SARJ Vol 21, No 2 (2015)

SouthAfrican African South

Respiratory Respiratory Journal Journal VOLUME 21

|

NUMBER 2

South African

Respiratory

Journal

OFFICIAL JOURNAL OF THE S.A. THORACIC SOCIETY

|

JUNE 2015

FOXAIR

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S4 FOXAIR® 50/100, 50/250 and 50/500 ACCUHALER® - 42/21.5.4/0581; 0582; 0583. Each blister contains a mixture of salmeterol xinafoate equivalent to 50 µg of salmeterol and microfine fluticasone propionate (100 µg, 250 µg or 500 µg). S4 FOXAIR® 25/50, 25/125 and 25/250 INHALER - 42/21.5.4/0244; 0245; 0246. Each single actuation provides salmeterol xinafoate equivalent to 25 µg of salmeterol and fluticasone propionate (50, 125 or 250 µg). Applicant: GlaxoSmithKline South Africa (Pty) Ltd. (Co. Reg. No. 1948/030135/07). 39 Hawkins Avenue, Epping Industria 1, Cape Town, 7460. For full prescribing information plese refer to the package insert approved by the Medicines Regulatory Authority. All adverse events should be reported by calling the Aspen Medical Hotline number or directly to GlaxoSmithKline on +27117456000.

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THE SOUTH AFRICAN

RESPIRATORY JOURNAL VOLUME 21 | NUMBER 2 | JUNE 2015

CONTENTS EDITORIAL 22

Male smokers see the light; females left puffing in the dark H Wainwright

ORIGINAL RESEARCH

23

A 2-year retrospective review of the effect of cigarette smoking status on the histological cell types of lung carcinoma in the Western Cape A S Pellizzon, C F N Koegelenberg, E M Irusen

ARTICLE 30 Endoscopic lung volume reduction with coils M J Vorster, J Theron, K Dheda, J W Bruwer, B W Allwood, F von GrooteBidlingmaier, C F N Koegelenberg 34

BREATH-TAKING NEWS

35

WHO’S WHO IN SATS

CONGRESS AND CME EVENTS

36

Abstracts of presentations at the congress of the South African Thoracic Society in Cape Town, 7 - 10 August 2015

47

PRODUCT NEWS

50

INSTRUCTIONS TO AUTHORS

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 Dr Sabs Abdool-Gaffar

HMPG

CEO AND PUBLISHER Hannah Kikaya Email: hannah.kikaya@hmpg.co.za EDITOR-IN-CHIEF Janet Seggie EXECUTIVE EDITOR Bridget Farham MANAGING EDITOR Ingrid Nye SCIENTIFIC EDITOR Simon Nye PRODUCTION MANAGER (CMC) Emma Jane Couzens DTP AND DESIGN (CMC) Carl Sampson HEAD OF SALES AND MARKETING Diane Smith | Tel. 012 481 2069 Email: dianes@samedical.org JOURNAL ADVERTISING Charles Duke Benru de Jager Reneé van der Ryst Ladine van Heerden ONLINE SUPPORT Gertrude Fani | Tel. 072 463 2159 Email: publishing@hmpg.co.za

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EDITORIAL

Male smokers see the light; females left puffing in the dark Tobacco smoking causes lung carcinoma in 90% of cases in developed countries.[1] Since the introduction of the antismoking laws in South Africa in 1993, there has been a dramatic reduction in cigarette smoking in men. In women, the number of smokers is much lower but unfortunately has not shown any reduction. Using the data from the South Africa Demographic and Health Survey in 2003, which provides detailed smoking history regarding age, sex and ethnicity, combined with longitudinal estimates of smoking prevalence from 1980 to 2010, Winkler et al.[1] predicted a decrease in adjusted lung cancer mortality in South Africa from 17.1 to 14.1 ASA (age-standardised mortality rates) per 100 000 among men over the period 2010 - 2025. Rates are stable for women. They also predicted the highest mortality rates for Asian men and lowest for black men. In women, the lowest rates were in Asian women and the highest in white and mixed ancestry women.

In this issue, the paper by Pellizzon et al.[2] provides information on the effect of smoking on the histological cell type of lung cancer in the Western Cape, and in particular the drainage area of Tygerberg Hospital, using 386 participants. They used immunohisto- and immunocytochemistry to assist in cell typing of the lung cancer. As they noted, Asian and black patients were underrepresented, so that their results cannot be applied elsewhere in South Africa.

Traditionally, squamous cell carcinoma was the most frequent cell type of lung cancer presenting as a central lung mass, like small cell carcinoma, and adenocarcinoma and large cell carcinoma were peripheral in distribution. Main bronchi should have the highest exposure to inhaled carcinogens in cigarette smoke whereas there would be less effect in the peripheral regions of the lung. Squamous carcinomas frequently undergo central necrosis and cavitation, which in a South African setting might provide diagnostic radiological confusion with tuberculosis and a delay in diagnosis. Adenocarcinoma was second in frequency.

Currently, the distinction between central and peripheral squamous tumours has become less well-defined, with equal numbers of squamous carcinomas arising peripherally and centrally. In many parts of the world, in particular the USA and Japan, adenocarcinomas have become the most frequent type of lung carcinoma. Cigarettes have undergone changes in manufacturing over the years with lowtar filters becoming more popular, and with this type of cigarettes the carcinogens now penetrate more deeply into the lungs, explaining in part the current change in distribution. Previously, cigarette smoking was a predominantly male custom, whereas currently many more women are smoking. Customs of smoking are also different in different ethnic groups.

Histological typing of lung cancer has always been problematic because of tumour heterogeneity, with the most accurate typing possible in surgically resected specimens. The current trend is towards small endoscopic biopsies, fine-needle aspiration and sputum cytology, all of which provide small samples of the cancer. Therefore, the histological typing of lung carcinomas will vary according to the source of the material. Biopsy and cytology usually have a predominance of cases being squamous carcinomas followed by adenocarcinomas. A surgical series will consist predominantly of resectable peripheral tumours.

A hospital-based postmortem series will reflect rapidly disseminated lung cancers. A large community-based survey for lung carcinomas over a 10-year period should be the most reliable. However, smoking

22 SARJ VOL. 21 NO. 2 2015

patterns may change with time and cause a difference in histologic type.

When mortality from lung cancer in workers with asbestosis is used, adenocarcinoma is the most frequent cell type.

The World Health Organization (WHO)’s criteria for diagnosing lung cancer has also changed over the last decade, with the use of immunostains and mucin stains enabling more adenocarcinomas to be diagnosed. Histological typing has become of paramount importance because of advances in cancer therapy requiring molecular testing in adenocarcinomas. Precursor lesions for adenocarcinomas have been described; previously precursor lesions were only known for squamous carcinomas. The WHO has created new entities in the adenocarcinoma group, such as solid adenocarcinoma with mucin production, resulting in a marked drop in the diagnosis of large cell carcinoma. If one includes electron microscopy (EM) as an adjunct in cell typing there would be no large cell carcinomas. Using EM adenosquamous carcinoma becomes the most common association of smoking in central tumours.

In addition, there is a genuine increase in adenocarcinoma in non-smokers and young women of Asian ethnicity. There may be geographic variations in the prevalence of adenocarcinoma: in Japan 3% arose centrally, whereas 17% occurred centrally in the UK. The other important aspect of adenocarcinomas is its high propensity to metastasise, so preoperative screening of the brain is important.

Pellizzon et al. found an increase in adenocarcinomas in nonsmokers.[2] It would be interesting to determine whether this finding is present in other academic centres in South Africa.

They found no difference between smokers and non-smokers with scar-associated lung cancer. Patients with fibrosing alveolitis have been shown to have an increased incidence of lung cancer due to fibrosis. The presence of fibrosis associated with and not preceding a lung cancer usually indicates an advanced aggressive cancer with lymphatic and vascular invasion.

Lung cancer is a devastating disease with an overall 5-year survival of 17% at best, owing to late presentation, early metastases and poor sustained response to chemotherapy or development of resistance.

Surgery offers a 5-year survival of 50% only with rigorous preoperative assessment excluding 80% of cases.

Further antismoking campaigns are required. Currently, smokers are permitted to smoke outdoors. Hospitals need to bring in regulations that require smokers to smoke outside the hospital perimeter, making it extremely inconvenient for staff and patients to smoke. This has been implemented in Australia. The high cost of cigarettes has had a beneficial effect in that many women cannot afford more than 2 3 cigarettes a day. The first campaign showed a significant reduction in childhood smoking and this is an ideal age to target. Targeting of specific ethnic groups could also be implemented.

1. Winkler V, Mangolo NJ, Becker H. Lung cancer in South Africa: A forecast to 2025 based on smoking prevalence data. BMJ open 2015 Mar 17;5(3):e006993. [http:// dx.doi.org/10.1136/bmjopen-2014-006993] 2. Pellizzon AS, Koegelenberg CFN, Irusen EM. A 2-year retrospective review of the effect of cigarette smoking status on the histological cell types of lung carcinoma in the Western Cape. S Afr Resp J 2015; 21(2):23-28. [http://dx.doi.org/10.7196/sarj.8441]

Helen Wainwright FFPath (Anat Path); Associate Professor, Department of Pathology, Faculty of Health Sciences, University of Cape Town, South Africa S Afr Resp J 2015;21(2):22. DOI:10.7196/sarj.8440

ORIGINAL RESEARCH

A 2-year retrospective review of the effect of cigarette smoking status on the histological cell types of lung carcinoma in the Western Cape A S Pellizzon, MB ChB, MMed (Int), FCP (SA); C F N Koegelenberg, MB ChB, MMed, FCP (SA), FRCP, Cert Pulm (SA), PhD; E M Irusen, MB ChB, FCP (SA), PhD Division of Pulmonology, Department of Medicine, Stellenbosch University and Tygerberg Academic Hospital, Cape Town, South Africa Corresponding author: A S Pellizzon (adrianojudith@yahoo.co.uk)

Background. Cigarette smoking is variably associated with the various histological cell types of lung cancer. The primary aim of this study was to analyse various strengths of association between the common histological cell types of lung cancer and smoking in a Western Cape population. The secondary aim examined whether an association exists between scar carcinoma and smoking.

Methods. We retrospectively analysed the records from 386 patients over a 2-year period. Both smokers and non-smokers were subdivided and analysed as two groups, which included those with non-small cell and small cell lung cancer. Smokers and non-smokers were also analysed separately according to the presence or absence of lung scarring.

Results. In total, 94.3% of all patients with lung cancer were current or past smokers. There was a disproportionately higher number of patients with adenocarcinoma who were non-smokers compared with all the other cell types (p=0.01), whereas patients with squamous cell carcinoma were more likely to be smokers (p=0.05). Although the vast majority of patients with and without lung scars were found to be smokers (96.4% v. 93.7% respectively), there was no statistically significant difference found between these two groups (p=0.43).

Conclusion. In a Western Cape population, patients with adenocarcinoma were more likely to be non-smokers, while those with squamous cell carcinoma were relatively more likely to be smokers. No clear association between scar carcinoma and smoking status was found.

S Afr Resp J 2015;21(2):23-28. DOI:10.7196/sarj.8441

Pulmonary malignancies are significant to South Africa (SA), with Bradshaw et al. demonstrating that cancer of the trachea, bronchi and lung ranks 17th among the top 20 causes of premature mortality burden in males.[1] Lung cancer, in 80 - 90% of cases, is attributed to smoking and a smaller proportion (10 - 20%) is attributed to occupational exposure to agents such as asbestos and silica.[2-4] Thus due to the high prevalence of cigarette smoking among people older than 15 in SA (27.1% in 2000), lung cancer remains a major public health concern in this country.[5] Cigarette smoking is often intimately associated with all the histo­ logical types of lung cancer but the strength of association tends to differ with each individual variant.[6] Data from the USA have shown a decreasing incidence of squamous cell carcinoma (SCC), small cell lung cancer (SCLC) and large cell carcinoma (LCC), while there has been a moderate increase in the incidence of adenocarcinoma (ADC).[7] Khuder[6] demonstrated that all histological types were significantly associated with cigarette smoking, with SCLC displaying the strongest overall relationship followed by SCC. ADC appeared to have the weakest overall relationship.[6] Research performed by Yang et al.,[8] and others,[9] also documented that more peripheral cancers (ADC and LCC) show weaker associations than more central tumours (SCLC and SCC). Non-smokers appear to have a greater proportion of ADC when compared with the other histological types, and this may suggest that other factors (genetic, occupational, environmental) are involved in its aetiology.[10-16] A controversial topic is the relationship between scarring of the lung and the development of lung cancer.[17] Scar carcinoma (SC) of the lung

is a clinical entity that was first described by Friedrich[18] and Rossle[19] as a group of lung cancers that originated around peripheral scars in the lung. Owing to further research performed in the 1940s, there was a subsequent evolution in the understanding of SC and the following clinical features were then thought to make the diagnosis of SC more likely: the tumour is peripherally located with a size of less than 3 cm in diameter, upper-lobe predominance, more commonly found in males, and usually of ADC histological subtype.[20-22] A large cohort analysis of the prostate, lung, colorectal and ovarian cancer screening trial demonstrated a clear correlation between scar presence and the development of a carcinoma.[23] Cigarette smoking has long been known to be associated with chronic lung destruction and the development of lung cancer.[17] The chronic inflammatory state induced by cigarette smoke eventually results in DNA mutations along with excessive bronchioalveolar stem cell proliferation, which is thought to cause the development of lung carcinoma.[24,25] Of particular interest is the possible link between SC and smoking. Research published by Auerbach et al.[26] suggested a lack of association between smoking and SC in their study population.

With the above in mind, and data of this nature lacking in the Western Cape, we performed a retrospective study with two objectives. The primary objective was to analyse various strengths of association between the common histological cell types of lung cancer and cigarette smoking in our population. The secondary objective was to examine whether an association exists between SC and smoking, with our hypothesis being that no such association exists.

SARJ VOL. 21 NO. 2 2015

23

ORIGINAL RESEARCH

Methods

Study population Tygerberg Academic Hospital is situated in Cape Town, SA. It comprises 1Â 380 beds and is one of two tertiary hospitals serving approximately three million people from various drainage areas. We retrospectively identified 424 patients with lung cancer that were presented at our weekly lung cancer board meetings from 1 January 2010 to 31 December 2011 (Fig. 1). Individuals were then excluded if no data could be found regarding a smoking pack year history (25 participants) or if either the staging computed tomography (CT) scan or tissue diagnosis were incomplete (13 participants). Cases of pleural malignancy, such as mesothelioma or secondary pulmonary malignancies, were excluded from the analysis. The Stellenbosch All patients with lung cancer (N=424)

Staging CT chest and tissue diagnosis

Incomplete (N=13)

Complete

Excluded Not known (N=25)

Smoking status Known Smoker (N=364)

University Human Research Ethics Committee granted approval for the study (study number S13/04/078) and a Chief Medical Superintendent of Tygerberg Academic Hospital granted access to patient medical records so as to collect the necessary data.

Data collection From the medical records of the study population, we collected basic demographic data as well as the histological cell type and the presence of a possible SC. Tumour, node and metastasis (TNM) staging, as well as cigarette smoking status were specifically documented.

Telephonic contact was made with various patients and their next of kin when no data could be found from our folders. The diagnosis of tissue subtypes was based on cytology or on histology done on adequate samples at a later stage. The diagnoses were further verified by ancillary immunohistochemistry or immunocytochemistry techniques in most cases. After exclusions, our study population (n=386) was split into smokers and non-smokers. Smokers were defined as those who had smoked a minimum of at least 5 pack years while non-smokers were defined as those who had never smoked or who had smoked less than 5 pack years.

We then sought to separately determine how many smokers and nonsmokers had non-small cell lung cancer (NSCLC) v. SCLC. The NSCLC group was further subdivided into common histological cell types to allow for added statistical analysis. Finally we determined how many patients with a recognised scar were smokers versus non-smokers and likewise the same analysis was completed for those patients without a scar. A scar was identified as an area of pulmonary fibrosis situated in any area of the lungs in a patient with a diagnosis of primary lung carcinoma. All diagnosed cases of bronchogenic carcinoma were staged radiologically according to the staging system set out by the Union Internationale Contre le Cancer in 2002 for lung cancer.[27]

Non-smoker (N=22) 250

Small cell (N=61)

Non-small cell (N=20)

Small cell (N=2)

Fig. 1. Study population distribution according to smoking status and lung cancer cell type.

200

Number of participants

Non-small cell (N=303)

150

Black White Mixed ancestry

100

Male Female

50

0

Fig. 2. Gender distribution of the study population.

24 SARJ VOL. 21 NO. 2 2015

Racial denomination

Fig. 3. Racial distribution of the study population.

ORIGINAL RESEARCH Statistical analysis Statistical indices utilised for this assignment included averages, ranges and standard measures of statistical significance (p-values).

All p-values were calculated with Fisher’s Exact Probability test, and in one case a p-value was calculated with the χ2 test (Yates corrected). All statistical analysis was completed using VassarStats (USA).

Adenocarcinoma Squamous cell Large cell Small cell

Results

We included 386 participants, with a total of 229 (59.3%) males and 157 (40.7%) females (Fig. 2). The average age for the male participants was 59.4 (range 30 85) years and the average age for female participants was 61.4 (36 - 88) years. The racial demographics demonstrated that the study population was composed of 237 (61.4%) participants of mixed ancestry, 122 (31.6%) white participants and 27 (7%) black participants (Fig. 3).

ADC predominated with 156 (40.4%) patients demonstrating this cell type at diagnosis. SCC was diagnosed in 93 (24.1%) participants, LCC was diagnosed in 70 (18.1%) participants and SCLC was diagnosed in 63 (16.3%) participants. A small category of NSCLC diagnoses not related to the cell types above accounted for 4 (1%) participants. The four cases included one case each of pleomorphic carcinoma, pleomorphic carcinoma with osteoclast giant cells, a solitary fibrous tumour, and an anaplastic carcinoma (Fig. 4).

There were 364 (94.3%) participants who smoked, while 22 (5.7%) did not. There was a disproportionately higher number of patients with ADC who were non-smokers compared with all the other cell types (15/22 non-smokers had ADC; p=0.01), whereas patients with SCC were more likely to be smokers (90/93 patients with SCC were smokers; p=0.05). Patients with ADC smoked on average 31.6 pack years compared with patients with SCC, who smoked on average 32.4 pack years. There were no statistically significant differences between smokers and non-smokers among the patients with LCC, other NSCLC or SCLC (Table 1).

Analysis of patients with lung scars demonstrated that 81 (96.4%) of them were smokers while 3 (3.6%) were not. Of those patients without lung scars, 283 (93.7%) of them smoked while 19 (6.3%) did not.

Patients without lung scars had smoked for

Other

Fig. 4. Study population distribution according to histological diagnosis.

Table 1. Differences in lung carcinoma tissue diagnoses among the study population Smokers (n)

Pack years (mean)

Nonsmokers (n)

p-value*

Adenocarcinoma

141

31.6

15

0.01†

Squamous cell

90

32.4

3

0.05

Large cell

68

40.1

2

0.40

Cell type Non-small cell

Other

4

55.0

0

1.00

Small cell

61

37.6

2

0.40

*Fisher’s Exact Probability Test, except †. †

χ2 test (Yates corrected).

Table 2. Differences between patients with lung scarring and those without Smokers (n)

Pack years (mean)

Nonsmokers (n)

p-value

SCAR

81

31.9

3

0.43

No SCAR

283

35.4

19

0.43

more years on average (35.4 pack years) than patients with lung scars (31.9 pack years).

However, no statistically significant difference between smokers and non-smokers was found in both groups (Table 2).

Only 22 (6.8%) patients with NSCLC had early-stage lung cancer (stages I (n=11) and II (n=11)). There were 18 (5.6%) patients with stage IIIA disease and 83 (25.7%) with stage IIIB disease. The majority of cases (200 (61.9%)) of NSCLC had metastatic disease at presentation (Table 3). Among patients with SCLC, 13 (20.6%) were found to have limited disease, while 50 (79.4%) had extensive disease at presentation (Table 3).

Of the 53 (13.7%) patients (NSCLC and SCLC) with potentially operable disease only 20 (5.2%) of them underwent surgical tumour resection.

Discussion

We found a disproportionately higher percentage of patients with ADC to be nonsmokers compared with the other cell types, whereas patients with SCC were more likely to be smokers. We again demonstrated that ADC has surpassed SCC as the most common histological cell type of lung cancer in the Western Cape.[28] Among smokers and non-smokers, we found no statistically significant difference between those with lung scars and those without. Finally, as has been previously documented,[28] we demonstrated that the majority of patients with NSCLC and SCLC had an advanced level of disease at presentation.

ADC in our study population was the most common cell type found and this appears to be similar in the USA, where increasing

SARJ VOL. 21 NO. 2 2015

25

ORIGINAL RESEARCH

Table 3. Summary of the TNM radiological staging of the study population Staging

Adenocarcinoma

Squamous cell

Large cell

Other NSCLC

Small cell

IA

1

1

0

0

-

IB

4

4

0

1

-

IIA

1

0

0

0

-

IIB

6

2

2

0

-

IIIA

9

5

4

0

-

IIIB

40

29

13

1

-

IV

95

52

51

2

-

Limited

-

-

-

-

13

Extensive

-

-

-

-

50

incidences of ADC are reported.[7] ADC, along with LCC, is more peripherally situated than SCLC and SCC. The higher incidences of ADC worldwide could possibly be explained on technical advancements made in fine-needle aspiration,[29-32] computerised scans,[33] video bronchoscopy, [34] immunohistochemistry and mucin staining,[35] which all improve the diagnostic yield of these peripherally situated tumours. Of particular interest in our study was the relation of histological cell types to smoking. Our data suggested that patients with ADC in this study population make up a disproportionately higher percentage of non-smokers, and this finding appears to be consistent with other research done in this field.[10-16] There have been suggestions that changes to cigarette design in the last few decades could help explain the rising incidence of ADC.[36] However, this is not enough to explain why non-smokers in our setting developed ADC more frequently than other cell types of lung cancer. A possible explanation in our country includes possible indoor air pollutants as the offending agents. A large proportion of SA households do not have full-time electricity and so have to rely on fossil fuels (coal and wood) to heat the house and to cook food.

The liberation of small coal dust particles in the process of burning these materials may be inhaled deeply into the distal airways, and prolonged exposure to this over time may incite the development of ADC. Furthermore, there may be carcinogens in our working environments and passive second-hand smoke exposure that could also cause ADC more frequently in non-smokers.

Genetic determinants and predisposition cannot be ruled out. However, more research

26 SARJ VOL. 21 NO. 2 2015

is needed to delineate exactly which gene, if any, is involved.

Of further interest from our study is that patients with SCC are more likely to be smokers. Other studies have also found this trend, demonstrating that SCC (more centrally located) tends to have an overall stronger relationship with cigarette smoking than does ADC (more peripherally located).[6,8,9,37,38] Our data found that on average patients with SCC smoked more than patients with ADC and this is further supported in the literature, where there appears, in general, to be a stronger dose-response relationship between centrally located tumours like SCC and cigarette smoking than with tumours situated more peripherally such as ADC.[9] One possible explanation for the closer association between SCC and smoking is nicotine.[39] Nicotine, a common ingredient in most cigarettes, is not only the addictive agent but is also a known carcinogen. In a study performed by Brown et al.,[39] nicotine was found to increase Îą7nAChR mRNA levels and transcription in SCC cell lines that ultimately promoted lung cancer proliferation. There is uncertainty at this point as to whether nicotine has exactly the same effect on other cell types of lung cancer.

With specific reference to the relationship between SC and smoking, we found no significant difference in our study population between smokers and non-smokers (both with scars and without). Our data are therefore similar to other studies, specifically that performed by Auerbach et al.,[26] who found a lack of association between smoking and SC. A possible explanation is that atypical epithelial cells exist around some scars that later undergo unregulated proliferation

with the development of metaplastic and then neoplastic cells,[40-45] which may occur irrespective of carcinogen exposure from smoking. There may be a genetic blueprint within a scar that gives it the ability to become neoplastic. More research is needed to uncover the most likely aetiology of SC and also identify its exact relationship to various environmental exposures.

Advanced-level disease was found in the vast majority of our sample whether that be patients with NSCLC or SCLC. Furthermore, very few of our patients with potentially operable disease underwent surgery. Data from the UK National Lung Cancer Audit in 2009 found that the overall unadjusted pro­ portion of patients who underwent surgical resection was approximately 11%, with regional variations ranging from less than 5% to greater than 25%.[46] Other countries in Europe had much higher rates of resection, such as Italy (24%),[47] the Netherlands (20%)[48] and Sweden (17.5%).[49] The group in the UK suggested that lower resection rates were due to diminished access to specialist thoracic surgeons. However, we believe our lower rates are owing to our own societal circumstances.

The vast majority of patients attending our hospital have impoverished socioeconomic circumstances as well as low levels of education, which tends to delay the presentation of patients with lung cancer to our specialist clinic. Transportation can be expensive and also unreliable, which further hinders access. The high prevalence of pulmonary tuberculosis in our setting (935 per 100 000),[50] also masks the diagnosis of lung cancer. For instance, patients with pulmonary tuberculosis and lung cancer often have similar symptoms, so patients may be initially treated inappropriately for tuberculosis when in fact they have lung cancer. The investigation done for tuberculosis at primary care level can often become protracted: waiting for results owing to a limited numbers of laboratories in the district and specimens getting lost on route. This means that patients with lung cancer get identified later than they should.

Lastly, since tuberculosis has a myriad of possible radiological features, the clinician may be misled into thinking that a lung lesion is secondary to tuberculosis instead of investigating further for lung cancer.

Korean data suggest that this problem is not isolated to SA, as they too have a high

ORIGINAL RESEARCH prevalence of tuberculosis.[51] The Korean data found an average delay of 11.7 months in diagnosing lung cancer for similar reasons to those mentioned previously.[51] We believe that our study has definite clinical application. Owing to the large number of females with lung cancer in our sample and their rising mortality rates in our country, more should be done by clinicians to try and inform females of this problem. Health education should begin at an early age in our communities and in our schools so as to prevent further increases in female mortality in later decades. More research is needed to understand the pathophysiology surrounding ADC of the lung in our setting and the environmental triggers that could lead to this disease. Simple public health measures, such as providing better electricity to poorer areas, may result in less reliance on fossil fuels for daily living and thereby limit exposure to possible harmful carcinogens in these fuels. Since most patients with SCC present many years after smoking is initiated, we need to educate our communities at an early age so as to limit smoking exposure. More audio-visual media should be made available in our clinics, schools and in major public places to discourage smoking. Furthermore, our data can also help to inform policy makers that are involved with tobacco regulation.

Study limitations

The retrospective nature of our study had inherent limitations. Recall bias was introduced into our study when contacting the next of kin in order to obtain the necessary information of those patients who have died. We were also unable to speculate on the aetiology of lung cancer in our study population owing to multiple confounders that may exist (e.g. occupational exposures). Finally, due to selection bias we were unable to generalise our findings to the SA population at large, since certain ethnic groups (e.g. rural blacks and Asian individuals) were underrepresented in our study population.

In conclusion, we found that more than 90% of all patients with lung cancer were smokers. In patients with ADC, there were a disproportionately higher percentage of non-smokers compared with the other cell types, whereas patients with SCC were more likely to be smokers. There was no statistically significant difference found between smokers and non-smokers, both in the group with lung scars and in the group without. Future research is needed for a better understanding of the aetiology of both the common histological cell types of lung cancer and SC in the Western Cape.

Authors’ contributions

Dr AS Pellizzon: conceived and designed the study. He analysed and interpreted data and then drafted and critically revised the manuscript.

He approved the published version.

Professor CFN Koegelenberg: conceived and designed the study.

He analysed and interpreted data and then critically revised the manuscript. He approved the published version.

Professor EM Irusen: conceived and designed the study and critically revised the manuscript. He approved the published version.

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7. Davis WD, Lubin J, Ries L, et al. United States lung carcinoma incidence trends: Declining for most histologic types among males, increasing among females. Cancer 1996;77(12):2464-2470.

8. Yang CP, Gallagher RP, Weiss NS, Band PR, Thomas DB, Russell DA. Differences in incidence rates of cancers of the respiratory tract anatomic subsite and histologic type: An etiologic implication. J Natl Cancer Inst 1989;81(23):1828-1831.

9. Morabia A, Wynder EL. Cigarette smoking and lung cancer cell types. Cancer 1991;68(9):2074-2078.

10. Franceschi S, Bidoli E. The epidemiology of lung cancer. Ann Oncol 1999;10(Suppl 5):S3-6.

11. Barbone F, Bovenzi M, Cavallieri F, Stanta G. Cigarette smoking and histologic type of lung cancer in men. Chest 1997;112(6):1474-1479.

12. Wynder EL, Kabat GC. The effect of low-yield cigarette smoking on lung cancer risk.

Cancer 1988;62(6):1223-1230.

13. Lubin JH, Blot WJ. Assessment of lung cancer risk factors by histologic category. J Natl Cancer Inst1984;73(2):383-389.

14. Schoenberg JB, Wilcox HB, Mason TJ, et al. Variation in smoking-related lung cancer risk among New Jersey women. Am J Epidemiol 1989;130(4):688-695.

15. Xu ZY, Blot WJ, Xiao HO, et al. Smoking, air pollution and high rates of lung cancer in Shenyang, China. J Natl Cancer Inst 1989;81(23):1800-1806.

16. World Health Organization International Agency for Research on Cancer. IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans.

Volume 38. Lyon; 1986.

17. Bobba RK, Holly JS, Loy T, Perry MC. Scar carcinoma of the lung: A historical perspective. Clin Lung Cancer 2011;12(3):148-154. [http://dx.doi.org/10.1016/j. cllc.2011.03.011] 18. Friedrich G. Periphere lungenkrebse auf Boden Pleuranaher Nerben. Virchows Arch 1939;304:230-247 (Pathol Anat J).

19. Rossle R. Die Narbenkrebse der Lungen. Schweiz Med Wochenschr1943; 39:1200-1203.

20. Freant LJ, Joseph WL, Adkins PC. Scar carcinoma of the lung. Fact or fantasy? Ann Thorac Surg 1974;17(6):531-537. [http://dx.doi.org/10.1016/S0003-4975(10)65693-7] 21. Yokoo H, Suckow EE. Peripheral lung cancers arising in scars. Cancer 1961;14:1205-1215.

22. Bennett DE, Sasser WF, Ferguson TB. Adenocarcinoma of lung in men. A clinicopathologic study of 100 cases. Cancer 1969;23(2):431-439.

23. Yu YY, Pinsky PF, Caporaso NE, et al. Lung cancer risk following detection of pulmonary scarring by chest radiography in the prostate, lung, colorectal, and ovarian cancer screening trial. Arch Intern Med 2008;168(21):2326-2332. [http:dx. doi.org/10.1001/archinte.168.21.2326] 24. Kim CF, Jackson EL, Woolfenden AE, et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 2005;121(6):823-835. [http:dx.doi. org/10.1016/j.cell.2005.03.032] 25. Hecht SS, Hoffman D. Tobacco-specific nitrosamines, an important group of carcinogens in tobacco and tobacco smoke. Carcinogenesis 1988;9(6):875-884.

26. Auerbach O, Garfinkel L, Parks VR. Scar cancer of the lung: Increase over a 21 year period. Cancer 1979;43(2):636-642.

27. Union Internationale Contre le Cancer. TNM Classification of Malignant Tumours, 6th edition. New York: Wiley-Liss, 2002:272.

28. Aubeelack K, Koegelenberg CF, Bolliger CT, von Groote-Bidlingmaier F, Irusen EM. Lung Cancer in the Western Cape of South Africa – urgent need to improve awareness and earlier detection. S Afr Resp J 2012;18(1):11-14.

29. Silver CE, Koss LG, Brauer RJ, et al. Needle aspiration cytology of tumors at various body sites. Curr Probl Surg 1985;22(1):6-67. [http://dx.doi.org/10.1016/00113840(85)90029-2] 30. Miller WE, Berquist TH. Percutaneous transthoracic needle biopsy. Semin Resp Med 1981;3(1):10-16.

31. Koss LG. Thin needle aspiration biopsy. Acta Cytol 1980;24:1-3. (editorial).

32. Lundgren R, Bergman F, Angström T. Comparison of transbronchial fine needle aspiration biopsy, aspiration of bronchial secretion, bronchial washing, brush biopsy and forceps biopsy in the diagnosis of lung cancer. Eur J Respir Dis 1983;64(5):378-385.

33. Wittenberg J. Computed tomography of the body. N Engl J Med 1983;309(2):1160-1165.

34. Ikeda S, Yanai N, Ishikawa S. Flexible bronchofiberscope. Keio J Med 1968;17(1):1-16.

35. Marchevsky AM. Classification of lung tumors. In: Marchevsky AM, ed. Surgical Pathology of Lung Neoplasms. New York: Marcel Dekker, 1990;63-68.

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ORIGINAL RESEARCH 36. Wynder EL, Hoffmann D. Smoking and lung cancer: Scientific challenges and opportunities. Cancer Res 1994;54(20):5284-5295.

37. Yun YH, Lim MK, Jung KW, et al. Relative and absolute risks of cigarette smoking on major histologic types of lung cancer in Korean men. Cancer Epidemiol Biomarkers Prev 2005;14(9):2125-2130. [http://dx.doi.org/10.1158/1055-9965.EPI-05-0236] 38. Lee PN, Forey BA, Coombs KJ. Systematic review with meta-analysis of the epidemiological evidence in the 1900s relating smoking to lung cancer. BMC Cancer 2012;12:385. [http:dx.doi.org/10.1186/1471-2407-12-385] 39. Brown KC, Perry HE, Lau JK, et al. Nicotine induces the up-regulation of the α7-nicotinic receptor (α7-nAChR) in human squamous cell lung cancer cells via the Sp1/GATA pathway.

J Biol Chem 2013;288(46):33049-33059. [http://dx.doi.org/10.1074/jbc.M113.501601] 40. Raeburn C, Spencer H. A study of the origin and development of lung cancer. Thorax 1953;8(1):1-10.

41. Kitagawa M. Autopsy study of lung cancer with special reference to scar cancer. Acta Pathol Jpn 1965;15(2):199-222.

42. Chaudhuri MR. Primary pulmonary scar carcinomas. Indian J Med Res 1973;61(6):858-863.

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44. Balo J, Juhasz E, Temes J. Pulmonary infarcts and pulmonary carcinoma. Cancer 1956;9(5):918-922.

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46. The NHS Information Centre. National Lung Cancer Audit 2009. http://www.hscic. gov.uk/catalogue/PUB02692/clin-audi-supp-prog-lung-canc-nlca-2009-rep.pdf (accessed 15 March 2013).

47. Imperator A, Harrison RN, Leitch DN, et al. Lung cancer in Teesside (UK) and Varese (Italy): A comparison of management and survival. Thorax 2006;61(3):232-239. [http://dx.doi.org/10.1136/thx.2005.040477] 48. Damhuis RA, Schütte PR. Resection rates and postoperative mortality in7,899 patients with lung cancer. Eur Respir J 1996;9(1):7-10.

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Lung Cancer 2009;63(1):16-22. [http://dx.doi.org/10.1016/j.lungcan.2008.05.011] 50. Western Cape Government. World TB Day, 24 March 2012. http://www.westerncape. gov.za/news/world-tb-day-24-march-2012 (accessed 29 October 2013) 51. Kim II Y, Goo MJ, Kim YH, et al. Coexisting bronchogenic carcinoma and pulmonary tuberculosis in the same lobe: radiological findings and clinical significance. Korean J Radiol 2001;2(3):138-144.

ARTICLE

Endoscopic lung volume reduction with coils M J Vorster,1 MB ChB, MRCP (UK), MMed (Int), FCP (SA); J Theron,1,2 MB ChB, MMed (Int), Cert Pulm (SA); K Dheda,3 MB ChB, FCP (SA), FCCP, PhD, FRCP (UK); J W Bruwer,4 MB ChB, MMed (Int), FCP (SA), Cert Pulm (SA); B W Allwood,1 MB ChB, FCP (SA), MPH, Cert Pulm (SA), PhD; F von Groote-Bidlingmaier,1 MD; C F N Koegelenberg,1 MB ChB, MMed (Int), FCP (SA), FRCP (UK), Cert Pulm (SA), PhD Division of Pulmonology, Department of Medicine, Stellenbosch University and Tygerberg Academic Hospital, Cape Town, South Africa Panorama Heart and Lung Unit, Panorama Mediclinic, Cape Town, South Africa 3 Division of Pulmonology, Department of Medicine, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa 4 Windhoek Mediclinic, Namibia 1 2

Corresponding author: M J Vorster (mvorster@sun.ac.za)

The use of endoscopic lung volume reduction (ELVR) as a minimally invasive procedure with significantly lower morbidity and mortality than surgery, is fast becoming a new treatment modality for a select group of patients with severe emphysema. Lung volume reduction can be achieved either by surgery (LVRS) or the use of endoscopic techniques. Although LVRS offers survival benefit and increased exercise capacity in selected patients, this comes at a price with significant associated morbidity and mortality. The use of endoscopic lung volume reduction (ELVR) aims to reduce the risks and costs of surgery with comparable physiological benefits. Current evidence suggests that not all classes and phenotypes of emphysema will benefit from lung volume reduction, and that individual techniques may benefit different subgroups of patients. It therefore remains paramount that a systematic approach is followed and selection criteria are met, given the high costs and potential complications related to both LVRS and ELVR. S Afr Resp J 2015;21(2):30-32. DOI:10.7196/sarj.8442

Lung volume reduction surgery (LVRS) has been shown to improve clinical and functional status and mortality in the subgroup of patients with predominant upperlobe emphysema and low exercise capacity.[1] LVRS has been marked by a significant 90-day mortality rate in experienced hands (4%) as well as post-procedural morbidity.[2] Interest has grown in the development of a minimally invasive way to reduce lung volume, which can minimise morbidity and mortality.

Endoscopic lung volume reduction (ELVR) is currently used as an alternative intervention, and there is a growing body of evidence that certain well-defined subgroups of patients with advanced emphysema may show significant benefit from ELVR. There are certain selection criteria that should be met and a systematic approach is recommended.[3] Several techniques are currently available, but only a few modalities have been properly evaluated in prospective trials.

Valves have been commercially available for some time in South Africa, though coils were only recently introduced to South Africa, with the first implantations performed in September 2014. This review gives an overview of the rationale, appropriate candidates, technical aspects and current evidence for the use of coils in achieving ELVR.

The rationale for lung volume reduction

ELVR, in principle, aims to achieve atelectasis of the targeted region, thereby reducing its volume and redirecting airflow to less affected regions.[3] Dynamic hyperinflation decreases and diaphragmatic and chest wall mechanics improve. The remaining lung tissue has better elastic properties, which then restores the outward radial pull on

30 SARJ VOL. 21 NO. 2 2015

the small airways, thereby increasing expiratory airflow. Reducing inhomogeneity of regional ventilation and perfusion improves ventilation/perfusion matching. Endobronchial coils, in theory, retension the airway network to mechanically increase elastic recoil in the emphysematous lungs and tether open airways, thereby preventing airway collapse.[4]

Caveats

Bronchial blocking devices have been shown to be less effective in homogeneous emphysema or in cases where significant collateral ventilation is present.[3,5] The degree of heterogeneity is generally determined from chest computed tomography scanning, either by visual inspection or with the aid of specifically designed software.

Collateral ventilation is a normal physiological phenomenon in some individuals. Significant interlobar collateral ventilation prevents atelectasis and thereby subverts the deflating effect of endobronchial blocking devices. Interlobar collateral ventilation is considered to be present if high-resolution computed tomography (HRCT) scans show incomplete fissures.[3] Most European centres, however, currently use an endobronchial catheter system (Chartis Pulmonary Assessment System, Pulmonx Inc., USA) to evaluate the presence and percentage of interlobar collateral ventilation. A balloon catheter, connected to a console, is inserted via a bronchoscope into an airway and then inflated to occlude the airway.[6] A near constant rate of expiratory airflow, measured at the occluded airway, is seen in cases with collateral ventilation, whereas a steady reduction in flow is observed in the absence of collateral ventilation. A recent study found that quantitative HRCT

ARTICLE achieved comparable results to the Chartis system for the use as a guide to effectively assess collateral ventilation and to select patients for valve-based ELVR procedures.[7] The evidence suggests that if the fissures are <75% intact, the Chartis system evaluation should not be performed, as collateral ventilation is always present, whereas with fissure integrity >90% the Chartis evaluation is always practically superfluous, as collateral ventilation is practically never present. The Chartis system is therefore of value in cases where collateral ventilation is questionable, as predicted by HRCT reporting 75 - 90% fissural integrity.

With endobronchial coils the evidence suggests that appropriate candidates with both heterogeneous and homogeneous emphysema could experience clinically significant benefit from ELVR using coils, irrespective of collateral ventilation or complete lobar collapse. The evidence for this is discussed below.

Technical aspects

Coils (RePneu, BTG Inc., USA) are nitinol devices (Fig. 1) that have been preformed to a shape that results in parenchymal retraction after deployment.[4] The device is currently available in three lengths (100, 125 and 150 mm) to accommodate different sized airways. The coils are implanted via a flexible bronchoscope under general anaesthesia or conscious sedation and fluoroscopic guidance using a proprietary delivery system. The airway in the selected segment is identified with a low-stiffness guidewire (under fluoroscopy), after which a catheter is passed over the guidewire and the length of the airway is measured. The guidewire is then removed and a straightened coil is introduced into the distal end of the catheter with a grasper, after which the catheter is removed while the proximal end of the coil is initially advanced and then released, assuming its preformed shape.

Evidence

A pilot study by Herth et al. [4] found endoscopic lung volume reduction with coils to be safe and feasible. In a subsequent study

by Slebos et al.,[8] 18 patients with severe heterogeneous disease showed significant improvement in functional parameters.

After 6 months, the St George’s Respiratory Questionnaire (SGRQ) improved by mean

(standard deviation (SD)) 14.9 (12.1) points (with 11 patients improving by >4 points), the forced respiratory volume in 1 second (FEV 1) by a mean of 14.9%, forced vital capacity (FVC) by 13.4%, residual volume (RV) by a mean of 11.4% and 6-minute walk distance (6MWD) by 84.4 m.

In a multicentre study by Shah et al.,[9] 47 patients with severe emphysema (both heterogeneous and homogeneous disease) were randomly allocated in a 1:1 ratio to either treatment with coils (treatment group, n=23) or best medical care (usual care group, n=24).

The primary endpoint was the difference in response in SGRQ between treatment and usual care groups at 90 days after final treatment (by intention-to-treat analysis). The SGRQ response at 90 days after final treatment was greater in the treatment group than in the usual care group (between-group difference from baseline — 8.36 points (95% confidence interval –16.24 to –0.47); p=0.04).[9] In a larger multicentre study that initially focused on mostly heterogeneous disease, 60 patients

were treated with coils (55 bilateral),[5] again looking at improvement in SGRQ but with a longer follow-up (6 months) and comparing that with baseline (ΔSGRQ). At 6 and 12 months, respectively, ΔSGRQ was a mean (SD) of −12.1 (12.9) points and –11.1 (13.3) points, Δ6MWD was +29.7 (74.1) m +51.4 (76) m, ΔFEV1 was +0.11 (0.20) L and +0.11 (0.30) L, and ΔRV was −0.65 (0.90) L and −0.71 (0.81) L (all p<0.01).[5] In both the studies there was a significant improvement in FEV1 with almost 60% of treated patients experiencing

Fig. 1. An endobronchial (RePneu) coil.

Table 1. General indications and contraindications for endoscopic lung volume reduction with endobronchial and intrabronchial coils in patients with stable emphysema Indication 40 - 75 yr Dyspnoea despite maximal medical therapy and pulmonary rehabilitation FEV1 15 - 45% Hyperinflation with TLC >100% and RV >150 - 175% PaCO2 <6.7 kPa (50 mmHg) PaO2 >6 kPa (45 mmHg) while breathing ambient air 6MWD ≥140 m (post-rehabilitation) Contraindications >75% parenchymal destruction on HRCT Current smoking (previous 6 months) DLCO <20% Giant bullae (>1/3 of hemithorax) α1-antitrypsin deficiency Previous thoracotomy, pleurodesis or chest wall deformity Excessive sputum Severe pulmonary hypertension (>50 mmHg) Active infection Unstable cardiac conditions Significant pleural or interstitial changes on HRCT Any type of antiplatelet or anticoagulant therapy that cannot be stopped for 7 days prior to procedure TLC = total lung capacity; PaCO2 = partial pressure of carbon dioxide in the arterial blood; PaO2 = partial pressure of oxygen in the arterial blood; DLCO = diffusing capacity.

SARJ VOL. 21 NO. 2 2015

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ARTICLE a >10% improvement in FEV1 in the initial study and at 6 months, 48.0% of patients were found to have a ≥12% increase in FEV1 in the latter group. Post hoc analyses showed significant responses for SGRQ, 6MWD and RV in patients with both heterogeneous and homogeneous emphysema. Serious adverse events that were observed within 30 days of treatment included 7 exacerbations (6.1%), 6 pneumonias (5.2%), 4 pneumothoraces (3.5%) and 1 haemoptysis (0.9%),[5] though no between-group difference in serious adverse events was observed when comparing with the control group.[9] A recent open-label study focused exclusively on the use of coils in homogeneous emphysema.[10] Ten patients with severe chronic obstructive pulmonary disease and hyperinflation were treated with a median of 11 (range 10 - 12) coils in each lung. At 6 months, 6MWD improved from 289 to 350 m (p=0.005); FVC from 2.17 to 2.55 L (p=0.047); RV from 5.04 to 4.44 L (p=0.007) and SGRQ decreased from 63 to 48 points (p=0.028). Two exacerbations and one small pneumothorax were recorded as serious adverse events.[10] Hartman et al.[11] recently reported their 3-year follow-up data of 38 patients who underwent ELVR using coils. The data showed that the coil treatment was safe, with no late pneumothoraces, coil migrations or unexpected adverse events. Although clinical benefit gradually declined over time, at 3 years post-treatment around 50% of the patients maintained improvement in 6MWD, SGRQ and dyspnoea scores.[11] Current evidence would therefore suggest that not all classes and phenotypes of emphysema would benefit from ELVR, and that each technique appears to provide greater benefit to specific subgroups of patients.[3] Appropriate candidates with both heterogeneous and homogeneous emphysema could experience clinically significant benefit from ELVR using coils, irrespective of collateral ventilation or complete lobar collapse.

Practical aspects

Generally speaking, patients with a high degree of hyperinflation with relatively preserved lung parenchyma are more likely to benefit from ELVR with bilateral coils, starting with the most affected side (irrespective of the collateral ventilation and heterogeneity of the disease),[5,10] whereas patients with heterogeneous disease, no collateral circulation and a low baseline perfusion (on ventilation: perfusion scanning) benefit from unilateral therapy with the goal to achieve complete lobar collapse. Only endoscopic valves and coils are currently commercially available in South Africa, and only a few centres currently have the capacity to properly evaluate prospective candidates and potentially offer the ELVR to appropriate cases. The high cost of these interventions makes careful patient selection imperative to prevent wasteful expenditure and insertion in patients unlikely to gain clinical benefit. An ongoing study in France is likely to soon provide information on the cost-effectiveness of ELVR with coils compared with other strategies.[12]

32 SARJ VOL. 21 NO. 2 2015

The general indications and contraindications for the endoscopic lung volume reduction with endobronchial and intrabronchial coils in patients with stable emphysema are summarised in Table 1. The Assembly on Interventional Pulmonology of the South African Thoracic Society are currently in the process of finalising a national guideline for the practical use of all devices related to ELVR, including the formal evaluation process. This statement will be published online within the next month.

Conclusions

Current evidence suggests that in well-defined subgroups of patients with severe emphysema, ELVR with coils may be of benefit. A well-structured, evidence-based approach to ELVR, including initial screening and subsequent referral to a specialised centre, is important to ensure against inappropriate use of devices, which may be both wasteful and harmful.

Patients with a high degree of hyperinflation and relatively preserved lung parenchyma are more likely to benefit from ELVR using bilateral coils, irrespective of the collateral circulation and heterogeneity of the disease. Moreover, there are currently numerous ongoing trials, and suggested approaches are likely to be refined during the next decade.

References

1. Fishman A, Martinez F, Naunheim K, et al. A randomized trial comparing lungvolume-reduction surgery with medical therapy for severe emphysema. N Engl J Med 2003;348(21):2059-2073. [http://dx.doi.org/10.1056/NEJMoa030287] 2. Yusen RD, Lefrak SS, Gierada DS, et al. A prospective evaluation of lung volume reduction surgery in 200 consecutive patients. Chest 2003;123(4):1026-1037.

3. Gasparini S, Zuccatosta L, Bonifazi M, Bolliger CT. Bronchoscopic treatment of emphysema: State of the art. Respiration 2012;84(3):250-263. [http://dx.doi.org/10.1159/000341171] 4. Herth FJ, Eberhard R, Gompelmann D, Slebos DJ, Ernst A. Bronchoscopic lung volume reduction with a dedicated coil: A clinical pilot study. Ther Adv Respir Dis 2010;4(4):225-231. [http://dx.doi.org/10.1177/1753465810368553] 5. Deslee G, Klooster K, Hetzel M, et al. Lung volume reduction coil treatment for patients with severe emphysema: A European multicentre trial. Thorax 2014;69(11):980-986. [http://dx.doi.org/10.1136/thoraxjnl-2014-205221] 6. Herth FJ, Noppen M, Valipour A, et al. Efficacy predictors of lung volume reduction with Zephyr valves in a European cohort. Eur Respir J 2012;39(6):1334-1342. [http:// dx.doi.org/10.1183/09031936.00161611] 7. Schuhmann M, Raffy P, Yin Y, et al. Computed tomography predictors of response to endobronchial valve lung reduction treatment: Comparison with Chartis. Am J Respir Crit Care Med 2015;191(7):767-774. [http://dx.doi.org/10.1164/rccm.201407-1205OC] 8. Slebos DJ, Klooster K, Ernst A, Herth FJ, Kerstjens HA. Bronchoscopic lung volume reduction coil treatment of patients with severe heterogeneous emphysema. Chest 2012;142(3):574-582. [http://dx.doi.org/10.1378/chest.11-0730] 9. Shah PL, Zoumot Z, Singh S, et al. Endobronchial coils for the treatment of severe emphysema with hyperinflation (RESET): A randomised controlled trial. Lancet Respir Med 2013;1(3):233-240. [http://dx.doi.org/10.1016/S2213-2600(13)70047-X] 10. Klooster K, ten Hacken NH, Franz I, Kerstjens HA, van Rikxoort EM, Slebos DJ. Lung volume reduction coil treatment in chronic obstructive pulmonary disease patients with homogeneous emphysema: A prospective feasibility trial. Respiration 2014;88(2):116-125. [http://dx.doi.org/10.1159/000362522] 11. Hartman JE, Klooster K, Gortzak K, ten Hacken NH, Slebos DJ. Long-term follow-up after bronchoscopic lung volume reduction treatment with coils in patients with severe emphysema. Respirology 2015;20(2):319-326. [http://dx.doi.org/10.1111/resp.12435] 12. Deslee G, Barbe C, Bourdin A, et al. [Cost-effectiveness of lung volume reduction coil treatment in emphysema: STIC REVOLENS]. Rev Mal Respir 2012;29(9):1157-1164. [http://dx.doi.org/10.1016/j.rmr.2012.09.010]

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74

South African Respiratory Journal Vol 20 No 2

BREATH-TAKING NEWS

The Xpert MTB/RIF assay: A game-changer, but not infallible Tuberculosis (TB) is a major problem in South Africa and increasing varieties of drug-resistant strains add to the burden. The roll-out of the rapid molecular diagnostic test – the Xpert Mycobacterium tuberculosis/ rifampicin (MTB/RIF) assay (Cepheid, USA) – was a major game-changer in its ability to not only confirm MTB but also rifampicin resistance within a few hours.

However, two caveats have emerged in the recent literature that necessitate that we reconsider. These refer to the ability to detect all rifampicin-resistant strains and, since the test is so sensitive, the duration that the test remains positive after a diagnosis of TB. The first investigators, in a study from Swaziland, used 24-loci mycobacterial interspersed repetitive unit – variable number tandem repeat (MIRU-VNTR) analysis and spoligotyping to perform classic genotypic analysis of MTB complex strains from their most recent national survey of tuberculosis drug resistance.[1] They found that 38 of 125 multidrug-resistant strains (30%) carried the rpoB I491F mutation, which confers resistance to rifampicin. This mutation, which was previously reported with low frequency in clinical isolates from other parts of the world, is not detected by the Xpert MTB/RIF assay. Xpert is designed to identify rifampicin-resistance mutations in an 81-base pair region of rpoB (codons 426 to 452). Its inability to detect the rpoB I491F outbreak strain will result in underdiagnosis of rifampicin-resistant MTB and potentially lead to inadequate treatment.

Thus, if putatively drug-sensitive TB patients don’t improve on treatment, think of adherence, suboptimal absorption, and so

34 SARJ VOL. 21 NO. 2 2015

on, but also consider this: has the test (Xpert) missed multidrugresistant TB? The second study examined the issue of persistence of Xpert pos­ itivity in patients who have previously been treated for TB.[2] Many of their patients were noted to have false positive Xpert results when the tests were repeated many months later. There have been case reports where the test remains positive for up to 5 years after the incident case of TB. Since the test amplifies DNA, how quickly the threshold for detection is reached is dependent on the mycobacterial load and is reflected in the cycle thresholds (CT). The higher the CT, the greater the likelihood that there will be a false positive result. There has therefore been a call for guidelines on the use of Xpert in treatment-experienced subjects. For now, in patients who are being assessed for persistent or recurrent TB, culturing is essential as Xpert alone is inadequate for a confident diagnosis, and the latter should preferably not be performed.

Elvis M Irusen Professor and Head, Division of Pulmonology, Department of Medicine, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa

References

1. Sanchez-Padilla E, Merker M, Beckert P, et al. Detection of drug-resistant tuberculosis

by Xpert MTB/RIF in Swaziland. N Engl J Med 2015;372():1181-1182. [http://dx.doi. org/10.1056/NEJMc1413930] 2. Metcalfe JZ, Makumbirofa S, Makamure B, et al. Suboptimal specificity of Xpert MTB/RIF among treatment-experienced patients. Eur Respir J 2015;45(5):1504-1506. [http://dx.doi.org/10.1183/09031936.00214114]

S Afr Resp J 2015;21(2):34. DOI:10.7196/sarj.8443

WHO’S WHO

Morné Vorster MB ChB, MRCP (London), MMED, FCP (SA)

Morné Vorster is a senior registrar working in respiratory and critical care medicine. After completing his undergraduate training in 2002 at Stellenbosch University, South Africa, he spent 5 years training in medicine in the UK, and he is currently a member of the Royal College of Physicians of London. He returned to South Africa to complete his training in internal medicine in 2013. Soon after graduating from both his MMed and college exams, he applied for a subspecialist training post in respiratory medicine; he is currently training, along with four other fellows, in an excellent programme under the supervision of Elvis Irusen, Coenie Koegelenberg and Brian Allwood.

Under supervision of his mentors, his research career has matured and he is author of four recent publications. These publications include infectious and pleural diseases, applied transthoracic ultrasound and interventional pulmonology. He is also currently actively involved with numerous related other studies. Working in the Division of Pulmonology, Tygerberg Academic Hospital and Stellenbosch University, has given him the opportunity to develop his interventional skills, where he has achieved competency and is now involved in training registrars in both bronchoscopic and pleural procedures. Morné is a member of Interventional Pulmonology South Africa (IPSA), which aims to improve the quality of interventional pulmonology in South Africa and to train as many pulmonologists as possible in the various techniques.

Donald Simon MB ChB , MMed (Int Med), FCP (SA)

Donald Simon is currently a fellow/ subspecialist trainee in the Division of Pulmonology at Tygerberg Hospital and has enrolled in the MPhilMed programme at Stellenbosch University, South Africa.

He obtained his MB ChB at Stellenbosch University in 2007. He then spent the following 3 years at Kimberley Hospital doing his internship and community service.

He started his registrar training in internal medicine at Stellenbosch University in 2011 and obtained his FCP(SA) and MMed (Internal Medicine) in 2014. In his MMed he addressed the progression of hepatitis B virus (HBV) in both mono-infected and co-infected patients, focusing on the need for more widespread HBV screening.

Donald started his fellowship training in pulmonology in February 2014. In addition to pulmonology, he also has a primary interest in critical care medicine and hopes to one day practise both.

Shinu Abraham MB ChB, FCP (SA)

Shinu Abraham is currently a respiratory fellow working at Tygerberg Hospital. She completed her undergraduate medical degree at the University of Transkei in 2004, and after her community service joined as a medical officer in internal medicine at Grey’s Hospital in Pietermaritzburg, South Africa.

In August 2008 she joined the internal medicine registrar programme and passed her fellowship exams in May 2011. From

2012, she subsequently worked as a consultant in general medicine at Edendale Hospital, Pietermaritzburg, for 3 years. Besides clinical work, she was involved in undergraduate and postgraduate training.

Currently, she is one of the recipients of the Discovery subspecialty foundation training grant in pulmonology for 2015 and has joined the Department of Respiratory and Critical Care at Tygerberg Hospital as of March 2015, under the supervision of Professor Elvis Irusen. She has registered for the MPhil and her current research project involves sedation during endobronchial ultrasound-guided transbronchial biopsy.

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ABSTRACTS

Abstracts of presentations at the congress of the South African Thoracic Society in Cape Town, 7 - 10 August 2015 S Afr Resp J 2015;21(2):36-46. DOI:10.7196/sarj.8444

POSTER PRESENTATIONS The utility of Xpert MTB/RIF performed on bronchial washings obtained in patients with suspected pulmonary tuberculosis in a high-prevalence setting DA Barnard,1* EM Irusen,1 JW Bruwer,1 D Plekker,2 A Whitelaw,3 JD Deetlefs,4 CFN Koegelenberg1 1 Division of Pulmonology, Department of Medicine, Stellenbosch University and Tygerberg Academic Hospital 2 Kuils River Respiratory Centre, Kuils River Netcare Hospital, Kuils River, South Africa 3 Division of Medical Microbiology and Immunology, Department of Pathology, Stellenbosch University and Tygerberg Academic Hospital; and National Health Laboratory Services 4 Ampath Laboratories, Cape Town, South Africa *dabarnard@live.com Background. Xpert MTB/RIF has been shown to have a superior sensitivity to microscopy for acid-fast bacilli (AFB) in sputum and has been recommended as a standard first-line investigation for pulmonary tuberculosis (PTB). Bronchoscopy is a valuable tool in diagnosing PTB in sputum-negative patients. There are limited data on the utility of Xpert MTB/RIF performed on bronchial lavage specimens.

Objective. To evaluate the diagnostic efficiency of Xpert MTB/RIF performed on bronchial washings in sputum-scarce/negative patients with suspected PTB. Methods. All patients with a clinical and radiological suspicion of PTB who underwent bronchoscopy between January 2013 and April 2014 were included. The diagnostic efficiencies of Xpert MTB/RIF and microscopy for AFB were compared with culture for Mycobacterium tuberculosis.

Results. Thirty-nine of 112 patients were diagnosed with culturepositive PTB. Xpert MTB/RIF was positive in 36/39 with a sensitivity of 92.3% (95% confidence interval (CI) 78 - 98%) for PTB, which was superior to that of smear microscopy (41%, 95% CI 26.0 - 57.8%, p=0.005). The specificities of Xpert MTB/RIF and smear microscopy were 87.7% (95% CI 77.4 - 93.9%) and 98.6% (95% CI 91.6 - 99.9%) respectively. Xpert MTB/RIF had a positive predictive value of 80% (95% CI; 65 - 89.9%) and negative predictive value of 95.5% (95% CI 86.6 - 98.8%). 3/9 patients with Xpert MTB/RIF-positive culture negative results were treated for PTB based on clinical and radiological findings.

Conclusion. Xpert MTB/RIF has a higher sensitivity than smear microscopy and similar specificity for the immediate confirmation of PTB in specimens obtained by bronchial washing and should be utilised in patients with a high suspicion of PTB. A rare cause of a solitary pulmonary nodule KV Dire,1,2* C Feldman,1 G Richards,1,2 C Leisegang,3 N Voorajee4 1 Department of Pulmonology, Charlotte Maxeke Johannesburg Academic Hospital, University of the Witwatersrand, Johannesburg, South Africa

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Department of Critical Care, Charlotte Maxeke Johannesburg Academic Hospital, University of the Witwatersrand, Johannesburg, South Africa 3 Division of Anatomical Pathology, National Health Laboratory Services, University of the Witwatersrand, Johannesburg, South Africa 4 Pathology Division of National Institute for Occupational Health, University of the Witwatersrand, Johannesburg, South Africa *kefilwedire@gmail.com 2

We present a case of a solitary pulmonary nodule owing to peri­ bronchial granulomatous process in a young female adult, who was also asthmatic, of which the aetiology is that of cosmetic talc inhalation. She was a newly diagnosed asthmatic with a previous history of tuberculosis (TB) and her HIV status was negative. She also had 7 pack years of smoking. Her initial presentation led to her work-up for infective disorders, of which TB and hydatid cyst were the differential diagnosis. Her TB work-up was negative and echinococcus serology was negative. A chest X-ray showed a solitary pulmonary nodule in the right upper zone, not associated with lymphadenopathy.

A computed tomography chest scan confirmed the findings. A wedge biopsy of the pulmonary mass confirmed peribronchial granulomatous inflammation with giant cells containing refractile material resembling talc under polarised light. Further history from the patient revealed a daily use of talc-based cosmetic powder as make-up for at least 5 years prior to presentation and she denied any use of illicit drugs in any form.

Her repeat chest X-ray post surgery showed postsurgical scarring and the inflammatory markers remained low. Her symptoms vanished post surgery and she was discharged on asthma medications only.

To explore the diagnostic value of endobronchial ultrasoundguided transbronchial needle aspiration (EBUS-TBNA) in diagnosing mediastinal lesions in a high-burden TB setting – Cape Town experience A Esmail,* L Mottay, G Calligaro, Z Laher, G Symons, K Dheda Groote Schuur Hospital and Division of Pulmonology, University of Cape Town, Cape Town, South Africa *a.esmail@uct.ac.za Background. Undiagnosed mediastinal lesions are a common cause for referral to our clinic. While mediastinoscopy is considered the ‘gold standard’ for diagnosing such patients, recent advances suggest that endobronchial ultrasound combined with transbronchial needle aspiration (EBUS-TBNA) is at least as valuable in obtaining suitable tissue samples for diagnosis, while reducing cost and expediting treatment, especially in our setting – where mediastinoscopy has a long waiting period.

Methods. We prospectively studied 146 patients who underwent EBUS-TBNA as a diagnostic tool between March 2013 and June 2015 at Groote Schuur Hospital. The first 10 patients were excluded from the analysis as they were considered part of our learning curve. All patients

ABSTRACTS with undiagnosed mediastinal adenopathy despite conventional workup, including fibreoptic bronchoscopy, were included.

Results. The indications for EBUS were undiagnosed mediastinal nodes, staging for already diagnosed lung cancer or undiagnosed mediastinal mass. The diagnostic accuracy of EBUS-TBNA, regardless of indication, was 79.1%, with a positive predictive value of 100% and negative predictive value of 60.9%. False negative results were obtained in 16 patients (11.8%) eight of whom had a malignant diagnosis (3 lymphoma, 1 leiomyoma, 2 non-small cell lung carcinoma, 1 metastatic cervical carcinoma, 1 malignant cells unable to type), 4 patients had TB, while another 4 of the false negative patients had sarcoidosis. The diagnostic accuracy was significantly higher for malignant diseases as compared to benign disease (77.8% v. 60%, p<0.01). EBUS made the diagnosis of TB in 13/17 patients (76.4%). The procedure was well tolerated in 97.8% of the patients with procedure-related complications occurring in only three patients: two patients had reversible hypoxia while the other had bleeding of more than 50 mL. Both complications resolved with symptomatic treatment.

Conclusion. EBUS-TBNA is a safe and useful diagnostic tool for both benign and malignant diseases. However, the diagnostic accuracy for malignant conditions is higher. This study also further highlights the fact that EBUS-TBNA potentially saved about 60% of the patients from having a mediastinoscopy, thereby reducing cost and expediting treatment.

Clinical and demographic predictors of pre-treatment loss to follow-up: A multicentre study J Jayakumar,* G Theron, J Peter, L Zijenah, P Clowes, D Stein, K Dheda Lung Institute and Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa *jaisubash@gmail.com Background. In southern Africa, tuberculosis (TB) eradication is a major stumbling block for the effective functioning of the healthcare system. Up to 40% of patients diagnosed with TB are not initiated on anti-TB treatment as they do not return to the healthcare facilities for their diagnostic results. These individuals, referred to as â&#x20AC;&#x2DC;pretreatment loss to follow-upâ&#x20AC;&#x2122;, represent an important defeat on both the national TB programme and provision of care.

Objectives. To identify clinical and demographic predictors of pretreatment loss to follow-up and to examine if these differ from cases that were initiated on TB treatment in five primary care healthcare facilities in South Africa, Zimbabwe, Zambia and Tanzania.

Methods. Sociodemographic (age, gender, smoking status, alcohol consumption, health literacy score, highest level of education, employment, personal and household income) and clinical information (HIV status, CD4 count, pre-TB status, culture time-to-positivity (TTP), clinic and laboratory Xpert MTB/RIF cycle threshold (CT) values, TB score and Kessler Psychological Distress Scale (K-10) score) were collected from a randomised controlled trial involving patients assigned to either the Xpert MTB/RIF arm or sputum smear microscopy arm.

Results. A total of 367 culture-positive TB cases were identified from both smear and Xpert arms, out of which 89% were initiated on treatment and 11% were pre-treatment loss to follow-up. The predictors, namely sputum bacterial load as measured by TTP and Xpert CT values and global psychological distress as determined by K-10 score, differed significantly in the pre-treatment loss to follow-up.

Conclusion. This study has identified that the patients with TB who appear well seem to not get initiated on treatment contributing to pre-treatment loss to follow-up.

Superior mediastinal masses: Two cases of lymphoma AC Jeevarathnum,* RJ Green Department of Paediatrics, Steve Biko Academic Hospital, University of Pretoria, Pretoria, South Africa *acjeevarathnum@gmail.com Background. The exact incidence of superior mediastinal masses in children is largely unknown. They present as a spectrum of disease ranging from an incidental finding on a chest X-ray to markedly symptomatic with superior vena cava syndrome or obstruction of the upper airways.

Certainly, tumours are the most common causes in children.

Objective. To describe the of outcome of two patients with superior mediastinal masses.

Methods. A 4-year-old male presented with a 1-week history of cough and shortness of breath with respiratory distress. Chest X-ray of this child revealed a left-sided pleural effusion with shift of the mediastinum; a widened superior mediastinum was also noted which became more apparent on drainage of the effusion. The effusion was exudative in nature with a very high adenosine deaminase of 184 U/L. Cytology of the effusion revealed atypical lymphocytes suggestive of a malignancy. Another patient, a 2-year-old male, presented with an acute history with cough and shortness of breath following a choking episode. This was a clinically well child with no respiratory symptomatology that had an incidental finding of a widened superior mediastinum. There were no peripheral lymph nodes to biopsy and haematological work-up was noncontributory. On awaiting theatre for a histological specimen of the mass, the patient had an unexpected cardiorespiratory arrest and failed resuscitation.

Results. The definitive diagnosis of a T-cell lymphoma was made on biopsy of the mass of the first patient. Portmortem samples of the second patient revealed a T-cell lymphoma.

Conclusion. T-cell lymphomas are one of the most common causes of superior mediastinal masses in the paediatric population. A mass in the superior mediastinum requires a histological diagnosis. These patients, despite appearing clinically stable, can be challenging to manage and caution should be employed, with intensive care unit facilities being readily available.

A descriptive analysis of thymic tumours at Chris Hani Baragwanath Academic Hospital RM Leibbrandt,* ML Wong Division of Pulmonology, Chris Hani Baragwanath Academic Hospital and University of the Witwatersrand, Johannesburg, South Africa *robertmleibbrandt@gmail.com Background. Thymic tumours are rare and may present to the pulmonologist for investigation of an abnormal chest radiograph.

Other medical conditions, such as myasthenia gravis, may occur in association.

Objective. To undertake a descriptive analysis of the demographics, thymic tumour type and HIV status of patients.

Methods. A retrospective analysis from 1992 to 2015 was undertaken, utilising records of the Division of Pulmonology at Chris Hani Baragwanath Academic Hospital.

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ABSTRACTS Results. Thymic tumours were diagnosed in 25 patients. Seventeen patients (68%) were female, of whom 6 (35.3%) had malignant tumours. Four out of the eight male patients (50.0%) had a malignant tumour. The median age was 39 (range 18 - 87) years. Myasthenia gravis was the presenting feature in 9 patients (36.0%), of whom 2 (22.2%) had malignant tumours. In the remaining 16 patients without myasthenia, 50.0% had malignant thymic tumours. Seven patients were HIV-seropositive, 7 were HIV-seronegative and the remainder were either not tested or the HIV status not recorded. There was no significant difference in the proportion of malignant tumours when stratified by HIV status, although the number of patients in each group was too small for useful statistical analysis.

Conclusion. In this select population, most patients with thymic tumours were female. Forty per cent had malignant thymic tumours.

Approximately one-third had associated myasthenia gravis. Fifty per cent of those whose HIV status was determined or recorded were seropositive.

Case report: Hypereosinophilia as a paraneoplastic phenomenon in non-small cell lung carcinoma L Nqwata,1* ML Wong,1 RD Mohanlal,2 A Lakha3 1 Division of Pulmonology, Chris Hani Baragwanath Academic Hospital and the University of the Witwatersrand, Johannesburg, South Africa 2 D epartment of Anatomical Pathology, Chris Hani Baragwanath Academic Hospital, National Health Laboratory Services and University of the Witwatersrand, Johannesburg, South Africa 3 Division of Clinical Haematology, Chris Hani Baragwanath Academic Hospital and University of the Witwatersrand, Johannesburg, South Africa *drlamla@yahoo.com Hypereosinophilia is a very rare paraneoplastic finding in malignant disease, particularly lung cancer. When it occurs, it usually is indicative of metastatic disease and poor prognosis. We report a case of a 52-yearold male patient with paraneoplastic hypereosinophilia associated with primary adenocarcinoma of the right lower lobe and extensive metastatic disease. Presenting features were cough and significant weight loss for 2 months on a background of chronic obstructive pulmonary disease and well-controlled long-standing epilepsy. Examination revealed a wasted patient, cognitive slowing without focal neurological signs, percussion dullness with diminished breath sounds over the right lower zone and hepatomegaly extending 8 cm below the costal margin. His full blood count showed a markedly elevated white cell count (peak level 114.18 × 109/L) with an absolute eosinophilia ranging from 29.81 to 82.33 × 109/L during the course of his admission. The bone marrow trephine showed marked eosinophilia with no malignant infiltrate or evidence of clonal eosinophilic proliferation. Radiological investigations revealed a right lower lobe mass measuring 9.1 × 6.0 × 6.7 cm, bilateral pulmonary nodules, multiple liver lesions and a left adrenal mass. No endoluminal lesion was visible on fibreoptic bronchoscopy. A core biopsy of the mass was consistent with poorly differentiated primary lung adenocarcinoma.

Surgery for bronchiectasis in HIV-positive children: Indications, complications and outcome H Peens-Hough,* J Janson, P Goussard, G Rossouw Division of Cardiothoracic Surgery, Department of Surgery and Department of Paediatrics and Child Health, Tygerberg Hospital and Stellenbosch University, Cape Town, South Africa *hyla.peenshough@gmail.com

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Background. Bronchiectasis in HIV-infected children remains a significant cause of morbidity and mortality, especially in areas that are endemic to tuberculosis. Currently, the treatment modalities for bronchiectasis in HIV-positive children focus mainly on prevention of subsequent infections and management of symptoms. The surgical management in non-CF bronchiectasis is well established. Surgery for bronchiectasis in HIV-positive children is often not even mentioned as a management strategy. This study aims to describe the indications and complications of surgical resection for bronchiectasis in HIVpositive children and investigate variables influencing outcome.

Methods. Between January 2007 and September 2014, a retrospective medical records review was conducted in all HIV-infected children 14 years and younger who underwent surgical resection for bronchiectasis. This analysis specifically considered the following variables: the immune status, antiretroviral treatment, Mycobacterium tuberculosis treatment, operative complications and symptom relief.

Results. Twelve HIV-positive children on antiretroviral treatment underwent surgical resection. The mean age was 7 years (range 22 159 months). Indications for surgery were recurrent infections, chronic cough and persistent lobar collapse. The most common procedures were left lower lobe lobectomy (42%), left pneumonectomy (16%) and right bi-lobectomy (16%). Complications were limited to a persistent pneumothorax in one child. There were no deaths. Ten children (83%) showed significant improvement of symptoms at follow-up.

Conclusion. Surgical resection for bronchiectasis in HIV-positive children can be safely performed with low complication rates and leads to significant improvement of symptoms and quality of life.

Aspergilloma complicated by fungal empyema and mycotic aneurysm AJ Peter Division of Pulmonology, Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa alanpeter@ymail.com Background. Patients with healed pulmonary tuberculosis may develop aspergillomas in residual pulmonary cavities. The most common complication is haemoptysis. Rarely, an aspergilloma may rupture into the pleural space, causing a fungal empyema. Aneurysm formation from pleuropulmonary sepsis is another rare complication.

Case presentation. A 30-year-old woman who previously had tuberculosis presented with a left-sided empyema from which Aspergillus fumigatus was cultured. She was wasted, not immunocompromised and tested HIV-negative. Radiologically, aspergillomas were evident in cavities in her right upper lobe and left lower lobe. A pigtail catheter was introduced for drainage of the left empyema. The patient subsequently suffered significant episodes of haemorrhage into the pleural space, requiring multiple blood transfusions. An angiogram demonstrated an aneurysm near the left hilum. A repeat angiogram 3 months later showed resolution of the aneurysm. An open pleural biopsy showed chronic inflammation but no invasion by Aspergillus hyphae. The Grocott stain of the necrotic material showed positive staining of fungal hyphae with acute angle branching. Ziehl Neelsen staining was negative. The morphological features favoured pleural aspergillosis from a fungal pneumonia or an aspergilloma with rupture into the pleural space. The patient was treated with voriconazole for 2 months and also underwent an open drainage procedure. On follow-up she had gained 8 kg. She remained

ABSTRACTS well for 8 months following discharge, but unfortunately demised from an upper gastrointestinal bleed.

Conclusion. Rupture of apergillomas into the pleural space is rare.

Consequent fungal empyemas require drainage and lengthy treatment with systemic anti-fungal treatment such as voriconazole for cure.

This patient also developed a haemothorax probably due to rupture of a mycotic aneurysm. However, iatrogenic vascular injury related to the insertion of a pigtail catheter cannot be excluded.

Mono- and multidrug-resistant tuberculosis SA van Blydenstein,1* CN Menezes,2 E Jong3 1 Pulmonology Division, Department of Medicine, Chris Hani Baragwanath Academic Hospital, University of the Witwatersrand, Johannesburg, South Africa 2 Infectious Diseases Unit, Department of Medicine, Chris Hani Baragwanath Academic Hospital, University of the Witwatersrand, Johannesburg, South Africa 3 Clinical HIV Research Unit, TB Focal point, Helen Joseph Hospital, University of the Witwatersrand, Johannesburg, South Africa *savanblydenstein@gmail.com Background. Drug-resistant tuberculosis (TB) is a rapidly emerging health problem in the Republic of South Africa, and there is a paucity of data on mono- and poly-resistant TB. Methods. This study is a retrospective analysis of a database for the period 1 March 2009 to 31 December 2011, of drug-resistant TB cases treated at TB Focal Point, Helen Joseph Hospital, a public hospital in Gauteng Province, South Africa.

Results. Rifampicin mono-resistant TB was the largest group in this study (34%), highlighting the presence of rifampicin mono-resistant TB as an entity separate to multidrug-resistant TB. Our study showed no clear patient characteristics in terms of risk factors for acquisition of mono- or poly-resistant TB, nor any clear predictors of outcome.

The majority (86.6%) of the patients were HIV-positive, with a median CD4 of 67 cells/mm3.

Conclusion. Rifampicin mono-resistant TB was the most prevalent drug-resistant TB type and treatment outcomes are poor. This study was unable to identify predictors for drug-resistant TB type and drugresistant TB treatment outcome, but research in this area should continue to enable the treating clinician to anticipate and aggressively manage patients with predicted poorer outcomes.

Factors affecting compliance and control of asthma at Chris Hani Baragwanath Academic Hospital, Department of Pulmonology SA van Blydenstein,* M Wong, L Nqwata, P Banda Pulmonology Division, Department of Medicine, Chris Hani Baragwanath Academic Hospital, University of the Witwatersrand, Johannesburg, South Africa *savanblydenstein@gmail.com Background. There is a sense among the respiratory physicians that asthma is not well controlled in the public sector hospitals. This may be due to lack of education in patients, poor compliance or lack of knowledge regarding inhaler technique.

Objective. To describe the status of control in patients attending the adult asthmatic outpatient department at Chris Hani Baragwanath Academic Hospital.

Methods. A retrospective record review was done on outpatient files

of asthmatics known to the respiratory clinic. Data obtained included demographics, level of control and number of admissions and exacerbations.

Results. A total of 525 patient files were obtained of which 86% were female. The mean (SD) age was 46 (16.5) years. 47.2% of patients were controlled, 30.5% partly controlled and 22.3% uncontrolled.

Most patients (88%) had no admissions in the previous year and 60% had no exacerbations. Most patients were only on short-acting beta agonists and inhaled steroids.

Conclusion. In this population of mostly middle-aged female asthmatics, less than half the patients were well-controlled despite very few admissions or exacerbations in the previous year. In a number of significant areas, such as FEV1 predicted and knowledge of inhaler technique, the majority (>60%) of the data had not been recorded in the files.

The effect of therapeutic pleural drainage on the short- and longterm sequelae of tuberculous pleural effusions E Wilken,* H Fengels, EM Irusen, E Batubara, JW Bruwer, F Swart, D Maree, CFN Koegelenberg Division of Pulmonology, Department of Medicine, Stellenbosch University and Tygerberg Academic Hospital, Cape Town, South Africa *elsimawilken@gmail.com Background. Tuberculosis remains a common cause of pleural exudates in many parts of the globe. Pleural fibrosis with restriction is a well-known complication of tuberculous pleuritis. Current evidence suggests that pleural drainage offers little benefit over and above antituberculous treatment in improving pulmonary function testing.

Methods. We enrolled 20 patients with proven tuberculosis pleural effusions (mean age 32.7 years, 10 males, 12 HIV-positive), and performed therapeutic pleural drainage in 10 randomly selected cases.

Pulmonary function testing, chest radiography and transthoracic ultrasound were performed on all patients prior to treatment, at 7 10 days, 3 months and 6 months.

Results. Complete therapeutic drainage was achieved in only 4/10 patients randomised to undergo drainage. No significant immediate benefit was achieved in the 10 patients assigned to intervention.

However, the intervention group showed significant changes compared with the non-intervention group in several functional parameters at 6 months, including change in forced vital capacity from baseline (FVC 1.40 L v. 0.65 L, p<0.001), change in forced expiratory volume in 1 sec (FEV1 1.37 L v. 0.60 L, p=0.002), change in total lung capacity (TLC 1.76 L v. 0.88 L, p=0.034) and change in the diffusion capacity for carbon monoxide (DLco 7.42 v. 2.19, p=0.013). No difference was observed in the change in the 6-minutes walking distance (6MWD 113.4 m v.

126 m, p=0.798) compared with the control group at 6 months.

Conclusion. Therapeutic drainage may offer additional medium- and long-term functional benefits to patients with pleural tuberculosis, as evident in the improvement of pulmonary function testing.

ORAL PRESENTATIONS Do specialist pulmonologists adhere to current treatment guidelines for thoracic surgery for drug-resistant pulmonary tuberculosis?

G Alexander Department of Cardiothoracic Surgery, Inkosi Albert Luthuli Hospital, Durban, South Africa; and Department of Cardiothoracic Surgery, King Dinuzulu Hospital, Durban, South Africa mdalexg@hotmail.com

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ABSTRACTS Background. Adjuvant lung resection in patients with drug-resistant tuberculosis (DR-TB) is cheaper than a 2-month course of drug therapy and, more importantly, has a higher cure rate than medical therapy alone. Cure rates for selected patients with multiple DR-TB, treated with adjuvant lung resection, is about 90% as compared with about 60% in patients treated with medical therapy alone. With the more severe forms of DR-TB, surgical cure rates remain equivocal while cure rates with medical therapy alone drastically diminish.

Despite this compelling evidence, it appears that the number of adjuvant lung resections undertaken for DR-TB is incongruent with the high incidence of DR-TB. Moreover, adjuvant lung resection in selected patients with DR-TB/HIV co-infection does not have a higher surgical complication rate despite an alarmingly high mortality with medical therapy alone. In South Africa, directly observed treatment, short-course has a 67% success rate. Repeated hospital admissions, inadequate laboratory facilities, lengthy treatment duration, discomfort from daily injectables, inadequate drug penetration into lung cavities/nodules and problems of malabsorption in HIV coinfected patients serve as a catalyst for this epidemic.

Objective. To determine whether specialist pulmonologists in South Africa adhere to the recommended guidelines for thoracic surgical intervention for DR-TB. Methods. A questionnaire (18 questions) was forwarded to all specialist adult pulmonologists who are members of the South African Thoracic Society to determine whether these doctors adhere to surgical guidelines for DR-TB. The questionnaire predominantly focused on how these doctors utilise thoracic surgery in their management of DR-TB. Results. There were 24 respondents. From a surgical perspective, 8/24 (33.3%) respondents did not know the indications for lung resection for DR-TB. 21/24 (87.5%) of respondents stated that if they knew these indications, it would influence referral for surgery.

Conclusion. The necessity of a multidisciplinary team will improve treatment outcomes in patients with DR-TB. The utility of intensified case finding combined with a package of novel TB diagnostics using a mobile clinic in Cape Town â&#x20AC;&#x201C; A randomised controlled trial G Calligaro,* G Theron, J Peter, A Esmail, R Meldau, K Dheda Lung Infection and Immunity Unit, Division of Pulmonology and UCT Lung Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa. *greg.calligaro@uct.ac.za Background. Intensified case finding (ICF) is identified by the World Health Organization (WHO) as one of the core prevention strategies necessary to reduce the prevalence of tuberculosis (TB) in highburden settings. Novel TB diagnostic tools have not been studied as part of a screening strategy for ICF, and their operational feasibility as a point-of-treatment diagnostic technology based in a mobile van has not been assessed.

Objective. To compare the impact of a package of novel intensivecase finding diagnostic tools with a standard intensive-case finding strategy on the proportions of patients initiating TB treatment, using a mobile van.

Methods. We prospectively recruited individuals with suspected TB from several community-based sites in Langa, Cape Town, using a mobile van and randomised them to either standard diagnostic tools

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(sputum smear performed at the lab and liquid culture) or a package of novel diagnostic tools (urine LAM strip testing if HIV-infected and sputum Xpert MTB/RIF performed in the van and liquid culture).

The proportion of culture-positive patients initiating treatment by 2Â months was the primary endpoint.

Results. 37/375 (14.51%) of patients with suspected TB had culturepositive TB. The sensitivity of Xpert at point of care was 71.4%, (47.8 - 88.7) v. 25.0% (7.3 - 52.4) for smear microscopy at the lab. No patients tested positive for LAM. Time-to-treatment initiation among culture-positives was 31 days in the standard arm and 4 days in the novel diagnostics arm (p=0.02). However, the proportion of patients initiated on TB treatment was the same (63% v. 81%, p=0.21).

Conclusion. A novel ICF strategy using Xpert dramatically decreases time-to-treatment initiation compared with smear microscopy, but does not improve on treatment initiation rates at 2 months if the conventional strategy has culture as a backup. Reduced diagnostic lead-time may have important effects on TB transmission and clinical outcome in this setting and requires further study.

Bronchial thermoplasty at Groote Schuur Hospital: A preliminary report Z Laher,* G Calligaro, A Esmail, K Dheda Groote Schuur Hospital and Division of Pulmonology, University of Cape Town, Cape Town, South Africa *drziyaadlaher@gmail.com Background. Bronchial thermoplasty (BT) is recommended for uncontrolled severe asthma despite optimised medical therapy, and has been endorsed by several guidelines including NICE, BTS and GINA. However, there are no data from Africa and patients with more severe forms of asthma (FEV1<60% predicted, on maintenance oral corticosteroid (OCS) and with previous intensive care unit (ICU) admission) are poorly represented in published studies.

Objective. To review the preliminary safety and efficacy of BT in patients treated at Groote Schuur Hospital.

Methods. Patients with severe asthma undergoing BT (three procedures, 1 month apart for each patient) were prospectively enrolled into a registry. Data in the 12 months prior to BT were compared with those 12 months after the procedure (ACT scores, exacerbation rates, OCS dose and spirometric data). Adverse events were recorded.

Results. Of 7 patients who underwent BT (21 procedures; 2 patients have insufficient post-BT data) the baseline median FEV1 was 62% predicted, 71% were on OCS >10Â mg/day, 67% had previous ICU admissions and 83% had an exacerbation rate of >6 per annum. BT was in general well tolerated, but 4 out of the 21 (19%) procedures were complicated by post-procedural bronchospasm necessitating overnight admission. A total of 83 months follow-up in the 5 patients (median 18 months) showed increased mean ACT scores (11/25 to 15/ 25 (p=0.03)); 64% reduction in exacerbations per year (8 v.

2.5; p=0.01) and 38% reduction in OCS dose (p=0.01). Mean FEV1 and FVC increased marginally by 4% (p=0.3) and 10% (p=0.02), respectively.

Conclusion. In this preliminary report of 21 BT procedures, although post-treatment exacerbations occurred, BT was overall well tolerated in patients with severe asthma not previously included in published clinical trials. All of the patients had improved ACT scores, significantly lower exacerbation rates, and significant reduction in OCS usage post BT.

ABSTRACTS Rapid point-of-care urine-based testing for tuberculosis and its impact on mortality: A multi-centre, randomised controlled trial J Peter, 1,8,9 D Chanda, 1,2,11 L Zijenah, 3 P Clowes, 4,5 C Mangu, 4 M Lesosky,1 G Calligaro,1 A Rachow,4,5,6 M Hoelscher,4,5,6 G Kadzirange,3 T Bandason,3 A Chansa,2 A Luisha,2 P Mwaba,2 G Theron,1* K Dheda1, 7,8,9 for the TB-NEAT team 1 Lung Infection and Immunity Unit, Division of Pulmonology and University of Cape Town Lung Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa 2 University Teaching Hospital, Lusaka, Zambia 3 University of Zimbabwe College of Health Sciences, Harare, Zimbabwe 4 National Institute of Medical Research, Mbeya Medical Research Centre, Mbeya, Tanzania 5 Division of Infectious Diseases and Tropical Medicine, Medical Centre of the University of Munich (LMU), Munich, Germany 6 German Centre for Infection Research (DZIF), Munich, Germany 7 Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa 8 University of Cape Town Lung Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa 9 Division of Clinical Immunology and Allergology, Department of Medicine, University of Cape Town, Cape Town, South Africa 10 Biomedical Research and Training Institute, Harare, Zimbabwe 11 Institute for Medical Research and Training (IMReT), Lusaka, Zambia *grant.theron@uct.ac.za Background. HIV-associated tuberculosis (TB) in hospitalised patients has high mortality but is difficult to diagnose. Frequent extra-pulmonary presentation, inability to obtain sputum, and the paucibaciliary nature of samples obtained often negate the usefulness of newer polymerase chain reaction-based diagnostic tests. We evaluated the impact of lateral flow-based point-of-care (POC) urine lipoarabinomannan (LAM) testing on the mortality of TB patients.

Method. In this pragmatic, randomised, parallel-group, multicentre trial, we randomly allocated 2 659 adult HIV-infected patients admitted to hospitals with possible TB in South Africa, Zimbabwe, Zambia and Tanzania. Eligible patients received urine LAM strip testing plus available routine diagnostics (smear microscopy, XpertMTB/RIF and culture) or routine diagnostics alone. The primary endpoint was all-cause mortality at 8 weeks.

Results. Urine LAM testing resulted in more patients starting TB treatment (52% v. 47%, p=0.024), a decrease in the median (inter­ quartile range (IQR)) days to treatment initiation (0 (0 - 2) v. 1 (0 3), p<0.001) and decreased empiric treatment (47% v. 71%, p<0.001).

There was a 16% (95% confidence interval (CI) 3 - 27%) relative risk reduction in all-cause mortality in the LAM group at 8 weeks (22.4% v. 26.7%; hazards ratio 0.82 (95% CI 0.70 - 0.96); p=0.016). Patients who received LAM testing had a similar length of hospitalisation (4 (2- 7) v. 4 (2 - 7) days, p=0.244) and in 8-week TB-related morbidity (median (IQR) change in TB score: 5 (3 - 6) v. 5 (3 - 6), p=0.637; and Karnofsky performance status: 30 (10 - 40) v. 30 (10 - 40), p=0.811).

Conclusion. In hospitalised patients from TB endemic settings with advanced HIV-related immunosuppression and possible TB, bedside urine LAM testing resulted in decreased all-cause mortality.

Funding. The European Developing Clinical Trials Partnership (EDCTP), ClinicalTrials.gov number: NCT01770730, https:// clinicaltrials.gov/ct2/show/NCT01770730) and the South African MRC and NRF.

The role of IL4 and Th2-like cytokines in pulmonary tuberculosis A Pooran,1* M Davids,1 A Nel,2 A Shoko,2 J Blackburn,2 K Dheda1 1 Lung Infection and Immunity Unit, Department of Medicine, University of Cape Town, Cape Town, South Africa 2 Department of Medical Biochemistry, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa *anil.pooran@gmail.com Background. What constitutes an effective protective immune response to tuberculosis (TB) remains a matter of contention. Despite high IFN-γ levels, the Th1 cytokine associated with protection at the site of disease, many individuals still progress to active disease.

Whether a Th2-like mechanism plays a role in TB pathogenesis remains unclear.

Objective. To determine (1) the levels of Th1/Th2/Th2-like cytokines in the lungs and blood of TB patients and latent TB infection (LTBI) controls and (2) if Th2 cytokines (IL-4) are detrimental to Mycobacterium tuberculosis-specific host immunity in vitro.

Methods. Blood and/or bronchoalveolar lavage (BAL) were obtained from individuals with pulmonary TB n=25) and LTBI (n=25). Th1 and Th2 cytokine mRNA and protein levels were determined by qPCR and Luminex, respectively. Human recombinant IL-4 (hrIL-4) was cloned and functionally assessed using 3H thymidine proliferation and B-cell flow cytometric assays. The effect of IL-4 on mycobacterial survival was determined using a mycobacterial containment assay. Mycobacterial survival was assessed by counting M. tuberculosis colony-forming units. The IL-4-modulating effects on cytokine and cell sub-type expression in this model were evaluated by flow cytometry.

Results. TB patients expressed higher IL-4 mRNA levels (p=0.02) and a lower IFN-γ/IL-4 ratio (p=0.01) compared with LTBI controls in whole blood. Similarly, IL-9 protein levels were increased in TB v. LTBI BAL (p=0.02). Functionally active hrIL-4 increased T-cell proliferation and B-cell CD23 expression. Addition of hrIL-4 reduced mycobacterial containment in an IL-4 dose-dependent manner. Flow cytometric analysis revealed that addition of IL-4 increased Treg levels (CD4+CD25+FoxP3+; p<0.01), decreased CD4+IFNg and TNFα expression (p<0.01) and increased macrophage DC-SIGN expression (p=0.02). These effects were abrogated with the addition of anti-IL-4 antibody.

Conclusion. TB patients exhibit a highly compartmentalised Th2skewed cytokine profile. In vitro, IL-4 subverts mycobacterial containment in human macrophages, possibly through a Treg effect and a subsequent down-regulated Th1 response. These finding have implications in TB vaccine design.

Integrated positron emission tomography/computed tomography for evaluation of mediastinal lymph node staging of non-small cell lung cancer in a tuberculosis-endemic area: A 5-year prospective observational study JA Shaw,1* EM Irusen,1 F von Groote-Bidlingmaier,1 JM Warwick,2 B Jeremic,3 R du Toit,1 CFN Koegelenberg1 1 Division of Pulmonology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Academic Hospital, Cape Town, South Africa 2 Division of Nuclear Medicine, Department of Medical Imaging and Clinical Oncology, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Academic Hospital, Cape Town, South Africa

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ABSTRACTS Division of Radiation Oncology, Department of Medical Imaging and Clinical Oncology, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Academic Hospital, Cape Town, South Africa *jane.shaw@stonedragon.co.za

3

Background. Integrated positron emission tomography/computed tomography (PET-CT) is a well-validated modality for assessing mediastinal lymph node metastasis in non-small cell lung cancer (NSCLC), which determines management and predicts survival.

Tuberculosis (TB) is known to lead to false positive PET-CT findings.

Objective. To assess the diagnostic accuracy of PET-CT in identifying mediastinal lymph node involvement of NSCLC in a high TB-endemic area.

Methods. Patients who underwent both PET-CT and lymph node tissue sampling for the investigation of suspected NSCLC were prospectively included in this observational study. Results were analysed per patient and per lymph node stage. A post hoc analysis was performed to test the validity of a maximum standardised uptake value (SUVmax) cut-off for lymph node positivity.

Results. PET-CT had a sensitivity of 92.6%, specificity of 48.6%, positive predictive value of 56.8% and negative predictive value (NPV) of 90.0% in the per-patient analysis. Diagnostic accuracy was 67.2%.

Similar values were obtained in the per-lymph node stage analysis. TB was responsible for 21.1% of false positive results. A SUVmax cut-off of 4.5 yielded an improvement in diagnostic accuracy from 64.0% to 84.7% compared with a cut-off of 2.5, but at the cost of decreasing the NPV from 90.6% to 83.5%.

Conclusion. In a high TB-endemic area, PET-CT remains a valuable method for excluding mediastinal lymph node involvement in NSCLC. Patients with a negative PET-CT may proceed to definitive management without further invasive procedures. However, PETCT-positive lymph nodes require pathological confirmation and the possibility of TB must be considered.

Long-term follow-up of symptomatic and silent myocardial scar in sarcoidosis patients â&#x20AC;&#x201C; LGE predicts adverse events JP Smedema,1* RJ van Geuns,2 J Ector,3 H Heidbuchel,3 G Ainslie,4 HJGM Crijns5 1 Netcare Blaauwberg Hospital, Heart and Stroke Unit, Cape Town, South Africa 2 Erasmus University Medical Centre, Department of Cardiology and Radiology, Rotterdam, The Netherlands 3 University Hospital Leuven, Department of Cardiology, Leuven, Belgium 4 Groote Schuur Hospital, Respiratory Unit, Cape Town, South Africa 5 Maastricht University Medical Centre, Department of Cardiology, Maastricht, The Netherlands *jansmedema@hotmail.com Background. Sarcoidosis is an inflammatory disorder that results in granulomatous myocardial infiltration and focal scar in at least 13 32% of patients. Cardiac involvement is the main determinant of poor outcomes. Recently, the presence of late gadolinium enhancement (LGE) in non-ischaemic cardiomyopathies was reported to be predictive of adverse outcome.

Objectives. To determine whether the presence and extent of LGE with contrast-enhanced cardiac magnetic resonance (CECMR) can predict adverse events during long-term follow-up of sarcoidosis patients.

42 SARJ VOL. 21 NO. 2 2015

Methods. We followed 84 consecutive biopsy-proven pulmonary sarcoidosis patients, who had baseline CECMR performed, which included inversion-recovery gradient-echo sequences. During a median follow-up of 59 (range 47 - 67) months, patients underwent regular outpatient follow-up and had additional diagnostic tests performed at the discretion of the managing physicians. Endpoints consisted of admission for congestive heart failure, cardiac death, appropriate implantable cardioverter defibrillator therapy, or pacemaker implantation for high-degree atrioventricular block.

Results. LGE was demonstrated in 27 patients (32%), and amounted to a median of 20% (range 8 - 45) of left ventricular (LV) mass. Patients with LGE had more cardiac symptoms (p<0.001), systolic LV impairment and dilation (both p<0.001). During follow-up, 8/10 endpoints occurred in the patient group with LGE. Presentation with ventricular tachycardia, LV or biventricular LGE yielded Cox hazard ratios of 8.452 (95% confidence interval (CI) 2.428 - 29.427), 9.22 (95% CI 1.96 - 43.45), and 12.093 (95% CI 3.427 - 42.677) for an endpoint, respectively. In a multivariate model, the predictive value of sustained ventricular tachyarrhythmias (VT) and LGE, particularly biventricular LGE, for adverse events was superior to symptoms of congestive heart failure, systolic LV dysfunction or ventricular dilation. Kaplan Meier event-free survival curves were most significant for LGE (log rank with p=0.001).

Conclusion. LGE in sarcoidosis patients strongly correlates with cardiac symptoms, ventricular volumes, function and ventricular arrhythmias at presentation. Sustained VT and LGE are the strongest, independent predictors of adverse events. Patients with small, asymptomatic myocardial scar have a favourable long-term outcome.

Interpreting Xpert MTB/RIF results in TB patients: Distinguishing true from false positive results G Theron,1* R Venter,1 G Calligaro,1 R Meldau,1 D Chanda,2 J Peter,2 K Dheda1, 4 1 Lung Infection and Immunity Unit, Division of Pulmonology and UCT Lung Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa 2 Institute for Medical Research and Training, Lusaka, Zambia 3 Department of Medicine, University of Cape Town, Cape Town, South Africa 4 Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa *grant.theron@uct.ac.za We prospectively evaluated the relationship between Xpert-MTB/RIF and culture status in 2Â 889 suspects (837 culture-positive). In retreatment cases, the false positive Xpert-MTB/RIF rate was 5% and was associated with a chest radiograph incompatible with active tuberculosis (TB), a high cycle threshold and shorter proximity to previous TB treatment.

However, these factors were unable to confidently distinguish false positive from true positive results. These data inform clinical practice.

Determinants of short-term serial changes in fractional exhaled nitric oxide (FeNO) in spice mill workers A van der Walt,1 R Baatjies,1,2 T Singh,3,4 MF Jeebhay1* 1 Centre for Environmental and Occupational Health Research, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa 2 Department of Environmental and Occupational Studies, Faculty of Applied Sciences, Cape Peninsula University of Technology, Cape Town, South Africa

ABSTRACTS ational Institute for Occupational Health (NIOH), National Health N Laboratory Services, Johannesburg, South Africa 4 Department of Clinical Microbiology and Infectious Diseases, School of Pathology, University of the Witwatersrand, Johannesburg, South Africa *mohamed.jeebhay@uct.ac.za 3

Background. This study evaluated the determinants of high fractional exhaled nitric oxide (FeNO) (>50 ppb) and serial changes in FeNO over a 24-hour period in spice mill workers at risk of work-related allergic respiratory disease and asthma.

Methods. A cross-sectional study of 150 workers used ECRHS questionnaires, Phadiatop, serum specific IgE (garlic, chilli pepper, wheat) (Phadia, ImmunoCAP), spirometry and FeNO. A hand-held portable nitric oxide sampling device (NIOX MINO, Aerocrine AB, Sweden) measured FeNO before and after the 8-hour shift and after 24 hours from baseline.

Results. The mean age of workers was 33 years, 71% were male, 46% current smokers and 45% atopic. Among workers with garlic sensitisation, 13% were monosensitised and 6% were cosensitised to chilli pepper. Baseline preshift FeNO geometric mean (GM=14.9 ppb) was similar to mean change across shift (GM=15.4 ppb) and across 24-hour period (GM=15.8 ppb). In multivariate linear models, chilli pepper (β=0.47) and smoking (β=–0.47) were more strongly associated with FeNO, than atopy (β=0.41) and recent green vegetable consumption (β=0.28). Cosensitisation to chilli pepper was more strongly correlated with FeNO (r=0.32) and FeNO >50 ppb (odds ratio=17.04, p=0.005) than garlic monosensitisation. FeNO increase (>12%) across 24 hours demonstrated a strong association with elevated exposures to general spice dust particulate (odds ratio = 3.77, confidence interval 1.01 - 14.24).

Conclusion. Cosensitisation to chilli pepper in garlic-sensitised individuals is a major determinant of high FeNO (>50 ppb) in spice mill workers. Elevated inhalant spice dust particulate is associated with a delayed elevation of FeNO across the 24-hour period.

Electronic cigarettes, nicotine and tobacco smoke impair human immune responses to tuberculosis infection R Chang,1 M Davids,1 K Dheda,1,2 E Bateman,1 R van Zyl-Smit1* 1 Division of Pulmonology and University of Cape Town Lung Institute, Department of Medicine, University of Cape Town, South Africa 2 Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa *richard.vanzyl-smit@uct.ac.za Background. Electronic cigarettes (E-cigs) are gaining widespread popularity as a ‘safer alternative’ to tobacco. There is a paucity of data evaluating their short-term impact on respiratory infections.

Tobacco cigarettes impair human immune responses to mycobacterial infection and double the risk of developing tuberculosis.

Methods. Human monocytes from healthy individuals were infected with BCG or virulent mycobacterium: H37Rv (laboratory strain) or CDC1551(clinical strain). Monocytes were cocultured with: E-cig liquid, E-cig vapour, cigarette smoke extract (CSE) or nicotine. E-cig liquid and vapour were obtained from nicotine containing Twisp brand E-cigs. E-cig vapour was collected through RPMI during a 3- and 5-minute ‘vape’ in a similar method to previously published data. Cell viability and tumour necrosis factor (TNF) responses were measured at 218 hours by ELISA.

Results. Toxicity experiments demonstrated a dose-dependent toxicity of CSE, nicotine and E-cig liquid. Using low concentrations of exposures, we demonstrated a consistent reduction in TNF-α production for all exposures: Nicotine 100 ug/mL reduced TNF-α production by mean (SD) 43% (24) (p<0.001), 10% CSE by 67%(23) (p<0.001), 1% E-cig liquid by 78% (23) (p<0.001) and 50% E-cig vapour 3 min 38% (26) (p<0.001) and 5 min 78% (20) (p<0.001).

Conclusion. Although E-cigs are reported to be less harmful than tobacco, these data demonstrate impairment to a key mycobacterial immune response. Caution should be advocated, especially in tuberculosis-endemic regions, about using E-cigs until the full effect on mycobacterial immunity is clarified.

Cytokine levels associated with acute lower respiratory infections and HIV in young South African children S Abbott,* A Annamalay, G Zhang, SK Khoo, J Bizzintino, BJ Hales, J Hibbert, C Sikazwe, GR Chidlow, DW Smith, J Gern, A Currie, J Goldblatt, PN Le Souëf, RJ Green Division of Paediatric Pulmonology, Steve Biko Academic Hospital, University of Pretoria, Pretoria, South Africa *info@healthylungs.co.za Background. It is widely accepted that altered host immune responses, such as cytokine responses, play a key role in the pathogenesis of acute lower respiratory infections (ALRI). The existing literature on cytokine responses in ALRI is largely limited to a select few cytokines, mainly in adults. The aim of this study was to determine that there are cytokine responses unique to ALRI, HIV-infection and specific viral infections.

Methods. Children admitted to the Steve Biko Academic Hospital or Tshwane District Hospital and diagnosed with ALRI (pneumonia or bronchiolitis) were enrolled as cases. Nasopharyngeal aspirates for viral identification and plasma concentrations of 19 cytokines (G-CSF, GM-CSF, IFN-α, IFN-γ, IL-1β, IL-1RA, IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17 and TNF-α), 7 chemokines (Eotaxin, IP-10, MCP-1, MIG, MIP-1α, MIP-1β and RANTES) and 4 growth factors (EGF, FGF-basic, HGF and VEGF) were measured using the Human Cytokine 30-Plex Panel.

Results. A total of 106 ALRI cases and 54 controls were enrolled.

Seventeen children were HIV-infected. At least one respiratory virus was identified in 72 (84.7%) ALRI cases and 33 (70.2%) nonrespiratory controls. Mean cytokine concentrations for G-CSF, IFN-γ, IL-5 and MCP-1 were significantly higher in ALRI cases than in non-respiratory controls. Mean cytokine concentrations for IFN-α, IFN-γ, IL-4, IL-5, IL-13, TNF-α and MIP-1α were significantly lower in HIV-infected cases than in HIV-uninfected cases while IP-10 and MIG were significantly higher in HIV-infected cases than in HIV-uninfected cases. For human rhinovirus (HRV), mean cytokine concentrations for IL-5, TNF-α, IL-2, G-CSF, IL-7 and IL-17 were significantly higher in HRV-positive ALRI cases than in HRV-negative ALRI cases.

Conclusion. Of the 7 cytokines that were significantly lower in HIVinfected children, TNF-α is a known pro-inflammatory cytokine while IL-4 and IL-13 are known anti-inflammatory cytokines. Hence, these findings challenge the pro-inflammatory v. anti-inflammatory hypothesis put forth by Tudela and colleagues. HRV has been shown to generate strong Th2 and Th17 cytokine responses, which are known to regulate airway inflammation during respiratory viral infections.

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ABSTRACTS Factors that predict for positive GeneXpert MTB/RIF on bronchoalveolar lavage samples in children with suspected tuberculosis P Goussard,1* E Walters,2 C Bosch,2 AC Hesseling,2 RP Gie1,2 1 Paediatric Pulmonology, Department of Paediatrics and Child Health, Tygerberg Academic Hospital, Cape Town, South Africa 2 Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Stellenbosch University, Cape Town, South Africa *pgouss@sun.ac.za Background. Pilot studies have reported that GeneXpert MTB/RIF (Xpert) testing of bronchoalveolar lavage (BAL) samples improves diagnostic yield and the rapid detection of drug resistance in children undergoing bronchoscopy for complicated intrathoracic tuberculosis (TB).

Objective. To determine factors predictive of positive Xpert on BAL in children with suspected TB. Methods. Children <13 years undergoing fibre-optic bronchoscopy for suspected complicated intrathoracic TB between October 2012 to January 2014 were studied. Clinical data, including duration of TB treatment prior to bronchoscopy and chest X-ray changes, were collected. During bronchoscopy under general anaesthesia, airways were evaluated for compression, severity of obstruction and lymph gland ulceration into the airways. BAL samples obtained were analysed by fluorescent smear microscopy, automated liquid culture and Xpert.

Results. Forty children (3 HIV-positive, median age 18 months) were studied. The median duration of TB treatment prior to bronchoscopy was 8 (range 0 - 85) days. TB was confirmed in 31 (78%) by either BAL Xpert or culture. Xpert and culture were positive in 29 (73%) (8 were also Ziehl Neelsen stain-positive) and 23 (58%) cases respectively. In 21 (53%) both Xpert and culture were positive. Incremental value of Xpert was 8 cases (35%); only 2 cases were culture positive but Xpert negative. The median time to culture positivity was 14 (range 7 - 44 days). Positive Xpert was associated with lymph nodes ulcerating into the airway (p=0.03) but not with airway obstruction (p=0.5), chest X-ray changes (p=0.6) or duration of treatment ≤14 days (p=0.8).

Conclusion. In children with complicated pulmonary TB, Xpert on BAL increases the diagnostic yield by >35% and is associated with lymph-node ulceration into the airways.

Lung function in the first year of life in African infants: Effect of early-life pneumonia D Gray,1* L Turkovic,2 L Willemse,1 A Alberts,1 A Vanker,1 D Stein,3 PD Sly,4 GL Hall,2 HJ Zar1 1 Department of Paediatrics and Child Health, Red Cross War Memorial Children’s Hospital and MRC Unit on Child and Adolescent Health, University of Cape Town, Cape Town, South Africa 2 Telethon Kids Institute, University of Western Australia, Perth, Australia 3 Department of Psychiatry, University of Cape Town, Cape Town, South Africa 4 Children’s Lung, Environment and Asthma Research, Child Health Research Centre, Unviversity of Queensland, Brisbane, Australia 4 Queensland Children’s Medical Research Institute, Brisbane, Australia *diane.gray@uct.ac.za Background. Early-life lung function is associated with increased risk of respiratory disease in later life. Identifying factors that impact lung

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function in the first years of life is important if we are to develop strategies to strengthen paediatric respiratory health.

Objective. To investigate the impact of early-life exposures, including pneumonia, on lung function during the first year.

Methods. Infants enrolled in the Drakenstein Child Health birth cohort had lung function tested at 6 weeks and 1 year of age. Testing, done during quiet natural sleep, included tidal breathing (TBFVL), exhaled nitric oxide (eNO) and SF6 multiple breath washout (MBW) measures. Early-life information was collected by questionnaire at scheduled study visits. Study staff examined infants at the time and 4 - 6 weeks after a pneumonia episode.

Results. Of 389 eligible infants, 304 were tested both at 6 weeks and 1 year; 279 (70%) TBFVL, 266 (68%) eNO and 262 (66%) MBW tests were successful with good-quality results. Lung function tracked strongly from 6 weeks through to 1 year. Pneumonia during the first year of life was independently associated with decreased tidal volume (average –3.6 mL lower, 95% confidence interval (CI) –6.6 - –0.5, p=0.02) and increased respiratory rate at 1 year (6% higher, 95% CI 1.01 - 1.10, p=0.01). This effect was stronger if the infant required hospitalisation. Repeat episodes of pneumonia further increased respiratory rate (5% higher, 95% CI 1.02 - 1.08; p=0.001), decreased tidal volume (–2.5 mL lower, 95% CI –4.7 - –0.3; p=0.02) and were associated with increased lung clearance index (0.2 turnovers, 95% CI 0.00 - 0.26, p=0.05).

Conclusion. Early-life pneumonia lowers lung function achieved at 1 year, an effect independent of baseline lung function. These data provide evidence that preventing early-life pneumonia is an important factor in optimising early lung growth and function and strengthening respiratory health in later childhood.

The effect of body position on regional distribution of ventilation and respiratory muscle activity in infants and children – An EIT study A Lupton-Smith,1* AC Argent,1 PC Rimensberger,2 BM Morrow1 1 Red Cross War Memorial Children’s Hospital, Cape Town, South Africa 2 University Hospital of Geneva, Geneva, Switzerland *aluptonsmith@gmail.com Background. The adult pattern of ventilation distribution towards the dependent lung is well established, recent studies contradict the common belief that ventilation preferentially distributes to the nondependent lung in paediatrics. Recent studies in older infants and children are limited. In addition, there are no studies reporting whether body position affects respiratory muscle activity.

Objective. To determine the effect of body positions on regional distribution of ventilation and respiratory muscle activity in healthy children.

Methods. Thoracic electrical impedance tomography (EIT) measure­ ments and surface electromyography (sEMG) readings were taken in the supine position and right- and left-side lying in spontaneously breathing, healthy children. Functional EIT images were produced offline and total regional relative tidal impedance (ΔZ) in the left and right lung (proportional to tidal volume) was calculated for each patient in each position. Muscle activity of the diaphragm and intercostal muscles was determined offline.

Results. Data on the 24 participants (13 male) aged 2 - 5 years are presented. The previous paediatric pattern was consistently demonstrated in two (9%) of participants. Forty-eight per cent of

ABSTRACTS participants demonstrated a varied pattern of ventilation distribution in side-lying positions. Diaphragm (p=0.068) and intercostal (p=0.36) activity was not significantly affected by body position.

Conclusion. Distribution of ventilation in children is not as straightforward as previously described. This study provides normative data with which future studies in respiratory disease and mechanical ventilation can be compared.

Adenoviral-associated pneumonia at Red Cross War Memorial Children’s Hospital in 2011: Presentation, clinical course and outcomes Z Mukuddem-Sablay,* Zampoli M Department of Paediatrics and Child Health, Red Cross War Memorial Children’s Hospital, University of Cape Town, Cape Town, South Africa *zakira.sablay@gmail.com Background. Pneumonia is an important cause of morbidity and mortality in children. Viruses have emerged as important aetiological agents in childhood pneumonia. The aim of this study was to document the clinical presentation, severity and outcome of adenoviral-associated pneumonia (AVP) at Red Cross War Memorial Children’s Hospital in children below 5 years of age and identify risk factors associated with poor outcome.

Methods. A retrospective study of laboratory-confirmed AVP cases was conducted between 1 January and 31 December 2011. The medical records of adenovirus polymerase chain reaction positive respiratory tract samples identified through the National Health Laboratory Service (NHLS) database were retrieved. Demographic, clinical and outcomes data of children with AVP were extracted and analysed. Outcome measures were death and development of chronic lung disease (CLD).

Results. 1910 respiratory samples were submitted to the NHLS from which 206/1910 (11%) AVP cases were identified. The median age was 12 months (inter-quartile range 6 - 24), 70 (34%) children were malnourished and 14 (7%) HIV-infected. Fever was the most common presenting symptom, occurring in 159 (77%) of cases. Seventy-six (37%) required intensive care unit (ICU) admission. There was a high prevalence of comorbid conditions, with 98 (47%) having at least one; cardiac disease was the most common, with 48 (23%), of which 35 (17%) had congenital heart disease. Twenty-nine (14%) developed CLD that was associated with hypoxia at presentation (26/29, 90%, p=0.01) and admission to ICU (18/29, 62%, p<0.01). Eighteen (9%) children died. Mortality was associated with hypoxia at presentation (17/18, 94%, p=0.02), admission to ICU (14/18, 78%, p<0.01), blood stream infection (4/18, 22%, p=0.01) and underlying cardiac disease (8/18, 44%, p=0.02).

Conclusion. Adenoviral-associated pneumonia is an important cause of pneumonia and CLD in children less than 5 years of age.

Underlying cardiac disease, hypoxia, blood stream infection and ICU admission were associated with poor outcome.

Tobacco smoke exposure and birth outcomes in a South African birth cohort A Vanker,1* W Barnett,1 K Brittain,1 RP Gie,2 HJ Zar1 1 Department of Paediatrics and Child Health, Red Cross War Memorial Children’s Hospital, and Medical Research Council Unit on Child and Adolescent Health, University of Cape Town, Cape Town, South Africa 2 Department of Paediatrics and Child Health, Tygerberg Children’s Hospital, Stellenbosch University, Cape Town, South Africa *aneesa.vanker@uct.ac.za

Background. Tobacco smoke exposure is a major risk factor for childhood respiratory disease, with exposures often beginning in early life. However, this has not been well described in an African setting.

Objective. To investigate the prevelance of antenatal and early-life tobacco smoke exposure and the association with birth outcomes in a South African birth cohort.

Methods. Tobacco smoking and exposure was assessed in pregnant women enrolled to the Drakenstein Child Health Study using selfreport questionnaires administered at the first antenatal care visit. This was validated using urine cotinine measures in the mother and infant antenatally, at birth and at 6 - 10 weeks of life; classifying exposure as active smoker, passive exposure or non-smoker. Multivariate regression models were used to explore the association between tobacco smoke exposure and birth outcomes.

Results. Of the 789 pregnant women included, 250 (32%) were active smokers on cotinine testing. The sensitivity of self-reported smoking compared with urine cotinine tests was 72%. At birth, 135/241 (56%) of neonates had passive exposure and 44(18%) were classified as active smokers on cotinine results. At 6 - 10 weeks, 154/291 (53%) of infants had cotinine tests indicative of passive exposure. Household smoking was reported in two-thirds of homes and was significantly associated with positive infant urine cotinine tests. There were marked differences in smoke exposure between black and mixed race participants. Antenatal maternal smoking was associated with decreased infant birth weight-for-age z-score (0.3, 95% confidence interval 0.1 - 0.5).

Conclusion. The high prevalence of antenatal and early-life smoke exposure may impact on birth and subsequent child health outcomes.

Smoking cessation and public health interventions are urgently needed to reduce maternal and household smoking in poor African communities.

Funding. Gates Foundation (OPP1017641), Discovery Foundation, South African Thoracic Society, AstraZeneca Respiratory Fellowship, CIDRI Clinical Fellowship, Medical Research Council, National Research Foundation.

The indications and role of paediatric bronchoscopy in a developing country with high incidence of pulmonary tuberculosis and HIV I Webster,* P Goussard, RP Gie Paediatric Pulmonology, Department of Paediatrics and Child Health, Tygerberg Academic Hospital, Cape Town, South Africa *docw2005@yahoo.com Background. Bronchoscopy is an important method of investigation and tool in the management of childhood respiratory pathology. A number of comprehensive studies have been carried out in FirstWorld and developed countries. There are limited studies carried out in developing countries such as South Africa.

Objectives. To describe our clinical experience in paediatric bronchoscopy over a period of 3 years 6 months, describing the indications, study population, clinical findings and complications.

Methods. A retrospective analysis of participants’ medical records, indications and outcomes of children who underwent a bronchoscopy.

Participants included in this study were traced from the bronchoscopy registry of the Paediatric Pulmonology Department at Tygerberg Academic Hospital, Cape Town, South Afrca.

Results. From January 2010 to June 2013, a total of 509 bronchoscopies were performed. There were 294 boys (57.8%) and 215 girls (42.2%). The mean age was 18 months. The youngest child was 1 day of age and the

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ABSTRACTS oldest was 14.6 years old. Twelve children (2.3%) were under 1 month of age and the largest group (43.0%) being 13 - 36 months of age. The HIV status was positive for 26 patients (5.1%). The procedure has precise indications: the most common are severe lower airway obstruction by nodal compression of the lower airways due to tuberculosis infection (93.3%), the aetiology of complicated pneumonia (14.1%), subglottic stenosis (4.4%) and removal of foreign bodies (6.9%).

Conclusion. Bronchoscopy is a safe and useful procedure and the results are very similar to those published from developed countries.

Except for tuberculosis nodal compression, the indications did not differ from those publish in the developed world. The yield is high as in this study with 72% having confirmed abnormalities. The value of interventional bronchoscopy is increasing, with nearly 25% of bronchoscopies done in this study for intervention purposes. It also highlights the importance that congenital vascular anomalies and interstitial lung disease need to be considered in the developing world.

Aetiology and incidence of empyema in South African children M Zampoli,1* A Kappos,1 N Wolter,2 A von Gottberg,2 C Verwey,1 R Mamathuba,1 JH Zar1 1 Division of Paediatric Pulmonology, Red Cross War Memorial Children’s Hospital, Cape Town, South Africa; and Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa 2 Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases of the National Health Laboratory Service and Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa *m.zampoli@uct.ac.za

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Background. South Africa introduced the 7-valent pneumococcal conjugate vaccine (PCV7) in 2009 and PCV13 in 2011. The aetiology and incidence of childhood empyema in an 8-year period overlapping the introduction of PCV were investigated.

Methods. Children less than 12 years of age admitted with empyema at a tertiary paediatric hospital in Cape Town, South Africa, from December 2006 to December 2011 (cohort A) and January 2012 to December 2014 (cohort B) were investigated. Pathogens were identified by culture of pleural fluid and blood. In addition, polymerase chain reaction (PCR) targeting bacterial pathogens and Streptococcus pneumoniae serotypes was conducted on pleural fluid in a subset of patients enrolled 2009 - 2011.

Results. Cohort A: 142 children were prospectively enrolled, with a median age of 17 months (inter-quartile range 8 - 43). Most (92%) children were unimmunised with PCV. S. pneumoniae and Staphylococcus aureus were the most common culture-identified pathogens (each 25/142; 18%); PCR of pleural fluid increased yield of S. pneumoniae detection by 31% (26/54 (48%) v. 9/54 (17%), p<0.001). Serotypes were identified for 24/26 (92%) patients with S. pneumoniae, of which 22/24 (92%) were included in PCV13. Cohort B: 22 patients were retrospectively identified. No pathogen was found in 12/22 (54.5%) patients and S. pneumoniae in one patient (4.5%).

Empyema incidence declined by 50% in cohort B compared with cohort A (4.2 v. 10.4 cases/1 000 pneumonia admissions; risk ratio 0.5; 95% confidence interval 0.3 - 0.7).

Conclusion. S. pneumoniae is the most common cause of childhood empyema in South Africa. PCV has been highly effective at reducing empyema incidence in South African children.

PRODUCT NEWS

SARJ VOL. 21 NO. 2 2015

47

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

48 SARJ VOL. 21 NO. 2 2015

FOXAIR

everyone and it’s yours to give

Air is for

Why wait to

prescribe?

S4 FOXAIR® 50/250 and 50/500 ACCUHALER® - 42/21.5.4/0582; 0583. Each blister contains a mixture of salmeterol xinafoate equivalent to 50 µg of salmeterol and microfine fluticasone propionate (250 µg or 500 µg). Applicant: GlaxoSmithKline South Africa (Pty) Ltd. (Co. Reg. No. 1948/030135/07). 39 Hawkins Avenue, Epping Industria 1, Cape Town, 7460. For full prescribing information plese refer to the package insert approved by the Medicines Regulatory Authority. All adverse events should be reported by calling the Aspen Medical Hotline number or directly to GlaxoSmithKline on +27117456000. FO/0713/933 A16772 08/13

INSTRUCTIONS TO AUTHORS

Author guidelines

The South African Respiratory Journal (SARJ) is the official journal of the South African Thoracic Society (SATS). The journal accepts submissions relating to both clinical and basic research in the respiratory field as well as state-of-the-art reviews on any topic related to the scope of the journal. It is important that authors comply with the format specified in these guidelines as failure to do so will result in delayed publication.

Submission of papers

The SARJ only accepts online submission of papers. Papers should be submitted through the SATS website, where there is a link for the SARJ. Authors may then submit their papers after registration with the Editorial Manager. The relevant links are provided on the SATS website (www.pulmonology.co.za).

As part of the submission process it will be necessary to provide a cover letter which should be used to explain why your manuscript should be published in the journal, to elaborate on any issues and to declare any potential competing interests. You will also be asked to provide the contact details (including email addresses) of potential peer reviewers for your manuscript. These should be experts in their field who will be able to provide an objective assessment of the manuscript. Any suggested peer reviewers should not have published with any of the authors of the manuscript within the past 5 years, should not be current collaborators and should not be members of the same research institution. Suggested reviewers will be considered alongside potential reviewers recommended by the Editor-in-Chief and/or Editorial Board members.

Types of manuscripts that will be accepted

Original articles should not exceed 3 500 words, although this may be reviewed on a case-by-case basis. References should preferably be limited to no more than 40. See document layout below for further details.

Brief reports: This should have an abstract of a maximum of 150 words, the total word content of the paper (excluding abstract and references) should be 1 500 words, with a maximum of 15 references.

The abstract should be structured in subheadings as outlined below.

This should contain a maximum of one table and one figure, i.e. a maximum of two inserts (or two figures/tables).

Case reports: A 50-word unstructured abstract is required.

Introduction, Methods/Results sections followed by a Discussion section. It should not exceed 800 words and should contain only one illustration or table and a maximum of five references. The key learning points should be provided in a table with bullet points – maximum 100 words.

Research letter: This should contain a 50-word unstructured abstract and may be divided into an Introduction, Methods/Results and a very brief Discussion section. The research letter should not exceed 800 words and a maximum of seven references. One insert (table or figure) is allowed.

Editorials may be solicited by the Editor, though contributors are invited to submit editorials or opinion pieces for consideration by the journal. These should normally not exceed 1 500 words.

Reviews: Contributors are encouraged to write to the Editor about

50 SARJ VOL. 21 NO. 2 2015

possible papers to be considered for review, and where appropriate a review outline will be submitted to experts in the field for consideration before a full review is commissioned. It is expected that an author or authors have substantial experience and track record in the field that the review is about. Reviews should be a maximum of 3 500 words unless an alternative word limit has been arranged with the Editorin-Chief. Contributors are encouraged to include tables and figures in their reviews to keep to the maximum word count. Contributors are encouraged to submit pulmonary puzzles, which should not exceed a maximum of 800 words.

The journal welcomes comments and opinions about the published work, even if they are controversial and differ from the views of the author or the journal.

Authorship Manuscripts must be submitted by one of the authors of the manuscript and should not be submitted by anyone on their behalf.

The submitting author takes responsibility for the article during submission and peer review. All named authors must consent to publication and confirmation of this consent should be noted in the cover letter.

Ethical approval SARJ publishes work subscribing to the highest ethical standards.

Any work involving human or animal subjects must be approved by the relevant institutional ethics committee. A statement to the effect that the work has been approved by the relevant ethical committee must be provided in the methods section of the paper.

Authors should provide evidence of Research Ethics Committee approval of the research where relevant. Authors must accept ethical responsibility for the work submitted to the journal and must agree to address ethical queries raised by the reviewers or the editor, should these arise.

Protection of patients’ rights to privacy Identifying information should not be published in written descriptions, photographs and pedigrees unless the information is essential for scientific purposes and the patient (or parent or guardian) gives informed written consent for publication.

Manuscript preparation

Manuscripts must be provided in UK English. There is a limit to the length of articles submitted and authors are encouraged to be concise.

There is no restriction on the number of figures or tables that can be included with each article online. However, authors should keep these to a minimum as appropriate.

It is important to note that the SARJ will not comprehensively edit submitted manuscripts for style or language and reviewers may advise rejection of a manuscript if it is compromised by grammatical errors. Qualification, affiliation and contact details of ALL authors must be provided in the manuscript and in the online submission process.

Abbreviations should be spelled out when first used and thereafter used consistently. Scientific measurements must be expressed in SI units except: blood pressure (mmHg) and haemoglobin (g/dL). Litres is denoted with an uppercase ‘L’ and ‘mL’ for millilitres.

INSTRUCTIONS TO AUTHORS

General formatting

The following file formats are acceptable for the main manuscript document: Microsoft Word, Rich text format (RTF) or Portable document format (PDF).

• Text should be single-spaced.

• Type in 12-point Times New Roman font.

• Text should not contain unnecessary formatting (type the text unjustified, without hyphenating words at line breaks and do not format the text in multiple columns).

• Use hard returns only to end headings and paragraphs, not to rearrange lines.

• Capitalise only the first word and proper nouns in the title.

• All pages should be numbered.

• Do not use lowercase letter ‘L’ (el) for ‘1’ (one) or ‘O’ for ‘0’.

• Be consistent with punctuation and only insert a single space between words and after punctuation.

• There should be no space between numbers and <, > and %.

Illustrations and tables

Acceptable file types (authors must be wary of image compression): EPS, PDF, TIFF, PNG and JPEG. Illustrations and graphs prepared in Microsoft PowerPoint or Excel are not acceptable.

It is the responsibility of the author/s to provide consent to republication obtained from the copyright holder for all tables or illustrations previously published elsewhere. Tables should be provided as ‘supplementary files’ and must be numbered in Arabic numerals (1, 2, 3...) and referred to in the text (e.g. ‘Table 1’).

Figures must be numbered in Arabic numerals and referred to in the text, e.g. ‘(Fig. 1)’. Figure legends should be listed at the end of the article. All illustrations/figures/graphs must be of high resolution/ quality: 300 dpi or more is preferable (a minimum of 250 dpi is required and images must not be resized to increase resolution. Unformatted and uncompressed images must not be embedded in the manuscript and must be attached as ‘supplementary files’ upon submission.

Document layout

Manuscripts submitted should include the following: • Title page • Abstract • Keywords • Introduction • Methods • Results • Discussion and Conclusions • List of abbreviations used • Conflict of interest • Authors’ contributions • Acknowledgements • References Title page The title page should provide the title of the article, list the full names, institutional addresses and email addresses for all authors and indicate the corresponding author. The title should include the study design and abbreviations should be avoided.

Abstract Please provide a structured abstract. This should not exceed 250 words and should be broken down into the following recommended headings: Objectives, Methods, Results and Conclusion. Please make sure that the conclusions in the abstract are backed up by the data presented in the abstract results section. Abbreviations should be avoided as far as possible and no references should be cited in the abstract.

Keywords Please provide 3 - 10 keywords representing the main content of the article.

Introduction This should be concise, reflect the underlying hypothesis or idea being tested, and in general should not exceed a maximum of 500 words.

Methods Authors should endeavour to keep this to a maximum of 600 words, depending on the type of article. It should include the design of the study, the setting, the type of participants/materials involved, a description of interventions and comparisons and the type of analysis used. Information about ethical approval and consent should also be detailed here.

Results The results and discussion may be combined into a single section or presented separately and may also be broken into subsections with short headings.

Discussion and conclusions This should state clearly the main conclusions of the research and give a clear explanation of their importance and relevance.

Conflict of interest All authors are required to declare all sources of support for the research and any association with a product or subject that may constitute conflict of interest. If the author does not have any conflict of interest to declare this should be stated (e.g. ‘The author(s) declare that they have no competing interests.’). Forms are available on the website and should be submitted via the Editorial Manager.

Authors’ contributions Authorship should be based on substantial contribution to: 1. conception, design, analysis and interpretation of data; 2. drafting or critical revision for important intellectual content; and 3. approval of the version to be published.

These conditions must all be met. All contributors who do not meet the criteria for authorship should be listed in an acknowledgements section.

Acknowledgements This section should be used to acknowledge anyone who contributed significantly towards the article but who does not meet the criteria for authorship. Permission to acknowledge from all those mentioned in the acknowledgements section should be obtained by the author/s.

SARJ VOL. 21 NO. 2 2015

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INSTRUCTIONS TO AUTHORS References Authors must verify references from the original sources. Only complete, correctly formatted reference lists will be accepted.

Reference lists must be generated manually and not with the use of reference manager software.

References should be inserted in the text as superscript numbers and all references (including URLs) should be listed consecutively at the end of the article in numerical order of appearance in the Vancouver style (not alphabetical order). Excessive referencing should be avoided. Unpublished data and personal communications should not be included in the reference list but may be included in the text and cited as unpublished data/personal communication provided the author has permission to do this.

For journal references, names and initials of all the authors should be included (if there are more than six authors, the first three names should be given followed by et al.), followed by the title of article, name

of journal (journal abbreviations follow Index Medicus/MEDLINE), year, volume, and first and last pages.

For example: 1. Tockman MS, Anthonisen MD, Wright EC. Airways obstructions and the risk of lung cancer. Ann Intern Med 1987;106:512-518.

For book references, the author(s) should be followed by the chapter title (if applicable), editor(s) (if applicable), book title, place of publication, publisher, year and page numbers.

For example: Colby VT, Carrington CB. Infiltrative lung disease.

In: Thurlbeck WM, editor. Pathology of the Lung. New York: Theime Medical Publishers, 1988.

Copyright notice

The SARJ reserves copyright of the material published. The SARJ does not hold itself responsible for statements made by the authors.

The South African Respiratory Journal PO Box 13725 Mowbray 7705 Any correspondence to the Editor should be sent to the same address or via email to: sarj@iafrica.com The website of The South African Thoracic Society can be found at www.pulmonology.co.za

52 SARJ VOL. 21 NO. 2 2015

Whatever the reason, whatever the season

®

S4 AVAMYS Nasal Spray (Suspension). Reg. No.: 41/21.5.1/0968. Each 50 µl spray contains 27,5 µg of fluticasone furoate. Preservative: Benzalkonium chloride 0,015 % m/m. PHARMACOLOGICAL CLASSIFICATION: A.21.5.1 Corticosteroids and analogues.

GlaxoSmithKline South Africa (Pty) Ltd, (Co. Reg. No.: 1948/030135/07), 39 Hawkins Avenue, Epping Industria 1, Cape Town, 7460. Tel: +27 11 745 6000.

Fax +27 11 745 7000. Marketed by Aspen Pharmacare, Building 12, Healthcare Park, Woodlands Drive, Woodmead, 2191. All adverse events should be reported by calling the Aspen Medical Hotline number or directly to GlaxoSmithKline on +27 11 745 6000. For full prescribing information refer to the package insert approved by the medicines regulatory authority. A19340 05/15 ZAF/FF/0001/15a

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