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THE SOUTH AFRICAN

RESPIRATORY JOURNAL VOLUME 21 | NUMBER 3 | SEPTEMBER 2015

CONTENTS EDITORIAL 54

How should laboratories measure mycobacterial load? G Theron

ORIGINAL RESEARCH

A comparison of cost for mycobacterial load determination in research laboratories A Pooran, R Meldau, K Dheda, R N van Zyl-Smit

REVIEWS 59 70

State of the art in the treatment of lung cancer B Jeremic Hypersensitivity pneumonitis H Khalfey

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EDITORIAL

How should laboratories measure mycobacterial load? The ability to accurately and reproducibly quantify mycobacteria in a cost-effective manner is essential for both basic and applied tuberculosis (TB) research. In immunology, laboratory-based experiments are frequently performed to compare the effect of regulatory T-cells on mycobacterial kill under different conditions.[1] In diag nostics research, bacilli in different specimens are often quantified to calculate the required limit of detection[2] or investigate whether in paucibacillary specimens (e.g. pleural fluid) a biomarker-based approach may be optimal.[3,4] In clinical research, the quantity of mycobacteria (bacillary load) is a predictor of disease severity,[5] clinical outcome,[6,7] and risk of transmission.[8-10] A variety of tools exist for quantifying bacillary load in specimens. However, there are few data about their comparative utility and cost. In this edition of the South African Respiratory Journal, Pooran and colleagues compare the cost of five methods (BACTEC MGIT 960 culture, manual colony counts on solid agar, radio-labelled uracil incorporation assays, luciferase reporter construct bioluminescence, and the Xpert MTB/RIF real-time PCR test) for the determination of mycobacterial load in a research setting. This is a follow-on study to their previous publication,[11] which evaluated the turnaround time, limit of detection, dynamic range, reproducibility and discriminative ability of each technique. Collectively, these two studies show that automated liquid culture is the most sensitive technique (~10 CFU/mL), with the highest reproducibility and discriminatory power, for a cost of approximately R240 per sample. The luminescence assay, which requires inserting a gene into Mycobacterium tuberculosis cells and quantifying the intensity of the expressed luminescent protein, was rapid and the least costly technique (R155), as it required the least hands-on time, but had a higher limit of detection than liquid culture (~100 v. 10 CFU/mL). Conversely, the radio-labelled uracil assay and the automated Xpert MTB/RIF assay were the most expensive methods (R349 and R388, respectively), with costs chiefly driven by expensive capital equipment and, in the case of Xpert MTB/RIF, the additional cost of the cartridge. Although both tests were able to provide results in hours, the uracil assay had a limit of detection 10-fold higher than Xpert MTB/ RIF (~1 000 v. 100 CFU/mL) and Xpert MTB/RIF was more userfriendly. Although sensitive (<10 CFU/mL), manual colony counts were expensive (R385), and the results are only available after several weeks. The authors conclude that the choice of test depends on the application. Where highly sensitive, accurate results are required and time is not an issue, liquid culture is suitable. If results are required within hours, a small offset in sensitivity is acceptable, and the extra expense affordable, then more rapid, user-friendly assays such as

Xpert MTB/RIF are ideal. Finally, it is important to note that in clinical settings where TB diagnostics are routinely performed, information about mycobacterial load is generated from both liquid culture (timeto-positivity) and Xpert MTB/RIF (cycle threshold values). References

1. Semple PL, Binder AB, Davids M, Maredza A, van Zyl-Smit RN, Dheda K. Regulatory T cells attenuate mycobacterial stasis in alveolar and blood-derived macrophages from patients with tuberculosis. Am J Respir Crit Care Med 2013;187(11):1249-1258. [http://dx.doi.org/10.1164/rccm.201210-1934OC] 2. Theron G, Peter J, Calligaro G, et al. Determinants of PCR performance (Xpert MTB/ RIF), including bacterial load and inhibition, for TB diagnosis using specimens from different body compartments. Sci Rep 2014;4:5658. [http://dx.doi.org/10.1038/ srep05658] 3. Meldau R, Peter J, Theron G, et al. Comparison of same day diagnostic tools including Gene Xpert and unstimulated IFN-gamma for the evaluation of pleural tuberculosis: A prospective cohort study. BMC Pulm Med 2014;14:58. [http://dx.doi. org/10.1186/1471-2466-14-58] 4. Pandie S, Peter J, Kerbelker Z, et al. Diagnostic accuracy of quantitative PCR (Xpert MTB/RIF) for tuberculous pericarditis compared to adenosine deaminase and unstimulated interferon-γ in a high burden setting: A prospective study. BMC Med 2014;12:101. [http://dx.doi.org/10.1186/1741-7015-12-101] 5. Theron G, Zijenah L, Chanda D, et al. Feasibility, accuracy, and clinical effect of pointof-care Xpert MTB/RIF testing for tuberculosis in primary-care settings in Africa: A multicentre, randomised, controlled trial. Lancet 2013;383(9915):424-435. [http:// dx.doi.org/10.1016/S0140-6736(13)62073-5] 6. Bark CM, Thiel BA, Johnson JL. Pretreatment time to detection of Mycobacterium tuberculosis in liquid culture is associated with relapse after therapy. J Clin Microbiol 2012;50(2):538. [http://dx.doi.org/10.1128/JCM.06193-11] 7. Pheiffer C, Carroll N, Beyers N, et al. Time to detection of Mycobacterium tuberculosis in BACTEC systems as a viable alternative to colony counting. Int J Tuberc Lung Dis 2008;12(7):792-798. 8. Fennelly KP, Martyny JW, Fulton KE, Orme IM, Cave DM, Heifets LB. Coughgenerated aerosols of Mycobacterium tuberculosis: A new method to study infectiousness. Am J Respir Crit Care Med 2004;169(5):604-609. [http://dx.doi. org/10.1164/rccm.200308-1101OC] 9. Theron G, Pinto L, Peter J, et al. The use of an automated quantitative polymerase chain reaction (Xpert MTB/RIF) to predict the sputum smear status of tuberculosis patients. Clin Infect Dis 2012;54(3):384-348. [http://dx.doi.org/10.1093/cid/cir824] 10. Hanrahan CF, Theron G, Bassett J, Dheda K, Scott L, Stevens W, et al. Xpert MTB/RIF as a measure of sputum bacillary burden: Variation by HIV status and immunosuppression. Am J Respir Crit Care Med 2014;189(11):1426-1434. [http:// dx.doi.org/10.1164/rccm.201312-2140OC] 11. van Zyl-Smit RN, Binder A, Meldau R, et al. Comparison of quantitative techniques including Xpert MTB/RIF to evaluate mycobacterial burden. PloS One 2011;6(12):e28815. [http://dx.doi.org/10.1371/journal.pone.0028815]

Grant Theron DST/NRF of Excellence for Biomedical Tuberculosis Research Medical Research Council Centre for Molecular and Cellular Biology, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa Lung Infection and Immunity Unit, Department of Medicine, University of Cape Town, South Africa S Afr Resp J 2015;21(3):54. DOI:10.7196/10.2015.v21i3.54

54 SARJ VOL. 21 NO. 3 2015

ORIGINAL RESEARCH

A comparison of cost for mycobacterial load determination in research laboratories A Pooran,1 MSc, BSc (Hon); R Meldau,1 BSc Med (Hon); K Dheda,1,2 MB BCh, FCP (SA), FCCP, PhD, FRCP; R N van Zyl-Smit,1,3 MB ChB, MRCP (UK), MMed, FCP (SA), Cert Pulm (SA), PhD Lung Infection and Immunity Unit, 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, South Africa 3 Lung Clinical Research Unit, University of Cape Town Lung Institute, South Africa 1

Corresponding author: R van Zyl-Smit (richard.vanzyl-smit@uct.ac.za)

Background. Mycobacterial load determination is a critical quantitative measure needed in many clinical and research laboratory studies and selection depends on several factors including sensitivity, dynamic range and turnaround time. However, there are no data about cost, which is an important selection determinant. We therefore performed a cost analysis of five quantitative mycobacterial load assays. Methods. The costs of five mycobacterial quantification techniques were compared in a hypothetical single experiment (control and intervention) performed in triplicate. Assays evaluated were: mycobacterial colony-forming units (MCFU) using 7H10-Middlebrook solid media, automated liquid culture (BACTEC-MGIT-960), [3H]-uracil incorporation assays, luciferase-reporter construct bioluminescence, and quantitative polymerase chain reaction (PCR) (Xpert-MTB/RIF) using serial dilutions of Mycobacterium tuberculosis. Costs associated with consumables, equipment and personnel were included and expressed in 2015 South African rands and US dollars. Results. The least costly technique was the luminescence reporter construct assay (R85.68/$6.72) whereas the most expensive technique was the Xpert MTB/RIF PCR (R388.02/$30.42). The high cost of the PCR assay was mainly attributable to the costly Xpert MTB/RIF cartridges. Although the MCFU by solid culture had a similar cost compared with uracil incorporation and Xpert MTB/RIF, the purchase price of the equipment required to perform the latter assays was ~2 - 10 times higher. Conclusion. Taking into consideration the turnaround time, capital costs, discriminatory ability, the running costs (excluding staff) of the luminescence reporter assay are the lowest. Where time to result is critical, more expensive techniques such as the Xpert MTB/RIF should be used. In a clinical setting where automated culture and Xpert are routinely performed, quantitative load from time to positivity and cycle thresholds will provide extra data without additional cost. S Afr Resp J 2015;21(3):55-58. DOI:10.7196/10.2015.v21i3.55

Basic science research is a critical part of the fight against tuberculosis. Better understanding of the targeted immunological response, effects of drugs on mycobacterial survival and immune responses to novel vaccines is needed. A key part of this research is defining the mycobacterial load in any given assay sample.[1-3] We have previously published a comparative study investigating the utility and performance characteristics of five quantitative load determination techniques, namely: mycobacterial colony-forming units (MCFU) using 7H10-Middlebrook solid media, automated liquid culture (BACTEC-MGIT-960), [3H]-uracil incorporation assays, luciferasereporter construct bioluminescence, and quantitative polymerase chain reaction (PCR) (Xpert-MTB/RIF) using serial dilutions of Mycobacterium bovis and M. tuberculosis H37RV.[4] In this study no single assay had ‘perfect’ performance characteristics: the automated BACTEC-MGIT-960 (MGIT) had the lowest detection threshold but a long turnaround time, the Xpert MTB/RIF assay had a rapid turnaround time but a higher (poorer) detection threshold. The bioluminescence and tritiated uracil showed poor discriminative ability at low CFU (<1 × 103 CFU) and were not suitable for clinical studies.[4] Drawing conclusions from this study, as

no single assay had the ‘ideal’ balance of performance characteristics (specifically turnaround time and detection threshold), the choice of assay will largely depend on the study design. Other factors influencing choice of assay include: experimental question, dynamic range in which the measurements are conducted, the need for rapid determination of the result, desired reproducibility and available financial and laboratory resources.[4] Additionally, if viability of the organisms needs to be determined, then assays such as the Xpert MTB/RIF will not be suitable as it is unable to differentiate between live or dead intact organisms. A formal costing analysis, missing from this original publication, would provide additional information to researchers upon which to base the choice of assay in the given context that they work. We therefore conducted a comparative costing exercise of each of the assays employed using a single hypothetical experiment.

Methods

Laboratory assays The methods for the mycobacterial load assays have been published in detail.[4] Briefly, both BCG and H37RV luciferase reporter constructs (pSMT1 luciferase) were used for all assays. [5] Triplicate serial

SARJ VOL. 21 NO. 3 2015

ORIGINAL RESEARCH

Test

Item

Xpert MTB/RIF

Estimated handson time to perform experiment (hours)

Local supplier Cost per purchase experiment price (ZAR) (ZAR/USD)

R278.90

R223 214

R57.28

Lab technician

0.33

R51.84

Total cost per experiment

R388.02/$30.42

Consumables

R110.43

R849 297

R118.93

R155.52

Equipment Gene Xpert IV machine Personnel

Equipment assay

Titrated uracil

PCR using

Consumables

Beta counter & harvester Personnel Lab technician Total cost per experiment Consumables

R384.88/$30.17 -

R51.42

Incubator

R22 000

R5.37

Autoclave

R56 940

R13.91

Microscope

R10 500

R2.56

Total equipment

R89 440

R21.84

R311.04

solid media

Culture on 7H10

Equipment

Personnel Lab technician Total cost per experiment

Luminescence assay using reported construct

Costing The cost of each technique was assessed by taking into account consumables used, personnel requirements and equipment. The purchase price of specific equipment and consumables for each experiment were obtained from local suppliers. Equipment costs per assay were determined using standard health economic methods. Costs were annualised using a 3% discount rate and the expected life years ranged from 10 to 20 years depending on the piece of equipment. It was assumed that 5% of the equipment usage would be allocated for each technique per year. Personnel costs were calculated by multiplying the per hour salary of a lab technician (University of Cape Town 2015 salary scales) by the estimated hands-on time to perform each assay. Costs were reported in 2015 South African rands and converted to United States dollars using an exchange rate of ZAR12.76 = USD1. Biosafety equipment costs were not included as they were assumed to be the same for all experiments. A hypothetical single experiment, containing two conditions (control and intervention) performed in triplicate, was used to standardise cost between assays. Where appropriate, ‘pooling of wells’ was allowed to reduce costs, e.g. a single Xpert MTB/RIF cartridge for each condition (total of 2) as opposed to a single cartridge for each replicate (total of 6). Each of three 1 mL volumes were combined into one well and then mixed thoroughly, 1 mL of the combined wells was then used for the mycobacterial load calculation. Details of the costing sheet for each experiment are contained in Table 1. Additionally, the potential benefits and limitations of each technique were assessed on a simple qualitative scale. Factors included were: number of technical steps, time required to perform the assay, degree of automation and use of specialised reagents such as radioactive isotopes or luminescence substrates, which require specialised handling.

Table 1. Single experiment costing overview of mycobacterial load quantification assays

Consumables

Liquid culture using MGIT 960 system

dilutions were prepared in sterile phosphate buffer solution from the frozen stock for each strain in aliquots ranging from 1 to 1 × 106 CFU/mL. The five predetermined assays were each performed using one of the prepared aliquots. In addition, all dilutions were inoculated onto solid media to confirm the number of CFUs at each dilution.

Consumables

R384.30/$30.13 -

R90.68

R102 575

R25.05

0.25

R38.88

Equipment Luminometer Personnel Lab technician Total cost per experiment

R154.61/$12.12 -

R92.84

R496 811

R121.34

0.17

R25.92

Equipment MGIT 960 machine Personnel Lab technician Total cost per experiment

56 SARJ VOL. 21 NO. 3 2015

R240.10/$18.82

ORIGINAL RESEARCH

Results

The component costs of for each assay are shown in Table 1. The cost per experiment for each technique ranged from R85.68/$6.72 for the Luminescence assay to R388.02/$30.42 for Xpert MTB/RIF PCR. The high cost of this assay was mainly attributable to the costly Xpert MTB/RIF cartridges. Although the CFU by solid culture had a similar cost compared with uracil incorporation and Xpert MTB/RIF, the purchase price of the equipment required to perform these assays was 2 - 10 times higher. CFU CFU counting had the lowest cost associated with reagents and did not require any specialised equipment other than that expected to routinely be in a Biosaftey Level 3 (BSL3) laboratory (autoclave, incubator and microscope). However, due to the time-consuming nature of the assay, personnel costs were the highest of any technique. The cost per experiment was estimated to be R384.30/$30.13. Automated liquid culture As a semi-automated assay, the complexity and labour intensiveness was less than that of the CFU counting. The major cost for the experiment was the culture bottles, and estimated experimental costs were R240.10/$18.82. However, start-up costs for this assay were also very high as the BACTEC MGIT system costs approximately R496 811 (developing country price). Luminescence The bioluminescence assay was the cheapest assay by far, costing R154.61/$12.12 per experiment. However, despite providing an automated readout, the assay still required a significant degree of expertise in preparing the standard curve as well as using a specific reporter strain. The assay also requires the purchase of a luminometer, which has to be permanently situated in the biosafety laboratory. Uracil The uracil assay had the second highest cost of all the techniques (R384.88/$30.17) and was attributable to the high personnel and equipment costs. This is particularly the case for the equipment, as both the cell harvester and liquid scintillation counter required for the assay costs ~R850 000. Additional requirements include expertise in handling radioactive material, appropriate storage and handling facilities and a complete lack of bacterial contamination in the sample. Xpert MTB/RIF For the costing analysis, the three replicates were pooled so that only two cartridges were used. Even using this strategy, the Xpert MTB/RIF PCR was still the most expensive, costing a total of R388.02/$30.42 per experiment, mainly because of the high cost of the Xpert MTB/ RIF cartridges. Start-up costs were also somewhat expensive as the Gene Xpert IV system costs ~R220 000($17 500) (developing country pricing). Further details of the comparative costing are described in Table 2 for each assay as part of the overall performance incorporating the

turnaround time and detection threshold from previously published data.[4]

Discussion

The range of costs in this hypothetical experiment varied from ~R150 to R400 ($10 - $30). The main driver of the costs varied for each technique. Consumables and equipment drove the costs in the more automated systems, while personnel drove the costs of the more complex and labour-intensive techniques. Adding cost to the originally published performance characteristics did not cause any one technique to rise to the top as the ‘best’, as time, staffing and quantity of experiments required all add to costs, depending on the research setting. Although the luminescence assay was the ‘cheapest option’, this assay has poor discriminative ability and requires the use of a reporter strain. Therefore the suitability of this assay is limited, particularly in clinical settings. In contrast, solid culture was more expensive at R240 ($18) per assay but had much better discriminative ability and no need for specialised equipment. Thus it is likely to remain a mainstay in many research institutions where equipment costs can be prohibitive. However, the long turnaround time, labour intensiveness, staffing time required and learning curve, may make automated options much more attractive where staffing costs are high and time is of the essence.[4] The choice of assay, even with cost taken into account, will ultimately be a comprehensive feasibility evaluation. For example, evaluating tuberculosis sputum in a community could be done using a mobile Xpert machine, whereas a MGIT-BACTEC system would not be a feasible option for this research question. Additionally, the cost of the major equipment may be highly relevant in areas setting up new research laboratories or in remote areas where transport is problematic. In other centres where the equipment already exists, only running costs would need to be taken into account. If many assays are to be performed, the capital costs may be offset by the platform’s high throughput capacity. Where time is critical and staffing costs higher than what was used in this study, Xpert MTB/RIF may be a more cost-effective assay – although sacrificing detection of low organism loads. Xpert also detects M. tuberculosis DNA from both live and dead bacilli and is not suitable for research studies that require this distinction. Where precise determination of load and accurate discrimination between two mycobacterial loads are important, the CFU, although time-consuming and labour-intensive, may still be the best option. Provided a given research laboratory has the basic equipment to conduct any given bio-hazardous experiment with virulent mycobacterium, additional costs and infrastructure would not generally be required except for the uracil assay. The infrastructure required to handle and dispose of radioactive chemicals and radioactive biohazardous waste is not available in many areas, making this unlikely to be cost-effective, especially in resource-poor settings. Biological samples are also not suitable for uracil or bioluminescence as the risk of contamination and spurious results are high and bioluminescence requires specific laboratory strains. In clinical studies where a degree of quantitation of mycobacterial load is required, leveraging off existing infrastructure may provide a

SARJ VOL. 21 NO. 3 2015

ORIGINAL RESEARCH Table 2. Comparison of performance characteristics and cost Characteristic

PCR using Xpert MTB/RIF

Titrated uracil assay

Liquid culture using MGIT 960 system

Luminescence assay using reporter construct

Culture on 7H10 solid media

Result turnaround time*

Very quick

Quick

Slow

Very quick

Slow

Estimated hands-on time to perform assay (minutes)

120

Detection threshold†

Good

Poor

Excellent

Good

Excellent

Start-up costs (equipment purchase price)

Medium-high R223 214/$17 500

Very high R849 297/$66 585

High R496 811/$38 950

Medium R102 575/$8 042

Low R89 440/ $7 012

Cost per experiment‡

High R388/$30

High R385/$30

Medium 240/$19

Low R155/$12

High R384/$30

Pros

Limited skills required prior to automated processing

Semi-automated

Limited training; Automated system once bottles inoculated

Very simple to perform; least costly

High discriminatory value; equipment required available in most BSL3 facilities

Cons

Expensive consumables (Xpert cartridges); cannot distinguish between live and dead M. tuberculosis

Requires radioactive isotope handling skills and regulatory approval

High start-up costs; equipment usually available only in specialised tuberculosis labs

Extensive optimisation required for each strain and batch; requires organism with a fluorescent reporter construct

Very labour intensive; learning curve for counting colonies

*Slow (days to weeks), quick 24 hours, very quick 2 hours. †

Excellent <10, good ≤100, poor ≥1 000, adapted from Van Zyl-Smit.[4]

‡

osts were calculated for the specific consumables, equipment and personnel for a hypothetical experiment containing two conditions performed in triplicate. For MGIT and PCR triplicate wells were C pooled into a single bottle/cartridge to reduce costs.

cost-effective option. To reduce the cost of preparing separate samples for CFU in the research laboratory, time to positivity using liquid culture (if performed) or cycle thresholds from the Xpert MTB/RIF assay could be used. These data are routinely determined as part of the automated assay but not always reported in a routine lab report as clinicians generally only need a yes/no answer upon which to make treatment decisions in acute hospital settings. Access to this information may provide (at no extra cost) a degree of quantification that will enhance the quantitative evaluation of clinical tuberculosis studies. Salaries and equipment usage allocations may vary between research settings and will likely influence the cost of each assay. Even in reference laboratories it is suggested that there is balance of choice between performance characteristics, costs and need for rapid results. [5,6] However, this is not expected to change the cost ranking of the techniques. Furthermore, batch processing of samples may also reduce consumable costs in some of these assays. In conclusion, the choice of assay remains largely dependent on the research context, study question and the relative trade-offs of cost (both capital layout and on-going staffing) v. turnaround time. Access

to quantitative information from liquid culture and Xpert MTB/RIF assays may enhance clinical studies at no extra cost where these assays are being routinely performed. References 1. Dheda K, van Zyl-Smit R, Badri M, Pai M. T-cell interferon-gamma release assays for the rapid immunodiagnosis of tuberculosis: Clinical utility in high-burden vs. low-burden settings. Curr Opin Pulm Med 2009;15(3):188-200. [http://dx.doi. org/10.1097/MCP.0b013e32832a0adc] 2. Pai M, Kalantri S, Dheda K. New tools and emerging technologies for the diagnosis of tuberculosis: Part II. Active tuberculosis and drug resistance. Expert Rev Mol Diagn 2006;6(3):423-432. [http://dx.doi.org/10.1586/14737159.6.3.423] 3. Urdea M, Penny LA, Olmsted SS, et al. Requirements for high impact diagnostics in the developing world. Nature 2006;444 Suppl 1:73-79. [http://dx.doi.org/10.1038/ nature05448] 4. van Zyl-Smit RN, Binder A, Meldau R, Mishra H, Semple PL, Theron G, et al. Comparison of quantitative techniques including Xpert MTB/RIF to evaluate mycobacterial burden. PLoS One 2011;6(12):e28815. [http://dx.doi.org/ 10.1371/ journal.pone.0028815] 5. Kampmann B, Gaora PO, Snewin VA, Gares MP, Young DB, Levin M. Evaluation of human antimycobacterial immunity using recombinant reporter mycobacteria. J Infect Dis 2000;182(3):895-901. [http://dx.doi.org/10.1086/315766] 6. Shah M, Chihota V, Coetzee G, Churchyard G, Dorman SE. Comparison of laboratory costs of rapid molecular tests and conventional diagnostics for detection of tuberculosis and drug-resistant tuberculosis in South Africa. BMC Infect Dis 2013;13:352. [http://dx.doi.org/ 10.1186/1471-2334-13-352]

58 SARJ VOL. 21 NO. 3 2015

REVIEW

State of the art in the treatment of lung cancer B Jeremic, MD, PhD Institute of Lung diseases, Sremska Kamenica and BioIRC Centre for Biomedical Research, Kragujevac, Serbia Corresponding author: B Jeremic (nebareje@gmail.com)

Lung cancer is the major cancer killer in both sexes. Despite many biological and technological achievements, it is still mostly an incurable disease, and survival figures are only modestly improved in the past few decades. Optimisation of treatment is usually sought through clinical studies, but unfortunately only a few per cent of lung cancer patients enter these world-wide. So it is in spite of the fact that we have witnessed the introduction of robotic surgery, computerised radiation therapy and targeted agents in daily clinical practice. More emphasis on clinical research is therefore needed to improve our capability to successfully treat lung cancer. S Afr Resp J 2015;21(3):59-69. DOI:10.7196/10.2015.v21i3.59

Lung cancer continues to be the major cancer killer in both sexes worldwide. [1] Approximately 1.6 million new cases of lung cancer are diagnosed each year. [2] While the number of cases continues to increase in many places around the world, the overall cure rate from lung cancer is modest (~17%) because the majority of patients present with advanced stage at diagnosis. This is irrespective of refinements in histological aspects, better diagnostic and staging tools, including the massive influence of positron emission tomography (PET) scanning, as well as a sharp shift towards molecular oncology already found its way to clinic. The most recent update of staging by the International Association for the Study of Lung Cancer (IASLC) provided an important addition to the issue. [3] Treatment paradigm may therefore be seen as even more important nowadays since it ultimately should match pre-treatment advances. Although there are many treatment modalities employed in lung cancer, each of which continues to develop, we will concentrate on the three most effective ones, namely surgery, radiation therapy (RT) and drug therapy, the latter one including both chemotherapy (CHT) and targeted therapy. This review article aims to summarise current aspects of treatment in lung cancer with the three treatment modalities being used in both non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC).

NSCLC

Early stage In patients with early-stage (I-II) NSCLC, surgical resection remains the cornerstone of treatment. Unfortunately, <30% of patients have their disease resectable at the time of presentation, and 50% of these have significant comorbidities. While being technically operable, they are considered medically inoperable. Furthermore, ~70% of the patients with early-stage resected disease develop recurrence at distant sites. Therefore, additional systemic therapy is needed to eradicate micrometastatic disease. In this setting, platinum-based CHT has emerged as an effective adjuvant systemic therapy after resection. The International Adjuvant Lung Trial (IALT), with more than 1 700 patients with stages I-III NSCLC, demonstrated a significant but modest

improvement in 5-year survival rate of 4% when adding cisplatinbased doublets after surgery (v. observation).[4] Similarly, cisplatinvinorelbine v. observation was compared in patients with stages IB and II NSCLC in the National Cancer Institute of Canada (NCIC) trial. [5] An overall 15% improvement in 5-year survival in the adjuvant CHT group was observed. Finally, a meta-analysis of trials with adjuvant cisplatin-based CHT demonstrated a 5% improvement in overall survival (OS)[6] ultimately leading to a shift of treatment paradigm. However, it must be clearly stated that the role of adjuvant CHT has been limited to stage II and III resected NSCLC due to a preferential benefit observed in these subgroups. However, controversy remains including the data to support its use in those with tumours >4 cm in size.[6] For patients with stage IA disease, adjuvant CHT is not usually recommended.[7] Cisplatin-based CHT is the ‘standard of care’ in the adjuvant setting. However, a controversy exists on whether carboplatin can be substituted for cisplatin in the adjuvant setting. A trial of carboplatin/paclitaxel combination in patients with stage 1B disease failed to show a survival benefit, despite improvement in disease-free survival.[7] The optimal number of cycles of adjuvant CHT has also not been addressed in randomised studies. Currently, 3 - 4 cycles of cisplatin-based CHT are administered in routine practice settings. Approximately two-thirds of all resected patients are able to receive adjuvant CHT as others have comorbidities of varying degree and/or postoperative complications. Neo-adjuvant (induction) CHT has also been investigated to improve the delivery and compliance of CHT. A phase III study demonstrated an improvement in overall survival with neo-adjuvant CHT followed by surgery versus surgery alone.[8] However, the difference was not significant and the trial was closed early because adjuvant CHT became the new ‘standard of care’. Similar data have also been reported from another trial that evaluated pre-operative therapy.[9] Neo-adjuvant CHT prior to surgery versus surgery alone versus surgery followed by adjuvant CHT was compared in the Spanish Study. The delivery of CHT was found to be superior in the preoperative setting (90% v. 66%). [10] Neo-adjuvant CHT in this trial was associated with a non-significant trend towards longer disease-free survival compared with surgery alone. The power of

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REVIEW this study was limited and there was a high proportion of stage I patients who supposedly do not benefit from systemic therapy. Neo-adjuvant CHT is an efficacious and safe approach for patients with early-stage NSCLC but the ‘standard of care’ for patients with R0 resection is adjuvant CHT. In the adjuvant setting, epidermal growth factor receptor (EGFR) inhibitors have also been investigated for patients with resected early-stage NSCLC. Though gefitinib as adjuvant therapy failed to demonstrate a benefit in this group, this was not conclusive as the study was stopped early.[11] Erlotinib has been evaluated in a randomised trial (RADIANT) in the adjuvant setting. The trial has completed accrual and the results are eagerly awaited. While surgery remains the gold standard in operable early NSCLC, there are patients who either cannot tolerate lobectomy or are considered borderline cases. Beside more limited surgery (e.g. segmentectomy or wedge resection) occasionally used in such cases, [12-15] standard fraction, hyper- or hypo-fractionated thoracic radiation therapy (TRT) and even TRT-CHT was used with modest success in this largely unfavourable patient population.[16,17] Importantly, stereotactic body radiotherapy (SBRT) has been used with excellent local control and overall survival largely surpassing results achievable with conventional RT.[18,19] Recent comparisons, though not done in a prospective randomised fashion, indicated similar outcomes with surgery v. SBRT.[20,21] Although both limited surgery and SBRT produce excellent results given exclusively, requests for more formal comparison of two treatment approaches led to two prospective randomised trials that are currently underway. Locally advanced disease Approximately one-third of all patients with NSCLC present with a locally advanced, mostly stage III disease. It has been the major battleground for investigating various treatment options. Surgery (e.g. in very selected T4N0), TRT (altered fractionation regimens with curative intention in stage III or palliative hypofractionated regimens in mostly stage IIIB patients) and various CHT agents (again, mostly in stage IIIB) can all be used alone in this disease. However, this is not so frequent practice nowadays in the majority of patients who can tolerate a more intensive (combined) treatment approach owing to the best success rate obtained with a bimodality (TRT-CHT) approach. In the domain of RT alone, standard fraction and altered fractionation regimens (e.g. hyperfractionation, hypofractionation) have been used to improve local control, showing promising results such as continuous hyperfractionated accelerated radiation therapy (CHART).[22] This treatment design (three daily fractions separated with a 6-hour interval) was unfortunately extremely complicated for daily clinical practice, which has prevented it from widespread use. TRT and platinum-based CHT have been increasingly practised around the world in the last three decades. A number of possible combinations have arisen. Neo-adjuvant CHT followed by radical TRT,[23,24] ‘sandwich’ CHT and TRT[25] as well as concurrent TRTCHT[26-28] have all gained widespread use. The latter of the three approaches denotes the administration of both modalities at the same time, meaning that CHT is given during the course of radical

TRT. Its main aim is to address the issue of locoregional and distant disease at the same time, from the beginning of the treatment as intensively as possible. Several clinical trials directly compared the two approaches with somewhat conflicting results. Therefore, meta-analyses were undertaken to solve the issue of the timing of administration of RT and CHT in this setting. In the analysis of O’Rourke et al.[29] with 19 randomised studies TRT and concurrent CHT significantly reduced overall risk of death (hazard ratio (HR) 0.71, 1 607 participants) and overall progressionfree survival (PFS) at any site (HR 0.69, 1 145 participants). Liang et al.[30] performed a systematic review of 11 trials (2 043 patients; 1 019 concurrent, 1 024 neo-adjuvant) to confirm that TRT and concurrent CHT offered a statistically significant increase in median survival time (MST) (16.3 v. 13.9 months; pooled median ratio = 1.17), response rate (64.0% v. 56.3%; odds ratio = 1.38), and tumour-relapse control (odds ratio = 0.82). Finally, Auperin et al.[31] used updated individual patient data of six trials (1 205 patients, 92% of all randomly assigned patients) to document a significant benefit of TRT and concurrent CHT on overall survival (pooled HR, 0.84; p=0.004), with an absolute benefit of 5.7% (from 18.1% to 23.8%) at 3 years and 4.5% at 5 years. For progression-free survival, the pooled HR was 0.90 (p=0.07). TRT and concurrent CHT decreased locoregional progression (pooled HR, 0.77; p=0.01); its effect was not different from that of induction treatment on distant progression (pooled HR, 1.04; p=0.69). With these meta-analyses the story of superiority of TRT and concurrent CHT over the neo-adjuvant CHT followed by radical TRT seems to finally be over, while further studies should attempt to optimise concurrent approach. It should not be forgotten that there is continued discussion regarding the role of surgery for these patients. Four randomised studies noted no overall survival differences comparing operative v. non-operative approaches in patients with (mostly) stage IIIA lung cancer.[32-35] An unplanned subset analysis of the most contemporary of these trials, Intergroup 0139, [35] did suggest a difference on survival based on surgical approach. Mortality rates with pneumonectomy were excessively high, while lobectomy patients appeared to have improved outcomes. It remains nonetheless appropriate to conclude that the sum of the evidence to date supports the proposition that a non-surgical approach constitutes the ‘standard’ for stage III patients. Contrary to curative approaches discussed above, about twothirds of the NSCLC population is diagnosed with incurable disease and should be treated with a palliative intent. Most of these patients will have symptoms from an intrathoracic tumour at diagnosis or have the propensity to develop symptoms in the near future. In this setting, any intervention should have the goal of effective palliation avoiding unacceptable toxicity. Various TRT fractionation schemes are in use for palliative treatment, ranging from as low as single fraction of 8 - 10 Gy to as high as fractionated 50 - 60 Gy. Until the first study from the Medical Research Council (MRC) UK was published in 1991,[36] a typical course was 30 Gy in 10 fractions. Since then, several randomised phase III trials[37-44] comparing a strict hypofractionated schedule with a normo-fractionated regimen have been published, with >2 500 patients being treated. All trials have either a single (8 or 10 Gy) or two large fractions (17 Gy/2 or 16 Gy/2) as the short-

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REVIEW course experimental arm. The comparative fractionated schedules ranged from 20 to 50 Gy. The trials included patients up to World Health Organization performance status (WHO PS) 3 with a huge shift towards stage III patients. One trial (MRC II)[37] included only patients with WHO PS 2 - 4 comparing a single fraction v. 17 Gy/2 fractions. In two trials,[42,43] the effect on symptoms was in favour of the higher dose, otherwise the effect on diseaserelated symptoms was equal. In three trials, [38,40,43] the survival was in favour of the high-dose arm: 39 Gy/13 fractions, 30 Gy/10 fractions and 30 Gy/10 fractions, respectively. One trial[44] reported a survival benefit for the low-dose arm: 16 Gy/2 fractions v. 20 Gy/5 fractions. In another trial,[41] 17 Gy/2 fractions (n=143) was compared with two high-dose arms: 42 Gy/15 fractions (n=140) and 50 Gy/25 fractions (n=124), with no difference in median survival found. Five randomised phase III studies[45-49] have compared different normo- to high-dose regimens, including more than 1 000 patients. Nearly all had stage III localised disease with a reasonably good performance status (WHO PS 0 - 2). One study reported better palliation in the high-dose arm.[46] Four studies provided data on survival, being equal in three and better for the high-dose arms in one.[48] The latter study[48] is particularly interesting since one arm in this three-armed trial was a ‘wait and see’ arm; 40 Gy10 (split) v. 50 Gy/25 v. ‘wait and see’. The survival in this ‘wait and see’ arm was inferior compared with the two actively treated arms. While the effect on symptoms and palliative effect may be similar regardless of dose and fractionation, the trend of more rapid relief of symptoms in favour of hypofractionation is observed with no major difference in median survival. To investigate the issue of whether some patients with localised stage III disease may benefit from a protracted high-dose TRT, an MRC study [38] was undertaken focusing only on stage III disease with good performance status. It compared 17 Gy/2 fractions (arm 1) with 39 Gy/13 fractions (arm 2). The median survival increased from 7 to 9 months in arm 2 (p>0.05), with a 1- and 2-year survival of 31% and 9% v. 36% and 12% in the arm 1 and arm 2, respectively. Another study [41] compared a strict low-dose with high-dose schedules and found a trend in better survival in the high-dose arms. Further analysis of the same study (restricted to stage III patients)[50] disclosed a 3- and 5-year survival in the three arms (17 Gy/2, 42 Gy/15, 50 Gy/25) of 1%, 8% and 6%, v. 0%, 4% and 3%, respectively. General observations from all of these studies can be extrapolated to patients with stage IV, which can also safely be treated with a hypofractionated schedule. Acute toxicity with dysphagia is mild, temporary and manageable. Late toxicity is rare, sporadic and usually not severe. Although there was no strong evidence that higher dose gives a better outcome concerning symptom relief and survival, and that a hypofractionated regimen is an option for most patients, patients with stage III disease with a reasonable performance status and less weight loss could be treated with a protracted fractionated regimen 30 - 45 Gy. Stage IV patients can be treated safely with a hypofractionated regimen in almost all cases. Not to be forgotten, palliative TRT can unexpectedly generate some longterm survivors.[50,51] Approximately 1 - 3% of patients with localised disease have been found with 5-year survival after palliative high-

dose TRT. This can perhaps be explained by the unpredictably high radiosensitivity of some lung tumours. In the last two decades the effect of CHT in advanced NSCLC has been recognised.[52] Treatment with CHT should be restricted to patients with a reasonably good performance status (WHO PS ≤ 2). Most patients with advanced NSCLC will therefore be offered CHT as first-line treatment. However, CHT can generate toxicity and not all patients are considered fit. For these patients, primary palliative TRT is a good option. Furthermore, it can be offered to patients progressing during or after CHT with less toxicity. Palliative TRT aims to treat symptoms from intrathoracic tumours. In otherwise symptom-free patients, however, immediate treatment is likely to give unnecessary side-effects like dysphagia and may not prevent development of later symptoms.[53,54] A ‘wait and see’ procedure is therefore advocated until the patient becomes symptomatic. Advanced/metastatic disease Systemic therapy remains the mainstay for treatment of advancedstage NSCLC. Combination CHT with a platinum-based regimen (cisplatin or carboplatin) has emerged as standard therapy for patients with advanced-stage disease.[55] Improvements in overall survival and quality of life have been demonstrated with platinumbased regimens over best supportive care alone in randomised clinical trials. [56] In general, carboplatin-based regimens have a favourable tolerability over cisplatin-based regimens.[57,58] Despite the marginally higher response rate with cisplatin-based regimens, and considering the palliative intent of therapy, carboplatin-based regimens have found wide applicability in routine care. Recent improvements in anti-emetic therapy have made cisplatin-based regimens more tolerable. A number of randomised clinical trials have established the superiority of platinum-doublets over single-agent therapy.[59-61] The ‘third-generation’ cytotoxic agents (paclitaxel, docetaxel, gemcitabine, vinorelbine, irinotecan and pemetrexed) have all demonstrated efficacy when given in combination with a platinum compound in patients with advanced NSCLC. [57,59,62-65] The use of triplets has generally resulted in higher toxicity without clear evidence of improvement in efficacy and has therefore largely been abandoned.[66] With the currently available platinum-based twodrug regimens, the median survival and 1-year survival rate are 8 - 11 months and 30 - 40% in patients with a good PS.[67] Histology-based treatment of advanced NSCLC Choice of systemic therapy based on the histological subdivision of NSCLC is a new paradigm. It was shown that the cisplatin-pemetrexed combination was associated with increased efficacy in non-squamous NSCLC.[68] In patients with adenocarcinoma, the median survival with the cisplatin-pemetrexed regimen was 12.6 compared with 10.9 months with cisplatin-gemcitabine (p<0.05). Improved efficacy of pemetrexed in adenocarcinoma may in fact be due to low levels of expression of thymidylate synthase (TS), a known target for pemetrexed (68, 69) in adenocarcinoma compared with squamous or small-cell carcinoma.[70] In addition, this regimen was also associated with a favourable tolerability profile. These results led to the approval of the cisplatin-pemetrexed regimen for patients with only non-squamous NSCLC.

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REVIEW Maintenance therapy Until recently, 4 - 6 cycles of combination CHT formed the ‘standard of care’ for patients with advanced NSCLC.[71,72] Extension of the same treatment failed to demonstrate any evidence of benefit. Recent trials of maintenance therapy in stable/responding patients to front-line regimen have shifted the treatment paradigm in favour of this approach. Pemetrexed and erlotinib, administered as single agents, are widely used for maintenance therapy based on the results of randomised trials,[73,74] including tolerability and the lack of a significant cumulative toxicity. The benefit is more provocative with erlotinib in those with activating mutations in the EGFR TK domain although it is modest at best in the overall populations. The meta-analysis of maintenance therapy studies demonstrates a significant improvement in progression-free survival and a modest improvement in overall survival.[75] Continued controversy among lung cancer care providers exists regarding the optimal patient type for the maintenance therapy and the choice of agent (continuation of the same agent v. switch to a new agent). For now ‘switch maintenance’ has been established until new data become available. Patients with poor or declining PS should not be offered maintenance therapy.[76] EGFR tyrosine kinase inhibitors (TKIs) EGFR pathway inhibitors gefitinib and erlotinib were evaluated in patients with refractory NSCLC, with a single agent activity observed in approximately 10 - 20% of the patients.[77-79] The NCIC-BR21 study documented significant improvement in overall survival and progression-free survival with erlotinib in patients with recurrent (second-line) advanced NSCLC.[80] However, gefitinib failed to show a difference in overall survival when compared with a placebo[81] but the subsets of never-smokers/Asian ethnicity patients demonstrated a benefit. Clinical characteristics for response for EGFR TKIs in the early trials included female sex adenocarcinoma histology, neversmokers and those with Asian ethnicity,[82] likely due to an incidence of EGFR activity mutations in the tyrosine kinase domain of the receptor responsible for the selective activity with EGFR TKIs being much higher (~40%) in those with Asian ethnicity. Recent landmark Asian phase III study confirmed the role of EGFR mutation as the main predictor of outcome with EGFR tyrosine kinase inhibitors.[83] It was also shown that administration of gefitinib in patients with wild-type EGFR was not warranted and CHT remains the preferred treatment. Another Asian study[84] confirmed these observations. Adding CHT and EGFR TKIs in the front-line setting in patients with tumours harbouring the EGFR mutation has no benefit.[85,86] Furthermore, a recent trial in never- or light-smokers investigated erlotinib alone or in combination with carboplatin and paclitaxel[87] and found no difference between the two groups even in patients with EGFR mutation, thus excluding a role for combination of EGFR TKIs with CHT. Cetuximab, a chimeric monoclonal antibody against the EGFR, has minimal activity when given as monotherapy for patients with advanced-stage NSCLC.[88] However, when given in combination with platinum-based CHT, a modest improvement in overall survival was noted (11.3 months v. 10.1 months) over CHT alone.[89] However, with other combination regimens, cetuximab has failed to demonstrate significant improvement in survival.[90]

Anti-angiogenic agents Bevacizumab was the first targeted agent to demonstrate survival advantage in patients with advanced-stage NSCLC and is now routinely used in the first-line setting for patients with metastatic non-squamous NSCLC. The ECOG4599 [91] trial tested 6 cycles of carboplatin-paclitaxel with or without bevacizumab given as monotherapy for non-progressive patients. The overall survival was superior for patients treated with bevacizumab (10.3 months v. 12.3 months, p=0.003). The progression-free survival duration was also improved with bevacizumab (6.2 v. 4.5 months, p<0.001). Treatment was tolerated well overall, with <5% incidence of major bleeding events. Another trial (cisplatin and gemcitabine with either bevacizumab or placebo) noted similar efficacy, though a survival benefit was not evident. [92] The AVAiL study also noted no increase in incidence of bleeding when bevacizumab-based regimens were given to patients on full dose anti-coagulation therapy. The safety and efficacy of bevacizumab have also been documented when used in combination with other commonly used platinum-based doublets for the treatment of advanced NSCLC.[93,94] Despite promising phase II data, the combination of bevacizumab with erlotinib failed to improve survival in a randomised study conducted for second-line therapy of advanced-stage NSCLC.[95,96] The same combination used as maintenance therapy also failed to improve survival compared with bevacizumab alone.[97] Other vascular endothelial growth factor receptor inhibitors A number of novel multi-kinase inhibitors, which also target the vascular endothelial growth factor (VEGF) receptor, have all been tested for the treatment of advanced NSCLC. When given in combination with CHT, sorafenib failed to show an improvement in survival [98] and in patients with squamous cell histology, the placebo group fared better. When combined with erlotinib in the second-line recurrent NSCLC, sorafenib demonstrated a modest improvement in efficacy in unselected patients when compared with erlotinib alone (PFS, 1.9 v. 3.1 months and OS 6.0 v. 8.1 months).[99] Vandetanib has also been studied in the frontline treatment of advanced NSCLC, where the combination of carboplatin and paclitaxel with vandetanib was associated with a modest improvement in median PFS over that of the same CHT given without vandetanib.[100] In the second-line setting, docetaxel was given alone or in combination with vandetanib, [101] with a modest and significant improvement in median PFS, though overall survival was not improved. In another study, vandetanib was added to pemetrexed for second-line therapy without significance. [102] Vandetanib was also compared directly with erlotinib in a phase III study for advanced NSCLC and was noted to have comparable efficacy.[103] Taken together, these results suggest a possible role of various VEGF receptor inhibitors.

SCLC

Small-cell lung cancer (SCLC) is a highly aggressive carcinoma and represents approximately 15 - 20% of all lung cancer cases.[104] It is an entity of lung cancer that is biologically and clinically different from non-small-cell lung cancer. The WHO classification of a lung tumour, revised in 2004[105] remains the cornerstone for lung cancer nomenclature. More than 4 decades ago, the Veterans

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REVIEW Administration Lung Group had proposed dividing all SCLC into the two-stage system: limited disease (LD) and extensive disease (ED). [106] The majority of clinicians and investigators still use it nowadays. The vast majority of patients (approximately two-thirds) fall into the ED SCLC, while LD SCLC occurs in approximately one-third of all SCLC. LD SCLC is defined as disease confined to the hemithorax of origin along with the involved regional lymph nodes (hilar and mediastinal), with or without ipsilateral supraclavicular lymph nodes. It can also be considered as a disease that can be incorporated within a single, tolerable TRT treatment field and may include patients with contralateral mediastinal or hilar lymph nodes. What has created confusion, and still does, is the term â&#x20AC;&#x2DC;tolerable TRT treatment fieldâ&#x20AC;&#x2122;. It was not always easy to denote and compare it between clinicians, especially radiation oncologists. The most recent staging classification of SCLC [107] represents an important refinement in overall approach in SCLC, while stratification by stage I - III also was recommended in clinical trials of LD SCLC. Limited disease Although surgery has occasionally been practised in this disease, it never became the standard treatment option owing to lack of data support. In addition, SCLC is known as a radio- and chemosensitive tumour and both CHT and TRT were used alone in LD SCLC in the past. However, results of two meta-analyses that appeared more than 2 decades ago[108,109] summarised the data from prospective randomised trials showing small but significant improvement in 2-year and 3-year survival, averaging 5 - 7% and an improvement in local control rates with combined TRT-CHT. Importantly, the widespread use of cisplatin/etoposide and its low toxicity when combined with TRT made more effective use of concurrent TRT and platinum-based CHT, which is nowadays considered as the standard treatment in LD SCLC. In addition, almost 15 years ago meta-analysis[110] established the necessity to incorporate prophylactic cranial irradiation (PCI) as a mandatory part of the combined treatment. Owing to its pronounced chemosensitivity, there are many CHT agents that achieve response rates of â&#x2030;Ľ30% in SCLC. They include cisplatin, carboplatin, etoposide, cyclophosphamide, doxorubicin, methotrexate and vincristine.[111] In a phase III study, the cisplatin/ etoposide appeared superior to cyclophosphamide, epirubicin and vincristine in a randomised study. The 5-year survival rates were 5% and 2% in the two treatment arms, respectively (p=0.0004). In subgroup analysis done for 214 patients with LD SCLC, this benefit was even more pronounced (5-year survival, 10% v. 3%; p=0.0001), while for patients having ED SCLC this benefit remained unreported.[112] The use of cisplatin/etoposide in this disease has been additionally supported by a systematic review using 36 randomised trials that have tested single agents, either cisplatin or etoposide, or both (doublet) against regimens not containing these agents. The significant improvement with use of these drugs in comparison with CHT with neither was demonstrated. [113] Furthermore, a meta-analysis of 19 trials that investigated the effects of CHT with or without cisplatin in more than 400 patients showed that patients receiving cisplatin had a survival advantage of 4.4% at 1 year.[114] In addition, there are long-known facts about

the favourable toxicity profile of cisplatin/etoposide regimen[108] in combination with TRT. Some studies advocated treatment of patients for the duration of their life. Only one study demonstrated a survival advantage for LD SCLC,[115] while numerous studies showed either no advantage at all[116-122] or even showing detrimental effects of continuous CHT.[123] Additionally, some studies investigated the optimal number of induction CHT courses. Here, no survival benefit was seen for eight cycles of cyclophosphamide/etoposide/vincristine compared with four cycles, when there was an option of a second-line CHT.[124] This was indirectly confirmed as early as 1996 by preliminary results of an Intergroup 0096 study that produced convincing results with only four cycles of cisplatin/etoposide and TRT. [125] Approaches to intensify the dose of CHT by giving higher doses including doxorubicin or alkylating-based CHT in the 1970s and 1980s,[126-128] cisplatin-based in the 1990s,[129] granulocyte colony-stimulating factor support,[130] by decreasing the interval between the cycles of CHT[131,132] or even using bone marrow support[133] all showed promising results but always and unequivocally accompanied with such high toxicity that prevented it becoming a standard treatment approach. Investigation of the place and the role of the thirdgeneration drugs (e.g. topotecan, paclitaxel) showed they had no effect on survival.[134-136] As a summary, there was no firm basis to recommend either dose intensification or the integration of new drugs into actual regimens owing to the risk of severe toxicity and the lack of clearly demonstrated improvement in overall survival. This is especially so when one considers the lack of data for CHT combined with TRT. Timing of combined TRT and CHT, and total dose and fractionation used, attracted most of the attention of researchers. When timing of combined RT and CHT is considered it is usually defined as either concurrent, sequential or alternating. While some of the initial studies showed promising results for alternating RT and CHT, this type of combined approach is mostly abandoned today. The main question with the remaining two modes of administration is simply whether any portion of TRT and CHT overlap and, if this is the case, when overlapping occurs. Early concurrent thoracic TRT and CHT studies used non-platinum regimens or alternated it with cisplatin/etoposide, while more recent ones were exclusively platinum-based regimens. Some studies[137-139] suggested that TRT delayed until the fourth cycle of CHT[137] or until day 120[138] may be superior to initial TRT or suggested no difference when compared with early TRT and CHT.[139] A likely explanation lies in marked reduction of CHT dose in trials[137,139] when TRT was applied early. More recent studies using cisplatin/etoposide[140,141] or cisplatin/etoposide alternating with cyclophosphamide/ doxorubicin/vincristine [142] showed clear superiority for early administration of TRT (concurrently given during the first or the second cycle of CHT). Early concurrent TRT and cisplatin/ etoposide chemotherapy was capable of achieving 5-year survival of >20%, while late TRT usually obtained only about 10%. Therefore, it became a common practice worldwide to offer TRT with curative doses as early as possible (cycle one or two of CHT). Recently, several meta-analyses and systematic reviews addressed this issue. However, while Huncharek and McGarry [143] observed significantly superior survival for early TRT and CHT, Fried et

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REVIEW al.[144] observed a significantly higher 2-year survival in the early group with a suggestion of a similar trend at 3 and 5 years, PijlsJohannesma et al.[145] did not find any advantage for early TRT and CHT. These analyses[143-145] brought somewhat conflicting results that were largely resolved by Jeremic, [146] who performed ‘metaanalysis of the meta-analyses’, identifying common findings in existing analyses. Overall, prevailing evidence is that nowadays, using a ‘standard’ approach consisting of hyperfractionated TRT and four courses of CHT based on cisplatin-etoposide, early administration seems favourable and should be practised as the standard approach. Reports showing that prolonged (e.g. 4 6 cycles) sequential administration of CHT followed by radical TRT is an inferior treatment approach when compared with early and concurrent TRT-CHT are unfortunately still occurring nowadays.[147,148] Regarding TRT dose and fractionation, total doses used for LD SCLC were usually about 50 Gy, given daily, but have ranged from as low as 30 Gy to as high as 70 Gy. In addition, many recent studies have used some form of hyperfractionation (b.i.d.). In the Intergroup study,[149] 45 Gy given in 30 fractions in 3 weeks (1.5 Gy b.i.d. fractionation) was compared with the same dose given once daily, both with concurrent cisplatin-etoposide CHT. While survival was significantly better in the b.i.d. arm (5-year, 26% v. 19%), this was however achieved with a somewhat higher incidence of acute toxicity. Beside hyperfractionation and conventional fractionation, hypofractionated RT regimens were also used, thought to cause more damage to SCLC cells.[142,150] Currently, two major clinical trials investigating this issue are recruiting patients. In a CONVERT trial, EORTC is evaluating 66 Gy using standard fractionation with the b.i.d. fractionation as used in the Intergroup study (45 Gy in 30 fractions in 15 treatment days in 3 weeks).[149] Similarly, joint CALGB 30610/RTOG 0538 is directly comparing the same control Intergroup regimen with two experimental arms, either conventional (QD) or concomitant boost regimen (CB). The better of the two experimental arms (CB) is then being directly compared with hyperfractionated regimen. Mature data from these trials should hopefully give better perspective about the fractionation issue. Other regimens of b.i.d. irradiation (e.g. 54 Gy in 36 fractions in 18 treatment days in 3.5 weeks) have been successfully implemented in practice concurrently with low-dose CHT.[140] Extensive disease For decades, clinicians and investigators considered platinumetoposide CHT as the standard treatment option for patients with ED SCLC. As an exclusive treatment, it can offer the median survival time of 9 - 12 months and 5-year survivals of 1 - 3%.[151-153] While up to 90% of patients eventually experience objective response following initial courses of CHT, ED SCLC remains a disease with very poor prognosis. This is because most patients unfortunately relapse, leading to outcomes virtually unchanged since platinumetoposide was introduced several decades ago. It is therefore not hard to see this disease as one of the most frustrating challenges in thoracic oncology. To combat poor prognosis in patients with this disease when treated with CHT alone, various approaches aiming intensification of the treatment have been attempted.

Unfortunately, maintenance CHT after 4 - 6 cycles of initial CHT with or without adding the third-generation CHT drug[134,154,155] and higher doses of chemotherapy[133,156] did not prove to be beneficial in this setting. Other approaches such as adding the third CHT agent or using targeted agents did not result in any improvement. In contrast stand findings of Slotman et al.,[157] who published the results of a trial that changed the practice in ED SCLC by showing that PCI offers significant brain metastasis-free survival, relapse-free survival and overall survival in patients after achieving any response after induction CHT. Similarly to the place and role of PCI in LD SCLC, it is now accepted worldwide as the standard treatment option in responding patients with ED SCLC. The case for curative TRT in ED SCLC is still an unsolved issue and is under active investigation. Although patients treated with CHT alone in ED SCLC frequently experience chest relapses, even in case of previous CR, TRT had not been systematically investigated in this setting. Also, one must take into account the systemic character of ED SCLC. It may obscure possible effects of TRT on survival (established on a local level), especially in adequately chosen subgroups of patients suitable for ‘curative’ role of TRT. Simply said, patients with ED SCLC may have systemic progression so fast that any possible effect on local control, and subsequently survival, may not be observed due to the short lifespan of these patients. The role of TRT in possible improvement in local (intrathoracic) tumour control and its subsequent impact, if any, on overall survival in favourable patient populations, was evaluated in a prospective randomised trial by Jeremic et al.[153] After three cycles of cisplatin/ etoposide regimen, complete patient re-evaluation and restaging was performed and patients achieving CR (at local and distant levels) and those achieving partial response (PR) within the thorax accompanied with the CR elsewhere were then randomised to receive either a) TRT and concurrent low-dose daily CHT, followed by PCI and then by additional two cycles of CHT (group I) or b) four additional cycles of cisplatin-etoposide and PCI (group II). Patients in group I achieved results that were significantly better than those in group I: the median survival time was 17 v. 11 months (p=0.041), and 5-year survival rates were 9.1% and 3.7% for groups I and II, respectively. Local recurrence-free survival was also better in group I than in group II, with median time to local recurrence of 30 and 22 months, respectively, and 5-year local recurrence-free survival of 20% and 8.1%, respectively (p=0.062). The study by Jeremic et al.[153] was the very first prospective randomised study that evaluated curative TRT in ED SCLC. It showed that TRT may have an important place and may have a substantial role in overall treatment of patients with ED SCLC. Emerging reports worldwide confirm this observation. In a Canadian trial of Yee et al.[158] the median time to disease progression was 8.4 months and the median overall survival time was 13.7 months, while in the study of Zhu et al.,[159] for TRT-treated group MST was 17.2 months, and 2- and 5-year survival was 36% and 10.1%, respectively (p=0.0001). Studies by Zhu et al.[159] and Yee et al.[158] should not only be seen as confirmatory data of the study of Jeremic et al.[153] but also as confirmatory of existing institutional practices among thoracic oncologists involved in the treatment of ED SCLC since the study of Jeremic et al.[153] This was recently brought to the evidence by the study of Ou et al.,[159] who retrospectively analysed the data

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REVIEW from the Cancer Surveillance programmes of Orange, San Diego and Imperial counties in Southern California that indicated the use of TRT in ED SCLC in 35.1% of patients. The 1-year, 2-year, and median overall survival were 27.8%, 9.3% and 8 months and were significantly better than corresponding figures in patients who did not receive TRT (16.2%, 3.8% and 4 months, respectively; p<0.0001). Two large ongoing studies (RTOG in the US and CREST in Holland) will add additional insight into the issue of place and role of TRT in ED SCLC.

Conclusion

Lung cancer has represented an active field of clinical research for many years. Treatment approaches have greatly improved over time, but unfortunately dismal treatment outcomes persist. It is expected that novel surgical and radiation oncology technologies as well as new drugs may help improve outcomes in patients with lung cancer. This should preferably be achieved using clinical trials as a vehicle to provide a high level of evidence, enabling its fast implementation in clinical practice worldwide. References

1. Jemal A, Center MM, DeSantis C, Ward EM. Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev 2010;19:1893-1907. [http://dx.doi.org/10.1158/1055-9965.EPI-10-0437] 2. Jemal A, Siegal R, Xu J, Ward E. Cancer Statistics,2010. CA Cancer J Clin 2010 July (epub). 2010;60(5):277-300. [http://dx.doi.org/10.3322/caac.20073] 3. Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA. The IASLC Lung Cancer Staging Project: Proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol 2007;2:706-714. [http://dx.doi.org/10.1097/JTO.0b013e31812f3c1a] 4. Arriagada R, Dunant A, Pignon JP, et al. Long-term results of the international adjuvant lung cancer trial evaluating adjuvant cisplatin-based chemotherapy in resected lung cancer. J Clin Oncol 2010;28:35-42. [http://dx.doi.org/10.1200/JCO.2009.23.2272] 5. Winton T, Livingston R, Johnson D, et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005;352:2589-9257. [http:// dx.doi.org/10.1056/NEJMoa043623] 6. Strauss GM, Herndon JE 2nd, Maddaus MA, et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 2008;26:5043-5051. [http://dx.doi.org/10.1200/JCO.2008.16.4855] 7. Pignon JP, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol 2008;26:3552-3559. [http://dx.doi.org/10.1200/JCO.2007.13.9030] 8. Pisters KM, Vallieres E, Crowley JJ, et al. Surgery with or without preoperative paclitaxel and carboplatin in early-stage non-small-cell lung cancer: Southwest Oncology Group Trial S9900, an intergroup, randomized, phase III trial. J Clin Oncol 2010;28:1843-1849.[http://dx.doi.org/10.1200/JCO.2009.26.1685] 9. Scagliotti G, Vansteenkiste J, Spaggiari L, et al. A phase III randomized study of surgery alone or surgery plus preoperative gemcitabine-cisplatin in early stage nonsmall cell lung cancer: Follow-up data of Ch.E.S.T. J Clin Oncol 2008;26(15s):399s. 10. Felip E, Rosell R, Maestre JA, et al. Preoperative chemotherapy plus surgery versus surgery plus adjuvant chemotherapy versus surgery alone in early-stage non-smallcell lung cancer. J Clin Oncol 2010;28:3138-3145. [http://dx.doi.org/10.1200/ JCO.2009.27.6204] 11. Goss G LI, Tsao MS, O’Callaghan CJ, et al. A phase II randomized, double-blind, placebo-controlled trial of the epidermal growth factor receptor inhibitor gefitinib in completely resected stage IB-IIIA non-small cell lung cancer (NSCLC): NCIC CTG BR.19. J Clin Oncol 2010;28(15s). 12. Jones DR, Stiles BM, Denlinger CE, et al. Pulmonary segmentectomy: Results and complications. Ann Thorac Surg 2003;76:343. [http://dx.doi.org/10.1016/S00034975(03)00437-5]

13. Schuchert MJ, Pettiford BL, Keeley S, et al. Anatomic segmentectomy in the treatment of stage I non-small cell lung cancer. Ann Thorac Surg 2007;84:926-932. [http://dx.doi.org/10.1016/j.athoracsur.2007.05.007] 14. Okada M, Nishio W, Sakamoto T, et al. Effect of tumor size on prognosis in patients with non-small cell lung cancer: The role of segmentectomy as a type of lesser resection. J Thorac Cardiovasc Surg 2005;129:87-93. [http://dx.doi.org/10.1016/j. jtcvs.2004.04.030] 15. Sugarbaker DJ. Lung cancer. 6: The case for limited surgical resection in non-small cell lung cancer. Thorax 2003;58:639-641. [http://dx.doi.org/10.1136/thorax.58.7.639] 16. Jeremic B, Classen J, Bamberg M: Radiation therapy alone in technically operable, medically inoperable early stage (I/II) non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2002;54:119-130. [http://dx.doi.org/10.1016/S0360-3016(02)02917-6] 17. Jeremic B, Milicic B, Acimovic L, Milisavljevic S. Concurrent hyperfractionated radiotherapy and low-dose daily carboplatin/paclitaxel in patients with early stage (I/II) non-small cell lung cancer (NSCLC). Long-term results of a phase II study. J Clin Oncol 2005;23:6873-6880. [http://dx.doi.org/10.1200/JCO.2005.22.319] 18. Nyman J, Johansson KA, Hulten U. Stereotactic hypofractionated radiotherapy for stage I non-small cell lung cancer - mature results for medically inoperable patients. Lung Cancer 2006;51:97-103. [http://dx.doi.org/10.1016/j.lungcan.2005.08.011] 19. Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 2010;303:1070-1076. [http://dx.doi. org/10.1001/jama.2010.261] 20. Yendamuri S, Komaki RR, Correa AM, et al. Comparison of limited surgery and three-dimensional conformal radiation in high-risk patients with stage I non-small cell lung cancer. J Thorac Oncol 2007;2:1022-1028. [http://dx.doi.org/10.1097/ JTO.0b013e318158d4cb] 21. Grills IS, Mangona VS, Welsh R, et al. Outcomes after stereotactic lung radiotherapy or wedge resection for stage I non-small-cell lung cancer. J Clin Oncol 2010;28:928935. [http://dx.doi.org/10.1200/JCO.2009.25.0928] 22. Saunders M, Dische S, Barrett A, Harvey A, Griffiths G, Palmar M. Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small cell lung cancer: mature data from the randomisedmulticentre trial. Radiother Oncol 1999;52:137-148. [http://dx.doi. org/10.1016/S0167-8140(99)00087-0] 23. Dillman RO, Seagren SL, Propert KJ, et al. A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III nonsmall-cell lung cancer. N Engl J Med 1990;323:940-945. [http://dx.doi.org/10.1056/ NEJM199010043231403] 24. Sause WT, Scott C, Taylor S, et al: Radiation Therapy Oncology Group 88-08 and Eastern Cooperative Oncology Group 4588: Preliminary results of a phase III trial in regionally advanced, unresectable non-small cell lung cancer. J Natl Cancer Inst 1995;87:198-205. [http://dx.doi.org/10.1093/jnci/87.3.198] 25. Le Chevalier T, Arriagada R, Tarayre M, et al. Significant effect of adjuvant chemotherapy on survival in locally advanced non-small cell lung carcinoma (letter). J Natl Cancer Inst 1992;84:58. [http://dx.doi.org/10.1093/jnci/84.1.58] 26. Schaake-Koning C, van den Bogaert W, Dalesio O, et al. Effects of concomitant cisplatin and radiotherapy on inoperable non-small cell lung cancer. N Engl J Med 1992;326:524-530. [http://dx.doi.org/10.1056/NEJM199202203260805] 27. Jeremic B, Shibamoto Y, Acimovic L, Djuric L. Randomized trial of hyperfractionated radiation therapy with or without concurrent chemotherapy for stage III non-smallcell lung cancer. J Clin Oncol 1995;13:452-458. 28. Jeremic B, Shibamoto Y, Acimovic LJ, Milisavljevic S. Hyperfractionated radiation therapy with or without concurrent low-dose daily carboplatin/etoposide for stage III non-small-cell lung cancer: A randomized study. J Clin Oncol 1996;14:10651070. 29. O’Rourke N, Roqué I Figuls M, Farré Bernadó N, Macbeth F. Concurrent chemoradiotherapy in non-small cell lung cancer. Cochrane Database Syst Rev 2010;6:CD002140. 30. Liang HY, Zhou H, Li XL, Yin ZH, Guan P, Zhou BS. Chemo-radiotherapy for advanced non-small cell lung cancer: Concurrent or sequential? It’s no longer the question: A systematic review. Int J Cancer 2010;127:718-728. [http://dx.doi. org/10.1002/ijc.25087] 31. Aupérin A, le Péchoux C, Rolland E, et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol 2010;28:2181-2190. [http://dx.doi.org/10.1200/JCO.2009.26.2543] 32. Shepherd FA, Johnston MR, Payne D, et al. Randomized study of chemotherapy and surgery versus radiotherapy for stage IIIA non-small-cell lung cancer: A National Cancer Institute of Canada Clinical Trials Group Study. Br J Cancer 1998;78:683-685.

References 33-160 can be found in the online version at: http://dx.oi.org/10.7196/10.2015.v21i3.59 or scan the QR code above.

SARJ VOL. 21 NO. 3 2015

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REVIEW

Hypersensitivity pneumonitis H Khalfey, MB ChB, FCP SA, Cert Pulm SA Pulmonologist, Life Vincent Pallotti Hospital, Pinelands, Cape Town Corresponding author: H Khalfey (hkhalfey@telkomsa.net)

Hypersensitivity pneumonitis (HP) refers to the inflammatory lung condition that arises from inhalational exposure to various (mostly organic) antigens with the development of lymphocytic alveolitis and granulomatous pneumonitis. A myriad of antigens have been implicated and the list continues to grow. The clinical features are varied, implicated antigens protean, and the investigations complementary in making a diagnosis, but the condition remains a difficult one to diagnose, mostly due to a lack of clinical suspicion. In this article we discuss HP, its aetiology, clinical features as well as diagnosis and management. S Afr Resp J 2015;21(3):70-76. DOI:10.7196/10.2015.v21i3.70

As early as 1713, an Italian medical professor by the name of Bernadino Ramazzini recorded the health hazards associated with 52 occupations. In this document he noted that: ‘Almost all who make a living by sifting or measuring grain are short of breath and cachectic and rarely reach old age; in fact, they are very liable to lapse into orthopnoea and finally dropsy’.[1] With this description, Ramazzini essentially provided the first description of hypersensitivity pneumonitis (HP) with the development of chronic respiratory failure and cor pulmonale. Subsequently in 1932, the first detailed descriptions of HP were made following an outbreak in 10 employees at a company that manufactured railroad ties.[2] These employees, who were required to strip bark from maple logs, developed symptoms of dyspnoea, cough, night sweats, weight loss and sputum production. It was subsequently discovered that beneath the bark of the maple logs a black sooty dust was present from which a fungus called Cryptostroma corticale was isolated. The chest X-ray and clinical features were compatible with what we now accept as HP. HP has long been considered an orphan disease, and over the last 10 - 15 years there remains one intriguing question – why do only a small percentage of those who are exposed develop the disease? There is a lack of consensus as to the definition of HP and this is reflected in the different definitions suggested by two major groups of international experts. The National Heart, Lung, and Blood Institute and the Office of Rare Diseases (NHLBI/ORD) workshop report defines HP as ‘a complex health syndrome of varying intensity, clinical presentation, and natural history. HP is the result of an immunologically induced inflammation of the lung parenchyma in response to inhalation exposure to a large variety of antigens’.[3] The HP Study group defined HP as ‘a pulmonary disease with symptoms of dyspnoea and cough resulting from the inhalation of an antigen to which the patient has been previously sensitised’.[4] More recently, HP has been accepted as a pulmonary disease consisting of a spectrum of granulomatous, interstitial, bronchiolar and alveolarfilling lung diseases with or without systemic manifestations (fever and weight loss) caused by the inhalation of a wide variety of organic aerosols and low molecular weight (LMW) chemical antigens to which the subject is sensitised and hyper-responsive. Sensitisation

and exposure alone in the absence of symptoms do not define the disease, which is characterised by a lymphocytic alveolitis and granulomatous pneumonitis, usually with improvement or complete recovery if exposure ceases, otherwise it leads to interstitial fibrosis if exposure continues.[5]

Aetiology

A wide group of causative antigens have been described for HP and new sources are continually being recognised (Table 1). The most commonly implicated antigens in the disease process are derived from thermophilic actinomycetes, such as Saccharopolyspora rectivirgula (which causes farmer’s lung) following exposure to mouldy hay, and others that cause Bagassosis and cheese-washer’s lung, as well as antigen derived from protein in the droppings, feathers or serum of birds (such as pigeons, budgerigars, ducks, parrots, etc.) which cause bird-fancier’s lung.[6,7] Increasingly duck and goose down used in duvets and feather pillows have been implicated as possible causes for chronic HP, often mistakenly labelled as idiopathic pulmonary fibrosis (IPF).[8] Some LMW chemicals such as isocyanates (used in polyurethane foams, paints and plastics), zinc, inks and dyes can act as haptens to induce HP. It may be useful to consider the implicated antigens in three groups: microbial (fungal, bacterial, mycobacterial), animal proteins (bird feathers, droppings and serum) and LMW chemicals (isocyanates).

Epidemiology

The prevalence of HP varies considerably around the world and is dependent on a number of factors including disease definition, diagnostic methods, occupational exposures (type and intensity), geographic conditions, industrial and agricultural practices, as well as host risk factors. Bird-fancier’s lung is usually the most common form of HP. HP is an uncommon condition that has been shown to make up 4 - 15% of all interstitial lung diseases,[9] and in Britain the incidence has been found to be 0.9 cases per 100 000 person-years.[10] What remains an enigma is the low proportion of patients who develop disease despite more widespread exposure, as was demonstrated in French dairy farmers, where only 0.5 - 3.0% developed disease.[11] In South Africa, in a single-centre tertiary

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Table 1. Common antigens implicated in HP Disease

Antigen

Source of antigen

Farmer’s lung (FLD)

Saccharopolyspora rectivirgula

Mouldy hay, grain

Bagassosis

Thermoactinomyces vulgaris

Mouldy sugarcane

Maple bark stripper’s lung

Cryptostroma corticale

Mouldy maple bark

Cheese-washer’s lung

Penicillium casei, Aspergillus clavatus

Mouldy cheese

Hot tub lung

Mycobacterium avium complex

Hot tub mists

Summer-type pneumonitis

Trichosporon cutaneum

Contaminated old Japanese houses in summer months

Bird-fancier’s lung (BFL)

Avian droppings, serum, feathers

Pigeons, budgerigars, parrots, ducks

Animal-handler’s lung

Rats, gerbils, hamsters

Urine, serum, fur

Painter’s lung

Isocyanates

Paint hardeners

Plastic-worker’s lung

Anhydrides

Plastic components

Microbial – fungal and bacterial

Animal proteins

Low molecular weight chemicals

referral hospital over a period of 30 years, 40 patients were diagnosed with HP due to bird exposure.[12] In this group there was no gender difference, 30/40 (75%) were of mixed race and 10/40 (25%) were white subjects, with no black or Asian subjects. The age range at presentation was 13 - 75 years (mean 49.2 (standard deviation 15.4) years). Fifty-five per cent were non-smokers, 20% ex-smokers and 25% were current smokers.

Pathogenesis

While up to 50% of exposed subjects develop sensitisation with positive antibodies, only about 3 -15% of bird fanciers develop HP.[13] This suggests that the phenotypic expression of disease depends on host and environmental factors. The underlying immune mechanisms implicated in disease development have been demonstrated to be a combination of a Type III hypersensitivity (in acute HP) and Type IV delayed-type hypersensitivity (in chronic HP). A two-hit hypothesis has been postulated where genetic susceptibility or environmental factors serve as the first hit and increase the risk of development of disease after antigen exposure (second hit).[14] There are few studies on the underlying genetic susceptibility in HP and available data increasingly point to abnormalities in the antigen processing and presentation pathways of the immune system. Polymorphisms associated with HLA-DR and DQ have been associated with increased risk for HP in populations with different genetic backgrounds.[15,16] PSMB8 is an immunoproteasome catalytic subunit that is important in the generation of peptides presented by MHC class 1 molecules, and the PSMB8 KQ genotype has been found with increased frequency in subjects with HP.[17] One study reported that Mexican patients with HP had increased expression of alleles Gly-637 and genotypes Asp637/Gly-637 and Pro661/Pro661 on the TAP1 (transporters associated with antigen processing 1) gene, which may lead to an exacerbated immune response and hence increased susceptibility to developing HP.[18] There is ongoing research into the immunopathogenesis of HP and we are likely to learn more in the future about the immune tolerance

occurring in most exposed individuals. Regulatory T cells (Treg) may play an important role in this process, as has been shown in in vitro studies.[19,20] In addition to underlying genetic susceptibility it has been shown that environmental factors such as exposure to parainfluenza viral infections in mice[21] and pesticide exposure in farmers may increase susceptibility to development of clinical HP.[22] The effects of smoking are interesting in that paradoxically smokers appear to have a reduced susceptibility to the development of HP and 95% of HP cases occur in non-smokers.[23] This may be due to a decrease in the production of specific antibodies to inhaled organic antigens due to various immunosuppressive effects of tobacco smoke. Despite these relative protective effects of smoking, the smokers who do develop HP have lower vital capacities and a poorer 10-year survival in comparison with non-smokers.[24]

Clinical features

Three clinical forms of HP have been described: acute, subacute and chronic. However, it is often difficult to distinguish subacute HP from either acute or chronic as there is often overlap in clinical features, which blurs this distinction. Acute HP Patients typically give a history of flu-like symptoms occurring 4 - 8 hours following exposure to antigen and complain of dry cough, dyspnoea, fever, rigors, myalgia and malaise, which reach peak intensity at 12 - 24 hours and usually resolve completely within 48 hours if exposure ceases. These episodes will recur upon subsequent re-exposure to the antigen and are usually more intense. Clinical examination will reveal an acutely ill patient with tachypnoea, tachycardia, bibasal inspiratory crackles on auscultation of the chest and, in severe cases, acute respiratory failure evident on arterial blood gas analysis. Serum precipitating antibodies are usually positive in most cases and chest X-ray will reveal bilateral patchy or diffuse reticulonodular infiltrates mostly in the lower zones, with apical

71 SARJ VOL. 21 NO. 3 2015

REVIEW sparing. High-resolution computerised tomography scanning (HRCT) will typically show multiple small nodules with bilateral areas of ground-glass opacification, pre dominantly in the bases. Spirometry usually reveals a restrictive pattern with a reduced gas transfer. Both spirometry and radiology may often return to normal within 4 - 6 weeks if antigen exposure ceases. Subacute HP This is a difficult entity to distinguish from acute HP and usually occurs due to repeated low-grade exposure to antigens with the development of similar symptoms to acute HP that resolve within 24 hours of exposure, but due to ongoing exposure is associated with repeated bouts over a period of time. These tend to become more severe over time with longer recovery periods, but patients usually feel well inbetween attacks. The chest X-ray may be completely normal in between attacks but usually demonstrates fine nodular infiltrates in the mid to upper zones. The HRCT may show areas of linear fibrosis due to repeated bouts of inflammation with areas of micronodules and mosaic attenuation in the mid to upper zones. Pulmonary function tests usually show mild restriction with or without a reduced gas transfer. Chronic HP Chronic HP is the form most commonly seen by pulmonologists, as patients most often present late or acute and subacute forms are not recognised as such. Chronic HP occurs in about 5% of patients with HP[25] and develops insidiously over months to years in those with ongoing exposure and is usually irreversible. Patients usually present with chronic, progressive cough often with sputum production and progressive dyspnoea. Examination usually reveals tachypnoea with bibasal fine inspiratory crackles. Clubbing may be present and usually represents a poorer prognosis.[26] Chronic respiratory failure occurs in severe cases leading to cor pulmonale. In chronic HP, precipitating antibodies or specific IgG may be negative if there is time latency between exposure and presentation. The chest X-ray typically shows features of volume loss with bilateral diffuse reticulonodular infiltrates with coarse linear opacities and reticulation in an upper and mid-zone distribution. Multiple areas of fibrosis with patchy ground-glass opacification

and centrilobular nodularity with mosaic attenuation on expiratory views are usual. Honeycombing may also be present, which makes chronic HP difficult to distinguish from IPF. The lung function tests usually demonstrate restriction with reduced lung volumes and a reduced gas transfer. In up to 10%, an obstructive defect may be evident.[27]

Diagnosis

No single diagnostic biomarker or procedure exists to confirm a diagnosis of HP and the clinician is thus faced with a diagnostic dilemma. HP lacks unique features that distinguish it from other interstitial lung diseases, and a diagnosis relies on a high index of suspicion when a history of antigen exposure is obtained, together with a constellation of clinical, radiological, laboratory and pathological findings.

Establish a history of exposure Careful history-taking is essential in order to elucidate a history of antigen exposure, which is the first critical prerequisite. This is especially difficult due to the fact that exposure may occur both directly and indirectly, such as may occur in bird-fancier’s lung where exposures to birds may occur in parks, railway stations and neighbours’ yards, as well as by birds in roofs of houses. Exposure to mouldy hay in barns is implicated in farmer’s lung. To further add to the difficulties in history taking, avian antigen has been reported to persist in a house for 6 months after removal of the bird.[28] Imaging Imaging by chest X-ray and HRCT is not always diagnostic, but adds the most value in reaching a diagnosis. A confident

Table 2. HRCT findings in HP.* Stage of disease

References

Sample size

Findings†

Acute

Cormier et al.[30]

N=20

Ground-glass opacities Micronodules Mosaic perfusion Emphysema Honeycombing Mediastinal lymphadenopathy

Subacute

N=17 (including 9 with pigeon breeder’s disease and 4 with Farmer’s lung)

Hansell et al.[31]

Generalised increase in attenuation of the lung Nodular pattern Reticular pattern Patchy air space opacification

Remy-Jardin et al.[32]

N=21 (pigeon breeder’s disease)

Micronodular pattern(<5 mm in diameter) Ground-glass attenuation Emphysematous change Honeycombing

Chronic

Adler et al.

N=16 (antigen = ?)

[33]

Fibrosis Ground-glass attenuation Nodules

Remy-Jardin et al.

[32]

N=24 (pigeon breeder’s disease)

Honeycombing Ground-glass attenuation Micronodules Emphysema

*Reproduced with permission from Lacasse.[55] †

The findings are ranked according to their decreasing order of prevalence in the study population.

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REVIEW radiological diagnosis has been shown to be accurate in up to 81%.[29] Radiological features of each HP subtype have been addressed previously in this article. In acute HP, the following features have been described in descending order of frequency: groundglass opacities, micronodules, mosaic perfusion, emphysema, honeycombing and mediastinal lymphadenopathy. [30] These usually have a lower and mid-zone predominance. In subacute HP, the most common features are a micronodular pattern followed by reticulation, patchy airspace opacification and in some cases honeycombing, emphysematous change and fibrosis which tend to have a mid-zone predominance as well.[31,32] In chronic HP, the predominant HRCT finding is that of fibrosis with ground-glass attenuation, honeycombing and micronodules as well as

Fig. 1a. Postero-anterior (PA) chest radiograph of acute HP due to pigeons showing diffuse ground-glass opacification. Reproduced with permission from Professor Ainslie.[12]

emphysema.[32,33] This often spares the bases but may be predominantly sub-pleural or peribronchovascular. See Table 2, and Figures 1a and b and Figures 2a and b. Specific circulating antibodies These techniques detect IgG to specific antigens and a positive result merely reflects sensitisation and not necessarily disease. A positive result can be obtained in up to 10% of farmers and 40% of pigeon breeders without any evidence of clinical disease. However, a positive test in the correct clinical scenario strongly supports the diagnosis of HP.[34,35] A negative test, however, does not exclude disease. Positive specific antibodies were shown to be a significant predictor of disease in the HP study.[4] Enzyme immunoassays have now largely replaced the precipitation techniques and have been shown to be a more reliable technique. The test has demonstrated varying sensitivity and specificity. In acute HP in bird-fancier’s lung disease, antibody titres were markedly increased and showed

Fig. 2a. Inspiratory HRCT film in patient with acute HP due to pigeons showing patchy ground-glass opacification and multiple small centrilobular nodules. Reproduced with permission from Professor Ainslie.[12]

high sensitivity and specificity ranging from 75 to 100%, while in chronic HP, titres were only slightly increased with a sensitivity between 27 and 73% and specificity of 45 100%.[36] False negatives may also be seen across the disease spectrum and this depends on the latency period between symptoms and testing, laboratory techniques and panels of antigens tested, etc. Inhalational provocation test This involves the inhalation of 2 mL of pigeon dropping extract (PDE 340 μg/mL) through a handheld nebuliser for a maximum period of 10 minutes. A number of parameters are recorded for 24 hours thereafter and a test is regarded as positive if three or more of the following are demonstrated: increased radiological abnormalities, increased A-a gradient >10 mmHg or decrease in transfer factor (TLCO) of >20%, decrease in forced vital capacity (FVC) >15%, increase in peripheral white blood cell count (WCC) of >30%, increase in C-reactive protein (CRP) >1.0 mg/dl, increase in body temperature >1 o C and/or development of systemic manifestations including chills and fatigue, development of respiratory symptoms such as cough and dyspnoea (Table 3).[37,38] Inhalational provocation testing has been considered to be the ‘gold standard’ by Morell, in whose series the test performed with a sensitivity of 92% and specificity of 100% in patients with bird-fancier’s lung disease.[39] Although it appears to be a useful test, it lacks standardisation with regards to antigen preparation, administration and monitoring and is not without risk to the patient. It is best conducted in research centres with expertise in the procedure. Table 3. Inhalation challenge testing Positive if 3 or more of the following: Increased radiological abnormalities Increased A-a gradient >10 mmHg or decrease in TLCO of >20% Decrease in VC of >15% Increase in peripheral WCC of >30% Increase in CRP >1.0 mg/dL

Fig. 1b. PA chest radiograph of patient with chronic HP due to pigeons showing small lungs with diffuse reticulonodular infiltration. Reproduced with permission from Professor Ainslie.[12]

Fig. 2b. Expiratory HRCT film in patient with acute HP due to pigeons showing patchy gas trapping (mosaic attenuation pattern). Reproduced with permission from Professor Ainslie.[12]

73 SARJ VOL. 21 NO. 3 2015

Increase in body temperature >1oC and/or development of systemic manifestations including chills and fatigue Development of respiratory symptoms – cough and dyspnoea

REVIEW Bronchoalveolar lavage (BAL) Demonstrating BAL lymphocytosis is a highly sensitive method of determining lung inflammation in patients with suspected HP but the test lacks standardisation. BAL lymphocytosis >50% characterises HP and distinguishes it from other conditions, but it may be lower in smokers and those with predominantly fibrotic disease. [5] Asymptomatic exposed individuals may also have a lymphocytosis that represents a lowgrade alveolitis, while other conditions (such as sarcoidosis and organising pneumonia) may also have elevated BAL lymphocytes. Demonstrating a CD4/CD8 ratio <1 is suggestive of HP in up to 34%[40] but the ratio may be as high as that seen in sarcoidosis and is thus not recommended routinely anymore.[41,42]

Biopsy Biopsy in the form of transbronchial biopsy or surgical lung biopsy is rarely needed for a diagnosis of acute HP. In chronic HP it is usually characterised by a triad of chronic

inflammatory infiltrates along small airways (cellular bronchiolitis), diffuse interstitial infiltrates of inflammatory cells (lymphocytes and plasma cells) and scattered non-necrotising granulomas (Figs. 3a and 3b).[43] Granulomas

Fig. 3a. Low-power image of a surgical lung biopsy in a patient with chronic HP showing patchy peribronchiolar inflammatory process.

Fig. 3b. High-power image of a surgical lung biopsy in a patient with chronic HP showing a peribronchiolar granuloma with multinucleated giant cells.

Table 4. Proposed diagnostic criteria for HP for clinical purposes.* Author

Major criteria

Minor criteria

Terho

1. Exposure to offending antigens (revealed by history aerobiological or microbiological investigations of the environment, or measurements of antigen-specific IgG antibodies)

1. Basal crepitant rales

[45]

2. Impairment of the diffusing capacity (TLCO) 3. Oxygen tension (or saturation) of the arterial blood either decreased at rest, or normal at rest but decreased during exercise

2. Symptoms compatible with HP present and appearing or worsening some hours after antigen exposure

4. Restrictive ventilation defect in the spirometry

3. Lung infiltrations compatible with HP visible on chest X-ray

5. Histological changes compatible with HP 6. Positive provocation test whether by work exposure or by controlled inhalation challenge Richerson et al.[46] 1. The history and physical findings and pulmonary function tests indicate an interstitial lung disease 2. The X-ray film is consistent 3. There is exposure to a recognised cause 4. There is antibody to that antigen Cormier et al.[47]

Schuyler et al.[48]

1. Appropriate exposure

1. Recurrent febrile episodes

2. Inspiratory crackles

2. Decreased transfer factor (TLCO)

3. Lymphocytic alveolitis (if BAL is done)

3. Precipitating antibodies to HP antigens

4. Dyspnoea

4. Granulomas on lung biopsy (usually not required)

5. Infiltrates on chest radiographs or HRCT

5. I mprovement with contact avoidance or appropriate treatment

1. Symptoms compatible with HP

1. Bibasilar rales

2. Evidence of exposure to appropriate antigen by history or detection in serum and/or BAL fluid antibody

2. Decreased TLCO 3. Arterial hypoxaemia, either at rest or during exercise

3. Findings compatible with HP on chest radiograph or HRCT 4. BAL fluid lymphocytosis 5. Pulmonary histological changes compatible with HP 6. Positive natural challenge *Reproduced with permission from Lacasse.[55]

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REVIEW occur in varying degrees across studies, and in an epidemiologic survey in Japan, it was demonstrated in 16.7% with BFL, 44.4% with summer-type HP and 60% with isocyanate HP.[44] Surgical lung biopsy was only helpful in 37% in the HP study.[4]

Diagnostic criteria

The diagnosis of HP remains a difficult one and, as mentioned before, rests on a high index of suspicion in a patient with a history of exposure, with compatible clinical and radiological features complemented by further investigations. A number of diagnostic criteria have been studied and recommended but none have been effectively validated. Most diagnostic criteria essentially correspond with definitions of the disease (Table 4).[45-48] The HP study was a multi-centred, multinational study that recruited patients with suspected HP with the aim of developing a predictive tool for the diagnosis of HP.[4] HP was diagnosed in 199 out of 661 subjects in the study and they identified six significant predictors useful in assisting clinicians to arrive at a more accurate estimate of probability of HP. The following were identified as significant predictors: The probability of HP in the HP study ranged from 98%, when all 6 predictors were present, to 0% when there were none. The authors Table 5. Significant predictors of NSCLC Predictor

Odds ratio (OR)

95% confidence interval (CI)

Exposure to a known offending 38.8 antigen

(11.6 - 129.6)

Symptoms 4 - 8 hours after exposure

7.2

(1.8 - 28.6)

Positive precipitating antibodies

5.3

(2.7 - 10.4)

Inspiratory crackles

4.5

(1.8 - 11.7)

Recurrent episodes of symptoms

3.3

(1.5 - 7.5)

Weight loss

2.0

(1.0 - 3.9)

0.5 mg/kg of prednisone for 4 - 6 weeks in patients with chronic HP, followed by a slow wean to a maintenance dose of 10 mg/day, which should eventually be weaned and discontinued in a manner similar to the treatment of sarcoidosis. Given the risks of systemic steroid therapy, it would be appropriate to wean as soon as possible in the event of a lack of response.

Prognosis

The long-term outcome in HP is highly variable and is related to the duration, type and intensity of antigen exposure. In a populationbased cohort study, patients with HP had a markedly increased risk of death (hazard ratio 2.98, 95% CI 2.05 - 4.33).[2] The 5-year mortality has been noted to be 29% and strongly related to the presence of fibrosis and honeycombing on HRCT scan.[51] In Ainslie’s South African series in bird-fanciers’ lung[12] with a mean follow-up period of 45.6 months, 18% died, with a suggestion that severe restriction on spirometry and a poorer response to steroids may be associated with poor outcome. Traction bronchiectasis and extent of honeycombing have shown to be superior to forced expiratory volume in 1 second (FEV1), FVC and gas transfer for predicting mortality.[52] Pulmonary hypertension holds a poorer prognosis and death may occur in up to 20%.[53] As in IPF, there is an increased prevalence of lung cancer, with a reported prevalence of 10.6%.[54]

Conclusion

HP remains a complex condition that is difficult to diagnose. Probability tools exist which are useful in reaching a diagnosis and may reduce the need for BAL and lung biopsy. The disease is completely reversible if detected early, and a high index of suspicion is required in order to detect and eliminate antigen exposure. Systemic steroids remain the mainstay of treatment but robust studies are lacking. The mechanisms of immune tolerance remain a point of interest and ongoing research.

Acknowledgements

suggested that a probability of >90% is sufficient to rule in and a probability <10% to rule out HP, especially in areas of high and low prevalence respectively. The results of this study are thus useful to assess probability of HP but are not by definition diagnostic criteria. They may be useful in reducing the number of unnecessary invasive procedures such as BAL and biopsy.

Professor Gillian Ainslie – Pulmonologist, University of Cape Town – for the use of her chest X-ray and HRCT images. Dr Fabio Crabbia and Dr Ellen Bolding – Histopathologists, Pathcare Cape Town – for the pathology slides. Professor Yves Lacasse – Centre de Pneumologie, Université Laval, Hôpital Laval, 2725 Chemin Ste-Foy, Ste-Foy, Quebec, G1V 4G5, Canada – for Tables 2 and 4.

Treatment

References

Complete antigen avoidance is the first and most important step in managing HP. In acute HP, this is usually sufficient to prevent disease progression. The treatment of subacute and chronic HP is usually the same. Evidence-based guidelines are lacking, and the strongest available evidence comes from a randomised, placebo-controlled trial of 36 patients with farmer’s lung disease who were randomised to receive either 40 mg prednisolone daily, tapering over 8 weeks, or a placebo.[49] This study showed no significant improvement in pulmonary function after 1 month of treatment apart from a small increase in the TLCO and there was no difference in the 5-year outcome. A reasonable recommendation by Selman[50] is to start with

1. Ramazzini B. Diseases of Workers (Wright WC, trans). New York, NY: Hafner, 1964:243. 2. Towey JW, Sweany HC, Huron WH. Severe bronchial asthma apparently due to fungus spores found in maple bark. JAMA 1932;99(6):453-459. [http://dx.doi.org/10.1001/ jama.1932.02740580021005] 3. Fink JN, Ortega HG, Reynolds HY, et al. Needs and opportunities for research in hypersensitivity pneumonitis. Am J Respir Crit Care Med 2005;171: 792-798. [http:// dx.doi.org/10.1164/rccm.200409-1205WS] 4. Lacasse Y, Selman M, Costabel U, et al. Clinical diagnosis of hypersensitivity pneumonitis. Am J Respir Crit Care Med 2003;168:952-958. [http://dx.doi. org/10.1164/rccm.200301-137OC] 5. Lacasse Y, Girard M, Cormier Y. Recent advances in hypersensitivity pneumonitis. Chest 2012;142:208-217. [http://dx.doi.org/10.1378/chest.11-2479] 6. Bice DE, Salvaggio LE, Hoffman EO, Salvaggio J. Adjuvant properties of Microspolyspora faeni. J Allergy Clin Immunol 1976;55:267-274.

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REVIEW 7. Riley DJ, Saldana M. Pigeon breeder’s lung: Subacute course and the importance of indirect exposure. Am Rev Respir Dis 1973;107:456-460. 8. Morell F, Villar A, Montero MA. Chronic hypersensitivity pneumonitis in patients diagnosed with idiopathic pulmonary fibrosis: A prospective case-cohort study. Lancet Respir Med 2013;1:685-694. [http://dx.doi.org/10.1016/S2213-2600(13)70191-7] 9. Thomeer MJ, Costabe U, Rizzato G, Poletti V, Demedts M. Comparison of registries of interstitial lung diseases in three European countries. Eur Respir J Suppl 2001;32:114s-118s. 10. Solaymani-Dodaran M, West J, Smith C, Hubbard R. Extrinsic allergic alveolitis: Incidence and mortality in the general population. QJM 2007;100(4):233-237. [http:// dx.doi.org/10.1093/qjmed/hcm008] 11. Dalphin JC, Debieuvre D, Pernet D, et al. Prevalence and risk factors for chronic bronchitis and farmer’s lung in French dairy farmers. Br J Ind Med 1993;50(10):941944. [http://dx.doi.org/10.1136/oem.50.10.941] 12. Ainslie GM. Birdfancier’s hypersensitivity pneumonitis in South Africa: Clinical features and outcomes. South African Respiratory Journal 2013;19(2):48-53. 13. Patel AM. Hypersensitvity pneumonitis: Current concepts and future questions. J Allergy Clin Immunol 2001;108:661-670. [http://dx.doi.org/10.1067/ mai.2001.119570] 14. Selman M, Pardo A, King TE Jr. Hypersensitivity pneumonitis: Insights in diagnosis and pathobiology. Am J Respir Crit Care Med 2012;186(4):314-324. [http://dx.doi. org/10.1164/rccm.201203-0513CI] 15. Ando M, Hirayama K, Soda K, Okubo R, Araki S, Sasazuki T. HLA-DQw3 in Japanese summer-type hypersensitivity pneumonitis induced by Trichosporon cutaneum. Am Rev Respir Dis 1989;140:948-950. [http://dx.doi.org/10.1164/ajrccm/140.4.948] 16. Camarena A, Juarez A, Mejia M, et al. Major histocompatibility complex and tumor necrosis factor-alpha polymorphisms in pigeon breeder’s disease. Am J Respir Crit Care Med 2001;163:1528-1533. [http://dx.doi.org/10.1164/ajrccm.163.7.2004023] 17. Camarena A, Aquino-Galvez A, Falfan-Valencia R, et al. PSMB8 (LMP7) but not PSMB9 (LMP2) gene polymorphisms are associated to pigeon breeder’s hypersensitivity pneumonitis. Respir Med 2010;104:889-894. [http://dx.doi. org/10.1016/j.rmed.2010.01.014] 18. Aquino-Galvez A, Camarena A, Monta-o M, et al. Transporter associated with antigen processing (TAP) 1 gene polymorphisms in patients with hypersensitivity pneumonitis. Exp Mol Pathol 2008;84(2):173-177. [http://dx.doi.org/10.1016/j. yexmp.2008.01.002] 19. Kim JM, Rasmussen JP, Rudensky AY. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol 2007;8:191-197. [http:// dx.doi.org/10.1038/ni1428] 20. Girard M, Israel-Assayag E, Cormier Y. Impaired function of regulatory T-cells in hypersensitivity pneumonitis. Eur Respir J 2011;37:632-639. [http://dx.doi. org/10.1183/09031936.00055210] 21. Cormier Y, Tremblay GM, Fournier M, Israel-Assayag E. Long-term viral enhancement of lung response to Saccharopolyspora rectivirgula. Am J Respir Crit Care Med 1994;149:490-494. [http://dx.doi.org/10.1164/ajrccm.149.2.8306051] 22. Hoppin JA, Umbach DM, Kullman GJ, et al. Pesticides and other agricultural factors associated with self-reported farmer’s lung among farm residents in the Agricultural Health Study. Occup Environ Med 2007;64:334-341. [http://dx.doi.org/10.1136/ oem.2006.028480] 23. Cormier Y, Gagnon L, Berube-Genest F, Fournier M. Extrinsic allergic alveolitis: The influence of cigarette smoking. Am Rev Respir Dis 1988;137:1104-1109. [http:// dx.doi.org/10.1164/ajrccm/137.5.1104] 24. Munakata M, Tanimura K, Ukita H, et al. Smoking promotes insidious and chronic farmer’s lung disease, and deteriorates clinical outcome. Intern Med 1995; 34:966-971. [http://dx.doi.org/10.2169/internalmedicine.34.966] 25. Pozzi E. Extrinsic allergic alveolitis (hypersensitivity pneumonitis). In: Grassi C, Brambella C, Costabel U, et al., eds. Pulmonary Diseases. London: McGraw-Hill International, 1999:289-294. 26. Sansores R, Salas J, Chapela R, Barquin N, Selman M. Clubbing in hypersensitivity pneumonitis: Its prevalence and possible prognostic role. Arch Intern Med 1990;150:1849-1851. [http://dx.doi.org/10.1001/archinte.1990.00390200053010] 27. Selman M, Vargas MH. Airway involvement in hypersensitivity pneumonitis. Curr Opin Pulm Med 1998;4:9-15. [http://dx.doi.org/10.1097/00063198-199801000-00003] 28. Craig TJ, Hershey J, Engler RJ, Davis W, Carpenter GB, Salata K. Bird antigen persistence in the home environment after removal of the bird. Ann Allergy 1992;69(6):510-512. 29. Tomiyama N, Müller NL, Johkoh T, et al. Acute parenchymal lung disease in immunocompetent patients: Diagnostic accuracy of high-resolution CT. Am J Roentgenol 2000;174(6):1745-1750. [http://dx.doi.org/10.2214/ajr.174.6.1741745] 30. Cormier Y, Brown M, Worthy S, Racine G, Muller NL. High-resolution computed tomographic characteristics in acute farmer’s lung and in its follow-up. Eur Respir J 2000;16:56-60. [http://dx.doi.org/10.1034/j.1399-3003.2000.16a10.x]

31. Hansell DM, Moskovic E. High-resolution computed tomography in extrinsic allergic alveolitis. Clin Radiol 1991;43:8-12. [http://dx.doi.org/10.1016/S00099260(05)80345-9] 32. Remy-Jardin M, Remy J, Wallaert B, Muller NL. Subacute and chronic bird breeder hypersensitivity pneumonitis: Sequential evaluation with CT and correlation with lung function tests and bronchoalveolar lavage. Radiology 1993;189:111-118. [http:// dx.doi.org/10.1148/radiology.189.1.8372179] 33. Adler BD, Padley SP, Muller NL, Remy-Jardin M, Remy J. Chronic hypersensitivity pneumonitis: High-resolution CT and radiographic features in 16 patients. Radiology 1992;185:91-95. [http://dx.doi.org/10.1148/radiology.185.1.1523340] 34. Cormier Y , Bélanger J , Durand P. Factors influencing the development of serum precipitins to farmer’s lung antigen in Quebec dairy farmers. Thorax 1985;40(2):138142. [http://dx.doi.org/10.1136/thx.40.2.138] 35. Dalphin JC, Toson B, Monnet E, et al. Farmer’s lung precipitins in Doubs (a department of France): Prevalence and diagnostic value. Allergy 1994;49(9):744-750. [http://dx.doi.org/10.1111/j.1398-9995.1994.tb02097.x] 36. Inase N, Unoura K, Miyazaki Y, Yasui M, Yoshizawa Y. Measurement of bird specific antibody in bird-related hypersensitivity pneumonitis. Nihon Kokyuki Gakkai Zasshi 2011;49(10):717-722. 37. Ramırez-Venegas A, Sansores RH, Perez-Padilla R, Carrillo G, Selman M. Utility of a provocation test for diagnosis of chronic pigeon breeder’s disease. Am J Respir Crit Care Med 1998;158:862-869. [http://dx.doi.org/10.1164/ajrccm.158.3.9710036] 38. Ohtani Y. Inhalation provocation tests in chronic bird fancier’s lung. Chest 2000;118(5):1382-1389. [http://dx.doi.org/10.1378/chest.118.5.1382] 39. Morell F, Roger A, Reyes L, Cruz MJ, Murio C, Mu-oz X. Bird fancier’s lung: A series of 86 patients. Medicine (Baltimore) 2008;87:110-130. [http://dx.doi.org/10.1097/ MD.0b013e31816d1dda] 40. Caillaud DM. Bronchoalveolar lavage in hypersensitivity pneumonitis: A series of 139 patients. Inflamm Allergy Drug Targets 2012;11(1):15-19. [http://dx.doi. org/10.2174/187152812798889330] 41. Ando M , Konishi K , Yoneda R , Tamura M . Difference in the phenotypes of bronchoalveolar lavage lymphocytes in patients with summer-type hypersensitivity pneumonitis, farmer’s lung, ventilation pneumonitis, and bird fancier’s lung: Report of a nationwide epidemiologic study in Japan. J Allergy Clin Immunol 1991; 87(5):10021009. [http://dx.doi.org/10.1016/0091-6749(91)90423-l] 42. Wahlström J, Berlin M, Lundgren R, et al . Lung and blood T-cell receptor repertoire in extrinsic allergic alveolitis. Eur Respir J 1997;10(4):772-779. 43. Coleman A. Histologic diagnosis of extrinsic allergic alveolitis. Am J Surg Pathol 1988;12(7):514-518. 44. Yoshizawa Y. Chronic hypersensitivity pneumonitis in Japan: A nationwide epidemiologic survey. J Allergy Clin Immunol 1999;103(2 Pt 1):315-320. [http:// dx.doi.org/10.1016/s0091-6749(99)70507-5] 45. Terho EO. Diagnostic criteria for farmer’s lung disease. Am J Ind Med 1986;10:329. [http://dx.doi.org/10.1002/ajim.4700100333] 46. Richerson HB, Bernstein IL, Fink JN, et al. Guidelines for the clinical evaluation of hypersensitivity pneumonitis. Report of the Subcommittee on Hypersensitivity Pneumonitis. J Allergy Clin Immunol 1989;84(5):839-844. [http://dx.doi. org/10.1016/0091-6749(89)90349-7] 47. Cormier Y, Lacasse Y. Keys to the diagnosis of hypersensitivity pneumonitis: The role of serum precipitins, lung biopsy, and high-resolution computed tomography. Clin Pulm Med 1996,3(2):72-77. [http://dx.doi.org/10.1097/00045413-199603000-00004] 48. Schuyler M, Cormier Y. The diagnosis of hypersensitivity pneumonitis. Chest 1997;111(3):534-536. [http://dx.doi.org/10.1378/chest.111.3.534] 49. Kokkarinen JI, Tukiainen HO, Terho EO. Effect of corticosteroid treatment on the recovery of pulmonary function in farmer’s lung. Am Rev Respir Dis 1992;145(1):3-5. [http://dx.doi.org/10.1164/ajrccm/145.1.3] 50. Selman M. Hypersensitivity pneumonitis. In: Schwarz M, King TE Jr, eds. Interstitial lung disease, 5th ed. Shelton, CT: People’s Medical Publishing House-USA, 2011:597-625. 51. Pérez-Padilla R. Mortality in Mexican patients with chronic pigeon breeder’s lung compared with those with usual interstitial pneumonia. Am Rev Respir Dis 1993;148(1):49-53. [http://dx.doi.org/10.1164/ajrccm/148.1.49] 52. Walsh SL, Sverzellati N, Devaraj A, Wells AU, Hansell DM. Chronic hypersensitivity pneumonitis: High resolution computed tomography patterns and pulmonary function indices as prognostic determinants. Eur Radiol 2012;22(8):1672-1679. [http://dx.doi.org/10.1007/s00330-012-2427-0] 53. Koschel DS, Cardoso C, Wiedemann B, Hoffken G, Halank M. Pulmonary hypertension in chronic hypersensitivity pneumonitis. Lung 2012;190:295-302. [http://dx.doi.org/10.1007/s00408-011-9361-9] 54. Kuramochi J. Lung cancer in chronic hypersensitivity pneumonitis. Respiration 2011;82(3):263-267. [http://dx.doi.org/10.1159/000327738] 55. Lacasse Y, Cormier Y. Review: Hypersensitivity pneumonitis. Orphanet Journal of Rare Diseases 2006;1:25. [http//:dx.doi.org/10.1186/1750-1172-1-25]

SARJ VOL. 21 NO. 3 2015

Asthma limits the full potential of millions of South Africans you can control your

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South African Respiratory Journal Vol 20 No 2

CASE REPORT

Pleural effusion in children associated with adenovirus infection G Tiva, FC Paed; T Gray, Cert Paed Pulm; M Zampoli, Cert Paed Pulm; A Vanker, Cert Paed Pulm Division of Paediatric Pulmonology, Department of Paediatrics and Child Health, Red Cross War Memorial Children’s Hospital, University of Cape Town, South Africa Corresponding author: A Vanker (aneesa.vanker@uct.ac.za)

Viral pathogens are rare causes of pleural effusion in children. We present two cases of pleural effusions in children associated with adenovirus infection. Hepatomegaly with transaminitis, pleural fluid lymphocytosis and poor response to antibiotics were common features. Adenovirus infection should be considered in the differential diagnosis of pleural effusion in children. S Afr Resp J 2015;21(3):78-79. DOI: 10.7196/10.2015.v21i3.78

Parapneumonic effusions constitute the majority of pleural effusions in children.[1] Common aetiological pathogens include Streptococcus pneumoniae, Staphylococcus aureus and Mycobacterium tuberculosis (TB). [2] The incidence of pneumococcal-related empyema is expected to decline since introduction of PCV13 in the South African immunisation programme in 2011.[3] TB and other pathogens, such as viruses, may therefore become relatively more important causes of pleural effusion in children. We report two cases of adenovirus-associated pneumonia and pleural effusion who presented with similar clinical features in which no other pathogen was identified.

Case reports

Case 1 A 16-month-old, previously well female was referred for pneumonia which was not improving despite 5 days of inpatient, broad-spectrum antibiotics. Perinatal history was uneventful and immunisations including PCV13 were up to date. She was febrile (temperature 38°C), tachypnoeic (RR 64 bpm) and hypoxic with subcostal and intercostal recessions. There was stony dullness and reduced breath sounds over the right-lower zone, consistent with a large pleural effusion. She had a 4 cm hepatomegaly. Chest radiograph showed opacification of the right hemithorax (Fig. 1). A pleural effusion was confirmed by ultrasound and successfully drained by pigtail pleural catheter. Pleural fluid was sent for cytology, biochemical analysis, routine bacterial and mycobacterial culture, GeneXpert and respiratory virus polymerase chain reaction (PCR) (Anyplex™ II RV16 Detection). Blood and microbiological investigations are presented in Table 1. Fever and symptoms persisted despite drainage and second-line antibiotics (ertapenem and clarithromycin). Anti-tuberculosis therapy was initiated but later withdrawn due to lack of evidence of TB disease. The patient showed gradual clinical and radiological improvement and the pleural drain was removed after 4 days. All bacterial cultures and TB investigations were negative. Adenovirus was isolated from the pleural fluid and induced sputum.

Fig. 1. Chest X-ray showing opacification of right lung and pleural effusion. Case 2 A 10-month-old HIV-exposed but HIV-uninfected female was referred from a local clinic with pneumonia, acute gastroenteritis and severe dehydration. Immunisations, including PCV13, were up to date. On presentation she was febrile (T 38°C), severely dehydrated and shocked. She had signs of severe pneumonia: tachypnoea (RR 55 bpm), subcostal and intercostal recessions and hypoxia. Over 48 hours the gastroenteritis and dehydration resolved, but the fever and respiratory symptoms persisted despite broad antibiotic cover (cloxacillin and ceftriaxone). On day 2 admission the patient had a generalised seizure. Lumber puncture was done and was normal. Furthermore, stony dullness and decreased breath sounds over the right hemithorax suggested a pleural effusion, which was confirmed on a chest radiograph. A pigtail pleural drain was inserted and pleural

SARJ VOL. 21 NO. 3 2015

CASE REPORT Table 1. Routine blood and microbiological investigations. Case 1

Case 2

Bloods HIV antibody test

Negative

WCC (×106/L)

13.66

10.99

CRP (mg/L)

16.1

14.5

Induced sputum (Gene Xpert Negative and TB culture)

Negative

Mantoux

Negative

Test unavailable

ALP (U/L) (75 - 316)

238

241

GGT (U/L) (1 - 39)

158

109

ALT (U/L) (4 - 35)

335

100

AST (U/L) (0 - 65)

986

132

LDH (U/L) (180 - 430)

306

2 888

Protein (g/L)

Glucose (mmol/L)

LDH (U/L)

763

5 464

Polymorphs cells/mm3

115

Lymphocytes cells/mm

560

1 120

Erythrocytes cells/mm

Liver enzymes

Pleural fluid analysis

480

880

Gene Xpert (PCR)

Negative

Bacterial culture

Negative

Viral panel PCR

Adenovirus

Blood culture

Negative

Induced sputum viral PCR

Adenovirus

WCC = white cell count, CRP = C-reactive protein.

fluid was sent for analysis. Blood and microbiological investigations are presented in Table 1. Anti-TB therapy was not initiated as there was no evidence of TB disease. The patient gradually improved and the pleural drain was removed after 7 days. All bacterial cultures and TB investigations were negative and adenovirus was isolated in the pleural fluid and induced sputum.

Discussion

We report two cases of adenoviral infection associated with pneumonia and unilateral pleural effusion. Parapneumonic effusions constitute the majority of paediatric pleural effusions, with bacterial infections being the most common.[1] Viral infections are unusual causes of pleural effusion. They generally cause smaller effusions than those caused by bacterial infections and tend to resolve without intervention. A few cases of adenoviral effusions have been reported in the literature and occur mainly in epidemics. Serotype 3 and 7 have been implicated and present with a severe clinical course and raised transaminitis has been reported in some cases.[1,2]

Our two cases presented with acute systemic illness, pneumonia with unilateral pleural effusions and extra-pulmonary manifestations: hepatic inflammation in both cases and probable febrile convulsion in case 2. Despite empiric antibiotic cover, both patients showed little clinical improvement, which made a bacterial aetiology unlikely. Unremarkable infective markers and negative blood cultures supported this. However, the possibility of bacterial co-infection could not be excluded as antibiotic treatment was commenced prior to admission. Molecular methods such as PCR to identify bacterial pathogens may be useful in such cases.[4] TB infection was considered the aetiology as both had pleural fluid lymphocytosis. However, the severe clinical course was not in keeping with TB. TB effusions present more indolently and are more common in older children and adults.[5] Both cases had received three doses of pneumococcal conjugate vaccine (PCV13) as per the South African immunisation schedule. Since the introduction of PCV13 in the immunisation programme, incidences of pneumococcal-related pneumonia and pleural effusion are expected to decrease. [3] TB and other pathogens including viruses may become more prominent causes of paediatric pleural effusion. Adenovirus was isolated from the pleural fluid and induced sputum of both cases, making adenovirus the most likely causative pathogen. Adenoviral serotyping was not done as it is not routinely available. Pleural fluid drainage and intensive supportive care management yielded a good outcome. In conclusion, adenovirus infection should be considered in the differential diagnosis of pleural effusion in children, particularly those not responding to antimicrobial cover as expected. Learning points • Parapneumonic pleural effusions in children can be caused by viral infections. • Pleural fluid analysis for respiratory viruses is a useful tool to confirm an underlying viral infection. • Thoracentesis and supportive management yielded good results. • Adenovirus infection should be considered in the differential diagnosis of pleural effusion in children, particularly those not responding to antimicrobial treatment. References

1. Utine GE, Ozcelik U, Kiper N, et al. Pediatric pleural effusions: aetiological evaluation in 492 patients over 29 years. Turk J Pediatr 2009;51(3):214-219. 2. Honh JY, Lees HJ, Piedra PA, et al. Lower respiratory tract infections due to adenovirus in hospitalizated Korean children: Epidemiology, clinical features, and prognosis. Clin Infect Dis 2001;32(10):1423-1429. [http://dx.doi.org/10.1086/320146] 3. Simonsen L, Taylor RJ, Schuck-Paim C, Lustig R, Haber M, Klugman KP. Effect of 13-valent pneumococcal conjugate vaccine on admissions to hospital 2 years after its introduction in the USA: A time series analysis. Lancet Respir Med 2014;2(5):387394. [http://dx.doi.org/10.1016/S2213-2600(14)70032-3] 4. Blaschke AJ, Heyrend C, Byington CL, et al. Molecular analysis improves pathogen identification and epidemiologic study of pediatric parapneumonic empyema. Pediatr Infect Dis J 2011;30(4):289-294. [http://dx.doi.org/10.1097/INF.0b013e3182002d14] 5. Sharma S, Sarin R, Khalid UK, Singla N, Sharma PP, Behera D. Clinical profile and treatment outcome of tubercular pleurisy in pediatric age group using DOTS strategy. Indian J Tuberc 2009;56(4):191-200.

79 SARJ VOL. 21 NO. 3 2015

SATS NEWS

SATS AGM August 2015: President’s Report It has been an honour serving as President of SATS for the last 2 years. My job has been made a lot easier by the council members and the SATS secretary (Emelia Ellapen), who have contributed immensely to the efficient running of the society. This report covers the last year, as I have submitted a report in June 2014 for the preceding year. 1. Membership The membership has grown significantly and sits at 172 members at present. 2. SATS website This has been regularly updated and run by Dr Anish Ambaram, to whom we are grateful. The website provides links to various other societies and resources. 3. CME activities and congresses There have been a number of CME meetings held since the last report, including: • A master class sponsored by Novartis and one by Aspen Pharmaceuticals. • A tuberculosis workshop at the University of Cape Town (UCT). • A paediatric pulmonology/neonatology workshop hosted by Pierre Goussard. • An interventional pulmonology workshop hosted by UCT and one by Stellenbosch University. • Pre-congress workshops have also grown in popularity and include thoracic surgery, interventional pulmonology, spirometry and paediatric pulmonology. • Smoking cessation symposium hosted by Richard van Zyl-Smit. The next SATS congress will be hosted by the University of the Witswatersrand in August 2016. 4. The South African Respiratory Journal (SARJ) Prof. Keertan Dheda has worked hard to continue the smooth running and publishing of the journal and is currently negotiating a contract with the Health and Medical Publishing Group to take over publishing of our journal. He has had certain challenges, which are being addressed, and we are confident that the journal will grow from strength to strength. I strongly encourage you to support the journal by submitting articles as requested by Keertan. 5. Guideline development The smoking cessation guideline was published last year. Richard van Zyl-Smit chaired this guideline committee and has done an

outstanding job. He has also contributed to the forum of International Respiratory Societies (FIRS) position statement on e-cigarettes. 6. Scholarship committee The committee is led by Richard van Zyl-Smit, who has done a sterling job. His report refers. The scholarships and awards have contributed immensely to the academic development of society members. The scholarships include the GSK, AstraZeneca, Novartis and CiplaMedpro scholarships as well as the SATS Senior and Junior Travel Fellowships and SATS best publication award. I urge society members to take advantage of these awards/scholarships. 7. The credentials committee This committee is led by Prof. Keertan Dheda. Examinations in adult and paediatric pulmonology have been held in 2014 and 2015. The committee ensures standards are maintained in training in these sub-specialities. 8. International relationships A number of SATS members have worked hard to maintain and promote partnerships with the Pan African Thoracic Society (PATS), American Thoracic Society (ATS), American College of Chest Physicians (ACCP) and the European Respiratory Society (ERS) as well as FIRS. We have signed a memorandum of understanding between SATS and the ERS, which has provided members with various opportunities including joint membership with ERS for all SATS members with no additional cost to the individual members. I encourage all of you to take advantage of this initiative and make others aware of it as well. Prof. Umesh Lalloo and I took part in the SPOI congress in November 2014 in our official capacities representing SATS. 9. Advocacy Dr Alan Peter has led this initiative to focus on public education. There have been activities around World Pneumonia Day, World COPD day, and World Asthma Day. The National Asthma Education Program (NAEP), led by Dr S Naidoo, continues to promote education and activities around asthma. I would like to take this opportunity to thank all the members of the executive council and council as well as Emelia Ellapen, who have worked tirelessly to help in the smooth running of the society. It has been a privilege and a great honour to have led SATS in the last 2 years and I am sure that the society will continue to grow under Prof. Umesh Lalloo’s leadership. Dr S Abdool-Gaffar SATS President

SARJ VOL. 21 NO. 3 2015

SATS AWARDS

AstraZeneca Respiratory Research. Dr Erica Shaddock not attending. Accepting the award: Ismael Kalla. Rep: Erika Koppers.

GSK Pulmonology Research Fellowship. Dr Shrish Budree not attending. Accepting the award: Prof. H Zar. Rep: Mr Pepe Sefike.

Cipla-Medpro Travelling Lectureship 2014. Dr Ivan Schewitz. Rep: Dr Jaco van Zyl.

Novartis Respiratory Fellowship 2015: Dr Lynelle Mottay. Rep: Nileshen Pillay.

New Boehringer Ingelheim Research Fellowship. Accepting the fellowship: Prof. R van Zyl-Smit. Rep: Andrew Eve.

SATS Best Publication award for 2014: Prof. R van Zyl-Smit. Rep: SATS President Prof. U Lalloo.

Best Poster Presentation: Dr Barnard. Accepting the award: Prof Irusen.

Best Adult Oral Presentations: Dr J Peter. Accepting the award: Prof. E Bateman.

Best Oral Paediatrics Presentation: Dr D Gray. Accepting the award: Prof. H Zar.

81 SARJ VOL. 21 NO. 3 2015

BREATH-TAKING NEWS

Pleural irrigation with normal saline for empyema Pleural infection remains a serious condition that has significant morbidity and mortality.[1] In wellresourced countries the mortality is estimated to be approximately 20% in the 6 months following the initial presentation.[2] Despite this alarming mortality, controversy remains regarding the management and specifically the role of fibrinolytic therapy.[3] The impact of pleural infections is likely to be greater in resource-limited countries like South Africa where there is a high prevalence of infectious diseases. Medical management with intravenous antibiotics and intercostal drainage is the mainstay of treatment, but this fails in a proportion of patients, mandating surgical intervention. Pre-emptive surgical management is of unproven benefit and may be costly. In 2011, The Multi-centre Intra-pleural Sepsis Trial (MIST 2) suggested that a combination of tissue plasminogen activator and DNase improves the chest radiographic appearance after a week, but this approach is expensive and requires further validation.[4] Intrapleural saline irrigation is a simple technique that has been performed in many European countries despite the lack of evidence of its efficacy from controlled trials. A recent randomised controlled pilot study – the Pleural Irrigation Trial (PIT) – was performed in 35 patients with pleural infection requiring chest-tube drainage in which pleural irrigation with saline plus best-practice management was compared with the latter alone.[5] Patients receiving the additional saline irrigation had a greater reduction in pleural collection volume on computed tomography compared with those receiving standard care: 32.3% v. 15.3%. Additionally, significantly fewer patients in the irrigation group were subsequently referred for surgery (odds ratio 7.1,

95% confidence interval 1.23 - 41.0; p=0.03). There was no difference in length of hospital stay, fall in C-reactive protein, white cell count, procalcitonin or adverse events between the treatment groups, and no serious complications were documented. This pilot study indicates that pleural irrigation with normal saline may increase pleural fluid drainage and reduce referrals for surgery in pleural infections. This may provide a simple and cost-effective alternative to more expensive regimens should the results of this pilot study be reproduced in larger controlled studies. Dr Donald Simon Pulmonology Fellow, Division of Pulmonology, Department of Medicine, Stellenbosch University, South Africa

References

1. Chapman SJ, Davies RJ. Recent advances in parapneumonic effusions and empyema. Curr Opin Pulm Med 2004;10(4):299-304. 2. Davies CW, Kearney SE, Gleeson FV, Davies RJ. Predictors of outcome and longterm survival in patients with pleural infection. Am J Respir Crit Care Med 1999;160(5):1682-1687. [http://dx.doi.org/10.1164/ajrccm.160.5.9903002] 3. Koegelenberg CFN, Diacon AH, Bolliger CT. Parapneumonic pleural effusion and empyema. Respiration 2008;75(3):241-250. [http://dx.doi.org/10.1159/000117172] 4. Rahman NM, Maskell NA, West A, et al. Intrapleural use of tissue plasminogen activator and DNase in pleural infection. N Engl J Med 2011;365(6):518-526. [http:// dx.doi.org/10.1056/NEJMoa1012740] 5. Hooper CE, Edey AJ, Wallis A, et al. Pleural irrigation trial (PIT): A randomised controlled trial of pleural irrigation with normal saline versus standard care in patients with pleural infection. Eur Respir J 2015;46(2):456-463. [http://dx.doi. org/10.1183/09031936.00147214]

S Afr Resp J 2015;21(3):82-83. DOI:10.7196/10.2015.v21i3.82-1

Three rapid tests for the diagnosis of drug-resistant tuberculosis Multidrug-resistant tuberculosis (MDR-TB) is more difficult and costly to treat than drug-susceptible TB and patient outcomes are unfortunately worse. In South Africa, detection of drug-resistant tuberculosis (DRTB) increases each year,[1] and curing and preventing the spread of these strains of TB bacteria requires a wide range of resources, including prompt diagnosis and effective antibiotics. One such antibiotic, Bedaquiline,[2] is the first drug in a new class of antiTB medications to be approved in more than 40 years by the US Food and Drug Administration (FDA). More effective treatment strategies mean that diagnosing MDR-TB becomes even more important in combating this increasing global burden. In a recent multicentre, prospective, head-to-head clinical evaluation study by Catanzaro et al.,[3] the performance of three rapid tests – two DNA-based rapid diagnostic assays (line probe assay and pyrosequencing) and one growth-based assay – were evaluated for diagnosing drug resistance in patients at risk for M/DR-TB, relative to the World Health Organization’s approved phenotypic reference standard of the Mycobacterium growth indicator tube and drug susceptibility testing (MGIT DST). Sputum from 1 128 study participants at TB clinics

in India, Moldova and South Africa were examined. The comparisons showed that all three rapid assays accurately identified resistance to first- and second-line oral antibiotic treatments (isoniazid, rifampin, moxifloxacin and ofloxacin). They were less accurate but still very good at detecting resistance to the injectable antibiotics (amikacin and capreomycin) but performed poorly in detecting resistance to only one drug, kanamycin. As expected, the molecular techniques were superior when comparing the time it took to obtain results, with a mean time of 1.1 days for both DNA testing methods, 14.3 days for the rapid culture method, and 24.7 days for the reference standard test. Although the two molecular techniques may be costly, the third technique employs a low-cost and easy-to-use version of the standard bacterial culture technique, making it suitable for resource-limited community clinics and hospitals. It would seem that the World Health Organization’s goal of reducing deaths due to TB by 95% by 2050 may be achievable with such developments in improved diagnostics. Dr Morné Vorster Pulmonology Fellow, Division of Pulmonology, Department of Medicine, Stellenbosch University, South Africa

SARJ VOL. 21 NO. 3 2015

BREATH-TAKING NEWS References

1. Hughes J, Osman M. Diagnosis and management of drug-resistant tuberculosis in South African adults. S Afr Med J 2014;104(12):894. 2. Diacon AH, Pym A, Grobusch MP, et al. Multidrug-resistant tuberculosis and culture conversion with Bedaquiline. N Engl J Med 2014;371(8):723-732. [http://dx.doi. org/10.1056/NEJMoa1313865]

3. Catanzaro A, Rodwell TC, Catanzaro DG, et al. Performance comparison of three rapid tests for the diagnosis of drug-resistant tuberculosis. PLoS One 2015;10(8):e0136861. [http://dx.doi.org/10.1371/journal.pone.0136861]

S Afr Resp J 2015;21(3):82-83. DOI:10.7196/10.2015.v21i3.82-2

Lung-function trajectories leading to chronic obstructive pulmonary disease Chronic obstructive pulmonary disease (COPD) is the third leading cause of morbidity and mortality worldwide. A gradual decline in forced expiratory volume in 1 second (FEV1) is a normal part of ageing. After maximal lung function is obtained, lung function remains steady with very minimal change from age 20 to 35 years and thereafter starts declining. However, this rate of decline is accelerated in patients with COPD and continued smokers,[1] with greater decline in the early stages of COPD (GOLD II and III),[2] emphasising the importance of early smoking cessation interventions. However, accelerated decline is not the only trajectory for the development of COPD. Lange et al.[3] recently reported that accelerated decline is not obligate in the genesis of COPD and low FEV1 attained during young adulthood increases the risk of developing COPD. This observation stemmed from a retrospective study involving three large cohorts – the Framingham Offspring Cohort, the Copenhagen City Heart Study, and the Lovelace Smokers Cohort. The FEV1 (≥80% or <80% of the predicted value) at cohort inception (before 40 years old) as well as at the last cohort visit were measured. The rate of decline in the FEV1 over time according to their FEV1 at cohort start and COPD status (GOLD grade 2/higher) at final visit was determined. There were 4 417 subjects and 495 had COPD at cohort end. Among the 657 participants who had an FEV1 of less than 80% of the predicted

value before 40 years of age, 174 (26%) had COPD, whereas among 2 207 subjects who had a baseline FEV1 of at least 80% of the predicted value before 40 years of age, 158 (7%) had COPD. Approximately half the persons with COPD had a normal FEV1 before 40 years of age and had a rapid decline in FEV1 thereafter, while the remaining half had a low FEV1 during early adulthood with a normal decline thereafter. This study suggests that a low lung function or FEV1 with normal rate of decline during early adulthood is an important risk factor for the development of COPD and that accelerated decline in lung function from a normal FEV1 is not a prerequisite for the genesis of COPD. Dr Shinu Abraham Discovery Sub-specialist Fellow, Division of Pulmonology, Department of Medicine, Stellenbosch University, South Africa

References

1. O’Hara P, Grill J, Rigdon MA, Connett JE, Lauger GA, Johnston JJ. Design and results of the initial intervention program for the Lung Health Study. Prev Med 1993;22(3):304-315. 2. Tantucci C, Modina D. Lung function decline in COPD. Int J Chron Obstruct Pulmon Dis 2012;7:95-99. [http://dx.doi.org/10.2147/COPD.S27480] 3. Lange P, Celli B, Agustí A, et al. Lung-function trajectories leading to chronic obstructive pulmonary disease. N Engl J Med 2015;373(2):111-122. [http://dx.doi. org/10.1056/NEJMoa1411532]

S Afr Resp J 2015;21(3):82-83. DOI:10.7196/10.2015.v21i3.83

83 SARJ VOL. 21 NO. 3 2015

WHOâ&#x20AC;&#x2122;S WHO

SATS council members (August 2015 - 2017) President

Prof. U Lalloo

Vice President

Prof. K Dheda

Secretary

Prof. M Wong

Treasurer

Prof. C Koegelenberg

Past President

Dr M S Abdool-Gaffar

Technology

Mr D Maree

Paediatric Pulmonology

Dr A Vanker

Private Practice

Dr C Smith

Thoracic Surgery

Dr I Schewitz

SARJ Editor

Prof. K Dheda

Scholarship Selection Committee

Prof. R van Zyl-Smit

Credentials Committee

Prof. K Dheda

CME Committee

Dr M S Abdool-Gaffar

NAEP Representative

Dr S Naidoo

Wits University Representative

Dr A Peter

Stellenbosch University Representative

Prof. E Irusen

Natal University Representative

Prof. R Masekela

University of the Free State Representative

Dr A E Kappos

University of Pretoria Representative

Prof. R Green

Sefako Makgatho Health Sciences University (SMU)

Prof. A Goolam-Mahomed

University of Limpopo

Dr S Risenga

Walter Sisulu University Representative

Prof. P Oluboyo

University of Cape Town Representative

Dr G Calligaro

Elected Members

Dr C Verwey

Dr G Alexander

Dr B Allwood

SARJ VOL. 21 NO. 3 2015

PRODUCT NEWS

85 SARJ VOL. 21 NO. 2 2015

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

SARJ VOL. 21 NO. 2 2015

EVENTS

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

87 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

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