, 2007.

20. Domingos MP, Caiaffa WT, Colosimo EA. Mortality, TB/HIV co-infection, and treatment dropout: Predictors of tuberculosis prognosis in Recife, Pernambuco State, Brazil. Cadernos de saúde pública/Ministério da Saúde, Fundação Oswaldo Cruz, Escola Nacional de Saúde Pública. 2008;24(4):887-896. https://doi.org/10.1590/s0102311x2008000400020.

21. Gajalakshmi V, Peto R, Kanaka TS, Jha P. Smoking and mortality from tuberculosis and other diseases in India: Retrospective study of 43 000 adult male deaths and 35000 controls. Lancet 2003;362(9383):507-515. https://doi.org/10.1016/s01406736(03)14109-8 22. Gupta PC, Pednekar MS, Parkin D, Sankaranarayanan R. Tobacco associated mortality in Mumbai (Bombay) India. Results of the Bombay Cohort Study. Int J Epidemiol 2005;34(6):1395-1402. https://doi.org/10.1093/ije/dyi196 23. Worodria W, Massinga-Loembe M, Mazakpwe D, et al. Incidence and predictors of mortality and the effect of tuberculosis immune reconstitution inflammatory syndrome in a cohort of TB/HIV patients commencing antiretroviral therapy. J AIDS 2011;58(1):32-37. https://doi.org/10.1097/qai.0b013e3182255dc2 24. Jacob ST, Moore CC, Banura P, et al. Severe sepsis in two Ugandan Hospitals: A prospective observational study of management and outcomes in a predominantly HIV-1 infected population. PLoS One 2009;4(11):e7782. https://doi. org/10.1371%2Fjournal.pone.0007782.

25. Pencina MJ, D’Agostino RB Sr. Evaluating discrimination of risk prediction models: The c-statistic. JAMA 2015;314(10):1063-1064. https://doi.org/10.1001/ jama.2015.11082.

26. World Health Organization. Treatment of Tuberculosis: Guidelines, 4th ed. Geneva: WHO, 2010. http://www.who.int/tb/publications/2010/9789241547833/en/ WHO reference number: WHO/HTM/TB/2009.420 (accessed 12 October 2016).

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ORIGINAL RESEARCH 27. Lahey T, MacKenzie T, Arbeit RD, et al. Recurrent tuberculosis risk among HIV-infected adults in Tanzania with prior active tuberculosis. Clin Infect Dis 2013;56(1):151-158. https://doi.org/10.1093/cid/cis798 28. Adams LV, Kreiswirth BN, Arbeit RD, et al. Molecular epidemiology of HIV-associated tuberculosis in Dar es Salaam, Tanzania: Strain predominance, clustering, and polyclonal disease. J Clin Microbiol 2012;50(8):2645-2650. https://doi.org/10.1128/jcm.00624-12.

29. World Health Organization. Global Tuberculosis Report 2016. Geneva: WHO, 2016. http://apps.who.int/iris/bitstream/10665/250441/1/9789241565394-eng.pdf?ua=1 WHO reference number: WHO/HTM/TB/2016.13 (accessed 12 October 2016).

30. World Health Organization. Ministry of health and partners review the National TB prevalence survey report. Geneva: WHO, 2017. http://www.afro.who.int/ news/ministry-health-and-partners-review-national-tb-prevalence-survey-report. (accessed 12 October 2016).

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31. Steingart KR, Schiller I, Horne DJ, Pai M, Boehme CC, Dendukuri N. XpertÂŽMTB/ RIF assay for pulmonary tuberculosis and rifampicin resistance in adults. Cochrane Database Syst Rev 2013;(1):1-131. https://doi.org/10.1002/14651858.cd009593.pub3 32. Theron G, Venter R, Calligaro G, et al. Xpert MTB/RIF Results in patients with previous tuberculosis: Can we distinguish true from false positive results? Clin Infect Dis 2016;62(8):995-1001. https://doi.org/10.1093/cid/civ1223

Accepted 31 August 2017.

ORIGINAL RESEARCH

Knowledge of the health consequences of tobacco smoking among Nigerian smokers: A secondary analysis of the Global Tobacco Survey B O Adeniyi,1 MB ChB,FWACP; O S Ilesanmi,2 MBBS, MBA, MSc, MPH, FWACP; O M Babasola,3 BSc, MSc (Epid); B I Awokola,4 MBBS, FMCFM, FWACP; A O Kareem,2 MB ChB; D Obaseki,5 MBBS, MPH, FWACP; G E Erhabor,5 MBBS, FWACP, FCCP, FRCP (Edin), FRCP, (Lond) Department of Internal Medicine, Federal Medical Centre, Owo, Ondo State, Nigeria Department of Community Medicine, Federal Medical Centre, Owo, Ondo State, Nigeria 3 Department of Public Health, Africare Nigeria, Lagos, Nigeria 4 Medical Research Council (UK) Unit, Fajara Camp, The Gambia.

5 Department of Internal Medicine, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria 1 2

Corresponding author: B O Adeniyi (bamidele.adeniyi@gmail.com)

Background. Tobacco smoking is a leading cause of preventable death in the world and a risk factor for several non-communicable diseases.

Based on current trends, it is estimated that tobacco smoking will account for 8.4 million premature deaths each year by 2030. Knowledge of the consequences of smoking is necessary to initiate smoking cessation.

Objectives. This study aimed to identify the knowledge and perceived risks of the health consequences of smoking with regard to cancer among smokers in Nigeria.

Methods. This was a secondary data analysis of the Global Adult Tobacco Survey (GATS). The 2012 Nigerian GATS was a national representative household survey of 9 765 non-institutionalised men and women aged 15 years and older. Associations between sociodemographic variables, beliefs and attitude about smoking and its consequences were explored using the Ď&#x2021;2 test. The level of statistical significance was 5%.

Results. The records of all current smokers (4.4%; N=429) were extracted. The mean (standard deviation) age of smokers was 43.7 (14.6) years. Only 3.5% (n=15) were female, and 57.2% (n=245) were rural dwellers. Of the 9 765 that participated in the study, a total of 335 (3.4%) were daily tobacco smokers while 94 (1.0%) smoke less often than daily. Knowledge that smoking can cause various cancers was reported as follows: lung cancer 58.3% (n=250); bladder cancer 31.0% (n=133); mouth cancer 34.0% (n=146); and stomach cancer 31.5% (n=135).

Overall, 67.8% (n=291) believed smoking tobacco caused serious illness. In the North Central region, 40.0% (n=32) knew that smoking could cause lung cancer compared with 75.0% (n=51) in the South East (p<0.001). Among rural dwellers, only 48.4% (n=119) knew that smoking could cause lung cancer compared with 71.6% (n=131) of urban dwellers (p<0.001).

Conclusion. The level of awareness of the adverse effects of tobacco smoking in Nigeria was low and varied by region and socioeconomic development. This presents a potential point of intervention through targeted health educational campaigns to change behaviour among smokers.

S Afr Respir J 2017;23(4):113-120. DOI:10.7196/SARJ.2017.v23i4.178

Tobacco use is a leading cause of preventable death in the world and a risk factor for several non-communicable diseases including cancers, cardiovascular diseases, diabetes mellitus, and chronic respiratory diseases.[1] About 6 million people die annually from tobacco use, and if nothing is done to reverse or halt the epidemic, tobacco-related deaths could rise to 8.4 million annually by 2030.[2] Up to 80% of deaths related to tobacco use are projected to be in the developing countries, which are now the prime target for transnational tobacco companiesâ&#x20AC;&#x2122; market expansion activities.[3] In Nigeria, the prevalence of tobacco smoking has been reported to vary between 4.1% and 8.6%.[4-6] This figure is expected to rise with increasing exposure of the younger population to tobacco smoking, coupled with the absence and weak enforcement of anti-smoking policies.

The World Health Organization (WHO) Framework Convention on Tobacco Control (FCTC) was an international treaty negotiated under the auspices of the WHO. [7] It was adopted by the World Health Assembly on 21 May 2003 and enforced on 27 February 2005. [7] Under the FCTC treaty, member countries were expected to monitor tobacco use, conduct population-based surveys that would create an understanding of disease patterns, assess the effect of tobacco control measures, and assist tobacco control policy.[7] The Global Tobacco Surveillance System (GTSS) was implemented in 1988 by the WHO, the Centers for Disease Control and Prevention (CDC), and the Canadian Public Health Association (CPHA) as a programme to assist countries in conducting tobacco surveillance

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ORIGINAL RESEARCH and establishing a monitoring system for key articles of the WHO’s FCTC.[8,9] The GTSS includes the collection of data through four surveys: the Global Youth Tobacco Survey (GYTS); the Global School Personnel Survey (GSPS); the Global Health Professional Student Survey (GHPSS); and the Global Adult Tobacco Survey (GATS). The GYTS focused on youth aged 13 - 15 years and collected information in schools. The GSPS surveyed teachers and administrators from the same schools that participated in the GYTS. The GHPSS focused on 3rd-year students pursuing degrees in dentistry, medicine, nursing and pharmacy. The GATS is a nationally representative household survey that monitors tobacco use among adults aged 15 years and older using a standard protocol.The use of a standardised protocol, is to enable cross-country comparisons and also comparisons in the changes in the prevalence of tobacco use that may occur over time for countries that repeat the survey.[10] The Nigerian GATS was conducted in 2012.[11] The aim of this study was to assess the knowledge of adverse health consequences of tobacco smoking with particular reference to it as a risk factor for cancers among smokers documented in the survey.

Methods

The GATS 2012 data for Nigeria[12] were analysed. The Nigerian GATS was conducted by the National Bureau of Statistics (NBS) under the coordination of the Federal Ministry of Health (FMOH).

Technical assistance was provided by the WHO and the US CDC. It was funded by the Bloomberg Initiative to Reduce Tobacco Use. The Nigerian GATS data were released to the public domain in 2014.[11] A total of 11 107 households were sampled; 9 911 households completed screening and 9 765 individuals aged ≥15 years were successfully interviewed. One individual was randomly chosen from each selected household to participate in the survey. Data were collected using handheld electronic devices. The questionnaire included core questions about background characteristics of the respondents, tobacco smoking habits, smokeless tobacco products usage, smoking cessation, exposure to second-hand smoke, and knowledge, attitudes and perceptions regarding adverse effects of tobacco smoking.

The overall response rate for the GATS of Nigeria was 89.1%.

The household response rate was 90.3% (86.8% urban, 94.1% rural), while the individual response rate was 98.6% (98.0% urban, 99.2% rural). Detailed information on the methodology has been published elsewhere.[11] For the purpose of our study, we extracted data for the smokers only. Selected sociodemographic variables were the independent variables while the dependent variable was the knowledge or belief that tobacco use causes cancer. All the independent variables were categorical. Smokers were defined as those who were using tobacco at the time of the survey as well as those who were using smokeless tobacco products, either daily or occasionally. Former tobacco users were not categorised as smokers. SPSS version 21 (IBM Corp., USA) was used to analyse the data.

The advantage of the GATS was that it was designed to produce nationally representative data, covering both rural and urban settings in all of the 6 geopolitical zones in Nigeria.

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Results

The socioeconomic profile of the respondents and the distribution by region is shown in Table 1. The majority of the smokers were observed to be in the young and middle-aged group (25 - 44 years and 45 - 64 years). The South West and North Central regions had the highest number of smokers at 19.1% (n=82) and 18.6% (n=80), respectively.

Table 1 shows the sociodemographic characteristics of current cigarette smokers. The highest smoking prevalence was found in those between 25 and 44 years of age (61.8%; n=265) and the lowest prevalence was recorded among those > 65 years of age (4.9%; n=21).

There were more male smokers (96.5%), mainly from rural regions (57.3%; n=246). In terms of regional variation, the South West had the highest number of smokers (19.1%, n=82), while the North East had the lowest (11.2%; n=48). Fig. 1 shows the knowledge or belief that tobacco smoking causes serious illness among smokers. As shown, 67.8% of current smokers answered ‘yes’ to the question on whether tobacco smoking causes serious illness.

Table 1. Sociodemographic characteristics of cigarette smokers and knowledge of tobacco smoking as a cause of lung cancer among smokers in Nigeria Variables

n (%)

Age (years) 15 - 24

37 (8.6)

25 - 44

265 (61.8)

45 - 64

106 (24.7)

65+

21 (4.9)

Sex Male

414 (96.5)

Female

15 (3.5)

Educational status No formal education

109 (25.4)

Primary school and below

120 (28.0)

Secondary

138 (32.2)

Post-secondary

62 (14.5)

Marital status (n=428) Single

105 (24.5)

Currently married

286 (66.8)

Ever married

37 (8.6)

Urban/rural status Urban

183 (42.7)

Rural

246 (57.3)

Region North Central

80 (18.6)

North East

48 (11.2)

North West

75 (17.5)

South East

68 (15.9)

South South

76 (17.7)

South West

82 (19.1)

Respondents, %

ORIGINAL RESEARCH 100 90 80 70 60 50 40 30 20 10 0

sociodemographic characteristics and knowledge of tobacco smoking as a cause of mouth cancer among smokers is shown in Table 5.

Only 15.0% (n=12) of participants from the North Central region believed that smoking cigarettes could cause stomach cancer, as shown in Table 6.

67.8

Discussion

19.1

12.8

0.2 Yes

No

Do not know

Refused

Responses

Fig. 1. Knowledge or belief that tobacco smoking causes serious illness among smokers.

Table 2. Knowledge of tobacco smoking as a cause of cancer among smokers Cancer

Frequency, n (%)

Lung Yes

250 (58.3)

No

179 (41.7)

Bladder Yes

133 (31.0)

No

296 (69.0)

Mouth Yes

146 (34.0)

No

283 (66.0)

Stomach Yes

135 (31.5)

No

294 (68.5)

Among the smokers, 58.3% (n=250) believed that lung cancer could occur as a result of cigarette smoking. Knowledge of tobacco smoking as a possible cause of other cancers was as follows: bladder cancer 31.0% (n=133); mouth cancer 34.0% (n=146); and stomach cancer 31.5% (n=135).

Table 3 shows the association between sociodemographic characteristics and the knowledge that cigarette smoking causes cancer. In the North Central region, 40.0% (n=32) knew that smoking could cause lung cancer compared with 75.0% (n=51) in the South East (p<0.001). Among rural dwellers, only 48.4% (n=119) knew that smoking could cause lung cancer compared with 71.6% (n=131) of urban dwellers p<0.001.

The sociodemographic characteristics and knowledge of tobacco smoking as a cause of bladder cancer among smokers are displayed in Table 4. Only 16.3% (n=13) of smokers in the North Central region believed smoking cigarettes could cause bladder cancer, while higher numbers of participants from other regions believed this was possible.

Only 16.3% (n=13) of smokers in the North Central region believed smoking cigarettes could cause cancer of the mouth, while in the other regions, a significantly higher percentage believed that smoking could be a cause of cancer of the mouth. The association between other

The prevalence of smoking according to the Nigerian GATS in 2012 was 4.4%.[11] The findings of this study conform with other reports that place tobacco smoking prevalence in Nigeria between 4.1 and 8.6%.[4-6] It was similar to the prevalence rates from Cameroon (6%), Ghana (4%) and Ethiopia (2.8%) previously reported in the WHO data on smoking in Africa.[13] This prevalence was low compared with the reports of other studies, which reported a 19.7% prevalence in the USA,[14] and as high as 34% in some European countries.[15]Â Smoking is largely seen as a social stigma in Africa and most people who smoke tend to do so secretly. This may account for the differences between the smoking prevalence in Nigeria and other parts of the world. It is possible that this trend may however be changing as there is an increase in the social acceptance of smoking, particularly among young adults.[16] The majority of the smokers were male and relatively young with a mean (SD) age of 43.7 (14.6) years. In addition, most of them were married at the time of the survey and were living in rural areas.

However, only ~14.5% of them had post-secondary level education.

The findings revealed that the proportion of cigarette-smoking female respondents was low, which was similar to previous studies in Nigeria,[17,18] and agreed with the low prevalence rate reported in a survey conducted in Osun State, Nigeria.[19] Though this was a positive improvement, the higher prevalence of tobacco use among males increases the risks associated with passive smoke and continues to endanger the health of non-smokers. Passive smoking has also been documented to be an equally potent risk factor for chronic respiratory diseases and cancers.[3,20,21] Previous studies showed that involuntary exposure to tobacco smoke puts non-smokers at a greater risk of diseases associated with smoking, including sudden infant death syndrome in infants.[22] The present analysis showed that knowledge about the health consequences of tobacco as it relates to cancers among respondents is sub-optimal and varies with location. Previous studies have explored the knowledge of the health consequences of tobacco smoking among the general population in Nigeria and most have reported varying levels of knowledge related to the health consequences of smoking; [23-25] however, our study focused on tobacco smokers which is one of the few studies in that regard.

The generally low level of knowledge of the adverse effects of smoking can be extrapolated to other African countries. Countries with a similar socioeconomic and literacy status to Nigeria would probably demonstrate similar levels of knowledge; however, this remains to be validated through relevant research.

Regarding the implication of tobacco use on cancer causation, more than half of the respondents believed that tobacco use could cause lung cancer. This might be due to the fact that most anti-tobacco campaigns have focused mainly on its adverse effects on the lungs, thus increasing the level of knowledge in this regard. Although various issues come to mind when discussing tobacco use, the hazards of smoking in relation to

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ORIGINAL RESEARCH Table 3. Sociodemographic characteristics and knowledge of tobacco smoking as a cause of lung cancer among smokers Yes, n (%)

No, n (%)

Ď&#x2021;2

p-value

15 - 24

18 (48.6)

19 (51.4)

0.398

0.264

25 - 44

159 (60.0)

106 (40.0)

45 - 64

64 (60.4)

42 (39.6)

65+

9 (42.9)

12 (57.1)

Male

243 (58.7)

171 (41.3)

0.861

0.427

Female

7 (46.7)

8 (53.3) 0.739

0.060

0.160

<0.001

0.160

<0.001

0.302

<0.001

Sociodemographic characteristics Age (years)

Sex

Educational status No formal education

52 (47.7)

57 (52.3)

Primary school and below

72 (60.0)

48 (40.0)

Secondary

89 (64.5)

49 (35.5)

Post-secondary

37 (59.7)

25 (40.3)

Marital status Single

57 (54.3)

48 (45.7)

Currently married

181 (63.3)

105 (36.7)

Ever married

11 (29.7)

26 (70.3)

Urban

131 (71.6)

52 (28.4)

Rural

119 (48.4)

127 (51.6)

North Central

32 (40.0)

48 (60.0)

North East

24 (50.0)

24 (50.0)

North West

52 (69.3)

23 (30.7)

South East

51 (75.0)

17 (25.0)

South South

36 (47.4)

40 (52.6)

South West

55 (67.1)

27 (32.9)

Urban/rural status

Region

lung cancer cannot be overemphasised. Despite being the second most common malignancy of the urogenital system after prostate cancer in Nigeria,[26] the knowledge of tobacco use in relation to bladder cancer was low among the respondents (31%). Smoking is a major contributor to the global burden of dental diseases as it is associated with up to half of all periodontal disease conditions among adults.[27] This association has been established in the literature.[28] Unfortunately, only 34% of the respondents knew that tobacco use is a risk factor for developing mouth cancer. Interestingly, much higher levels of awareness (72%) were reported among dental patients in a South-Western tertiary hospital in Nigeria[29] and a comparable level of awareness was noted in a population-based study in North Carolina[30] in the USA, where 86% of the respondents had heard of oral cancer and 56% had knowledge of the risk factors. The knowledge regarding tobacco as a cause of stomach cancer was equally poor as only about a third of the smokers associated smoking with stomach cancer.

The majority of the respondents in our study agreed that smoking had adverse health effects, but the knowledge of smoking as a cause of specific cancers was rather low.

116 SARJ VOL. 23 NO. 4 2017

It is obvious from this study, that there is a slightly better level of awareness regarding the association between smoking and lung cancer compared with cancers of other parts of the body. This has been reported in various countries represented in the international tobacco control (ITC) and the global tobacco surveillance system (GTSS) data â&#x20AC;&#x201C; both data sets showed that the lack of awareness that smoking caused heart disease, heart attacks, and strokes was highest in China. Among Chinese smokers, the awareness that smoking causes lung cancer was however over 80% in both data sets. Other countries with striking unawareness (â&#x2030;Ľ25%) of the effects of smoking on the heart were the Netherlands, Bangladesh, Thailand, India, Russia, and Vietnam. The lack of awareness of smoking as a cause of stroke was even higher.[31] Most of the previous efforts of anti-smoking campaigns in Nigeria have largely focused on the prevention of lung cancer. It is thus possible that most people do not readily link the adverse effects of smoking with other body organs that appear not to be directly exposed to smoke. Even in more economically advanced regions of the world, fewer people associated smoking with adverse effects other

ORIGINAL RESEARCH Table 4. Sociodemographic characteristics and knowledge of tobacco smoking as a cause of bladder cancer among smokers Yes, n (%)

No, n (%)

Ď&#x2021;2

p-value

15 - 24

13 (35.1)

24 (64)

0.582

0.901

25 - 44

79 (29.8)

186 (70.2)

45 - 64

34 (32.1)

72 (67.9)

65+

7 (33.3)

14 (66.7) 0.588

0.570

0.102

0.796

0.563

0.060

0.670

0.010

0.175

0.004

Sociodemographic characteristics Age (years)

Sex Male

127 (30.7)

287 (69.3)

Female

6 (40.0)

9 (60.0)

No formal education

30 (27.5)

79 (72.5)

Primary school and below

37 (30.8)

83 (69.2)

Secondary

45 (32.6)

93 (67.4)

Post-secondary

21 (33.9)

41 (66.1)

Single

27 (25.7)

78 (74.3)

Currently married

99 (34.6)

187 (65.4)

Ever married

7 (18.9)

30 (81.1)

Urban

69 (37.7)

114 (62.3)

Rural

64 (26.0)

182 (74.0)

North Central

13 (16.3)

67 (83.8)

North East

16 (33.3)

32 (66.7)

North West

34 (45.3)

41 (54.7)

South East

22 (32.4)

46 (67.6)

South South

19 (25.0)

57 (75.0)

South West

29 (35.4)

53 (64.6)

Educational status

Marital status

Urban/rural Status

Region

than affecting the lungs.[31] This is an important point to note and also a potential point of intervention.

Other findings from this study showed that smokers who were single were less knowledgeable about tobacco smoking as a cause of lung cancer. This was an interesting finding as it may highlight the role of marriage partners in the communication of the adverse effect of smoking to their spouse with a view to protecting both parties. This assertion needs to be validated.

A larger proportion of the smokers in rural areas did not know that smoking could lead to lung cancer. Smokers from the North Central region of Nigeria had poor knowledge of tobacco smoking as a risk factor for lung, bladder, mouth and stomach cancer. The regional variation in the level of knowledge regarding the adverse effects of tobacco smoking also appeared to parallel the level of socioeconomic development in northern Nigeria compared with the southern region.

It is generally known that the northern part of Nigeria has a lower literacy level compared with the southern regions of the country.[32] In a landmark study that investigated socioeconomic and country variations in smokersâ&#x20AC;&#x2122; knowledge that smoking causes heart disease,

stroke, impotence and lung cancer, and involving adult smokers from four countries (USA, Canada, the UK, and Australia) higher education and income were associated with higher awareness, while lower socioeconomic status was associated with lower awareness of the harms of smoking and misunderstandings about nicotine.[33] This may account for the observed differences highlighted above. It is important to point out that <15% of participants in our study had at least post-secondary education and above, thus the low level of awareness may be related to the low literacy level.

Conclusion

We concluded that among smokers in Nigeria, there is a gross lack of knowledge of the health consequences of smoking, particularly of cancers other than that affecting the lungs.

This low level of knowledge varies according to region and possibly levels of socioeconomic development.

This is a potential point of intervention to change behaviour in regions most affected. Concerted efforts geared towards smokertargeted cessation health education needs to be organised and

SARJ VOL. 23 NO. 4 2017

117

ORIGINAL RESEARCH Table 5. Sociodemographic characteristics and knowledge of tobacco smoking as a cause of mouth cancer among smokers Yes, n (%)

No, n (%)

χ2

p-value

15 - 24

14 (37.8)

23 (62.2)

0.129

0.730

25 - 44

86 (32.5)

179 (67.5)

45 - 64

37 (34.9)

69 (65.1)

65+

9 (42.9)

12 (57.1)

Male

141 (34.1)

273 (65.9)

0.003

0.100

Female

5 (33.3)

10 (66.7)

No formal education

34 (31.2)

75 (68.8)

0.185

0.602

Primary school and below

45 (37.5)

75 (62.5)

Secondary

49 (35.5)

89 (64.5)

Post-secondary

18 (29.0)

44 (71.0)

Single

28 (26.7)

77 (73.7)

0.757

0.023

Currently married

110 (38.7)

176 (61.5)

Ever married

8 (21.6)

29 (78.4)

Urban

71 (38.8)

112 (61.2)

0.322

0.080

Rural

75(30.5)

171 (69.5)

North Central

13 (16.3)

67 (83.8)

0.175

0.004

North East

21 (43.8)

27 (56.7)

North West

30 (40.0)

45 (60.0)

South East

21 (30.9)

47 (69.1)

South South

26 (34.2)

50 (65.8)

South West

35 (42.7)

47 (57.3)

Sociodemographic characteristics Age (years)

Sex

Educational status

Marital status

Urban/rural status

Region

executed to promote better lung health and thus reduce diseases associated with cigarette smoking in Nigeria. It may be better to state the specific adverse effects that smoking can cause on cigarette packs rather than a blanket statement like ‘smoking is injurious to your health’. Billboards and media messages depicting the adverse effects of smoking should also be optimised, particularly in strategic public places like airports, campuses, shopping malls and the local markets. More importantly, healthcare practitioners should create adequate time to educate smokers and encourage tobacco smoking cessation.

A strength of our study was that it targeted the smoking population; however its finding might not represent current realities as timechanging trends might have altered its findings. We recommend a possible repeat of the GATS in Nigeria in order to update our knowledge and also encourage workers from other countries with the GATS data to carry out similar secondary analysis.

Author contributions. AB conceptualised the study and wrote the manuscript. OI analysed the data. OB wrote an initial draft. AB edited the manuscript and wrote the discussion. AK captured and cleaned the data.

118 SARJ VOL. 23 NO. 4 2017

OD helped in the writing the manuscript and the abstract. EG provided mentorship throughout from conceptualisation to the writing up of the manuscript.

Acknowledgements. We would like to thank members of staff of the community health department who provided administrative support for this work.

Funding. None.

Conflicts of interest. None.

1. Samet JM. Tobacco smoking: The leading cause of preventable disease worldwide.

Thoracic Surg Clin 2013;23(2):103-112. https://doi.org/10.1016/j.thorsurg.2013.01.009 2. Murray CJ, Lopez AD. Evidence-based health policy – lessons from the Global Burden of Disease Study. Science 1996;274(5288):740-743. https://doi.org/10.1126/ science.274.5288.740 3. World Health Organization. World Report on the Global Tobacco Epidemic. The MPOWER package. Geneva: WHO, 2008.

4. Hussain NA, Akande M, Adebayo ET. Prevalence of cigarette smoking and the knowledge of its health implications among Nigerian soldiers. East Afr J Public Health 2010;6(2):81-83. https://doi.org/10.4314/eajph.v6i2.51754 5. Ibeh CC, Ele PU. Prevalence of cigarette smoking in young Nigerian females. Afr J Med Med Sci 2003;32:335-338.

ORIGINAL RESEARCH Table 6. Sociodemographic characteristics and knowledge of tobacco smoking as a cause of stomach cancer among smokers Yes, n (%)

No, n (%)

χ2

p-value

15 - 24

13 (35.1)

24 (69.4)

0.111

0.774

25 - 44

79 (29.8)

186 (70.2)

45 - 64

35 (33.0)

71 (67.0)

65+

8 (38.1)

13 (61.9)

Male

131 (31.6)

283 (68.4)

0.166

0.784

Female

4 (26.7)

11 (73.3)

No formal education

32 (29.4)

77 (70.6)

0.152

0.677

Primary school and below

43 (35.8)

77 (64.2)

Secondary

42 (30.4)

96 (69.6)

Post-secondary

18 (29.0)

44 (71.0)

Single

29 (27.6)

76 (72.4)

0.342

0.181

Currently married

98 (34.3)

188 (65.7)

Ever married

8 (21.6)

2 (78.4)

Urban

65 (35.5)

118 (64.5)

0.242

0.119

Rural

70 (28.5)

176 (71.5)

North Central

12 (15.0)

68 (85.0)

0.196

0.001

North East

16 (33.3)

32 (66.7)

North West

32 (42.7)

43 (57.3)

South East

17 (25.0)

51 (75.0)

South South

24 (31.6)

52 (68.4)

South West

34 (41.5)

48 (58.5)

Sociodemographic characteristics Age (years)

Sex

Educational status

Marital status

Urban/rural status

Region

6. Desalu OO, Adekoya AO, Elegbede AO, Dosunmu A, Kolawole TF, Nwogu KC. Knowledge of and practices related to smoking cessation among physicians in Nigeria. J Bras Pneumol 2009;35(12):1198-1203. https://doi.org/10.1590/S180637132009001200006 7. World Health Organization. History of the World Health Organization Framework Convention on Tobacco Control. Geneva: WHO, 2009.

8. Mochizuki‐Kobayashi Y, Richter‐Airijoki H, Asma S, et al. The global tobacco surveillance system. Tob Control 2006;15(Suppl 2):ii1-ii3. https://doi.org/10.1136/ tc.2006.015719 9. Global Tobacco Surveillance System Collaborating Group. Global Tobacco Surveillance System (GTSS): Purpose, production, and potential. J School Health 2005;75(1):15-24. https://doi.org/10.1111/j.1746-1561.2005.tb00004.x 10. Global Tobacco Control - GTSS - Smoking & Tobacco Use Centre for Disease Control and Prevention. Atlanta: CDC, 2016. www.cdc.gov/tobacco/global/gtss/index.htm (accessed 21 June 2017).

11. World Health Organization. Global Adult Tobacco Survey: Country Report 2012.

Geneva: WHO, 2012. http://www.who.int/tobacco/surveillance/survey/gats/nigeria_ country_report.pdf (accessed 21 June 2017).

12. CDC Foundation, Centers for Disease Control and Prevention (CDC), Federal Ministry of Health (Nigeria), Johns Hopkins Bloomberg School of Public Health, National Bureau of Statistics (Nigeria), World Health Organization. Federal Ministry of Health (Nigeria). Nigeria Global Adult Tobacco Survey 2012. Atlanta: CDC, 2012..

13. Ali AYM, Safwat T, Onyemelukwe G, et al. Smoking prevention and cessation in the Africa and Middle East Region: A consensus draft guideline for healthcare providers – executive summary. Respiration 2012;83(5):423-432. https://doi. org/10.1159/000337726

14. Solberg LI, Flottemesch TJ, Foldes SS, Molitor BA, Walker PF, Crain AL. Tobacco-use prevalence in special populations taking advantage of electronic medical records. Am J Prev Med 2008;35(6 Suppl):501-507. https://doi.org/10.1016/j.amepre.2008.08.033 15. Kaleta D, Kozieł A, Miskiewicz P. Global Adult Tobacco Survey in Poland – the aim and current experiences. Med Pr 2009; 60(3):197-200.

16. Rudatsikira E, Abdo A, Muula AS. Prevalence and determinants of adolescent tobacco smoking in Addis Ababa, Ethiopia. BMC Public Health 2007;7(1):176. https://doi. org/10.1186/1471-2458-7-176 17. Ehizele AO, Azodo CC, Ojehanon PI, Akhionbare O, Umoh AO, Adeghe HA. Prevalence of tobacco use among dental patients and their knowledge of its health effects. Nig J Clin Pract 2012;3:(1):270-275. https://10.4103/1119-3077.100619 18. Ayankogbe OO, Inem OA, Bamgbala OA, Robert OA. Attitudes and determinant of cigarette smoking among rural dwellers South West. Nigeria Niger Med Pract 2003; 44(1):70-74.

19. Adepoju EG, Oloowokere SA, Adeleke NA Afolabi OT, Olajide FO, Aluko OO. A population based study on the prevalence of cigarette smoking and smokers’ characteristics at Osogbo, Nigeria. Tob Use Insights 2013;6:1-5. https://doi. org/10.4137/TUI.S10763.

20. Mathers CD, Bernard C, Iburg KM, et al. Global burden of disease in 2002: Data sources, methods and results. Global programme on evidence for health policy discussion paper. Geneva: WHO, 2003. https://www.who.int/healthinfo/paper54.pdf (accessed 14 November 2017).

21. Desalu OO, Onyedum CC, Adewole OO, Fawibe AE, Salami AK. Second hand smoke exposure among non-smoking adults in two Nigerian cities. Ann Afr Med 2011;10(2):103-111. https://doi.org/10.4103/1596-3519.82069 22. Anderson HR, Cook DG. Passive smoking and sudden infant death syndrome: review of the epidemiological evidence. Thorax 1997;52:1003-1009.

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119

ORIGINAL RESEARCH 23. Onyeonoro UU, Chukwuonye II, Madukwe OO, Ukegbu AU, Akhimien MO, Ogah OS. Awareness and perception of harmful effects of smoking in Abia State, Nigeria.

Nig J Cardiol 2015;12(1):27. https://doi.org/10.4103/0189-7969.148483 24. Salawu F, Danburam A, Isa B, Agbo J. Cigarette smoking habits among adolescents in northeast Nigeria. Int J Epidemiol 2010;8(1):8-11. https://doi.org/10.5580/6e2.

25. Dania MG, Ozoh OB, Bandele EO. Smoking habits, awareness of risks, and attitude towards tobacco control policies among medical students in Lagos, Nigeria. Ann Afr Med 2015;14(1):1-7. https://doi.org/10.4103/1596-3519.14870 26. Mandong BM, Iya D, Obekpa PO, Orkar KS. Urological tumours in Jos University Teaching Hospital (a hospital-based histopathological study). Nig J Surg Res 2000;2(3):108-113.

27. Tomar SL, Asma S. Smoking attributable periodontitis in the United States. Findings from NHANES III. J Periodontol 2000;71(5):743-751. https://doi.org/10.1902/ jop.2000.71.5.743 28. Bergstrom J, Eliasson S, Dock J. 10-year prospective study of tobacco smoking and periodontal health. J Periodontol 2000;71(8):1338-1347. https://doi.org/10.1902/ jop.2000.71.8.1338 29. Lawoyin JO, Aderinokun GA, Kolude B, Adekoya SM, Ogundipe BF. Oral cancer awareness and prevalence of risk behaviours among dental patients in South-Western Nigeria. Afr J Med Med Sci 2003;32(2):203-207.

120 SARJ VOL. 23 NO. 4 2017

30. Patton LL, Agans R, Elter JR, Southerland JH, Strauss RP, Kalsbeek WD. Oral cancer knowledge and examination experiences among North Carolina adults. J Public Health Dent 2004;64(3):173-180. https://doi.org/10.1111/j.1752-7325.2004.tb02748.x 31. Wood S. Lung Cancer? Yep, But Smokers, Globally, Are Less Aware of CVD Risks. www.medscape.com/viewarticle/762451 (accessed 14 November 2014).

32. United Nations Educational Scientific and Cultural Organization (UNESCO). Action Plan Nigeria. Paris: UNESCO, 2012. www.unesco.org/fileadmin/MULTIMEDIA/HQ/ ED/pdf/Nigeria.pdf (accessed 27 June 2017).

33. Siahpush M, McNeill A, Hammond D, et al. Socioeconomic and country variations in knowledge of health risks of tobacco smoking and toxic constituents of smoke: Results from the 2002 International Tobacco Control (ITC) Four Country Survey. Tob Control 2006;15(Suppl 3):iii65. https://doi.org/10.1136/tc.2005.013276

Accepted 21 September 2017.

PATS & SATS

CONGRESS 2018 12 - 15 April Durban ICC - South Africa

WWW.PATS2018.COM CALL FOR ASBTRACT

The Scientific committee invites the submission of abstracts to be considered for oral and poster presentations.

The deadline for the submission of abstracts is 12 January 2018.

Registrars and post graduate students are specifically invited to present.

Please submit your abstract online.Faxed abstracts will not be accepted.

All appropriate abstracts will be reviewed by the Scientific Committee. All abstracts received will be acknowledged, and authors will be sent acceptance or rejection letters by the 15th February 2018.

Please note that authors of accepted abstracts must be registered delegates. All costs, including registration, are for the authors' own expense.

Young Investigator awards are available for best abstracts by young investigators working in African institutions or linked to an African University. A young investigator is defined as any individual who obtained their last qualification (such as an Undergraduate degree in general medicine; Masters degree as a Physician or Paediatrician; or Certificate in Paediatric Pulmonology or Adult Pulmonology) within the last 5 years. The awards will cover congress registration, travel and accommodation. In order to be considered for these awards, kindly check the 'Young Investigator Award' box on the abstract submission page.

INSTRUCTIONS TO AUTHORS: 1. Each abstract must clearly state the following: -Abstract title (the title of the abstract must not exceed 25 words) -Name of list of author(s). The name of the presenting author must appear first in the list of authors.

-Affiliation of author(s).

-Contact details of first author (telephone numbers, e-mail address etc) 2. Abstracts must be typed in English, single line spacing, Arial font size 12.

3. The body of the text must not exceed 350 words (this excludes the information listed in point 1) 4. Please adhere to the following format: -Introduction: should be brief and informative and state the aim of the study -Methods: include description of subjects and research methodology -Results: outline the findings of the study supported by statistics as appropriate. Do not use figures, graphs or tables in the abstract. The data provided must be sufficient to permit peer review of the abstract -Conclusion: provide summary and relevance of the main findings

Supported by:

BREATH-TAKING NEWS

Real-world effectiveness of once-daily fluticasone furoate plus vilanterol in the maintenance treatment of asthma: The Salford Lung Study Guidelines for the routine management of medical conditions, including asthma, are based on efficacy from randomised controlled trials in highly selected and closely monitored patient populations, thereby limiting their relevance to everyday clinical practice. This is particularly important in asthma, where issues relating to compliance, inhaler technique and comorbidities can influence patients’ response to treatment. This necessitates the need for integrated comparative effectiveness trials to be conducted in more representative patients in routine care settings.

Woodcock et al.[1] investigated the effectiveness of fluticasone furoate plus vilanterol (FF/VI) on asthma control in clinical practice in an open-label, parallel group, randomised controlled trial set in the town of Salford in the United Kingdom. Participants were allocated to receive one of two experimental treatments: the combination of 100 μg fluticasone furoate and 25 μg vilanterol, or 200 μg fluticasone furoate and 25 μg vilanterol, according to the general practitioner’s assessment of severity. The treatments were administered once daily as a dry powder, through the novel Ellipta device, or continuation of optimised usual care. They used the well-validated Asthma Control Test as the primary instrument of asthma control; an improvement of 3 is considered the minimal clinical difference, while a score of ≥20 suggests that asthma is likely to be well controlled. Taking the latter two parameters into consideration, they showed that patients on the FF/VI regimens had twice the likelihood of achieving asthma control (p<0.001 in 74% of subjects) compared with those receiving usual care (60%).

122 SARJ VOL. 23 NO. 4 2017

In addition, the quality-of-life measurements, work productivity and activity impairment questionnaires also demonstrated improvements in favour of FF/VI. The incidence of serious adverse events was not increased with the new agents.

In a similar effectiveness trial by the same group,[2] the combination of FF/VI was shown to be associated with a lower rate of exacerbations when compared with usual care in patients who also had COPD. Their effectiveness study emphasises the potential benefits of the combination of FF/VI administered once daily to asthma patients in a wider practice setting. Poor compliance with complicated regimens is not uncommon among asthmatic patients; a once-daily regimen with more potent agents in a device that is easier to use could ameliorate this problem.

Donald Simon Division of Pulmonology, Department of Medicine, Tygerberg Academic Hospital and Stellenbosch University, Cape Town, South Africa 1. Woodcock A, Vestbo J, Bakerly ND, et al. Effectiveness of fluticasone furoate plus vilanterol on asthma control in clinical practice: An open-label, parallel group, randomised controlled trial. Lancet 2017;390(10109):2247-2255. https://doi.org/10.1016/S0140-6736(17)32397-8 2. Vestbo J, Leather D, Bakerly ND, et al. Effectiveness of fluticasone furoatevilanterol for COPD in clinical practice. N Engl J Med 2016;375(26):1253-1260. https://doi.org/10.1056/nejmoa1608033

S Afr Respir J 2017;23(4):122. DOI:10.7196/SARJ.2017.v23i4.189

BREATH-TAKING NEWS

Tezepelumab: A new pathway to asthma control Our understanding of the complex mechanisms of inflammation, which result in the clinical entity we call â&#x20AC;&#x2DC;asthmaâ&#x20AC;&#x2122;, has improved exponentially over the last few decades. This knowledge has resulted in the development of targeted biological therapy with several monoclonal antibodies, including those directed against IgE (omalizumab), interleukin-13 (tralokinumab), interleukin-5 (mepolizumab and reslizumab), and the alpha subunits of the interleukin-4 and interleukin-5 receptors (dupilumab and benralizumab). [1] One might be tempted to think that tezepelumab is simply another agent in this group; however, it is distinct from its predecessors in a way that may result in it having a far broader application. It is an investigational humanised IgG2 monoclonal antibody that blocks the action of thymic stromal lymphopoietin (TSLP) on its receptor complex, and exerts its effects on the inflammatory cascade far upstream of the agents mentioned previously. TSLP is an epithelial cell-derived cytokine produced in response to environmental and proinflammatory stimuli including tobacco, diesel smoke and viruses.

It is central to the regulation of type 2 inflammation through its activity on dendritic cells, T and B cells, as well as mast cells, basophils, natural killer T cells, innate lymphoid cells, and even neutrophils.[2] Corren et al.[2] examined the efficacy and safety of tezepelumab in uncontrolled asthmatics, in a recent industry-sponsored, phase 2, randomised, double-blind, placebo-controlled trial (PATHWAY). The group reported encouraging results: 3 dose levels of tezepelumab were compared with a placebo and resulted in a reduction in the annualised

exacerbation rate by 61%, 71%, and 66% at week 52, respectively.

Importantly, these differences were independent of baseline blood eosinophil counts and other Th2 biomarkers, though there was a substantial and persistent decrease in blood eosinophil count and fractional expired nitric oxide levels observed in the treatment groups.

In all tezepelumab groups, the pre-bronchodilator forced expiratory volume in 1 second at week 52 was >100 mL higher than in the placebo group. Though there was one fatal serious adverse event in the treatment group, the overall rate of adverse events did not differ in comparison with the rate observed in the placebo group.

These results highlight the potential advantages of targeting an upstream cytokine such as TSLP, which suggests that the future of asthma biologics may be in agents that affect disease activity more broadly than inhibition of a single downstream pathway.

Jane A Shaw Division of Pulmonology, Department of Medicine, Tygerberg Academic Hospital and Stellenbosch University, Cape Town, South Africa 1. Israel E, Reddel HK. Severe and difficult-to-treat asthma in adults. N Engl J Med 2017;377:965-976. https://doi.org/10.1056/NEJMra1608969 2. Corren J, Parnes JR, Wang L, et al. Tezepelumab in adults with uncontrolled asthma.

N Engl J Med 2017;377:936-946. https://doi.org/10.1056/nejmoa1704064

S Afr Respir J 2017;23(4):123. DOI:10.7196/SARJ.2017.v23i4.190

SARJ VOL. 23 NO. 4 2017

123

PRODUCT NEWS

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Asthma: RELVAR ELLIPTA is indicated for the maintenance, preventive treatment of asthma.11 One inhalation of RELVAR 92/22 µg once daily or one inhalation of RELVAR 184/22 µg once daily.11 A starting dose of RELVAR 92/22 µg should be considered for patients who require a low to mild dose of inhaled corticosteroid in combination with a long acting beta2-agonist.11 RELVAR 184/22 µg should be considered for patients who require a higher dose of inhaled corticosteroid in combination with a long acting beta2-agonist.11 If patients are inadequately controlled on RELVAR 92/22 µg, consider

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S.E.P. (incl. VAT)

RELVAR ELLIPTA 92/22 µg

ELLIPTA Inhaler ELLIPT

30 Doses

723300001

R 357,99

R 408,11

RELVAR ELLIPTA 184/22 µg

ELLIPTA Inhaler ELLIPT

30 Doses

723303001

R 456,48

R 520,38

For further information, please contact me directly on +27 11 239 6067, or our Customer Careline on 0800 122 912.

Aspen and GSK strive to provide access to treatment with practical efficacy that answers unmet needs identified through patient preference research.3,9,12 RELVAR ELLIPTA provides an evolution in the ICS/LABA market that can make a difference to patients’ lives with 24 hour efficacy from a once daily dose in an easy to use device.5,6,8-11 Regards, Adele Beyl Respiratory Portfolio Brand Manager abeyl@aspenpharma.com

NEW

Practical efficacy 3,9 * Data based on clinical studies with either metered dose inhalers or dry powder inhalers.7 COPD = Chronic Obstructive Pulmonary Disease ICS = Inhaled corticosteroid LABA = Long acting beta2-agonist

SIDE EFFECTS: Very Common: headaches, nasopharyngitis. Common: pneumonia, upper respiratory tract infection, bronchitis, influenza, candidiasis of mouth and throat, oropharyngeal pain, sinusitis, pharyngitis, abdominal pain, arthralgia, back pain, fractures, pyrexia. Uncommon: extrasystoles. WARNINGS AND SPECIAL PRECAUTIONS: Not to be used to treat acute asthma symptoms or an acute exacerbation in COPD. Increasing use of short-acting bronchodilators to relieve symptoms indicates deterioration of control and patients should be reviewed by a medical practitioner. CONTRA-INDICATIONS: Patients with severe milk-protein allergy or who have demonstrated hypersensitivity to either fluticasone furoate, vilanterol or any of the excipients.

References: 1. GSK data on file HO-15-15502. 2016. 2. IMS Data. May 2017. 3. Bernstein DI, et al. Fluticasone furoate (FF)/vilanterol (100/25 mcg or 200/25 mcg) or FF (100 mcg) in persistent asthma. J Asthma. 2015;52(10):1073–1083. 4. Boscia JA, et al. Effect of once-daily fluticasone furoate/vilanterol on 24-hour pulmonary function in patients with chronic obstructive pulmonary disease: a randomized, three-way, incomplete block, crossover study. Clin Ther. 2012;34(8):1655–1666.e5. 5. Price D, et al. Types, frequency and impact of asthma triggers on patients’ lives: a quantitative study in five European countries. J Asthma 2014;51(2):127-135. 6. Rennard S, Higenbottam T. Exacerbation-free COPD: A goal too far? Proc Am Thorac Soc. 2007;4:583–585. 7. NAC Inhaler technique in adults with asthma or COPD 2008. 8. Svedsater H, et al. Ease of use of the ElliptaTM dry powder inhaler: data from three randomised controlled trials in patients with asthma. npj Prim Care Resp Med. 2014;24:14019. 9. Svedsater H, et al. Qualitative assessment of attributes and ease of use of the Ellipta™ dry powder inhaler for delivery of maintenance therapy for asthma and COPD. BMC Pulm Med 2013;13:72. 10. Riley JH, et al. Correct usage, ease of use, and preference of two dry powder inhalers in patients with COPD analysis of five phase III, randomized trials. Int J Chron Obstruct Pulmon Dis. 2016;11:1873–1880. 11. RELVAR ELLIPTA Package Insert, 16 February 2017. 12. Svedsater H, et al. Qualitative interviews and focus groups with COPD and asthma patients: understanding patient burden, life impact and treatment preferences ATS. 2016; A1747.

S4 RELVAR ELLIPTA 92/22 µg (48/21.5.1/0249) Powder for Inhalation. S4 RELVAR ELLIPTA 184/22 µg (48/21.5.1/0250) Powder for Inhalation. INGREDIENTS: Each pre-dispensed dose contains 100/25 µg (delivers 92/22 µg) or 200/25 µg (delivers 184/22 µg) of fluticasone furoate/vilanterol (as trifenatate). INDICATIONS: Asthma: the maintenance, preventive treatment of asthma. COPD: the maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD) including chronic bronchitis and/or emphysema and to reduce exacerbations of COPD in patients with an exacerbation history. CONTRA-INDICATIONS: In patients with severe milk-protein allergy or who have demonstrated hypersensitivity to either fluticasone furoate, vilanterol or any of the excipients. WARNINGS AND SPECIAL PRECAUTIONS: Not to be used to treat acute asthma symptoms or an acute exacerbation in COPD. Increasing use of short-acting bronchodilators to relieve symptoms indicates deterioration of control and patients should be reviewed by a medical practitioner. Do not stop therapy without HCP supervision. Paradoxical bronchospasm may occur - treat immediately with a short-acting inhaled bronchodilator. Discontinue immediately and assess patient and alternative therapy instituted if necessary. Asthma-related adverse events and exacerbations may occur. Patients should be asked to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation. Use with caution in patients with cardiovascular disease, or heart rhythm abnormalities, hyperthyroidism or uncorrected hypokalaemia. Hypokalaemia may occur. High dosages may increase the risk of serious side effects, including cardiac dysrhythmias. This risk is further aggravated if administered concomitantly with other medicines that cause hypokalaemia and cardiac dysrhythmias, or in the presence of hypoxia and acidosis. The maximum dosage should not be exceeded. Beta-adrenergic blockers may cause bronchospasms and may weaken or antagonise the effect of beta2adrenergic agonists - concurrent use of both non-selective and selective beta-blockers should be avoided unless there are compelling reasons for their use. Increases in blood glucose levels in diabetic patients have occurred. Systemic corticosteroid effects (e.g.

HPA axis suppression, decrease in bone mineral density, growth retardation in children and adolescents, cataract and glaucoma) may occur, especially at high doses. Administer with caution in patients with pulmonary tuberculosis or with chronic or untreated infections. An increase in pneumonia has been observed in patients with COPD. Risk factors for pneumonia in patients with COPD include current smokers, patients with a history of prior pneumonia, patients with a body mass index < 25 kg/m2 and patients with a (forced expiratory volume) FEV1< 50 % predicted. These factors should be considered when RELVAR is prescribed and treatment should be re-evaluated if pneumonia occurs. Contains lactose/fructose: Do not use in patients with rare hereditary problems of galactose intolerance e.g. galactosaemia, Lapp lactase deficiency or glucose-galactose malabsorption or fructose intolerance. Ability to drive and operate machinery: No studies. INTERACTIONS: Beta-adrenergic blockers may cause bronchospasms and may weaken or antagonise the effect of beta2-adrenergic agonists and concurrent use of both non-selective and selective beta-blockers should be avoided. Care is advised when co-administering with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir) as there is potential for an increased systemic exposure. PREGNANCY AND LACTATION: Safety not established. DOSAGE AND DIRECTIONS FOR USE: Asthma: Adults and adolescents aged 12 years and over: One inhalation once daily. A starting dose of RELVAR 100/25 µg should be considered for patients who require a low to mild dose of inhaled corticosteroid in combination with a long acting beta2-agonist. RELVAR 200/25 µg should be considered for patients who require a higher dose of inhaled corticosteroid in combination with a long acting beta2-agonist. If patients are inadequately controlled on RELVAR 100/25 µg, consider increasing the dose to 200/25 µg. Children less than 12 years: not recommended. COPD: Adults: One inhalation of RELVAR 100/25 µg once daily. RELVAR 200/25 µg is not indicated for patients with COPD. Special Populations (Asthma and COPD): Elderly: No dosage adjustment. Renal impairment: No dose adjustment. Hepatic Impairment: Caution should be exercised as patients with hepatic impairment may be more at risk of systemic adverse reactions associated with corticosteroids. SIDE EFFECTS: Very Common: headaches, nasopharyngitis. Common: pneumonia, upper respiratory tract infection, bronchitis, influenza, candidiasis of mouth and throat, oropharyngeal pain, sinusitis, pharyngitis, abdominal pain, arthralgia, back pain, fractures, pyrexia. Uncommon: extrasystoles. MANAGEMENT OF OVERDOSAGE: No specific treatment for an overdose. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary. Cardioselective beta-blockade should only be considered for profound vilanterol overdose effects that are clinically concerning and unresponsive to supportive measures. Cardioselective beta-blocking medicines should be used with caution in patients with a history of bronchospasm. Further management should be as clinically indicated or as recommended by the national poison centre, where available. HCR: GlaxoSmithKline South Africa (Pty) Ltd (Co. reg. no. 1948/030135/07), 39 Hawkins Avenue, Epping Industria 1, 7460. Trademarks are owned by or licensed to the GSK group of companies. For full prescribing information, refer to package insert approved by the Medicines Regulatory Authority. All adverse events should be reported by calling the Aspen Medical Hotline number or directly to GlaxoSmithKline on +27 11 745 6000. ZAF/FFT/0021/17 08/17

RELVAR ELLIPTA was developed in collaboration with

Marketed by Aspen Pharmacare www.aspenpharma.com Medical Hotline 0800 118 088

SARJ VOL. 23 NO. 4 2017

125

PRODUCT NEWS

Concepts and misconceptions in oral anticoagulation Anticoagulants like warfarin (vitamin K antagonists (VKAs)) still have their place, however, direct oral anticoagulants (DOACs) offer unlimited advantages. This was the take-home message by Prof. Jan Beyer-Westendorf, head of the Thrombosis Research Unit in the Centre for Vascular Medicine at the Carl Gustav Carus University Hospital in Dresden, Germany. He was in South Africa (SA) from 19 to 23 September 2016, as a guest of Bayer, stating categorically that he only uses VKAs when it is unavoidable.

Anticoagulation treatment has evolved rapidly; in ~5 years, newer agents have become available, with dramatically increased use, ‘In 2010 2011, only 4.2% of patients in the GARFIELD AF registry received DOACs. By 2014 - 2015 this figure had increased to 37%.’

DOACs offer safer alternatives to warfarin, and have been shown to facilitate patient persistence with and adherence to treatment. ‘Sideeffects, treatment failure and bleeding all affect compliance. The one-year discontinuation rate for warfarin is in the region of 50% v. only 15% with factor Xa inhibitors such as rivaroxaban, suggesting that the DOACs are better accepted for long-term treatment by both prescribers and patients.’

An adherence study in Canada suggests rivaroxaban’s once-daily dosing regimen may offer a slight advantage over twice-daily regimens.

However, it demonstrated that 25 - 30% of twice-daily prescribed DOACs are taken once daily. Regardless, dosing is a challenge. In atrial fibrillation (AF) cohorts, ~20% of patients have dose reduction owing to moderate to severe renal impairment. Prescription data suggest that 35 - 50% of DOAC prescriptions indicate insufficient dosage, so a large proportion of AF patients may be undertreated.

Real-world studies are biased by patient selection, differing designs, baseline characteristics, and treatments. Prof. Beyer-Westendorf ’s advice was to ‘Never look at effectiveness and safety alone – look rather for net clinical benefit.’ Comparing DOACs is not possible in these studies.

Collectively, however, they consistently help to prevent strokes in correctly-dosed patients. They have also shown consistent safety: ‘Compared to real-life studies with VKAs, not a single current study has shown higher bleeding rates with DOACs.’

Dispelling misconceptions

Prof. Beyer-Westendorf debunked four myths regarding DOACs: Misconception one: Stable VKA-treated patients will not benefit from a switch to a DOAC. ‘Guidelines actively discourage switching. But is there such a thing as a stable VKA-treated patient – and is there any evidence that they can safely continue warfarin treatment? The evidence suggests otherwise. One could argue that patients with a very stable international normalised ratio (INR) (defined as a time-in-therapeutic range or TTR of at least 70%, preferably 75%) may be regarded as stable VKA patients. However, none of the phase III DOAC studies, which evaluated only carefully selected patients treated in dedicated trial units, achieved an INR-TTR of 70% with warfarin. Furthermore, data from the ORBIT-AF study from the USA indicated that only a few patients are truly stable on warfarin and a past record of stability only weakly predicts future results’ Misconception two: With renal impairment, VKAs should be preferred. However, post hoc and meta-analyses of phase-III DOAC trials showed DOACs being as effective and safe, and in the case of factor Xa inhibitors, superior to VKAs. ‘While not all thromboembolic events can be prevented, one out of five clots that would have developed with warfarin in renally impaired patients will not occur if a DOAC is used.

Using a DOAC can also prevent bleeding. Pooled EINSTEIN deep vein thrombosis and pulmonary embolism data showed a 4-fold increase in major bleeding with warfarin, but not with rivaroxaban.’

Misconception three: DOACs cause more gastrointestinal (GI) bleeding than VKAs. This perception was propagated by a meta-analysis in 2013.[1] Prof. Beyer-Westendorflamented it as ‘poor science’, leading to gross overestimation of DOAC-related GI bleeding.[2] A subsequent study debunked this.[3] Furthermore, in GI bleeding the focus on bleeding rates may be misleading because the GI bleeding site, management and outcome need to be considered. Aspirin and VKA bleeds usually occur in the upper GI tract, while most DOAC bleeds occur in the lower GI tract. Most lower GI bleeds are haemorrhoid bleeds, which are easily managed compared with gastric ulcer bleeds. The mortality of different types of GI bleeding varies significantly and data indicate that DOACs may offer advantages in GI bleeding.

Misconception four: Managing major bleeding is simpler and better for VKAs v. DOACs. The DOAC AF studies showed the opposite.

VKA major bleeding is associated with increased mortality, with worse patients experiencing less bleeding on DOACs. Prothrombin complex concentrate is praised in VKA treatment, but is often ineffective in obese patients, dosed incorrectly, and associated with thromboembolic complications. It’s needed less often in DOAC patients, where it is effective. Regardless, the new agents have, or will soon have reversal options: idarucizumab for dabigatran reversal, while andexanet alfa, with anti-factor Xa activity, is an excellent alternative for rivaroxaban, apixaban and edoxaban patients. Both antidotes have yet to be registered in SA. Prof. Beyer-Westendorf recapitulated: In real-world settings, compared with warfarin, the DOACs are associated with high persistence and adherence, as well as acceptably low stroke and major bleeding rates. VKA-associated major bleeding rates are much higher than in DOAC cohorts but since we cannot prevent major bleeding in every patient, the survival benefit in cases of major bleeding with DOACs is the main advantage over VKAs. 1. Holster IL, Valkhoff VE, Kuipers EJ, Tjwa ETTL. New oral anticoagulants increase risk for gastrointestinal bleeding: A systematic review and meta-analysis. Gastroenterology 2013;145(1):105-112. https://doi.org/10.1053/j.gastro.2013.02.041 2. Beyer-Westendorf J, Pannach S. Increase of gastrointestinal bleeding with new oral anticoagulants: Problems of a meta-analysis.

Gastroenterology 2013;145(5):1162-1163. https://doi.org/10.1053/j.gastro.2013.09.041 3. Caldeira D, Barra M, Ferreira A, et al. Systematic review with meta-analysis: The risk of major gastrointestinal bleeding with nonvitamin K antagonist oral anticoagulants. Aliment Pharmacol Ther 2015;42(11-12):1239-1249. https://doi.org/10.1111/apt.13412

Approval Number L.ZA.COM.GM.11.2016.1398

126 SARJ VOL. 23 NO. 4 2017

SATS NEWS

Incoming statement of the SATS president, 2017 to 2019 I would like to thank my predecessors, including Professor Lalloo and others, for their excellent leadership of SATS over the last few years. This has stood the Society in good stead but there are many challenges that SATS faces over the next decade.

There are several priority areas that I would like to give attention to over the next couple of years.

As outlined at the SATS 2017 conference, there is a major crisis in pulmonary medicine. This includes the collapse of academic units nationwide, the lack of training posts, and funding for teaching and training of nascent pulmonologists. SATS will have to play a greater role in engaging stakeholders to address these concerns. Another major problem is the increasing lack of access to basic and newer respiratory drugs with proven benefit. In this regard, I will, on behalf of SATS, be engaging with the relevant stakeholders.

Another major priority is to facilitate greater involvement of newly qualified pulmonologists and junior faculty who are the lifeblood of the society. An unmet need is further engagement with the pulmonologists from the private sector. We are a very small community and we have to hold hands together to confront the threats and challenges faced by pulmonologists. I will also, together with Council, take steps to address the financial position of SATS. In order to remain sustainable, we need to investigate alternative funding models other than raising funds through conferences. SATS will

be developing a policy on continuing medical education (CME) nationally, and will also adopt policies with regards to the changing landscape of education and managing conflicts of interest.

The South African Respiratory Journal has done well under my leadership as the Chief Editor but, together with the editorial board, we now need to take the journal to a new level, and PubMed accreditation is included in our plans for next year. The aim is also, with Council’s approval and after consultation with relevant stakeholders, to launch the African Journal of Respiratory and Critical Care Medicine so that we have a continental platform through which we can advance lung health of the country and continent as a whole.

Nevertheless, if the research presentations at the 2017 SATS congress are anything to go by, we should rightfully be reassured and enthused by the emerging cadres of extremely bright and energetic individuals who will be the future leaders of our society. I enthusiastically look forward to working with Council, and all of you, to address these challenges over the next 2 years.

Professor Keertan Dheda President: South African Thoracic Society

SARJ VOL. 22 NO. 3 2017

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SATS NEWS

SATS/PATS Joint Congress, Durban, 12 - 15 April 2018 Dear Colleagues, On behalf of the South African Thoracic Society (SATS), I would like to encourage you to attend the 2018 SATS/PATS (Pan African Thoracic Society) Joint Congress in Durban from 12 to the 15 of April 2018. The congress will be hosted by SATS and PATS and the meeting will therefore also serve to replace the 20th National SATS congress. The last congress was held at Century City, Cape Town, in August 2017.

The combined congress will comprise several parallel tracks covering adult pulmonology, paediatric pulmonology, thoracic surgery, and physiotherapy, among others. Several internationally renowned experts have already confirmed their attendance. A thought-provoking programme is being planned with an appropriate session devoted to showcasing health priorities and challenges facing African pulmonologists, and research from Africa. A broad range of 'bread and butter' topics will be covered, and topical areas that will be discussed will include the use of electronic cigarettes, new combination inhalers, new drugs and diagnostics for TB, advances in the management of interstitial lung disease, pulmonary vascular and thromboembolic diseases, and sleep medicine. New techniques and technologies such as medical lung volume surgery and bronchial thermoplasty will also be covered. There will be several pre-conference workshops, and an exciting array of events has been planned including a gala dinner, awards evening, evening entertainment, as well as a comprehensive congress exhibition with many industry partners attending. Durban is an exotic and interesting city to visit with excellent connections to Cape Town and other cities in South Africa – it would be an ideal starting location for a back-to-back post-congress holiday.

On behalf of SATS, I wish to extend a very warm welcome to delegates from the public and private sectors, and all our exhibitors and sponsors.

See you in April 2018! Do not miss it!

Professor Keertan Dheda President: South African Thoracic Society

2018 SATS membership fees SATS R500 IPSA R350 Register online via the SATS website: www.pulmonology.co.za

128 SARJ VOL. 23 NO. 4 2017

SATS NEWS

Council Members â&#x20AC;&#x201C; August 2017 to 2019 President

University of the Witwatersrand representative

Vice President

Stellenbosch University representative

Secretary

University of KwaZulu-Natal representative

Treasurer

University of the Free State representative

Past President

University of Pretoria representative

Clinical Technology representative

Sefako Makgatho Health Sciences University representative

Paediatric Pulmonology representative

Prof. R Chauke

Prof. K Dheda Prof. C Koegelenberg Prof. M Wong Prof. C Koegelenberg Prof. U Lalloo Mr D Maree

Dr A Vanker

Private Practice representative Dr C Smith

Thoracic Surgery representative Dr I Schewitz

South African Respiratory Journal Editor Prof. K Dheda

Scholarship selection committee chairperson Prof. R van Zyl-Smit

Credentials committee Prof. K Dheda

Dr A Peter

Prof. E Irusen

Prof. R Masekela

Dr Y Ramkillawan

Dr A Jeevarathnum

University of Limpopo representative Dr G Tiva

Walter Sisulu University representative Prof. P Oluboyo

University of Cape Town representative Dr G Calligaro

Elected members Dr C Verwey Dr G Alexander Dr P Goussard

Co-opted member Dr I Kalla

CME committee

SATS website

NAEP representative

2019 SATS congress convenor

Dr MS Abdool-Gaffar Dr O Kitchin

Dr A Ambaram

Prof. A Goolam-Mahomed

SARJ VOL. 23 NO. 4 2017

129

OBITUARY

Citation of the late Professor Abolade Ajani Awotedu Senior academic and professional positions He was appointed lecturer I/consultant in the Department of Medicine, University of Ibadan and the UCH, Ibadan in 1981. He rose through to senior lecturer and readership to full professorial positions, which culminated in his last appointment as professor and head of the Department of Medicine in 1990.

I write this citation as a long-term acquaintance, friend and colleague of the late Professor Abolade Ajani Awotedu, who passed into eternal glory of the Lord on Wednesday, the 26th of July, 2017 at the Donald Gordon Medical Centre, Johannesburg, South Africa (SA). It is a great honour for me to be asked to write this citation. I have known Bola since our younger days at the medical school of the University of Ibadan, Nigeria. We completed our medical residency training programme at the University College Hospital (UCH) in Ibadan, Nigeria, together and spent our early consultant years in Ibadan. Years later, we were working colleagues at the Walter Sisulu University and the Nelson Mandela Academic Hospital in Mthatha, SA. Professor Bola Awotedu was born at Osogbo, Osun State, Nigeria on the 24th of February in 1949 to parents who were from Ipara in Ogun State. He received his primary school education at the Methodist Primary School, Ibadan, Oyo State and his secondary school education at Molusi College, Ijebu-Igbo, Ogun State from 1961 to 1965. Bola then went on to the Government College in Ibadan from 1966 to 1967 where he obtained the Higher School Certificate. In 1968, he taught at St Charles Secondary School, Osogbo, for 9 months before proceeding to the University of Ibadan to read for Medicine later that year. He qualified as a medical practitioner in June 1973. He had his internship at the University College Hospital (UCH), Ibadan from July 1973 to June 1974.

Postgraduate residency (Internal medicine and pulmonology) Bola completed his rotating residency in Internal Medicine at the Department of Medicine, UCH, Ibadan, from 1975 to 1978.

He was a clinical assistant at the respiratory units of New Cross Hospital, London and Guys Hospital, London from 1978 to 1980.

Upon his return to Nigeria, he was a senior registrar at the Department of Medicine, UCH, Ibadan from 1980 to 1981.

130 SARJ VOL. 23 NO. 4 2017

International positions after an early retirement at Ibadan To further his quest for excellence and international exposure for his career in medicine and medical education, Professor Awotedu accepted a number of international appointments: Associate Professor, Department of Medicine, University of Zimbabwe and Consultant Physician, Parirenyatwa Hospital, Harare, Zimbabwe, 1990 to 1992.

Senior Consultant Physician, Nyangabgwe Referral Hospital, Francistown, Botswana from 1992 to May 1997.

Associate Professor and Head, Department of Pulmonology, University of Transkei, Mthatha, SA, May 1997 to 2004.

Acting Head of Internal Medicine, University of Transkei, Mthatha, SA from 2000 to 2003.

Professor and Head of Medicine, Walter Sisulu University, from January 2004 to June 2016.

Contract Professor, Walter Sisulu University from June 2016 to June 2017.

Professional certificates and diplomas Prof Bola Awotedu’s academic and professional attainments are highly distinguished: Bachelor of Medicine and Bachelor of Surgery (MBBS), Ibadan - 1973 Fellow of the Nigerian Postgraduate Medical College of Physicians (FMCP) - 1980 Fellow of the West African College of Physicians (FWACP) - 1985 Fellow of the American College of Chest Physicians (FCCP) - 1988 Fellow of the College of Physicians of South Africa (FCP (SA)) - 2000 Fellow of the Royal College of Physicians (Edinburg) (FRCP) - 2009 Fellow Royal College of Physicians (London) (FRCP) - 2012 Scholarships and prizes Notable amongst his achievements in this regard are: Federal Government of Nigeria Scholarship from 1968 to 1973.

French Government Scholarship for Research in 1985.

American College of Chest Physicians Governors Community Service Award Nominee in 2001. Topic of submission ‘Building a Pulmonology Division to serve a large, poor and underserved population’ Membership of learned societies Professor Bola Awotedu was a member of several professional bodies: Nigerian Medical Association South African Medical Association Association of Physicians of Nigeria Association of Physicians of West Africa

OBITUARY Nigerian Thoracic Society British Thoracic Society South African Thoracic Society American Thoracic Society Honours Professor Awotedu was a man of distinction. He received the following honours: Recipient of the Nigerian achievement award in Medicine by the Nigerian High Commission. The award was presented by His excellency, President Goodluck Jonathan and the Speaker of the House of Parliament of SA, Mrs Baleka Mbete, in 2009.

Featured in the 2nd edition (February - March 2017) of the OMOLUABI, an e-magazine of the Association of Yorubas in Diaspora, SA, in an article titled ‘Professor Abolade Ajani Awotedu: A Quintessential Personality’.

Service to the Community While Head of Medicine at the University of Ibadan, he served in various Committees of the Senate and of the Faculty Board, including the Disciplinary Committee of the university. He was also the Hall Warden of the Clinical Students’ Hostel (Alexander Brown Hall) from 1987 to 1990. This tenor was well-noted for discipline and fairness at the same time.

He served as external examiner to various universities in Nigeria, including the Universities of Lagos, Jos, Shagamu, as well as the Obafemi Awolowo University. Similarly, in SA, he served as external examiner to the universities of Kwazulu-Natal, Stellenbosch, Cape Town. He was also an external examiner for the National University of Rwanda in Kigali. He examined at both the Part I and the Part II examinations of the College of Physicians of SA. Prof. Bola Awotedu served in the councils of both the South African Thoracic Society and the National Asthma Education Programme.

He was a member of the Hamilton Naki Scholarship Board of South Africa, a body that awards scholarships to poor but deserving students.

He was a council member of the College of Physicians of South Africa.

He also served in the Consultancy of the NEPARD of the African Union on ‘Harmonization of Policy on regulation and registration of drugs in Africa’.

As the principal investigator for a Medical Research Council of SA Flagship Research Project, he attracted funds totaling R18 million ($1.5 million) to the Walter Sisulu University.

Prof. Bola Awotedu was a patron of the Association of Yorubas in Diaspora, SA (AYIDSA).

He was the longest-serving council member and a great pillar of selfless service at the Full Gospel House of Prayers Church at Mthatha, where we worshiped for 18 years.

Scientific publications Prof. Bola Awotedu was widely published academically, and to his credit are: Journal articles He published over 50 articles in local and international scientific journals.

Professorial Inaugural Lecture, Walter Sisulu University, 2008, ‘Breath of Life: Trends in the Pathogenesis and Management of Asthma.’

Books Science, Technology and Innovation for Public Health in Africa, 2009.

Asthma in Africa, 2012 (Co-edited and authored more than 50% of the chapters.)

Major conferences He attended over 45 national and international conferences in his chosen field of pulmonology.

Hobbies In his younger days in Ibadan, he played table tennis and had a passion for photography. Later in life, Bola had a keen interest in medical history, current affairs and world news, and was a football and cricket enthusiast.

Family life Bola was family-orientated and showed remarkable dedication to the care of each and every member of his nuclear and extended families.

It is remarkable that he bred a family of medical doctors: himself a physician; his wife a family physician with a doctorate in physiology; the first daughter is on the way to achieving a doctorate in law in a medically related subject. His second daughter is a paediatrician, his second son-in-law is an obstetrician and gynaecologist, and the third and last daughter is a dermatologist in training. What a gift to the medical confraternity. He was blessed with 7 lovely grandchildren.

I will summarise the gentleman, Bola Awotedu, as a distinguished physician, academic, researcher, and family man who was, above all, a child of God. In one of his epistles to the Corinthians, Saint Paul said, ‘I am made all things to all men, that I might by all means save some’ (cf. I Cor 9:19-22). Bola Awotedu was a faithful and dutiful child of God, a humane person who touched everyone that he met with a tremendous power of the love of God, through genuine interest in peoples’ lives and a kind and generous helping hand.

Adieu my brother and friend, rest in perfect peace.

Professor Patrick Oluwole Oluboyo Consultant Pulmonologist, Department of Pulmonology, Nelson Mandela Academic Hospital, Walter Sisulu University, Mthatha, South Africa

SARJ VOL. 23 NO. 4 2017

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NOTES

132 SARJ VOL. 23 NO. 4 2017

COPD

RELVAR ELLIPTA 92/22 μg is an ICS/LABA indicated for the maintenance treatment of airflow obstruction including chronic bronchitis and/or emphysema and to reduce exacerbations of COPD in patients with a history of exacerbations1

“THEY GO TO EXPLORE. I STAY IN THE CAR.”2 Patients with COPD fear exacerbations, which compromise function and quality of life.3 You can help these patients get back moments they’ve been missing with: 24 hours of continuous efficacy4 Convenient, once daily dosing1 An easy to use device5,6

NEW

COPD = Chronic Obstructive Pulmonary Disease ICS = Inhaled corticosteroid LABA = Long acting beta2-agonist

Practical efficacy 5,7

SIDE EFFECTS: Very Common: headaches, nasopharyngitis. Common: pneumonia, upper respiratory tract infection, bronchitis, influenza, candidiasis of mouth and throat, oropharyngeal pain, sinusitis, pharyngitis, abdominal pain, arthralgia, back pain, fractures, pyrexia. Uncommon: extrasystoles. WARNINGS AND SPECIAL PRECAUTIONS: Not to be used to treat acute asthma symptoms or an acute exacerbation in COPD. Increasing use of short-acting bronchodilators to relieve symptoms indicates deterioration of control and patients should be reviewed by a medical practitioner. CONTRA-INDICATIONS: Patients with severe milk-protein allergy or who have demonstrated hypersensitivity to either fluticasone furoate, vilanterol or any of the excipients.

11929

References: 1. RELVAR ELLIPTA Package Insert, 16 February 2017. 2. GSK data on file HO-15-15502. 2016. 3. Rennard S, Higenbottam T. Exacerbation-free COPD: A goal too far? Proc Am Thorac Soc. 2007;4:583–585. 4. Boscia JA, et al.

Effect of once-daily fluticasone furoate/vilanterol on 24-hour pulmonary function in patients with chronic obstructive pulmonary disease: a randomized, three-way, incomplete block, crossover study. Clin Ther. 2012;34(8):1655–1666.e5.

5. Svedsater H, et al. Qualitative assessment of attributes and ease of use of the Ellipta™ dry powder inhaler for delivery of maintenance therapy for asthma and COPD. BMC Pulm Med 2013;13:72. 6. Riley JH, et al. Correct usage, ease of use, and preference of two dry powder inhalers in patients with COPD: analysis of five phase III, randomized trials. Int J Chron Obstruct Pulmon Dis. 2016;11:1873–1880. 7. Bernstein DI, et al. Fluticasone furoate (FF)/vilanterol (100/25 mcg or 200/25 mcg) or FF (100 mcg) in persistent asthma. J Asthma. 2015;52(10):1073 -1083.

S4 RELVAR ELLIPTA 92/22 µg (48/21.5.1/0249) Powder for Inhalation. S4 RELVAR ELLIPTA 184/22 µg (48/21.5.1/0250) Powder for Inhalation. INGREDIENTS: Each pre-dispensed dose contains 100/25 µg (delivers 92/22 µg) or 200/25 ug (delivers 184/22 ug) of fluticasone furoate/vilanterol (as trifenatate). INDICATIONS: Asthma: the maintenance, preventive treatment of asthma. COPD: the maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD) including chronic bronchitis and/or emphysema and to reduce exacerbations of COPD in patients with an exacerbation history. CONTRA-INDICATIONS: In patients with severe milk-protein allergy or who have demonstrated hypersensitivity to either fluticasone furoate, vilanterol or any of the excipients. WARNINGS AND SPECIAL PRECAUTIONS: Not to be used to treat acute asthma symptoms or an acute exacerbation in COPD. Increasing use of short-acting bronchodilators to relieve symptoms indicates deterioration of control and patients should be reviewed by a medical practitioner. Do not stop therapy without HCP supervision. Paradoxical bronchospasm may occur treat immediately with a short-acting inhaled bronchodilator. Discontinue immediately and assess patient and alternative therapy instituted if necessary. Asthma-related adverse events and exacerbations may occur. Patients should be asked to seek medical advice if asthma symptoms remain uncontrolled or worsen after initiation. Use with caution in patients with cardiovascular disease, or heart rhythm abnormalities, hyperthyroidism or uncorrected hypokalaemia.

Hypokalaemia may occur. High dosages may increase the risk of serious side effects, including cardiac dysrhythmias. This risk is further aggravated if administered concomitantly with other medicines that cause hypokalaemia and cardiac dysrhythmias, or in the presence of hypoxia and acidosis. The maximum dosage should not be exceeded. Beta-adrenergic blockers may cause bronchospasms and may weaken or antagonise the effect of beta2-adrenergic agonists concurrent use of both non-selective and selective beta-blockers should be avoided unless there are compelling reasons for their use. Increases in blood glucose levels in diabetic patients have occurred. Systemic corticosteroid effects (e.g.

HPA axis suppression, decrease in bone mineral density, growth retardation in children and adolescents, cataract and glaucoma) may occur, especially at high doses. Administer with caution in patients with pulmonary tuberculosis or with chronic or untreated infections. An increase in pneumonia has been obsaerved in patients with COPD. Risk factors for pneumonia in patients with COPD include current smokers, patients with a history of prior pneumonia, patients with a body mass index < 25 kg/m2 and patients with a (forced expiratory volume) FEV1< 50 % predicted. These factors should be considered when RELVAR is prescribed and treatment should be re-evaluated if pneumonia occurs.

Contains lactose/fructose: Do not use in patients with rare hereditary problems of galactose intolerance e.g. galactosaemia, Lapp lactase deficiency or glucose-galactose malabsorption or fructose intolerance. Ability to drive and operate machinery: No studies. INTERACTIONS: Beta-adrenergic blockers may cause bronchospasms and may weaken or antagonise the effect of beta2-adrenergic agonists and concurrent use of both non-selective and selective beta-blockers should be avoided. Care is advised when co-administering with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir) as there is potential for an increased systemic exposure. PREGNANCY AND LACTATION: Safety not established.

DOSAGE AND DIRECTIONS FOR USE: Asthma: Adults and adolescents aged 12 years and over: One inhalation once daily. A starting dose of RELVAR 100/25 µg should be considered for patients who require a low to mild dose of inhaled corticosteroid in combination with a long acting beta2-agonist. RELVAR 200/25 µg should be considered for patients who require a higher dose of inhaled corticosteroid in combination with a long acting beta2-agonist. If patients are inadequately controlled on RELVAR 100/25 µg, consider increasing the dose to 200/25 µg. Children less than 12 years: not recommended. COPD: Adults: One inhalation of RELVAR 100/25 µg once daily. RELVAR 200/25 µg is not indicated for patients with COPD. Special Populations (Asthma and COPD): Elderly: No dosage adjustment. Renal impairment: No dose adjustment. Hepatic Impairment: Caution should be exercised as patients with hepatic impairment may be more at risk of systemic adverse reactions associated with corticosteroids. SIDE EFFECTS: Very Common: headaches, nasopharyngitis. Common: pneumonia, upper respiratory tract infection, bronchitis, influenza, candidiasis of mouth and throat, oropharyngeal pain, sinusitis, pharyngitis, abdominal pain, arthralgia, back pain, fractures, pyrexia. Uncommon: extrasystoles. MANAGEMENT OF OVERDOSAGE: No specific treatment for an overdose. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary. Cardioselective beta-blockade should only be considered for profound vilanterol overdose effects that are clinically concerning and unresponsive to supportive measures. Cardioselective beta-blocking medicines should be used with caution in patients with a history of bronchospasm. Further management should be as clinically indicated or as recommended by the national poison centre, where available. HCR: GlaxoSmithKline South Africa (Pty) Ltd (Co. reg. no. 1948/030135/07), 39 Hawkins Avenue, Epping Industria 1, 7460. Trademarks are owned by or licensed to the GSK group of companies. For full prescribing information, refer to package insert approved by the Medicines Regulatory Authority. All adverse events should be reported by calling the Aspen Medical Hotline number or directly to GlaxoSmithKline on +27 11 745 6000. ZAF/FFT/0024/17 08/17.

RELVAR ELLIPTA was developed in collaboration with

Marketed by Aspen Pharmacare www.aspenpharma.com Medical Hotline 0800 118 088

The South African Respiratory Journal acknowledges with thanks the invaluable sponsorship of the following companies: Aspen GSK Division Bayer Healthcare