SARJ Vol 22, No 4 (2016)

Journal ISSN 2304-0017

SouthAfrican African South

Respiratory Respiratory Journal Journal VOLUME 22

|

NUMBER 4

South African

Respiratory

Journal

OFFICIAL JOURNAL OF THE S.A. THORACIC SOCIETY

|

DECEMBER 2016

FOXAIR

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THE SOUTH AFRICAN

RESPIRATORY JOURNAL VOLUME 22 | NUMBER 4 | DECEMBER 2016

CONTENTS Editorial 91

Can we prevent the transmission of tuberculosis?

S T Malherbe, G Walzl

Research 93

The diagnostic gap: Characterising the profile of undiagnosed infectious tuberculosis patients in the community G Calligaro, A Esmail, T Mnguni, L Mottay, K Dheda

Review 98

The use of macrolides and corticosteroids as immunomodulators in community-acquired pneumonia A Peter

Case Report 101 Massive haemoptysis in pregnancy S Mothilal, A Esmail, K Dheda

Article 103 ‘On the shoulders of giants’ – The evolution of paediatric pulmonology in South Africa A Vanker 104

Who’s who

105

Breath-taking News

108

Product News

112

SATS Awards 2016

The Editor The South African Respiratory Journal PO Box 13725, Mowbray, 7705 Telephone: 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.

The SARJ is published by the Health and Medical Publishing Group (Pty) Ltd, Co. registration 2004/0220 32/07, a subsidiary of SAMA. HEAD OFFICE: Block F, Castle Walk Corporate Park, Nossob Street, Erasmuskloof Ext. 3, Pretoria, 0181 EDITORIAL OFFICE: Suite 11, Lonsdale Building, Lonsdale Way, Pinelands, 7405 | (021) 532 1281 All letters and articles for publication must be submitted online at www.sarj.org.za E-mail: publishing@hmpg.co.za

SARJ EDITOR-IN-CHIEF Prof. K Dheda DEPUTY EDITOR Prof. C Koegelenberg SECTION EDITOR Breath-taking News: Prof. E Irusen EDITORIAL BOARD Prof. G Ainslie, Prof. E Bateman, Prof. R Green, Prof. E Irusen, Prof. M Jeebhay, Prof. P Jeena, Prof. U Lalloo, Prof. A Linegar, Prof. R Masekela, Dr K Nyamande, Dr J O’Brien, Dr R Raine, Prof. G Richards, Dr R van Zyl Smit, Prof. M Wong, Prof. H Zar INTERNATIONAL EDITORIAL BOARD Prof. Adithya Cattamanchi - USA Prof. Fan Chung - UK Prof. GB Migliori - Italy Prof. Surendra Sharma - India Prof. Wing Wai Yew - China PRESIDENT SA THORACIC SOCIETY Prof. U Lalloo

HMPG

CEO AND PUBLISHER Hannah Kikaya Email: hannahk@hmpg.co.za EXECUTIVE EDITOR Bridget Farham MANAGING EDITORS Ingrid Nye | Claudia Naidu TECHNICAL EDITORS Emma Buchanan Paula Van Der Bijl PRODUCTION MANAGER Emma Jane Couzens DTP AND DESIGN Clinton Griffin | Travis Arendse HEAD OF SALES AND MARKETING Diane Smith | Tel. 012 481 2069 Email: dianes@hmpg.co.za ONLINE SUPPORT Gertrude Fani | Tel. 072 463 2159 Email: publishing@hmpg.co.za FINANCE Tshepiso Mokoena HMPG BOARD OF DIRECTORS Prof. M Lukhele (Chair), Dr M R Abbas, Dr M J Grootboom, Mrs H Kikaya, Prof. E L Mazwai, Dr M Mbokota, Dr G Wolvaardt PRINTED BY TANDYM PRINT

FIRST ANNOUNCEMENT

Theme | INNOVATION FOR RESPIRATORY SOLUTIONS Local and international experts will be discussing the LATEST RESEARCH and HOT TOPICS in pulmonology

Venue | CENTURY CITY CONVENTION CENTRE www.satsconference2017.co.za | www.pulmonology.co.za for more details, please contact Deidre Raubenheimer: deidre.raubenheimer@uct.ac.za

EDITORIAL

Can we prevent the transmission of tuberculosis?

Current strategies to reduce the burden of tuberculosis (TB) are symptom- and patient-centred, and mainly focus on accurate diagnosis of cases, adequate follow-up, adherence to treatment and contact tracing.

This has shown modest success, with the global TB burden dropping at an average of 1.8% annually since 2001.[1] The goals of the World Health Organization (WHO)’s End TB strategy include reducing the incidence of TB disease by 50% by 2025 and 90% by 2035.[2] To achieve this, the drop in the global burden of TB disease needs to improve to a 10% annual reduction. Clearly, improved tools and interventions are required urgently.

An article in the current issue of SARJ, by Calligaro et al.,[3] ‘The diagnostic gap: Characterising the profile of undiagnosed infectious TB patients residing in the community’, highlights the importance of innovative new approaches to reduce TB incidence, and identifies a possible target population for such new interventions. They cite references pointing to important issues including the following: (i) roughly 30 - 50% of the TB disease burden is undiagnosed; (ii) transmission often occurs outside the home, in places where the community congregates during daily living. They performed active case finding in some of these suspected high-transmissionrisk public areas, and found a higher than anticipated prevalence of active disease. In addition, they found that almost half of these cases were acid-fast bacilli smear-positive, indicating a highly infectious potential. Furthermore, all these cases were symptomatic. It is not clear why these community members failed to seek healthcare, in spite of living in an area where facilities are relatively accessible.

In HIV-positive patients, intensified screening, prophylactic treatment of TB and campaigns to reduce the prevalence of HIV have yielded success, yet no other high-risk groups have been targeted.

Other possible high-risk groups include people with known exposure to active cases, people frequenting transmission hotspots, people with previous TB episodes, smokers, diabetics and alcoholics.

Proactive campaigns are crucial to allow earlier detection and treatment, which will greatly reduce the transmissions originating from a single case. Urgent research and pilot programmes to test the effectiveness and cost-effectiveness of systematic screening interventions are required. The shortcomings of available testing options, however, play a major role in the lack of such interventions.

Screening programs would be made more feasible by improved tools, such as a point-of-care test that does not require sputum. In addition, it could provide the added benefit of detecting TB cases prior to infectious risk and lung damage.

To reach the ambitious targets of the WHO End TB strategy, it is clear that out-of-the-box solutions will have to be explored. The work

by Calligaro et al.[3] suggests that one such approach might be the interruption of transmission by screening and initiation of treatment in people who have not yet self-reported to primary health care services, in high TB prevalence communities.

Stephanus T Malherbe Gerhard Walzl Department of Science and Technology/National Research Foundation Centre of Excellence for Biomedical Tuberculosis Research and South African Medical Research Council Centre for Tuberculosis Research and Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa malherbe@sun.ac.za 1. World Health Organization. Global Tuberculosis Report. 2015. http://www.who.int/ tb/publications/global_report/en/ (28 October 2016) 2. World Health Organization. The End TB Strategy. 2015. http://www.who.int/tb/ strategy/en (28 October 2016) 3. Calligaro G, Esmail A, Mnguni T, Mottay L, Dheda K. The diagnostic gap: Characterising the profile of undiagnosed infectious TB patients residing in the community. S Afr Resp J 2016;22(4):93-98. http://dx.doi.org/10.7196/SARJ.2016.v22i4.100

S Afr Respir J 2016; 22( 4) : 91. D O I : 10.7196/S A R J .2016.v22i 4.106

91 SARJ VOL. 22 NO. 4 2016

ORIGINAL RESEARCH

The diagnostic gap: Characterising the profile of undiagnosed infectious tuberculosis patients in the community G Calligaro,1,2 MB BCh, FCP, MMed, Cert Pulm; A Esmail,1,2 MD, FCP, Cert Pulm; T Mnguni,1 MB ChB, FCP, MMed; L Mottay,1 MB BCh, FCP, Cert Pulm; K Dheda,1 MB BCh, FCP, FCCP, FRCP, PhD 1 2

Division of Pulmonology, Department of Medicine, University of Cape Town, South Africa Lung Infection and Immunity Unit, University of Cape Town Lung Institute, Groote Schuur Hospital, Cape Town, South Africa

Corresponding author: K Dheda (keertan.dheda@uct.ac.za)

Background. In tuberculosis (TB)-endemic countries, about half the total TB caseload remains undiagnosed within the community. The proportion of such patients that can potentially transmit the disease has been poorly characterised, and there is insufficient data to inform on strategies to target potentially infectious TB cases in the community.

Objective. To characterise the nature and profile of smear-positive patients diagnosed with TB in the community.

Methods. We analysed data from culture-positive TB cases in the community during the course of an intensified case finding (ICF) study.

The parent study was a randomised controlled trial comparing conventional and novel diagnostics for ICF in communities in Cape Town, South Africa and Harare, Zimbabwe, where trained healthcare workers screened patients at transmission hotspots. The results of the parent study are reported elsewhere.

Results. A total of 2 261 persons were screened and 875 (39%) met the criteria for diagnostic testing. A total of 53/630 (8.4%) had confirmed tuberculosis. Smear microscopy detected 22/53 (42%) of the culture-positive patients. The specificity, positive predictive value (PPV) and negative predictive value (NPV) for smear microscopy were 98.4%, 70.0% and 95.3%, respectively. No clinical or demographic variable predicted smear positivity. Only decreased culture time-to-positivity was associated with smear grade (odds ratio 0.93, 95% confidence interval 0.91 - 0.96; p<0.001).

Conclusion. A considerable proportion of patients with undiagnosed TB in the community (almost half) were smear positive and hence potentially infectious. Interestingly, neither HIV status nor symptoms identified those patients who were potentially infectious, despite them having a higher mycobacterial burden.

S Afr Respir J 2016;22(4):93-98. DOI:10.7196/SARJ.2016.v22i4.100

Tuberculosis (TB) remains one of the world’s most devastating infectious diseases, with an estimated 9.6 million incident cases globally in 2014.[1] A major problem hampering control efforts and driving the TB epidemic is the large reservoir of undiagnosed TB disease in the community, which may comprise ~30 to 50% of the total TB burden.[2] Particularly in highburden settings, a large number of people in the community do not access healthcare or do so late in the course of the disease, and are responsible for ongoing disease transmission. Intensified case finding (ICF) seeks to address this problem by screening targeted populations for active pulmonary disease.[2] Historically, households have been deemed to be a major focus of Mycobacterium tuberculosis transmission, but molecular epidemiological studies from sub-Saharan Africa have pointed to high transmission risk also occurring outside the home in indoor congregate settings such as the workplace or schools, or on public transport.[3-5] Much of our current understanding of the transmissibility of pulmonary tuberculosis derives from early published reports on various community outbreaks.[6-10] These studies have demonstrated repeatedly that a single variable – smear status – strongly predicts which patients are the most contagious. Smear-positive persons expectorate 108 1010 bacilli daily, or about 106 - 107 per millilitre (mL) of sputum, while smear-negative sputum contains <103 bacilli per mL.[11] Despite the contribution of undiagnosed TB in the community to the destabilisation of TB control, and the importance of undetected smearpositive cases in transmission dynamics, little is known about these potentially infectious cases. An ICF study recently performed in the

impoverished communities of Cape Town, South Africa (SA), found the incidence of smear-positive disease to be 36%, but the characteristics of these patients were not described.[12] Because of this knowledge gap, we set out to characterise the nature and profile of smear-positive patients with TB, identified as part of an ICF strategy in the community.

This study was nested within a larger two-country parallelgroup randomised controlled trial comparing a routine package of diagnostic tools (smear microscopy plus culture) with a novel one (sputum Xpert MTB/RIF (Cepheid, USA), urine lipoarabinomannan and culture) for ICF, which is reported elsewhere. The incidence of smear positivity and the potential implications for infectiousness and community-based transmission of TB are described here.

Methods

Study population The study was conducted in two southern African communities: the Langa informal settlement, in Cape Town, SA, and the Mabvuku suburb, in Harare, Zimbabwe. Both have high TB and HIV prevalence, a high density of informal dwellings and high unemployment rates. The weekly screening locations were chosen in advance and were systematically clustered around community congregate settings or suspected transmission ‘hot-spots’ such as shops, hostels or transit hubs. The study vehicle was parked at these locations, and passersby were encouraged to participate via advertising banners displayed next to the vehicle, and by local advertising at schools, churches, supermarkets and social clubs. In

SARJ VOL. 22 NO. 4 2016

93

ORIGINAL RESEARCH SA, the vehicle was equipped with an awning for shelter, fold-up tables and capability for rapid HIV testing (Determine HIV-1/2, Alere, USA; HIV 1/2 3.0, Standard Diagnostics, South Korea) and point-of-care CD4count testing (PIMA, Alere, USA). The vehicle also included facilities to securely house and operate a GeneXpert machine (Cepheid, USA) and a small portable collapsible tent for sputum and urine acquisition. For patients unable to spontaneously produce sufficient sputum, facilities for sputum induction with an ultrasonic nebuliser and hypertonic saline using a standard protocol[13] were also available in the tent. In Zimbabwe, a similar set-up was used for ICF but eligible participants were driven to the local Mabvuku community clinic where the same diagnostic tests were performed by a qualified technologist. Ethical approval to conduct the study was obtained from the relevant institutional review boards of the University of Cape Town and the University of Zimbabwe.

Study procedures After obtaining informed consent, participants were counselled and their HIV status confirmed by fingerprick tests using two commercially available assays. The screening protocol asked about cough of any duration, haemoptysis, weight loss, fever and night sweats, according to a World Health Organization (WHO)-recommended screening algorithm,[2] and enrollment depended on HIV status. We consecutively enrolled all consenting HIV-uninfected patients aged 18 years or older with at least one symptom of TB, but enrolled all consenting adult HIVinfected patients regardless of symptoms. The rationale for this latter strategy was that the ‘rule-out’ utility of the WHO screening algorithm is suboptimal in HIV-infected persons.[14] Patients who refused HIV testing were screened as though they were HIV-infected. We excluded all patients who had previously self-presented to a TB community clinic in the last 2 months, had received treatment in the last 60 days, or who were unwilling or unable to give informed consent. At least two spot sputa were then obtained sequentially from each participant at recruitment, either spontaneously or via sputum induction. One specimen, selected arbitrarily, was sent to a reference laboratory for liquid culture for M. tuberculosis using the BACTEC MGIT 960 system (BD, USA).[15] The other was used for either smear microscopy or Xpert MTB/RIF, according to assignment in the parent study. If possible, additional sputum specimens were collected for later analysis. We tested stored sputa of culture-positive patients for smear positivity in patients randomised to Xpert MTB/RIF in the parent study, at the end of the study.

Statistical analysis Sputum culture positivity for M. tuberculosis complex was the diagnostic reference standard. Participants with contaminated cultures were excluded.

We used χ2 and Fisher’s exact test for comparisons between proportions. The Wilcoxon rank-sum test was used to compare non-parametric measures e.g. time to culture positivity. We also conducted a multivariable regression analysis of predictors of culture positivity, smear positivity and smear grade.

Results

Study population Between October 2013 and April 2015, 2 261 people were screened and 875 patients with suspected pulmonary TB were enrolled. A total of 646 had a valid smear microscopy result (Fig. 1). Overall, 16 were excluded from the primary analysis, of whom 13 had contaminated cultures and 3 were unable to produce additional sputum samples for culture.

94 SARJ VOL. 22 NO. 4 2016

Characteristics of culture-positive patients Fifty-three participants (8.4%) had a positive sputum culture for M. tuberculosis. The median (interquartile range (IQR)) age in patients with culture-positive TB was slightly lower (36 (29 - 42) v. 39 (31 - 48) years; p=0.0377), and the median CD4 count significantly lower (185 (79 - 363) v. 306 (163 - 515) cells/mm3; p=0.0033), than in those participants who were culture negative (Table 1). The median number of WHO screening algorithm symptoms observed per patient with culture-positive TB was 3 (2 - 4). The association between the duration of each symptom and either culture or smear positivity was not explored as this information was not recorded. Despite the screening protocol including all HIV-infected patients regardless of symptoms, <1% of HIV-positive participants were completely asymptomatic and none of the culture-positive patients were asymptomatic. There was also no difference in the median number of symptoms in patients with and without TB (3 (2 - 4) v. 3 (2 - 4); p=0.1946).

The most frequent symptom was cough of more than 2 weeks, which had the highest sensitivity of the WHO symptoms for a positive TB culture but the lowest specificity (95.9% and 4.6%, respectively; data reported in parent study). Each symptom either alone or in combination had poor discriminant ability for culture-positive disease.

Characteristics of smear-positive patients The characteristics of smear-positive and smear-negative patients are shown in Table 2. The only significant difference was that night sweats were more common in the smear-negative patients (97 v.

68%, p=0.004). Unsurprisingly, smear-positive patients had higher mycobacterial load, as measured by a shorter median culture time (in days) to positivity (8 (2 - 11) v. 24 (15 - 30); p<0.0001).

Diagnostic accuracy Smear microscopy detected 22/53 (42%) of the culture-positive patients. The specificity, positive predictive value (PPV) and negative predictive value (NPV) for smear microscopy were 98.8, 75.9 and 94.8% overall (Table 3). There was no difference in sensitivity of smear microscopy in HIV-infected v. HIV-uninfected participants (A% (95% CI 22.9 - 57.7%) v. 45.0%, (23.1 - 68.5%); p=0.06881).

Predictors of smear positivity and smear grade In a multivariable analysis, no clinical or demographic variable predicted smear positivity. Only decreased time-to-positivity was associated with smear grade (odds ratio (OR) 0.93, 95% CI 0.91 - 0.96; p<0.001) (Fig. 2).

Each symptom either alone or in combination had poor discriminant ability for smear-positive disease (Table 4). A symptom screen positive for all four WHO TB symptoms had the highest area under receiver operator curve (AUROC) characteristics, but a very low sensitivity (0.55, 95% CI 0.46 - 0.64; 37.9%, 95% CI 20.7 - 57.7%, respectively).

Discussion

We conducted a study to investigate novel strategies for detecting TB using community-based ICF in which we were able to study smearpositive (and thus potentially infectious) cases among participants with culture-proven TB. Our key findings were: (i) a considerable proportion of patients with undiagnosed TB in the community (42%) were smear positive, and hence potentially infectious; (ii) despite previous reports from primary care clinics suggesting a significant rate of subclinical disease, all cases of HIV-associated TB were symptomatic; (iii) no

ORIGINAL RESEARCH

1 386 patients not enrolled: • 884 HIV −ve, no symptoms • 175 out of area* • 123 no consent** • 117 current/recent TB† • 87 no contact details

2 261 participants screened

875 participants with possible TB 27 patients excluded: • 14 protocol violations†† • 13 sputum scarce after induction

646 patients with smear microscopy result

30 smear positive: • 22 culture positive • 7 culture negative • 1 culture not done

202 patients with Xpert result only

616 smear negative: • 31 culture positive • 570 culture negative • 13 cultures contaminated • 2 cultures not done

Fig. 1. CONSORT study diagram. *Patients temporarily visiting area of screening site but living elsewhere in the country and therefore unable to be followed up. **Patients unable to consent (impaired/underage) or withdrawing consent. †Patients previously self-presenting to a TB community clinic in the last 60 days, or who had received treatment in the last 60 days. ††Received test from the wrong diagnostics arm in error.

Table 1. Baseline characteristics of all patients receiving smear microscopy Demographics Age (years), median (IQR) Males, n (%) HIV indices HIV status, n (%) Negative Positive Refused Not done CD4 count (cells/mm3), median (IQR) ART use (if HIV +ve), n (%) Duration of ART use (years), median (IQR) Symptoms Cough of any duration, n (%) Weight loss, n (%) Fever, n (%) Night sweats, n (%) Number of WHO screening symptoms, median (IQR)

Total (N=646)

Culture negative* (n=557)

Culture positive (n=53)

p-value

39 (31 - 48) 285 (44)

39 (31 - 48) 249 (43)

36 (29 - 42) 26 (49)

0.0377 0.4070

307 (48) 329 (51) 4 (1) 4 (1) 289 (148 - 500) 144/376 (38) 2.90 (1.21 - 5.15)

279 (48) 290 (50) 4 (1) 4 (1) 306 (163 - 515) 130/334 (39) 2.98 (1.16 - 5.73)

20 (38) 32 (60) 0 (0) 1 (2) 185 (79 - 363) 11/34 (32) 2.23 (1.32 - 4.53)

0.0856 0.2467 0.5359 0.3672 0.0033 0.5634 0.6149

608 (94) 489 (76) 282 (44) 482 (75) 3 (2 - 4)

545 (95) 432 (75) 254 (44) 421 (73) 3 (2 - 4)

50 (94) 44 (83) 23 (43) 45 (85) 3 (2 - 4)

0.9720 0.1860 0.9300 0.0580 0.1936

ART = antiretroviral treatment; ATT = antituberculous treatment. *Excluding contaminated cultures or cultures not done.

SARJ VOL. 22 NO. 4 2016

95

ORIGINAL RESEARCH demographic variable (including HIV infection) or clinical symptom reliably identified participants at risk of smear-positive disease; and (iv) despite a clear relationship between smear grade and mycobacterial load

Smear grade

3+

2+

1+

Scanty

0

10

20

30

40

50

Culture time-to-positivity Culture time-to-positivity (days)

Fig. 2. Correlation with smear grade and culture time-to-positivity.

(as measured by time-to-positivity), no demographic or clinical variable was associated with worsening smear grade.

Our study demonstrates the staggering burden of undiagnosed TB in the community in high-burden settings in sub-Saharan Africa. The prevalence of culture-positive TB among all participants presenting for screening was 3.27%. This is considerably higher than the median of 0.8% reported from population-based surveys from sub-Saharan Africa.[16] This may be explained by the high prevalence hotspots that were targeted in our study, with poor infrastructure and high rates of poverty, and the high prevalence of both HIV infection and symptoms of pulmonary tuberculosis in our participants. Furthermore, our findings are within the range of widely varying TB prevalence across eight studies (0.02 to 3.5%) depending on the incidence of HIV, burden of TB, and whether all HIV-infected persons or only those with symptoms were screened.

The prevalence of smear-positive disease in our study was also high, approximating that seen in studies of symptomatic patients seeking care at primary health clinics for TB-related symptoms,[17] or in patients investigated for TB symptoms in hospital.[18] The consequences for

Table 2. Baseline characteristics of patients by smear status among TB cases Total (N=53)

Smear negative (n=31)

Smear positive (n=22)

p-value

Demographics Age (years), median (IQR)

36 (29 - 42)

36 (31 - 42)

36 (27 - 44)

0.8637

Males, n (%)

26 (49)

13 (42)

13 (59)

0.2180

Negative

20 (38)

11 (35)

9 (41)

0.6881

Positive

32 (60)

20 (66)

12 (55)

0.4646

Refused

HIV status, n (%)

1 (2)

0 (0)

1 (5)

0.2308

CD4 count, cells/mm3, median (IQR)

185 (79 - 363)

190 (107 - 372)

180 (52 - 289)

0.4910

ART use (if HIV +ve), n (%)

11/32 (34)

8/20 (40)

3/12 (25)

0.3870

Duration of ART use (years), median (IQR)

22.3 (1.32 - 4.53)

2.22 (1.21 - 2.98)

4.53 (1.32 - 4.57)

0.4142

50 (94)

28 (90)

22 (100)

0.1330

Symptoms Cough of any duration, n (%) Weight loss, n (%)

44 (83)

25 (81)

19 (86)

0.5850

Fever, n (%)

23 (43)

11 (35)

12 (55)

0.1680

Night sweats, n (%)

45 (85)

Number of WHO screening symptoms, median (IQR) 3 (2 - 4)

30 (97)

15 (68)

0.0040

3 (2 - 4)

3 (2 - 4)

0.7166

24 (15 - 30)

8 (2 - 11)

<0.0001

Measures of infectivity Time-to-positivity (days), median (IQR)

15 (8 - 28)

Table 3. Diagnostic accuracy of smear microscopy, paired culture positive (excluding contaminated/unpaired cultures or cultures not done) Test performance, n (%, 95% CI) Sensitivity

Specificity

All patients

22/53 (41.5, 28.1 - 55.9)

570/577 (98.8, 97.5 - 99.5) 22/29 (75.9, 56.5 - 89.7)

570/601 (94.8, 92.8 - 96.5)

HIV uninfected

9/20 (45.0, 23.1 - 68.5)

281/283 (99.3, 97.5 - 99.9) 9/11 (81.8, 48.2 - 97.7)

281/292 (96.2, 93.4 - 98.1)

HIV infected

13/33 (39.4, 22.9 - 57.7)

289/294 (99.3, 97.5 - 99.9) 13/18 (72.2, 46.5 - 90.3)

209/221 (93.5, 90.2 - 96.0)

96 SARJ VOL. 22 NO. 4 2016

PPV

NPV

ORIGINAL RESEARCH transmission dynamics in these high burden settings is considerable: it is estimated that an infectious, smear-positive case is responsible for 15 - 20 transmission events per year[19,20] and a strategy that could identify and treat these individuals in 28 days or less could be estimated to avert 1 - 2 transmission events per infectious case. The importance of ICF as a strategy for TB control in these communities is underscored.

Although we have focused on smear-positive disease, smear-negative cases, although less infectious than their smear-positive counterparts, are still responsible for between 17 - 20% of all TB transmission,[21,22] and these patients comprised 58% of our cohort. Smear-negative cases (if undetected) eventually become smear-positive ones, and any ICF strategy should consider novel tools (such as Xpert) that allow early detection, as this is likely to have important downstream effects on transmission too.

The WHO advocates a simple â&#x20AC;&#x2DC;rule-outâ&#x20AC;&#x2122; screening algorithm for TB in resource-limited settings whereby the absence of cough, fever, weight loss and night sweats portends a low probability of TB, but the sensitivity of this approach has been shown to be suboptimal in HIV-infected individuals.[14] For example, a study from Durban, SA, found that up to 22% of patients screened with sputum cultures prior to entering an ART programme had asymptomatic or subclinical TB.[23] However, despite modifying our screening protocol to include all HIV-infected patients regardless of symptoms, we did not find any subclinical or asymptomatic TB among HIV-infected patients participating in our study. This finding is likely to be influenced in part by a selection bias, as HIV-positive individuals in the community were not screened in a systematic way. Overall, participants identified by this study were highly symptomatic, with a median number of three WHO symptoms reported. The symptom screen had poor discriminant ability for both TB disease and smear positivity. The social, logistical and behavioural reasons for why these highly symptomatic individuals do not access healthcare or do so late in the course of the disease, despite the local availability of TB and HIV services, require urgent further study, and would seem to contradict the findings of a previous case-finding study, also attached to a mobile testing service and conducted in Cape Town, which found that 44% of HIV-infected patients were asymptomatic.[12] There were several limitations to our study. Firstly, although we focused on smear positivity, there were several other unmeasured patient factors

that may impact infectiousness. Recent cough aerosol experiments have shown that the characteristics of the bioaerosol produced in patients with pulmonary TB (particle quantity and size) may be just as important as measures of mycobacterial load as smear grade or culture time-topositivity.[24] The collection of cough aerosol was beyond the scope of the study. We also did not perform chest X-rays as part of our ICF strategy.

Cavitary disease, smear positivity and bacillary burden are known to be highly correlated,[25-27] and radiological features may have outperformed clinical predictors of smear positivity. However, chest radiology was not included in our ICF algorithm in the parent study, by design: the necessity of transporting patients to an additional healthcare facility would have diluted the value of point-of-contact diagnosis, and would have affected both the cost and complexity of the ICF strategy. In addition, we only collected a single sputum specimen for smear microscopy on each patient.

The collection of additional specimens is associated with incremental yield, and so the true proportion of smear-positive cases in this study has almost certainly been underestimated. Lastly, extrapulmonary samples were not routinely collected, so the number of TB cases in this study may also be an underestimate. However, this is less relevant to this study, as patients with extrapulmonary TB are less likely to contribute to the infectious pool targeted by ICF.

Conclusion

Almost half of patients with TB in the community detected by an ICF strategy were smear positive and hence potentially infectious. Neither HIV status nor symptoms identified those patients who were smear positive despite them having a higher mycobacterial burden. Further research is required to understand the epidemiology, behaviour and biology of symptomatic patients who fail to seek healthcare, or who do so late in the course of their disease, and what factors might identify potentially infectious patients so that limited resources can be appropriately targeted.

Role of the funding source. The funders of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Table 4. Diagnostic accuracy of WHO symptom screen for smear-positive TB Test performance, n (%, 95% CI) Sensitivity

Specificity

PPV

NPV

AUROC

Cough of any duration

28/29

34/601

28/595

34/35

0.51

(96.6, 82.2 - 99.9)

(5.7, 3.8 - 7.8)

(4.7, 3.1 - 6.7)

(97.1, 85.1 - 99.9) (0.48 - 0.55)

Weight loss

26/29

151/601

26/476

151/154

Fever

0.57

(89.7, 72.6 - 97.8) (25.1, 21.7 - 28.8) (5.5, 3.6 - 7.9)

(98.1, 94.4 - 99.6) (0.51 - 0.63)

14/29

393/429

338/601

14/277

(48.3, 29.4 - 67.5) (56.2, 52.2 - 60.2) (5.1, 2.8 - 8.3) 153/601

18/466

0.52

(95.8, 93.1 - 97.6) (0.43 - 0.62) 153/164

0.44

Night sweats

18/29

(62.1, 42.3 - 79.3) (25.5, 22.0 - 29.1) (3.9, 2.3 - 6.0)

(93.3, 88.3 - 96.6) (0.35 - 0.53)

Night sweats plus weight loss

17/29

242/254

(58.6, 38.9 - 76.5) (40.3, 36.3 - 44.3) (4.5, 2.7 - 7.1)

(95.3, 91.9 - 97.5) (0.40 - 0.59)

All four WHO screening symptoms

11/29

430/448

242/601 430/601

17/376 11/171

(37.8, 20.7 - 57.7) (71.5, 67.8 - 75.1) (6.0, 3.1 - 10.6)

0.49 0.55

(96.0, 93.7 - 97.6) (0.46 - 0.64)

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REVIEW 1. Dheda K, Barry CE 3rd, Maartens G. Tuberculosis. Lancet 2016;387(10024):1211-1226. http://dx.doi.org/10.1016/S0140-6736(15)00151-8 2. World Health Organization. Systematic screening for active tuberculosis: Principles and recommendations. 2013. http://www.who.int/tb/publications/Final_TB_Screening_ guidelines.pdf (accessed 1 April 2015).

3. Glynn JR, Guerra-Assuncao JA, Houben RM, et al. Whole genome sequencing shows a low proportion of tuberculosis disease is attributable to known close contacts in rural Malawi. PLoS One 2015;10(7):e0132840. http://dx.doi.org/10.1371/journal.pone.0132840 4. Middelkoop K, Mathema B, Myer L, et al. Transmission of tuberculosis in a South African community with a high prevalence of HIV infection. J Infect Dis 2015;211(1):53-61. http:// dx.doi.org/10.1093/infdis/jiu403 5. Verver S, Warren RM, Munch Z, et al. Proportion of tuberculosis transmission that takes place in households in a high-incidence area. Lancet 2004;363(9404):212-214. http:// dx.doi.org/10.1016/S0140-6736(03)15332-9 6. Loudon RG, Williamson J, Johnson JM. An analysis of 3 485 tuberculosis contacts in the city of Edinburgh during 1954-1955. Am Rev Tuberc 1958;77(4):623-643.

7. Sepkowitz KA. How contagious is tuberculosis? Clin Infect Dis 1996;23(5):954-962. http:// dx.doi.org/10.1093/clinids/23.5.954 8. Shaw JB, Wynn-Williams N. Infectivity of pulmonary tuberculosis in relation to sputum status. Am Rev Tuberc 1954;69(5):724-732.

9. Grzybowski S, Barnett GD, Styblo K. Contacts of cases of active pulmonary tuberculosis.

Bull Int Union Tuberc 1975;50(1):90-106.

10. Riley RL, Moodie AS. Infectivity of patients with pulmonary tuberculosis in inner city homes.

Am Rev Respir Dis 1974;110(6):810-812. http://dx.doi.org/10.1164/arrd.1974.110.6P1.810 11. Yeager H, Jr, Lacy J, Smith LR, LeMaistre CA. Quantitative studies of mycobacterial populations in sputum and saliva. Am Rev Respir Dis 1967;95(6):998-1004. http://dx.doi. org/10.1164/arrd.1967.95.6.998 12. Kranzer K, Lawn SD, Meyer-Rath G, et al. Feasibility, yield, and cost of active tuberculosis case finding linked to a mobile HIV service in Cape Town, South Africa: A cross-sectional study. PLoS Med 2012;9(8):e1001281. http://dx.doi.org/10.1371/journal.pmed.1001281 13. Peter JG, Theron G, Singh N, Singh A, Dheda K. Sputum induction to aid diagnosis of smear-negative or sputum-scarce tuberculosis in adults in HIV-endemic settings. Eur Respir J 2014;43(1):185-194. http://dx.doi.org/10.1183/09031936.00198012 14. Getahun H, Kittikraisak W, Heilig CM, et al. Development of a standardized screening rule for tuberculosis in people living with HIV in resource-constrained settings: Individual participant data meta-analysis of observational studies. PLoS Med 2011;8(1):e1000391. http://dx.doi.org/10.1371/journal.pmed.1000391 15. Cruciani M, Scarparo C, Malena M, Bosco O, Serpelloni G, Mengoli C. Meta-analysis of BACTEC MGIT 960 and BACTEC 460 TB, with or without solid media, for detection of mycobacteria. J Clin Microbiol 2004;42(5):2321-2325.

16. Kranzer K, Houben RM, Glynn JR, Bekker LG, Wood R, Lawn SD. Yield of HIVassociated tuberculosis during intensified case finding in resource-limited settings: A systematic review and meta-analysis. Lancet Infect Dis 2010;10(2):93-102. http:// dx.doi.org/10.1016/s1473-3099(09)70326-3 17. Theron G, Zijenah L, Chanda D, et al. Feasibility, accuracy, and clinical effect of point-of-care Xpert MTB/RIF testing for tuberculosis in primary-care settings in Africa: A multicentre, randomised, controlled trial. Lancet 2014;383(9915):424-435. http://dx.doi.org/10.1016/s0140-6736(13)62073-5 18. Theron G, Peter J, Zyl-Smit R, Mishra H, Streicher E, Murray S. Evaluation of the Xpert MTB/RIF assay for the diagnosis of pulmonary tuberculosis in a high HIV prevalence setting. Am J Respir Crit Care Med 2011;184(1):132-140. http://dx.doi. org/10.1164/rccm.201101-0056OC 19. Houben RM, Dowdy DW, Vassall A, et al. How can mathematical models advance tuberculosis control in high HIV prevalence settings? Int J Tuberc Lung Dis 2014;18(5):509-514. http://dx.doi.org/10.5588/ijtld.13.0773 20. Zwerling A, White RG, Vassall A, Cohen T, Dowdy DW, Houben RM. Modeling of novel diagnostic strategies for active tuberculosis - a systematic review: Current practices and recommendations. PLoS One 2014;9(10):e110558. http://dx.doi. org/10.1371/journal.pone.0110558 21. Behr MA, Warren SA, Salamon H, et al. Transmission of Mycobacterium tuberculosis from patients smear-negative for acid-fast bacilli. Lancet 1999;353(9151):444-449. http://dx.doi.org/10.1016/S0140-6736(98)03406-0 22. Tostmann A, Kik SV, Kalisvaart NA, et al. Tuberculosis transmission by patients with smear-negative pulmonary tuberculosis in a large cohort in the Netherlands.

Clin Infect Dis 2008;47(9):1135-1142. http://dx.doi.org/10.1086/591974 23. Bassett IV, Wang B, Chetty S, et al. Intensive tuberculosis screening for HIV-infected patients starting antiretroviral therapy in Durban, South Africa. Clin Infect Dis 2010;51(7):823-829. http://dx.doi.org/10.1086/656282 24. Fennelly KP, Jones-Lopez EC, Ayakaka I, et al. Variability of infectious aerosols produced during coughing by patients with pulmonary tuberculosis. Am J Respir Crit Care Med 2012;186(5):450-457. http://dx.doi.org/10.1164/rccm.2012030444OC 25. Lau A, Barrie J, Winter C, Elamy AH, Tyrrell G, Long R. Chest radiographic patterns and the transmission of tuberculosis: Implications for automated systems. PLoS One 2016;11(4):e0154032. http://dx.doi.org/0.1371/journal.pone.0154032 26. Lohmann EM, Koster BF, Le Cessie S, Kamst-van Agterveld MP, van Soolingen D, Arend SM. Grading of a positive sputum smear and the risk of Mycobacterium tuberculosis transmission. Int J Tuberc Lung Dis 2012;16(11):1477-1484. http:// dx.doi.org/10.5588/ijtld.12.0129 27. Palaci M, Dietze R, Hadad DJ, et al. Cavitary disease and quantitative sputum bacillary load in cases of pulmonary tuberculosis. J Clin Microbiol 2007;45(12):40644066. http://dx.doi.org/10.1128/JCM.01780-07

The use of macrolides and corticosteroids as immunomodulators in community-acquired pneumonia A Peter, MB BCh, DA (SA), FCP (SA), Cert Pulm (SA), FCCP Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa Corresponding author: A Peter (alan.peter@wits.ac.za)

The mortality rate in community-acquired pneumonia (CAP) has remained high. A single episode of pneumonia has an increased mortality rate across all age groups v. controls. Research continues to find ways to decrease the mortality rate associated with pneumonia. Corticosteroids and macrolides have been shown to influence inflammation; their immunomodulatory effect decreases the production of inflammatory cytokines.

Their use in CAP is proposed to improve mortality and morbidity. However, controversy over their use has been evident in several trials. Recent trials have shown that beta lactam antibiotic use without a macrolide is non-inferior and that corticosteroid use only confers a mortality benefit in patients requiring ionotropic support. In one study, corticosteroid use reduced hospital stay by 1 day, but had no effect on mortality. The regular use of macrolides and corticosteroids solely as immunomodulators in CAP cannot be advocated at this stage.

S Afr Respir J 2016;22(4):98-101. DOI:10.7196/SARJ.2016.v22i4.45

98 SARJ VOL. 22 NO. 4 2016

REVIEW Despite much advancement in antibiotics and hospital care, mortality from community-acquired pneumonia (CAP) seems to defy all our efforts at reduction. Mortality rates are 12% for CAP without a proven organism and in proven Streptococcus pneumoniae infections.[1] Macrolide antibiotics reduce the activation of nuclear factor kB (NF-kB). NF-kB is responsible for the production of inflammatory cytokines in response to infection, in particular interleukin 8 (IL-8). [2] In addition, they decrease mucus production and reduce cytokine production by the inhibition of pro-inflammatory cytokines (Fig. 1).

Macrolides also prevent the formation of biofilm by bacteria, which is an alginate mucoid film that makes the bacteria resistant to antibiotic attack. Biofilms are produced by bacterial signaling (quorum sensing), which macrolides disrupt.[3] Corticosteroids also decrease the transcription of inflammatory cytokines by inhibition of NF-kB.[4] The widespread use of corticosteroids in the control of asthma is a potent example of its anti-inflammatory effect. Could these two agents be of benefit in the acute inflammatory state in CAP, by modifying the host’s immune response to prevent unwanted side-effects from inflammation and thereby reducing mortality?

The controversy that surrounds macrolide use in CAP is highlighted by opposing results in several studies.[5]

The macrolide debate

A retrospective cohort study by Restrepo et al.[6] showed significant benefits in 30-day and 90-day mortality rates with macrolide use in patients with severe sepsis and pneumonia. However, there was no record of corticosteroid use in patients and the benefit of macrolides to non-intensive care unit (ICU) patients was not evaluated. The same authors, in a later collaborative study selecting Pseudomonas aeruginosa as the causative organism in 402 patients from 150 hospitals, against which macrolides have no antibacterial effect, found no effect in mortality by adding a macrolide to the antibiotic regimen.[7] The importance of the study was to isolate the pure immunomodulation effect of macrolides from any possible bacteriostatic or synergistic action with antibiotics in treating pseudomonas infections.

T he of ten-cited meta-analy sis b y A sadi et a l . [ 8] assessed 23 ob serv ational cohort stu dies and 5 randomised controlled trials that showed an overall benefit from macrolide use. However, a macrolide was compared with a non-macrolide antibiotic, and dual therapy of b eta lactam and macrolide ( B L M ) v . b eta lactam ( B L ) alone w as not assessed. BLM was only compared with fluoroquinolone (FQ) and showed no added benefit. This meta-analysis favoured the use of a Macrolides

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macrolide regimen. However, if the five randomised control trials were considered without the observational cohort studies, the benefit of adding a macrolide was lost, since all the randomised controlled trials showed non-significance.

T he meta-analy sis condu cted b y N ie et a l .[ 9] inv olv ed 4 p rosp ectiv e and 12 retrosp ectiv e cohort stu dies. T he analy sis of all the stu dies combined showed a clear mortality benefit in favour of macrolide use. However, when the retrospective studies were excluded and only the four prospective studies were analysed, the benefit of macrolide use was lost; three studies showed no benefit, two of which had also inclu ded p atients in intensiv e care. T he au thors ack now ledg ed the need f or a randomised control trial to demonstrate the ef f ectiv eness of dua l therapy w ith B L M compa red w ith monotherapy w ith B L .

One such study was the Community Acquired Pneumonia Study on the initial T reatment w ith A ntib iotics of the low er R esp iratory T ract infections (CAP-START) trial by Postma et a l .[ 10] T he inv estig ators examined the effect of BL v. BLM v. FQ. This trial was a cluster randomised stu dy condu cted in 4-month b lock s and rotated throu g h sev en hosp itals ov er 2.5 y ears. E ach hosp ital u sed the dif f erent treatment reg imens according to the D u tch g u idelines and all three reg imens w ere rotated ev ery 4 months in each of the sev en hosp itals. O f the 2 283 patients included in the study, 656 received a BL, 739 received a BLM and 888 received an FQ. The median patient stay was equal in all three antib iotic g rou p s. T he 90-day mortality f or the B L g rou p w as 9.0%, 11.1% for the BLM group and 8.8% for the FQ group, and this difference was not statistically significant. All the patients included in the stu dy w ere non-I C U admissions. A dv erse ef f ects w ere hig her in the BLM group compared with the BL group (7.2% v.1.7%), necessitating a chang e of antib iotic. T he stu dy demonstrated non-inf eriority of a B L reg imen comp ared w ith a B L M reg imen.

A cav eat to the addition of an antib iotic f or p u re immu nomodu lation is the dev elop ment of resistance b y org anisms. A stu dy b y M alhotra-K u mar et a l .[ 11] analy sed the resistance of orop hary ng eal strep tococci that dev elop ed af ter a cou rse az ithromy cin or clarithromycin. In 74 healthy volunteers there was a 50% increase in resistance to clarithromy cin and a 54% increase in resistance to azithromycin. Six months were required for these acquired resistance lev els to retu rn to lev els p rior to antib iotic u se.

T he hig h b u rden of immu ne-comp romised p atients created b y the HI virus may well negate the possible immunomodulatory effects of macrolides. This may be why HIV seropositive patients were excluded in all trials u sing macrolides if their C D 4 cou nt w as < 350 cells/μL .

Until there is a clear mortality benefit demonstrated by randomised prospective trials using a macrolide, adding a macrolide risks creating increased resistance and hence cannot b e recommended as reg u lar additional therapy in CAP for immunomodulation purposes only.

The corticosteroid debate

The use of corticosteroids as immunomodulators in patients with acute respiratory distress syndrome (ARDS) and septic shock from pneumonia is already established.[12] What is not certain is the benefit of the use of steroids for patients with CAP who do not require intensive care management. In these circumstances, the effect of steroids as immunomodulators is tested outside the arena of shock and ARDS. The use of steroids was so successful in oxygenation improvement in a study by Confalonieri et al.[13] that the study was stopped prematurely.

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REVIEW In this study of 46 patients, one of the following major criteria was required for inclusion: patient requiring mechanical ventilation, chest X-ray appearance worsening by 50% or more, or vasopressor use of longer than 4 hours’ duration. Two of the following minor criteria were required: a PaO2/FiO2 (PF ratio) of <250 mmHg, systolic blood pressure <90 mmHg, bilateral involvement, a respiratory rate >30 breaths/minute or a diastolic blood pressure <60 mmHg. Forty-five of the 46 patients had a PF ratio of <250 mmHg. According to the Berlin criteria[14] for ARDS, a PF ratio of <250 mmHg is already classified as mild ARDS. Fifty-seven percent of the placebo arm had a PF ratio of <200 mmHg. This study was, effectively, a demonstration of the efficacy of steroids in ARDS secondary to CAP rather than in uncomplicated CAP. A recent double blind randomised controlled trial (RCT) showed that the use of adjunct corticosteroids in CAP led to an earlier time to stability by 1 day, 1 day less of intravenous antibiotics and, consequently, a 1-day earlier discharge from hospital.[15] The time benefit of 1 day could amount to a large cost saving across hundreds of thousands of admissions. There was no mortality benefit from use of corticosteroids in the 800 patients in the study. Those who had active tuberculosis and who were HIV seropositive with a CD4 count of <350 cells/μL were excluded from the trial. The Pneumonia Severity Index (PSI) score grades into five classes and is equivalent to the CURB-65 score, which rates from 1 to 5. Of note in this study by Blum et al.[15] was that only 40% of patients in the placebo arm had a PSI category of 3 or less. Fifty-two percent of the patients in the placebo arm were in the two most-ill categories, both requiring ICU care. Of these, 38% were PSI class IV (CURB-65 score 4) and 14% were PSI class V (CURB-65 score 5). There was also an equivalent proportion (47%) of very sick patients in the corticosteroid arm. Therefore, it was difficult to measure which patients benefited the most from steroid use – those who were more severely ill or those in PSI class III or less.

The beneficial effect of corticosteroids may have been in the more sick patients, since patients in shock and with ARDS benefit from corticosteroids; however, there was no reduction in the time spent in ICU, with both groups having a mean stay of 3 days. Therefore, we may speculate that steroids do have benefit in non-ICU patients. In the South African (SA) context, many patients with CAP would then be necessarily excluded for adjunct corticosteroid use because of high prevalence of HIV <350 cells/μL and tuberculosis. Patients with these two conditions were excluded from the CAP corticosteroid trials.

The Polverino et al. [16] prospective observational study, conducted over 10 years, also showed benefits for corticosteroid use in 260 patients, bringing them to stability 1 day earlier than the 2 997 patients not treated with a corticosteroid. However, in sicker patients with pneumonia CURB-65 score 4 or 5, no mortality benefit or faster time to stability was observed.

In contrast to the Blum study,[15] the prospective double blind randomised controlled trial by Snijders,[17] which enrolled 213 patients randomised into groups of 104 patients who received prednisone and 109 who received a placebo, showed no corticosteroid benefit either in mortality or time to stability. The majority of the patients in both groups had CURB-65 scores of between 1 and 3: 90% in the prednisone and 91% in the placebo group. Macrolides were not used as antibiotics in either study group. The time to clinical stability was 4.9 days in each group. The C-reactive protein (CRP) levels had a more rapid decline in the corticosteroid group. Commentary on this study by Meduri et al.[18]

100 SARJ VOL. 22 NO. 4 2016

acknowledged that steroids did not have a role to play in CAP outside the realm of associated severe sepsis.

A study by Tagami et al.[19] assessed the use of corticosteroids in severe CAP in patients requiring mechanical ventilation. A total of 6 295 patients from 983 hospitals were divided into those who received catecholamines (n=2 524) and those who did not (n=4 401).

In those patients who received catecholamines, two groups of patients were matched using a propensity score with similar physiological variables. The investigators matched 491 patients into two groups, both receiving catecholamines with one group receiving corticosteroids.

The mortality rate at 28 days was 25.3% in those receiving additional corticosteroids v. 32.6%. This demonstrated a clear benefit in the use of corticosteroids in patients requiring iontropic support in severe CAP. In the group of 4 401 patients with severe CAP who did not need catecholamine support, patients were matched according to the same propensity scores to give two groups of 943 patients. The mortality in those receiving steroids was 17.7% v. 15.6% (p=0.22), showing no benefit for corticosteroids in ventilated patients who did not receive ionotropic support.

If mechanically ventilated patients with severe CAP who are not in shock do not benefit from the addition of steroids, then the use of steroids in the routine use of CAP treatment in the wards cannot be supported, let alone prescribing steroids with antibiotics for the outpatient management of pneumonia.

Conclusion

Both macrolides and corticosteroids act on inflammatory pathways in infection. It is difficult to target a few pathways in the hope of controlling the body’s natural multifaceted response to infection.

Studies have struggled to demonstrate a clear benefit for the use of macrolides and corticosteroids to reduce inflammation and thus reduce mortality in CAP. Overwhelming infection causing septic shock appears to be the only clinical indication where corticosteroids have proven to be of benefit in reducing the mortality rate.

The greatest effect clinicians can presently have in reducing the CAP mortality rate is with the widespread use of the pneumococcal vaccine. The adage ‘prevention is better than cure’ rings true in the realm of CAP, especially as there is increased mortality across all ages in patients with CAP v. control subjects, as much as 10 years after an initial pneumonia.[20] 1. Metersky ML, Waterer G, Nsa W, Bratzler DW. Predictors of in-hospital vs. post discharge mortality in pneumonia. Chest 2012;142(2):476-481. http://dx.doi. org/10.1378/chest.11-2393 2. Desaki M, Okazaki H, Sunazuka T, Omura S, Yamamoto K, Takizawa H. Molecular mechanisms of anti-inflammatory action of erythromycin in human bronchial epithelial cells: Possible role in the signaling pathway that regulates nuclear factorkB activation. Antimicrob Agents Chemother 2004;48(5):1581-1585. http://dx.doi. org/10.1128/aac.48.5.1581-1585.2004 3. Kanoh S, Rubin BK. Mechanisms of action and clinical application of macrolides as immunomodulatory medications. Clin Microbiol Rev 2010;23(3):590-615. http:// dx.doi.org/10.1128/CMR.00078-09 4. Adcock IM, Lane SJ. Corticosteroid-insensitive asthma: Molecular mechanisms. J Endocrinol 2003;178(3):347-355. http://dx.doi.org/10.1677/joe.0.178034 5. File TM, Marrie TJ. Does empiric therapy for atypical pathogens improve outcomes for patients with CAP? Infect Dis Clin North Am 2013;27(1):99-114. http://dx.doi. org/10.1016/j.idc.2012.11.005 6. Restrepo MI, Mortensen EM, Waterer GW, Wunderink RG, Coalson JJ, Anzueto A. Impact of macrolide therapy on mortality for patients with severe sepsis due to pneumonia. Eur Respir J 2009;33(1):153-159. http://dx.doi.org/10.1183/09031936.00054108 7. Laserna E, Sibila O, Fernandez JF, et al. Impact of macrolide therapy in patients hospitalized with pseudomonas aeruginosa community-acquired pneumonia. Chest 2014;145(5):1114-1120. http://dx.doi.org/10.1378/chest.13-1607

CASE REPORT 8. Asadi L, Sligl WI, Eurich DT, et al. Macrolide-based regimens and mortality in hospitalized patients with community-acquired pneumonia: A systematic review and meta-analysis. Clin Infect Dis 2012;55(3):371-380. http://dx.doi.org/10.1093/cid/cis414 9. Nie W, Li B, Xiu Q. β-lactam/macrolide dual therapy versus β-lactam monotherapy for the treatment of community-acquired pneumonia in adults : A systematic review and meta-analysis. J Antimicrob Chemother 2014;69(6):1441-1446. http://dx.doi. org/10.1093/jac/dku033 10. Postma, DF, Van Wekhoven CH, Van EL, et al. Antibiotic treatment strategies for community-acquired pneumonia in adults. N Engl J Med 2015;372(14):1312-1323. http://dx.doi.org/10.1056/nejmoa1406330 11. Malhotra-Kumar S, Lammens C, Coenen S, Herck K, Van Goossens H. Effect of azithromycin and clarithromycin therapy on pharyngeal carriage of macrolide-resistant streptococci in healthy volunteers: A randomised, double-blind, placebo-controlled trial.

Lancet 2007;369(9560):482-490. http://dx.doi.org/10.1016/s0140-6736(07)60235-9 12. Annane D. Corticosteroids for severe sepsis: An evidence-based guide for physicians.

Ann Intensive Care 2011;1(1):7. http://dx.doi.org/10.1186/2110-5820-1-7 13. Confalonieri M, Urbino R, Potena A, et al. Hydrocortisone infusion for severe community-acquired pneumonia a preliminary randomized study. Am J Respir Crit Care Med 2003;171(3):242-248. http://dx.doi.org/10.1164/rccm.200406-808oc 14. ARDS Definition Task Force. Acute respiratory distress syndrome: The Berlin definition.

JAMA 2012;307(23):2526-2533. http://dx.doi.org/10.1001/jama.2012.5669

15. Blum CA, Nigro N, Briel M, et al. Adjunct prednisone therapy for patients with community-acquired pneumonia: A multicentre, double-blind, randomised, placebocontrolled trial. Lancet 2015;385(9977):1511-1518. http://dx.doi.org/10.1016/s01406736(14)62447-8 16. Polverino EVA, Cillóniz CA, Dambrava PO, et al. Systemic corticosteroids for community-acquired pneumonia: Reasons for use and lack of benefit on outcome.

Respirology 2013;18(2):263-271. http://dx.doi.org/10.1111/resp.12013 17. Snijders D, Daniels JM, De Graaff CS, Van der Werf TS, Boersma WG. Efficacy of corticosteroids in community-acquired pneumonia: A randomized double-blinded clinical trial. Am J Respir Crit Care Med 2010;181(9):975-982. http://dx.doi.org/10.1164/ rccm.200905-0808oc 18. Meduri GU, Bell WE, Confalonieri M. Glucocorticoid treatment in communityacquired pneumonia without severe sepsis. Am J Respir Crit Care Med 2010;181(9):880882. http://dx.doi.org/10.1164/rccm.201001-0034ED 19. Tagami T, Matsui H, Horiguchi H, Fushimi K, Yasunaga H. Low-dose corticosteroid use and mortality in severe community-acquired pneumonia patients. Eur Respir J 2014;45(2):463-472. http://dx.doi.org/10.1183/09031936.00081514 20. Eurich DT, Marrie TJ, Minhas-Sandhu JK, Majumdar SR. Ten-year mortality after community-acquired pneumonia. A prospective cohort. Am J Respir Crit Care Med 2015;192(5):597-604. http://dx.doi.org/10.1164/rccm.2015010140oc

Massive haemoptysis in pregnancy S Mothilal, MB ChB, FCP, MMed; A Esmail, MD, FCP, Cert Pulm; K Dheda, MB ChB, FCP, FRCP, PhD Division of Pulmonology, Department of Medicine, University of Cape Town Lung Institute and Groote Schuur Hospital, Cape Town, South Africa Corresponding author: S M ot hi l al

( sh1k

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)

Haemoptysis in pregnancy may be due to a myriad of causes, including pulmonary embolism, heart failure, vasculitides and infective or post-infective aetiologies. Pulmonary arteriovenous malformations (PAVMs) are a rare cause of massive haemoptysis that involve an abnormal communication between the pulmonary arteries and the pulmonary veins. The majority of PAVMs are congenital and associated with hereditary haemorrhagic telangiectasia (HHT). To illustrate the complexity of the diagnosis and management of PAVM in pregnancy, we report the case of a 32-year-old woman presenting with massive haemoptysis at 36 weeks of gestation.

S Afr Respir J 2016;22(4):101-103. DOI:10.7196/SARJ.2016.v22i4.104

Case presentation

A 32-year-old woman presented with a 1-day history of ~500 mL of haemoptysis at 36 weeks’ gestation. This was her first episode of haemoptysis, which was preceded by a dry cough for 6 months. She did not experience chest pain, orthopnoea, paroxysmal nocturnal dyspnoea or constitutional symptoms. Her two previous pregnancies were uncomplicated.

She tested negative for HIV during antenatal screening and she had no comorbidities. She was not using any chronic medication or illicit drugs.

She had a 10 pack-year smoking history and consumed alcohol in moderation prior to her pregnancy. She had no significant family history, travel history or environmental exposure.

On examination, her blood pressure was 130/80 mmHg, heart rate 90 beats per minute, respiratory rate 24 breaths per minute and temperature 36°C. Her pulse

oximetry measured 97% on ambient air. She exhibited digital clubbing but had no features to suggest deep vein thrombosis, petechia, purpura, telangiectasia or connective tissue disease. Her respiratory examination revealed a patent airway with bilateral equal breath sounds and no added sounds. Her heart sounds were normal with no murmurs.

Her abdomen was soft and non-tender. Her neurological examination was normal.

She had a normal full blood count, renal function, liver function, coagulation studies, vasculitic screen and urinalysis. Her sputum microscopy, culture and mycobacterium tuberculosis polymerase chain reaction (GeneXpert MTB/RIF PCR) were negative.

Her chest X-ray and computed tomography pulmonary angiogram (CTPA) with 3D reconstruction are shown in Figs 1, 2 and 3, respectively.

Fig. 1. Chest X-ray demonstrating a peripheral wedge-shaped opacity (arrow) in the right mid-zone and a linear opacity extending from the right hilum representing a feeding vessel (arrowhead).

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CASE REPORT In view of the severity of the patientâ&#x20AC;&#x2122;s symptoms and her abnormal chest X-ray, CTPA was regarded as the imaging modality of choice. The CTPA demonstrated a large pulmonary arteriovenous malformation (PAVM). The patient subsequently underwent successful coiling of her PAVM (Fig. 4) and had an uncomplicated vaginal delivery.

Repeat CTPA confirmed retraction of the aneurysmal sac. Prior to discharge, the patient was counselled regarding the risks related to PAVM in future pregnancy and was offered contraception.

Fig. 2. Axial slice of CTPA demonstrating the pulmonary arteriovenous malformation (arrow) with surrounding haemorrhage and a feeding vessel (arrowhead) extending from the right hilum.

Discussion

Haemoptysis in pregnancy may be due to a myriad of causes, including pulmonary embolism, heart failure, vasculitides and infective or post-infective aetiologies.

Although no standardised definition exists, massive haemoptysis is generally associated with ~500 mL of expectorated blood in a 24hour period, or a rate of haemoptysis greater than ~200 mL per hour.[1] PAVMs are a rare cause of massive haemoptysis but should be considered in the differential diagnosis of a patient presenting with this clinical problem.

PAVMs were first described in 1897.[2] They consist of abnormal communications between the pulmonary arteries and the pulmonary veins. Ninety-five percent of the feeding arteries arise from the pulmonary circulation, while 5% arise from the bronchial artery, internal mammary artery or descending aorta. Furthermore, 53 - 70% of PAVMs are found in the lower lobes and are commonly multiple.[3] Over 80% of PAVMs are congenital, and of these, 47 - 96% (depending on the context) are associated with the autosomal dominant disorder hereditary haemorrhagic telangiectasia (HHT), also known as OslerWeber-Rendu disease. Conversely, it is Table 1. Aetiology of PAVM Primary HHT Secondary Congenital Chest trauma Thoracic surgery Hepatic cirrhosis Metastatic carcinoma

Fig. 3. 3D reconstruction demonstrating the angio-architecture of the pulmonary circulation with the arrow showing the PAVM.

Mitral stenosis Infections (actinomycosis, schistosomiasis) Systemic amyloidosis

estimated that, overall, 5 - 15% with HHT have a PAVM.[4] Secondary or acquired causes of PAVM, although uncommon, have also been reported (Table 1).

The pathogenesis of PAVMs is poorly understood.[4] It is proposed that a defect in the terminal arteriole occurs, leading to dilatation of thin-walled capillary sacs. Blood then bypasses the normal oxygen-exchanging pulmonary capillary bed, returning to the pulmonary veins in a desaturated state. The fundamental defect is therefore a right-to-left shunt.[5] Dyspnoea, especially with exercise, develops over many years. [6] In severe cases, dyspnoea in the upright position (platypnoea) with associated cyanosis (orthodeoxia) is present. Haemoptysis occurs rarely, accounting for 0.2% of all causes of haemoptysis, [7] which may sometimes be massive. On examination, patients may demonstrate digital clubbing while the presence of telangiectasia is a valuable clue to the association with HHT. Machinery murmurs or bruits are heard over large PAVMs. Hypoxia, if present, does not correct fully after the administration of 100% oxygen. PAVMs are also associated with a variety of complications, some of which are life-threatening, including strokes, brain abscesses and heart failure.

Chest X-ray is an important diagnostic tool and shows abnormalities in more than 90% of patients.[8] CTPA, however, remains the gold standard for evaluating the angio-architecture of the PAVM, and when combined with 3D helical scanning can produce images of the entire vascular structure with a sensitivity of up to 95%.[9] The classical radiographical features of PAVM are a rounded, sharply defined mass of uniform density, frequently lobulated, and ranging from 1 - 5 cm in diameter. There may sometimes be a connecting vessel radiating from the hilum.

Until 1977, surgery was the only method of treatment, in which ligation, local excision,

Table 2. Indications and complications of embolotherapy

Fig. 4. Catheterisation (a) and successful coiling (b) of the PAVM.

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Indications

Complications

Hypoxaemia

Device migration

Haemoptysis

Haemorrhage

Paradoxical embolisation

Vascular injury

Feeding vessels 2 - 3 mm

Arterial/venous thrombosis

Progressive enlargement

ARTICLE lobectomy or pneumonectomy was performed. Nowadays, embolotherapy is the treatment of choice as it avoids major surgery, anaesthesia, loss of lung parenchyma and additional cost.[10] Moreover, embolotherapy has comparable success rates with surgery.[11] It is performed by catheterisation of the feeding artery and either coiling or balloon deployment into the PAVM. The indications and complications of embolotherapy are listed in Table 2.

Untreated, PAVMs confer a high mortality risk of up to ~30%.[12] Furthermore, genetic counselling is an important aspect of management in patients with HHT.[13] PAVM in pregnancy PAVM in pregnancy is rare and is associated with an increased rate of growth and complications such as haemoptysis.[14] This is due to the increase in blood volume and the vasodilatory effect of pregnancy hormones, most marked during the second trimester, which leads to increased pulmonary blood flow, PAVM dilatation and subsequent rupture.

Therefore, female patients with a history of PAVM must be counselled regarding the substantial risks associated with pregnancy and be offered suitable contraception.

Conclusion

PAVM is a rare cause of massive haemoptysis, however it must be considered in the differential diagnosis of a patient presenting with this clinical problem. Embolotherapy is the treatment of choice for symptomatic or large lesions. Furthermore, PAVMs are associated with an increased rate of complications in pregnancy, and female patients should be counselled regarding this risk and offered contraception.

1. Jean-Baptiste E. Clinical assessment and management of massive hemoptysis. Crit Care Med 2000;28(5):1642-1647. http://dx.doi.org/10.1097/00003246-200005000-00066 2. Churton T. Multiple aneurysms of the pulmonary artery. Br Med J 1897;1:1223-1225.

3. Boscher Lea. An analysis of the pathologic anatomy of pulmonary arteriovenous aneurysms with particular reference to the applicability of local excision. Surgery 1959;45:91-104.

4. Hodgson CH. Hereditary hemorrhagic telangiectasis and pulmonary arteriovenous fistula. N Engl J Med 1959;26(3)1:625-636. http://dx.doi.org/10.1056/ nejm195909242611301 5. Gossage JR, Kanj G. Pulmonary arteriovenous malformations. A state of the art review. Am J Respir Crit Care Med 1998;158(2):643-661. http://dx.doi. org/10.1164/ajrccm.158.2.9711041 6. Moyer JH, Glantz G, Brest A. Pulmonary arteriovenous fistulas: Physiologic and clinical considerations. Am J Med 1962;32(3):417-425. http:// dx.doi.org/10.1016/0002-9343(62)90131-6

7. Abdulmalak C, Cottenet J, Beltramo G, et al.

Haemoptysis in adults: A 5-year study using the French nationwide hospital administrative database.

Eur Respir J 2015;46(2):503-511. http://dx.doi. org/10.1183/09031936.00218214 8. Dines DE, Arms RA, Bernatz PE, Gomes MR. Pulmonary arteriovenous fistulas. Mayo Clin Proc 1974;49:460-465. http://dx.doi.org/10.1016/s00034975(10)66398-9 9. Remy J, Remy-Jardin M, Wattinne L, Deffontaines C. Pulmonary arteriovenous malformations: Evaluation with CT of the chest before and after treatment.

Radiology 1992;182(3):809-816. http://dx.doi. org/10.1148/radiology.182.3.1535899 10. Meek ME, Meek JC, Beheshti MV. Management of pulmonary arteriovenous malformations. Semin Intervent Radiol 2011;28(1):24-31. http://dx.doi. org/10.1055/s-0031-1273937 11. Saluja S, Sitko I, Lee DW, Pollak J, White RI Jr. Embolotherapy of pulmonary arteriovenous malformations with detachable balloons: Longterm durability and efficacy. J Vasc Interv Radiol 1999;10(7):883-889. http://dx.doi.org/10.1016/s10510443(99)70132-6 12. Khurshid I, Downie GH. Pulmonary arteriovenous malformation. Postgrad Med J 2002;78(918):191-197. http://dx.doi.org/10.1136/pmj.78.918.191 13. Guttmacher AE, Marchuk DA, White RI Jr. Hereditary hemorrhagic telangiectasia. N Engl J Med 1995;333(14):918-924. http://dx.doi.org/10.1056/ nejm199510053331407 14. Ference BA, Shannon TM, White RI, Jr, Zawin M, Burdge CM. Life-threatening pulmonary hemorrhage with pulmonary arteriovenous malformations and hereditary hemorrhagic telangiectasia. Chest 1994;106(5):1387-1390. http://dx.doi.org/10.1378/ chest.106.5.1387

‘On the shoulders of giants’ – The evolution of paediatric pulmonology in South Africa A Vanker, MB ChB, FCPaed, MMed, Cert Pulm Paed Paediatric Pulmonologist, Red Cross War Memorial Children’s Hospital, University of Cape Town, South Africa and Paediatric Representative, South African Thoracic Society (2015 - 2017) Corresponding author: A Vanker (aneesa.vanker@uct.ac.za)

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‘Children are not small adults’ is a common adage we were taught at medical school. This was recognised as far back as the first century, when the Roman medical encyclopaedist Celsus wrote, ‘In general, boys should not be treated in the same way as men.’

These differences in size and physiology have led to the development of paediatrics as a speciality. Likewise, so developed the different subspecialities of paediatrics, including pulmonology.

In 2016, paediatric pulmonology is a well-established subspeciality in South Africa (SA) with accredited units at most of the academic centres as well as a number of pulmonologists in the private sector, nationally. The SA Thoracic Society (SATS) has 25 registered

paediatric pulmonologists as members, compared with 87 adult pulmonologists. However, arriving where we are today has not been without hard work, dedication and the perseverance of some ‘giants’ of paediatric pulmonology.

The birth of paediatric pulmonology in SA most likely lies in the famed adult respiratory unit of Prof. Attie de Kock. Prof. de Kock was trained at the University of California, Los Angeles (UCLA) in San Francisco in the 1960s, where he worked with one of the doyens of adult pulmonology, Prof. Jay Nadel. When he returned to SA, Prof. de Kock started performing rigid bronchoscopies as well as medianoscopies.

He also acquired a paediatric bronchoscopy set which led to paediatric

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WHO’S WHO bronchoscopies being performed, mostly for suspected foreign bodies and tuberculosis gland obstruction of the airways. Prof. de Kock’s unit was the incubator for two names synonymous with the development of paediatric pulmonology in SA: initially, the late Prof. Max Klein, and some years later, Prof. Robert Gie. Paediatric pulmonology in its infancy was closely linked to adult pulmonology through the then named SA Respiratory Society. It was under the guidance of the credentials committee headed by Prof. J Joubert that paediatric pulmonology became a subspeciality recognised by the Health Professions Council of South Africa in 1993, and a ‘grandfather’ clause saw the registration of a number of paediatricians as pulmonologists, including Profs M Klein, R P Gie, P Jeena, A Argent, R Green and Drs D Richards, A van Niekerk and SA Thula. Prof. H J Zar and Dr S Ponde, who each trained overseas, were also subsequently registered as paediatric pulmonologists.

The growth of paediatric pulmonology saw the development of a curriculum by Profs Zar, Green, Gie and Jeena, and from around 2002 the paediatric pulmonology training programme was renewed with the establishment of training programmes in the Western Cape and Pretoria. In 2010, the College of Paediatricians revised the rules and regulations for the Certificate in Paediatric Pulmonology to standardise the examination, strengthen diversity and create a legal framework for examinations.

Prof. Refiloe Masekela was the first person in SA to achieve the Certificate Pulmonology Paeds, in October 2007. Since then, 31 trainees have successfully achieved this. The speciality has attracted a group of people both transformative and representative of SA diversity. Successful trainees are working in both academic and private sectors. There is much research being conducted in various aspects pertaining to childhood respiratory health, from pneumonia

and tuberculosis to pulmonary function tests in young children, resulting in the development of a number of clinician researchers.

Further growth has included the establishment of new training units at the universities of the Witwatersrand (Wits) and Limpopo.

In the Department of Paediatrics at the University of Cape Town (UCT), a successful African paediatric pulmonology fellowship has been running since 2006, training paediatric pulmonologists for Africa in partnerships with African academic institutions.[1] Through this, several African trainees have been trained in the past 5 years, including seven from Kenya, one from Uganda, two from Nigeria and one from Ghana; this has built considerable capacity in Africa for child lung health. At UCT a 1-year postgraduate Diploma in Paediatric Pulmonology has recently been established, enabling general paediatricians or specialists to acquire additional training and skills in this area. Of note, Dr Leah Githinji (Kenya), who trained at the University of KwaZulu-Natal and UCT, and Dr Edgar Kalimba (Rwanda), a Wits trainee, successfully achieved the certificate in paediatric pulmonology.

Paediatric pulmonology is also recognised as an integral part of respiratory health, with active participation in the SA Thoracic Society (SATS). Prof. Heather Zar was the first paediatric pulmonologist to serve as president of SATS, a testament to the importance of childhood respiratory health in the SA context. The first SA Paediatric Asthma Guideline was published in 1992. Since then, SATS has endorsed 11 guidelines with a paediatric interest (including asthma, communityacquired pneumonia, bronchiolitis, ventilator-associated pneumonia and influenza). Paediatric pulmonology has also been prominent in the Pan-African Thoracic Society (PATS), with Prof. Zar currently serving as the PATS president and Prof. Masikela as the current secretary.

Who’s who Ivan Schewitz is a cardiothoracic surgeon in Johannesburg. He is an honorary consultant at Pretoria University and trained under Profs Barnard and Kingsley. Dr Schewitz introduced minimally invasive thoracic surgery into South Africa (SA). The Nuss procedure for pectus excavatum was first performed in SA by him and has now become the standard procedure for this condition. Over the last few years, he has run a number of minimally invasive

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thoracic surgery workshops, in an effort to popularise this aspect of thoracic surgery.

Dr Schewitz is an executive member of the Chest Wall International Group, as well as the surgical representative of the SA Thoracic Society. He has contributed to many local and international meetings as a presenter, as well as a number of peer-reviewed articles, and a book chapter for a book on uniportal thoracic surgery.

BREATH-TAKING NEWS

B M P R 2 mutations and survival in pulmonary arterial hypertension: An individual participant data meta-analysis Pulmonary arterial hypertension (PAH) is a rare disorder characterised by progressive remodelling of the small pulmonary arteries, resulting in increased pulmonary vascular resistance and ultimately right ventricular failure and death.[1,2] The diagnosis of PAH requires a mean pulmonary artery pressure of 25 mmHg or more with a pulmonary artery wedge pressure of 15 mmHg or less at right heart catheterisation in the absence of chronic thromboembolic, left heart or respiratory disease. The classification of PAH includes both inheritable and idiopathic forms. Heterozygous germline mutations in the gene encoding the bone morphogenetic protein receptor type II (BMPR2) have been identified as the main genetic cause of familial PAH.[3,4] It is estimated that over 300 different BMPR2 mutations have been identified, with a prevalence of greater than 75% in families with PAH.[5,6] BMPR-II is a receptor for the bone morphogenetic proteins (members of the transforming growth factor-β superfamily).

Mutations in the BMPR2 gene cause loss of function and reduced signalling downstream of the receptor. It has been hypothesised that abnormal pathway activity may permit excess endothelial cell growth and proliferation in response to a variety of injuries.[7] In a recent article, Evans et al.[8] analysed the individual patient data of 1 550 patients with idiopathic, heritable and anorexigenassociated PAH from eight cohorts that had been systematically tested for BMPR2 mutations. The primary outcome was the composite of death or lung transplantation; all-cause mortality was the secondary outcome.

The findings of this data meta-analysis showed that 448/1 550 (29%) patients had a BMPR2 mutation. Mutation carriers were younger at diagnosis (mean age (standard deviation) 35.4 (14.8) v. 42.0 (17.8) years), had a higher mean pulmonary artery pressure (60.5 (13.8) v.

56.4 (15.3) mmHg) and pulmonary vascular resistance (16.6 (8.3) v.

12.9 (8.3) Wood units), and lower cardiac index (2.11 (0.69) v. 2.51 (0.92) L/min per m²) (all p<0.0001).

Patients with BMPR2 mutations were less likely to respond to acute vasodilator testing (3% (10/380) v. 16% (147/907); p<0.0001). Among the 1 164 individuals with available survival data, age-adjusted and sex-adjusted hazard ratios (HRs) comparing BMPR2 mutation carriers with non-carriers were 1.42 (95% confidence interval 1.15 1.75; p=0.0011) for the composite of death or lung transplantation and 1.27 (1.00 - 1.60; p=0.046) for all-cause mortality.

The HRs were attenuated after adjustment for potential mediators including pulmonary vascular resistance, cardiac index and

vasoreactivity. HRs for death or transplantation and all-cause mortality associated with BMPR2 mutation were similar in men and women, but higher in patients with a younger age at diagnosis (p=0.003 for death or transplantation, p=0.011 for all-cause mortality).

These findings therefore show that patients with PAH and BMPR2 mutations are more likely to present at a younger age and with more severe disease, and are at an increased risk of death or transplantation, compared with those without BMPR2 mutations. The recently revised 2016 European guidelines for the diagnosis and treatment of PAH now recommend offering genetic counselling and screening for BMPR2 mutations in patients diagnosed with idiopathic, heritable and anorexigen-associated PAH, mainly to enable the predictive genetic testing of relatives.[9] T Mnguni Senior Registrar in Pulmonology, Groote Schuur Hospital and University of Cape Town, South Africa eirusen@sun.ac.za 1. McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation 2006;114(13):1417-1431. http://dx.doi.org/10.1161/circulationaha.104.503540 2. Humbert M, Morrell NW, Archer SL, et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 2004;43(12):13S-24S. http:// dx.doi.org/10.1016/j.jacc.2004.02.029 3. Deng Z, Morse JH, Slager SL, et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene.

Am J Hum Genet 2000;67(3):737-744. http://dx.doi.org/10.1086/303059 4. Lane KB, Machado RD, Pauciulo MW, et al. Heterozygous germline mutations in BMPR2, encoding a TGF-β receptor, cause familial primary pulmonary hypertension.

Nat Genet 2000;26(1):81-84.

5. Soubrier F, Chung WK, Machado R, et al. Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol 2013;62(25 Suppl):D13-D21. http://dx.doi. org/10.1016/j.jacc.2013.10.035 6. Machado RD, Southgate L, Eichstaedt C, et al. Pulmonary arterial hypertension: A current perspective on established and emerging molecular genetic defects. Hum Mutat 2015;36(12):1113-1127. http://dx.doi.org/10.1002/humu.22904 7. Kimura N, Matsuo R, Shibuya H, Nakashima K, Taga T. BMP2-induced apoptosis is mediated by activation of the TAK1-p38 kinase pathway that is negatively regulated by Smad6. J Biol Chem 2000;275(23):17647-17652. http://dx.doi.org/10.1074/jbc.m908622199 8. Evans JDW, Girerd B, Montani D, et al. BMPR2 mutations and survival in pulmonary arterial hypertension: An individual participant data meta-analysis. Lancet Respir Med 2016;4(2):129-137. http://dx.doi.org/10.1016/s2213-2600(15)00544-5 9. Galiè N, Humbert M, Vachiery J-L, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2016;37(1):67-119. http:// dx.doi.org/10.1093/eurheartj/ehv317

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Pulmonary artery size as a predictor of outcomes in idiopathic pulmonary fibrosis Pulmonary hypertension (PH) is a well-recognised complication of idiopathic pulmonary fibrosis (IPF) and is predictive of a worse outcome. The prevalence of PH in the setting of IPF has not been well described in the literature, but has ranged from 32 to 85%.[1,2] Recognising underlying PH in a patient with IPF is a challenging diagnostic dilemma because of the nonspecific clinical symptoms and unreliable non-invasive ancillary tests. The treatment of PH and the need for transplantation in patients with IPF is based on factors that include disease severity, functional status and the degree of hypoxaemia.[3,4] Given the high mortality rate and propensity for acute decompensation, PH in IPF patients should be evaluated early owing to the prognostic implications and potential need for transplant early in the disease course. Shin et al.[5] performed a retrospective review of 98 patients with IPF who attended a tertiary-care centre between 2008 and 2013. The objective was to establish whether there was an independent relationship between pulmonary artery size and outcomes (either lung transplant or death) over a 5-year period.

The pulmonary artery and ascending aorta diameter ratio (PA:A) was calculated after being measured by high-resolution computed tomography (HRCT) of the chest. The independent influence of different variables on overall outcomes was evaluated using the Cox proportional hazards model. The patients were divided into two groups based on those with a PA:A ratio ≤1 and a PA:A ratio >1. The baseline characteristics were not significantly different between the two groups except for the forced vital capacity (FVC) % predicted, forced expiratory volume in 1 second % predicted and diffusing capacity of the lung for carbon monoxide (DLCO) % predicted. The mean pulmonary artery diameter and PA:A ratio were 32.8 mm and 0.94, respectively. Patients with a PA:A ratio >1 had higher risk of death or transplant compared with a PA:A ratio ≤1 (p<0.001). A

PA:A ratio >1 was also an independent predictor of outcomes in the adjusted outcomes analyses (hazard ratio 3.35, p=0.002). This ratio also appeared to perform better in predicting outcomes than the well-established gender, age and physiology (GAP) index – the latter referring to pulmonary function parameters, including FVC and DLCO.[6] This study highlights that an HRCT PA:A ratio >1 in IPF patients is associated with worse outcomes and may be helpful in risk stratification and prognostication.

V Moodley Senior Registrar in Pulmonology, Groote Schuur Hospital and University of Cape Town, South Africa venudhiram@gmail.com 1. American Thoracic Society/European Respiratory Society. International multidisciplinary consensus classifications of the idiopathic interstitial pneumonias.

Am J Respir Crit Care Med 2002;165:277-304. http://dx.doi.org/10.1164/ ajrccm.165.2.ats01 2. Zisman DA, Karlamangla AS, Ross DJ, et al. High-resolution chest CT findings do not predict the presence of pulmonary hypertension in advanced idiopathic pulmonary fibrosis. Chest 2007;132:773-779. http://dx.doi.org/10.1378/chest.07-0116 3. Tan RT, Kuzo R, Goodman LR, et al. Utility of CT scan evaluation for predicting pulmonary hypertension in patients with parenchymal lung disease. Chest 1998;113:1250-1256. http://dx.doi.org/10.1378/chest.113.5.1250 4. Shorr AF, Wainright JL, Cors CS, et al. Pulmonary hypertension in patients with pulmonary fibrosis awaiting lung transplant. Eur Respir J 2007;30:715-721. http:// dx.doi.org/10.1183/09031936.00107206 5. Shin S, King CS, Puri N, et al. Pulmonary artery size as a predictor of outcomes in idiopathic pulmonary fibrosis. Eur Respir J 2016;47(5):1445-1451. http://dx.doi. org/10.1183/13993003.01532-2015 6. Ley B, Ryerson CJ, Vittinghoff E, et al. A multidimensional index and staging system for idiopathic pulmonary fibrosis. Ann Intern Med 2012;156:684-691. http://dx.doi. org/10.7326/0003-4819-156-10-201205150-00004

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Present and future utility of CT phenotypes in the assessment and management of COPD Chronic obstructive pulmonary disease (COPD) is currently defined on the basis of spirometric evidence of airway obstruction in the setting of well-recognised risk factors. The Global Initiative for Obstructive Lung Disease (GOLD) system has been widely used to identify and classify the severity and risk predisposition of individual patients with COPD. However, individuals with identical GOLD stages have different morphologic appearances at computed tomography (CT) which may reflect important differences in the underlying pathophysiology and genomic profile of COPD.[1] A recent statement from the Fleischner Society[2] described the phenotypic abnormalities recognisable at visual and quantitative

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evaluation of CT in subjects with COPD. Although CT is a wellvalidated tool to assess the presence, pattern and extent of emphysema, its role in COPD has not been clearly determined and is not routinely recommended.[3] Subsequently, Ostridge and Wilkinson[4] reported on the present and future utility of CT in the assessment and management of COPD. They highlight the visually defined and quantitative CT subtypes of COPD. These include emphysema, which may be centrilobular (CLE), panlobular (PLE) or paraseptal (PSE); airway disease such as bronchial or small airways disease; and other associated features (large airways disease, interstitial lung disease, pulmonary artery enlargement and bronchiectasis).

BREATH-TAKING NEWS CLE is characterised by small, well-defined areas of low attenuation surrounded by normal lung. Micro-CT scan of the primary lesion shows dilatation and destruction of proximal respiratory bronchioles with sparing of alveoli near lobular septa. This is the most common type of smoking-related emphysema and is usually upper-lung predominant.

Quantifying the extent of CLE subcategorises it into mild, moderate and, in its most severe forms, confluent or advanced destructive emphysema. In the latter, CT confers the advantage of identifying patients who may benefit from lung volume reduction surgery, nonsurgical interventions (e.g. coils, valves, sealant and airway bypass) and bullectomy.[5] It is important to recognise that while the extent of CLE correlates well with histopathology, it often does not correspond with the GOLD classification for COPD. Furthermore, when quantified with densitometry, CT serves as a better predictive value for respiratory and cardiac mortality than GOLD staging.[6] PLE specifically refers to diffuse emphysematous destruction across the entire lobule. It has been associated with alpha-1 antitrypsin deficiency and is often lower-lobe predominant. In general, the extent and severity of alveolar destruction in PLE is milder than that in CLE. PSE describes lesions located distal to the acinus near the pleural surface, which includes the fissures. PSE may occur together with CLE but when it occurs alone is often not associated with significant symptoms or physiological impairment. It is the most common type of emphysema associated with bullous lung disease and subsequent pneumothorax.

Bronchial wall thickening is commonly observed in heavy cigarette smokers, particularly those with chronic bronchitis, presumably because of bronchial inflammation and remodelling.[7] Small airway disease is often the major cause of obstruction in COPD.[8] It can occur as a primary expression of COPD and can be difficult to detect physiologically. CT can thus be helpful in identifying signs of inflammatory small airway disease and small airway obstruction.

Interstitial abnormalities, which may appear as ground-glass or reticular infiltrates, likely correspond to variable combinations of respiratory bronchiolitis, airspace enlargement with fibrosis, and smoking-related interstitial fibrosis.[9] Pulmonary hypertension can be a complication of advanced COPD and is due to hypoxic vasoconstriction, pulmonary vascular obliteration, sleep apnoea or left heart abnormality.

This important comorbidity is a predictor of hospitalisation and death in COPD.[10] Bronchiectasis, which is most often cylindrical in character, is associated with more severe airflow obstruction, and acute exacerbations resulting in hospitalisation and higher mortality.[11]

Integration of visual characterisation of emphysema and airway abnormalities in quantitative CT assessment, together with lung function tests, permit categorisation of COPD into distinct structurally and functionally defined subtypes. This will identify significant disease in subjects with mild or absent physiological evidence of airway obstruction and help determine the progression of these specific patterns of disease and possibly predict treatment response. In summary, CT phenotyping may have an important role in therapeutic decision-making and understanding the natural history of COPD. S Mothilal Fellow in Pulmonology, Groote Schuur Hospital and University of Cape Town, South Africa 1. Friedlander AL, Lynch D, Dyar LA, Bowler RP. Phenotypes of chronic obstructive pulmonary disease. COPD 2007;4(4):355-384. http://dx.doi.org/10.

1080/15412550701629663 2. Lynch D, Austin JH, Lynch JC, et al. CT-definable subtypes of chronic obstructive pulmonary disease: A statement of the Fleischner Society. Radiology 2015;277(1):192205. http://dx.doi.org/10.1148/radiol.2015141579 3. Schroeder JD, McKenzie AS, Zach JA, et al. Relationships between airflow obstruction and quantitative CT measurements of emphysema, air trapping, and airways in subjects with and without chronic obstructive pulmonary disease. Am J Roentgenol 2013;201(3):W460-W470. http://dx.doi.org/10.2214/ajr.12.10102 4. Ostridge K, Wilkinson TMA. Present and future utility of computed tomography scanning in the assessment and management of COPD. Eur Respir J 2016;48(1):216– 228. http://dx.doi.org/10.1183/13993003.00041-2016 5. Fishman A, Martinez F, Naunheim K. A randomized trial comparing lung-volumereduction surgery with medical therapy for severe emphysema. N Engl J Med 2003;348(21):2059-2073. http://dx.doi.org/10.1056/nejmoa030287 6. Johannessen A, Skorge TD, Bottai M, et al. Mortality by level of emphysema and airway wall thickness. Am J Respir Crit Care Med 2013;187(6):602-608. http://dx.doi. org/10.1164/rccm.201209-1722oc 7. Hogg JC, Macklem PT, Thurlbeck WM. Site and nature of airway obstruction in chronic obstructive lung disease. N Engl J Med 1968;278(25):1355-1360. http://dx.doi. org/10.1056/nejm196806202782501 8. Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004;350(26):2645-2653. http://dx.doi. org/10.1056/nejmoa032158 9. Washko GR, Lynch DA, Matsuoka S, et al. Identification of early interstitial lung disease in smokers from the COPDGene study. Acad Radiol 2010;17(1):48-53. http:// dx.doi.org/10.1016/j.acra.2009.07.016 10. Chaouat A, Naeije R, Weitzenblum E. Pulmonary hypertension in COPD. Eur Respir J 2008;32(5):1371-1385. http://dx.doi.org/10.1183/09031936.00015608 11. Martínez-García MA, Soler-Cataluña JJ, Donat Sanz Y, et al. Factors associated with bronchiectasis in patients with COPD. Chest 2011;140(5):1130-1137. http://dx.doi. org/10.1378/chest.10-1758

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PRODUCT NEWS

AstraZeneca Pharmaceuticals responds to the chronic obstructive pulmonary disease crisis with the launch of a non-interventional study – COPVAR According to World Health Organization (WHO) reports, chronic obstructive pulmonary disease (COPD) is the third-leading cause of deaths worldwide.[1] Further, it is the sixth-leading cause of disabilityadjusted life years (DALYs) in middle-income countries – a figure that is expected to change to the fifth-leading cause worldwide in 2030 – and the significance of the disease is becoming quite evident. In response to this, AstraZeneca, a global, research-based biopharmaceutical company with a vested interest in the development of life-changing respiratory medications, has launched a cross-sectional study of patients with severe COPD that assesses patient perception of symptom variability in Middle East and African (MEA) countries.

COPD is characterised by persistent airflow limitation associated with a chronic inflammation of the small airways.[2] This is manifested in multiple respiratory symptoms, including dyspnoea, cough, sputum production, wheezing and chest tightness. Anorexia, fatigue and weight loss may also be expressed in more severe disease.

AstraZeneca’s non-interventional cross-sectional study of Global Initiative for Chronic Obstructive Lung Disease (GOLD) risk category C and D patients with severe COPD is primarily intended to assess patient perception of daily and weekly symptoms and their impact on daily life activities.

According to Dr Jasvanti Bhana, AstraZeneca South Africa (SA) Vice President for Medical and Regulatory Affairs, it is believed that the spike in COPD mortality rates is directly linked to the expanding smoking epidemic, exposure to biomass fuel (particularly in the developing world), reduced mortality from other common causes of death (ischaemic heart disease, infectious diseases) and the aging of the world population. Adding to this, she states that regardless of the cause and contributing factors, AstraZeneca is a research-based organisation and committed to being part of a solution that eases the healthcare burden through studies such as COPVAR. ‘Although COPD symptoms have been extensively reviewed in the literature, daily and weekly variation of symptoms and their impact on daily life activities have received less attention, especially in the MEA region,’ says Bhana. ‘No published study in MEA has investigated the fluctuation of COPD symptoms, the COPD treatment patterns, and their consistency with the GOLD guidelines.’

This non-interventional study also aims to explore current practice in the management of stable GOLD C and D COPD patients. ‘On conclusion of this study we must be able to describe the current treatment practice for the management of GOLD C and D COPD in MEA countries and their adherence to the GOLD 2016 guidelines,’ says Bhana. ‘We also want to draw comparisons between GOLD categories C and D to uncover patient perceptions of symptom variability and their impact. The identification of demographic, behavioural and clinical factors associated with symptom variability is another important study outcome sought by our [non-interventional study] NIS researchers.’

108 SARJ VOL. 22 NO. 4 2016

With SA now included in the study, there are nine participating countries. The other countries taking part are Algeria, Egypt, Jordan, Kuwait, Lebanon, Qatar, Turkey and the United Arab Emirates. It is expected that approximately 3 085 stable GOLD C and D COPD patients will be recruited during the 12-month multicentre study, of whom 350 will be SA patients. ‘Data collation – directly gathered from patients via self-administered questionnaires – will take place during a one-visit assessment; no follow-ups will be performed.

By design, there also are no specific tests or examinations carried out for the purpose of the study.’ Bhana concludes, ‘[Research and development] R&D is the life blood of medical solutions that save lives. Despite its pressures, we embrace the significant scientific leadership role we have achieved as a result of ethical, high quality research outputs, and SA is at the forefront of research for our Group.’

For 40 years, AstraZeneca has pushed the boundaries of science in respiratory disease. Starting with our first bronchodilator, through to our currently marketed products and a pipeline of respiratory products for both asthma and COPD, AstraZeneca scientists continue to transform disease management and patient outcomes in asthma and COPD. AstraZeneca continues to follow the science by developing targeted inhaled and biological therapies, unique drug combinations, and devices to ensure the right treatments for the right patients.

For further information on the COPVAR study contact AstraZeneca: AstraZeneca Pharmaceuticals (Pty) Ltd. South Africa Reg. No. 1992/005854/07 Building 2, Northdowns Office Park, 17 Georgian Crescent West, Bryanston, 2191, South Africa. Private Bag X23, Bryanston, 2021, South Africa.

Tel: +27 (0)11 797 6000. Fax: +27 (0)11 797 6001. www.astrazeneca.com.

1. World Health Organization. Fact sheets. Geneva: WHO, 2014. http://www.who.int/ mediacentre/factsheets/fs310/en/ (accessed November 2014).

2. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease.

2014. http://goldcopd.org/ (accessed November 2014).

Notes

Disease area COPD patients may experience acute intensifications of symptoms requiring additional treatment, commonly called exacerbations (Burge & Wedzicha, 2003).

Grading and exacerbations Although COPD is considered a stable condition in the absence of exacerbations, there is recent evidence of weekly and daily variability in symptom perception (Kessler et al., 2011).

PRODUCT NEWS GOLD recommends grading disease severity into risk groups (A - D) based on symptoms, lung function and exacerbation risk. Symptoms are assessed by COPD assessment test (CAT) or modified Medical Research Council (mMRC) dyspnoea scale. A CAT ≥10 indicates high impact of symptoms (risk groups B and D). Exacerbation risk is determined by the degree of airflow limitation using lung function impairment grades I - IV or by the number of exacerbations in the previous 12 months.

Patients with a forced expiratory volume in 1 second <50% predicted and those with ≥2 past-year exacerbations or >1 exacerbation that leads to hospitalisation have a high exacerbation risk (risk group C and D).

Adding to exacerbations, patients have reported experiencing seasonal, weekly or even daily worsening of symptoms not consistently fitting an exacerbation episode. The foregoing perceived symptom variability is a factor directly affecting disease impact on daily activities, quality of life and prognosis (Lopez-Campos, Calero & Quintana-Gallego, 2013).

COPD symptom variability and its effect on patients have been substantially examined. The first study to document daily variability in symptoms was an internet interview of 803 COPD patients in Europe and USA. Forty-six percent of the interviewed patients reported that morning was the worst time of the day, and shortness of breath was the most reported symptom, which was highly correlated with the reported limitations encountered during morning periods (Partridge, Karlsson & Small, 2009).

In addition, a pan-European cross-sectional study that aimed to observe COPD symptom variability in daily life surveyed 2 441 patients from 17 countries during a 7-day period. Of the patients, 72.5% reported experiencing dyspnoea, among other symptoms, and 59.5% perceived seasonal variability with symptoms worsening (NIS Primary Protocol (NISP) NIS D-code: D2287R00105, edition number: V1.0, date: 16 July 2015, 11(40)).

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PRODUCT NEWS NEW Antistatic Chamber: small, solid and effective ®

Aspen is proud to announce the launch of VORTEX , an innovative aluminium antistatic holding chamber with ‘cyclone twist’ principle, as an addition to our respiratory portfolio.

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Reference: 1. Laube BL, Janssens HM, de Jongh FHC, et al. What the pulmonary specialist should know about the new inhalation therapies. Eur Respir J 2011;37:1308-1331.

Reference: 1. Laube BL, Janssens HM, de Jongh FHC, et al. What the pulmonary specialist should know about the new inhalation therapies. Eur Respir J 2011;37:1308-1331.

Reference: 1. Laube BL, Janssens HM, de Jongh FHC, et al. What the pulmonary specialist should know about the new inhalation therapies. Eur Respir J 2011;37:1308-1331.

Reference: 1. Laube BL, Janssens HM, de Jongh FHC, et al. What the pulmonary specialist should know about the new inhalation therapies. Eur Respir J 2011;37:1308-1331.

1 1

110 SARJ VOL. 22 NO. 4 2016

PRODUCT NEWS Rivaroxaban reduces length of hospital stay in patients with symptomatic venous thromboembolism The phase III EINSTEIN deep vein thrombosis (DVT) and EINSTEIN pulmonary embolism (PE) trials demonstrated the potential of oral rivaroxaban (Xarelto, Bayer) – 15 mg twice daily for 21 days, followed by 20 mg once daily – for the treatment of venous thromboembolism (VTE), a term that embraces DVT and PE. A subsequent study by van Bellen et al.,[1] published in Current Medical Research and Opinion in 2014, was undertaken to assess the length of initial hospitalisation in patients presenting with either symptomatic DVT or PE using hospitalisation records from these trials.

The authors found that overall 52% of EINSTEIN DVT patients and 90% of EINSTEIN PE patients were admitted to hospital. The proportion of hospitalised DVT patients with a length of stay 5 days or fewer, receiving rivaroxaban, was 54% compared with 31% for those receiving enoxaparin/vitamin K antagonist (VKA), the current standard of care for the treatment of patients with symptomatic DVT and PE. For patients with PE, the corresponding values were 45% and 33%. Stays of 6 - 10 days were observed in 29% of rivaroxaban-treated patients compared with 45% for enoxaparin/VKA-treated patients for DVT. For patients with PE, these values were 39% and 46% in the rivaroxaban and enoxaparin/ VKA groups, respectively. Overall, length of stay was significantly shorter in the rivaroxaban group, compared with the enoxaparin/VKA group across all analyses performed (p<0.0001).

VTE is associated with significant morbidity and mortality and therefore carries a considerable healthcare burden. Rivaroxaban is as effective as enoxaparin/VKA for the treatment of acute symptomatic DVT or PE, with the additional benefit of significantly reducing the period of hospitalisation in patients being treated for an initial DVT or PE. ‘Coupled with improved patient treatment satisfaction and no requirement for routine monitoring or dose adjustment, this presents strong advantages for treating patients with VTE with rivaroxaban,’ the authors wrote.

They concluded that a single-drug regimen with rivaroxaban may reduce the burden on healthcare systems and patients by providing effective and well-tolerated treatment. ‘The convenience of a single-drug approach with oral rivaroxaban has the potential to allow discharge based on a patient’s clinical condition and to facilitate the transition from in-hospital to outpatient care. […] However, assessment of patient risk is still warranted to identify candidates who can safely receive outpatient treatment, and patient monitoring is essential to ensure adherence to the specified dosing regimen.’

Reference

1. van Bellen B, Bamber L, Correa de Carvalho F, et al. Reduction in the length of stay with rivaroxaban as a single-drug regimen for the treatment of deep vein thrombosis and pulmonary embolism. Curr Med Res Opin 2014; 30(5):829-837. [http://dx.doi.org/10.1185/03007995.2013.879439]

For full prescribing information, refer to the package insert approved by the Medicines Regulatory Authority (MCC).

PHARMACOLOGICAL CLASSIFICATION: A.8.2 Anticoagulants.

S4 XARELTO® 10. Reg. No.: 42/8.2/1046. Each film-coated tablet contains rivaroxaban 10 mg.

INDICATION: Prevention of VTE in patients undergoing major orthopaedic surgery of the lower limbs.

S4 XARELTO® 15 and XARELTO® 20. Reg. No.: 46/8.2/0111 and 46/8.2/0112. Each film-coated tablet contains rivaroxaban 15 mg or 20 mg, respectively.

INDICATIONS: Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation; Treatment of DVT and for the prevention of recurrent DVT and PE; Treatment of PE and for the prevention of recurrent PE and DVT. Bayer (Pty) Ltd, Co. Reg. No.: 1968/011192/07, 27 Wrench Road, Isando, 1609. Tel: 011 921 5044 Fax: 011 921 5041.

L.ZA.GM.06.2014.1007

© Bayer HealthCare Pharmaceuticals June 2014

SARJ VOL. 22 NO. 4 2016

111

SATS AWARDS 2016

SATS Awards 2016

AstraZeneca Respiratory Research Fellowship Award 2015, awarded to Dr Ali Esmail (UCT). Accepting the award is Prof. Dheda (UCT).

With South African Thoracic Society President Prof. U Lalloo and AstraZeneca representative Rodney Gillespie.

SATS Best Publication Award 2016, awarded to Dr G Calligaro (UCT).

Accepting the award is Prof. Dheda (UCT). With SATS President Prof.

U Lalloo, and Chairperson of the SATS Scholarship Selection Committee Prof. R van Zyl-Smit.

Glaxo-Smith-Kline Pulmonology Research Fellowship 2015, awarded to Dr Charl Verwey (Wits). With SATS President Prof. U Lalloo and GSK representative Ms A Beyl.

Cipla-Medpro Travelling Lectureship 2016, awarded to Prof. Refiloe Masekela (UKZN) and Prof. Richard van Zyl-Smit (UCT). With SATS President Prof. U Lalloo and Cipla representative Ms Lisl De Villiers.

112 SARJ VOL. 22 NO. 4 2016

SATS Honorary Award for 2016, awarded to Dr MS Abdool Gaffar (KZN). With SATS President Prof. U Lalloo.

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S3 FLIXOTIDE® 50/125/250 INHALER CFC-FREE. Reg No.: 35/21.5.1/0377-0082/3. Delivers 50/125/250 µg of fluticasone propionate per actuation. INDICATIONS: Prophylactic management of atopic asthma in adults and children of 6 years and older. CONTRA-INDICATIONS: History of allergy to any of its components.

PREGNANCY AND LACTATION: Safety not established. DOSAGE AND DIRECTIONS FOR USE: For inhalation use only. Should be taken regularly even when asymptomatic. The onset of therapeutic effect is 4 to 7 days. Should not be used for relief in acute attacks but for routine long term management. Patients will require a fast- and short-acting inhaled bronchodilator to relieve acute symptoms. If patients find that relief with short-acting bronchodilator treatment becomes less effective or they need more inhalations than usual, medical attention must be sought. Adults and children over 16 years of age: 100-1000 µg twice daily.

Starting dose should be appropriate for severity of the disease. Dose may be adjusted until control is achieved or reduced to the minimum effective dose, according to the individual response. Children over 6 years of age: 50-100 µg twice daily. The dose may be adjusted until control is achieved and should be reduced to the minimum effective dose according to the individual response. Special patient groups: No dose adjustment in elderly patients. For the transfer of patients being treated with oral corticosteroids: Patients treated with systemic steroids for long periods of time or at a high dose may have adrenocortical suppression and adrenocortical function should be monitored regularly and their dose of systemic steroid reduced cautiously. After approximately a week, gradual withdrawal of the systemic steroid may be commenced. Decrements in dosages should be appropriate to the level of maintenance systemic steroid, and introduced at not less than weekly intervals. In some patients on oral corticosteroids the dose reduction or replacement with inhaled corticosteroids may not be possible. Some patients feel unwell in a non-specific way during the withdrawal phase despite maintenance or even improvement of the respiratory function. They should be encouraged to persevere with inhaled fluticasone propionate and to continue withdrawal of systemic steroid, unless there are objective signs of adrenal insufficiency. SIDE EFFECTS AND SPECIAL PRECAUTIONS: Treatment should not be stopped abruptly as adrenal insufficiency may be precipitated. Candidiasis of the mouth and throat (thrush) may occur. May be helpful to rinse out mouth with water after use. Symptomatic candidiasis can be treated with topical anti-fungal therapy whilst continuing treatment. Hoarsenes. Paradoxical bronchospasm with an immediate increase in wheezing. Treat immediately with a fast-acting inhaled bronchodilator.

Treatment should be discontinued immediately, the patient assessed, and if necessary alternative therapy instituted. Cutaneous hypersensitivity. Systemic corticosteroid effects may occur. Patients transferred from other inhaled steroids or oral steroids remain at risk of impaired adrenal reserve for a considerable time after transferring to inhaled fluticasone propionate. Increasing use to control symptoms indicates deterioration of asthma control and patient should be reassessed. Sudden and progressive deterioration in asthma control is potentially life-threatening and may have several causes. Consideration should be given to increasing corticosteroid dosage if not caused by otherwise treatable causes of deterioration. Severe asthma requires regular medical assessment as death may occur. Sudden worsening of symptoms may require increased corticosteroid dosage which should be administered under urgent medical supervision. Patients weaned off oral steroids whose adrenocortical function is still impaired should carry a steroid warning card indicating that they may need supplementary systemic steroid during periods of stress, e.g. worsening asthma attacks, chest infections, major intercurrent illness, surgery, trauma, etc. Inhaled therapy may unmask underlying eosinophilic conditions (e.g. Churg Strauss syndrome). These cases have usually been associated with reduction or withdrawal of oral corticosteroid therapy. Similarly replacement of systemic steroid treatment with inhaled therapy may unmask allergies such as allergic rhinitis or eczema previously controlled by the systemic drug. These allergies should be symptomatically treated with antihistamine and/or topical preparations, including topical steroids. Patients in a medical or surgical emergency, who require high doses of inhaled steroids and/or intermittent treatment with oral steroids, are at risk of impaired adrenal reserve. The extent of the adrenal impairment may require specialist advice before elective procedures. The possibility of residual impaired adrenal response and elective situations likely to produce stress and appropriate corticosteroid treatment must be considered. Lack of response or severe exacerbations of asthma should be treated by increasing the dose of inhaled fluticasone propionate or by giving a systemic steroid and/or an antibiotic if there is an infection. Special care is necessary in patients with active or quiescent pulmonary tuberculosis. Patients on corticosteroid therapy may have adrenocortical suppression. MANAGEMENT OF OVERDOSAGE: Monitoring of adrenal reserve may be indicated. Treatment with inhaled fluticasone propionate should be continued at a dose sufficient to control asthma. APPLICANT: GlaxoSmithKline South Africa (Pty) Ltd; (Co. reg. no.1948/030135/07). 39 Hawkins Avenue, Epping Industria 1, Cape Town, 7460.

Reference: 1. Laube BL, Janssens HM, de Jongh FHC, et al. What the pulmonary specialist should know about the new inhalation therapies. Eur Respir J 2011;37:1308-1331. 2. VORTEX® package insert.

For full prescribing information, please refer to the package inserts 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/FP/0004/15a A19615 04/16

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