SARJ Vol 23, No 1 (2017)

South African

Respiratory Journal VOLUME 23

|

NUMBER 1

|

MARCH 2017

OFFICIAL JOURNAL OF THE S.A. THORACIC SOCIETY ISSN 2345-4678

FOXAIR

everyone and it’s yours to give

Air is for

Why wait to

prescribe?

S4 FOXAIR® 50/250 and 50/500 ACCU HALER® - 2/21.5. /05 2 05 . ach blister contains a mi ture of salmeterol inafoate equivalent to 50 µg of salmeterol and microfine fluticasone propionate 250 µg or 500 µg . pplicant la oSmith line South frica Pty td. Co. eg. o. 1 /0 01 5/0 . awkins venue, pping Industria 1, Cape Town, 0. or full prescribing information plese refer to the package insert approved by the edicines egulatory uthority. ll adverse events should be reported by calling the spen edical otline number or directly to la oSmith line on 2 11 5 000. /0 1 / 1 2 0 /1

24343 Foxair COPD A4 ad_12.8.13_8.46.indd 1

2013/08/12 8:52 AM

THE SOUTH AFRICAN

RESPIRATORY JOURNAL VOLUME 23 | NUMBER 1 | MARCH 2017

CONTENTS EDITORIAL 2

Start with the simple steps first – inhaler technique R van Zyl-Smit

ORIGINAL RESEARCH 4 7

Inhaler technique in patients attending an urban pulmonology practice J Vanderwagen, C Smith Outcome of resectable pulmonary aspergilloma and the performance gap in a high TB prevalence setting: A retrospective study S R Masoud, E M Irusen, C F N Koegelenberg, L J Du Preez, B W Allwood

REVIEW 12

Vitamin D in respiratory diseases A Goolam Mahomed

CASE REPORT 17

Interstitial lung disease-associated antisynthetase syndrome I Hassan

19

BREATH-TAKING NEWS

20

PRODUCT NEWS

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

HMPG

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EDITORIAL

Start with the simple steps first – inhaler technique Asthma is a chronic disorder affecting both children and adults. Great strides have been made in directed asthma therapy over the years. We have primarily targeted inhaled medications depositing directly into the lungs and systemic therapy targeting specific inflammatory receptors and pathways. Despite these pharmacological advances, asthma control remains globally poor when assessed according to the standard of the Global Initiative for Asthma (GINA) recommendations.[1] Regular use of background controllers should ideally be accompanied by a less than twice-weekly need for rescue medication, no nocturnal awakenings and normal day-to-day living. This poor control is no more evident than in South Africa where our clinics are filled with inadequately controlled patients and we have an unacceptably and disproportionately high mortality relating to asthma.[2] As with all chronic conditions, adherence to therapy is complex, but critical to outcomes.[3] We have seen this locally with adherence and outcomes in hypertension, HIV and tuberculosis.[4,5] In asthma and chronic obstructive pulmonary disease (COPD), where the mainstay of therapy is in the form of an inhaler, an additional element is cast into the mix: inhaler technique. Although it may be good enough to take your antihypertensive daily, for inhaled medication ‘using it’ does not necessarily mean it will reach its desired target in the lung.

The correct use of an inhaler is critical for the adequate deposition of the medication into the lower airways where it is required to act. Unless the technique is correctly demonstrated, understood, put into practice and followed up on, simple but critical errors will continue unchecked, and disease control is likely to remain poor. The study by Vanderwagen and Smith[6] in this issue of SARJ highlights a few significant issues. Firstly, the choice of inhaler device may be significant – we are spoilt in pulmonology with the array of devices and drugs available. Each device type, however, requires a different set of steps to ensure adequate lung deposition. This may complicate matters as patients could have several different devices, each requiring distinctive techniques to use. In stark contrast to this state of affairs stands the state sector, where there is no choice of devices and patients who are not able to use pressured metered devices (pMDI) have no alternatives.

2 SARJ VOL. 23 NO. 1 2017

Secondly, correct use of the device is rarely well taught and the poor technique is perpetuated by the fact that instructors may not know how to use the devices correctly themselves.

The authors rightly call for more training at all levels of healthcare provision, including specialists, pharmacists, nursing staff and students. Keeping the number and types of devices to a minimum (using combination inhalers rather than two single ones) will reduce the chance of inhalation errors with multiple devices.

Tailoring the best device and medication for a particular patient is essential to promote adherence, drug delivery and treatment efficacy.

If the device is easy to use, is used correctly and the patient feels it is working, they would be more likely to use it regularly. In medicine we often focus on the rare and complicated whereas, if we just did the simple things better, we would achieve a great deal more (for less), especially in the treatment of asthma and COPD. Richard van Zyl-Smit University of Cape Town Lung Institute, Division of Pulmonology and Department of Medicine, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa richard.vanzyl-smit@uct.ac.za 1. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. http://www.ginasthma.org/ (accessed 16 January 2016).

2. The Global Asthma Network. The Global Asthma Report. Auckland: GAN, 2014.

3. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005;353(5):487-497. https://dx.doi.org/10.1056/nejmra050100 4. O’Donnell MR, Wolf A, Werner L, Horsburgh CR, Padayatchi N. Adherence in the treatment of patients with extensively drug-resistant tuberculosis and HIV in South Africa: A prospective cohort study. J Acquir Immune Defic Syndr 2014;67(1):22-29. https://dx.doi.org/10.1097/qai.0000000000000221 5. Schneider M, Bradshaw D, Steyn K, Norman R, Laubscher R. Poverty and noncommunicable diseases in South Africa. Scand J Public Health 2009;37(2):176-186. https://dx.doi.org/10.1177/1403494808100272 6. Vanderwagen J, Smith C. Inhaler technique in patients attending an urban pulmonology practice. S Afr Respir J 2017;23(1):5-7. https://dx.doi.org/10/7196/ SARJ.2017.v23i1.150

S Afr Respir J 2017;23(1):2. DOI:10.7196/SARJ.2017.v23i1.150

CALL FOR ABSTRACTS:

Abstract Submission The Organising Committee invites the submission of abstracts for consideration for presentation at the meeting. The deadline for the submission of abstracts is 31 May 2017.

The format for all the abstracts will preferably be both as a poster, which can be viewed throughout the congress, as well as an oral presentation of 5 minutes that will be scheduled within the sessions of the meeting. Authors may wish to choose to have their presentation as an electronic poster only.

Choice of Format • Poster • Oral presentation Authors are requested to indicate their preference, but should note that the final decision lies with the Scientific Committee.

Abstracts accepted for oral platform presentation may be published in SARJ, and authors are requested to take note of the additional instructions listed.

Abstract Format The abstract should be a maximum of 300 words.

The format should be as follows: Research Abstract Introduction, Methods, Results & Conclusions Case Report Introduction, Case & Discussion Note: If visuals of patients are going to be shown, this must be accompanied by patient informed consent.

Only Abstracts conforming to this format will be considered for presentation.

Conference Theme: ‘Innovation for Respiratory Solutions’ Categories for Submission 1. Adult Pulmonology 2. Paediatric Pulmonology 3. Critical Care 4. Thoracic Surgery

The official language of the conference is English.

For further information contact Ange Bukasa – ange.bukasa@uct.ac.za Poster Presentations Full details for preparation of posters will be included in the abstract acceptance letter Acceptance Abstracts will be reviewed by the Scientific Committee.

All presenters of accepted abstracts must be registered as congress delegates.

ORIGINAL RESEARCH

Inhaler technique in patients attending an urban pulmonology practice J Vanderwagen, Registered Nurse and Midwife; C Smith, MB BCh, FCP (SA), MMed (Int), FCCP Morningside Mediclinic, Johannesburg, South Africa Corresponding author: J Vanderwagen (csmithtrials@mweb.co.za )

Objective. To evaluate the use of inhaler therapy, primarily focusing on the source of the initial inhaler training and the effects of regular monitoring of inhaler use.

Methods. We conducted a prospective study of 200 adult patients using either a metered dose inhaler (MDI) or dry powder inhaler (DPI), attending a private pulmonology practice for the treatment of asthma, chronic obstructive pulmonary disease (COPD) or asthma-COPD overlap. Each patient was evaluated once, and assessed by the investigators irrespective of the patient’s background and inhaler technique training.

Results. The MDI and DPI techniques were found to be 45% and 79% adequate, respectively (p<0.001). Patients who had initial training in a specialist or pulmonology practice showed 100% adequacy. In stark contrast, inadequate technique was observed where initial MDI training was performed by family members, general practitioners, hospital staff, pharmacy staff and self (p<0.05). Similarly, inadequate technique was seen in the DPI group when taught by family members, general practitioners, hospital staff and pharmacy staff (p<0.001).

The Accuhaler was used by 59% of the patients using a DPI; 41% used the Turbuhaler. The percentage of inadequate inhaler technique in the Accuhaler was 28%, while the percentage of inadequate inhaler use in the Turbuhaler group was lower at 10% (p<0.001).

Conclusion. In an urban private practice environment, the adequacy of inhaler technique was shown to be suboptimal. DPI technique was found to be superior to MDI technique, and the Turbuhaler was employed more adequately than the Accuhaler. There was no correlation between the duration of inhaler use and technique, but patients initially taught by non-pulmonology specialists and pulmonologists showed superior technique to that of other groups, i.e. patients taught by family members, general practitioners and hospital staff.

S Afr Respir J 2017;23(1):5-7. DOI:10.7196/SARJ.2017.v23i1.97

It is well known that difficulty in the use of inhalers may negatively impact their subsequent benefit. Control of lung disease is essential, as it has a significant effect on the number of admissions and exacerbations, which leads to higher healthcare costs.[1] Numerous devices have been marketed with adaptations to suit different patient preferences, but the proper and regular training of patients when the device is prescribed is lacking.[2] An inhaled corticosteroid is the drug of choice in the treatment of patients with persistent asthma,[3] and successful delivery of the drug is crucial.

The aim of this study was to prospectively evaluate the use of inhaler therapy, primarily focusing on the source of the initial inhaler training and the effects of regular monitoring of inhaler use.

Methods

We conducted a prospective study on 200 adult patients over a 6-month period from August 2015 to January 2016, using either a metered dose inhaler (MDI) or dry powder inhaler (DPI) in a private pulmonology practice, for the treatment of asthma, chronic obstructive pulmonary disease (COPD) or asthma-COPD overlap syndrome (ACOS).

The data apply to a single evaluation episode per patient, which assessed: (i) the device used; (ii) inhaler technique; and (iii) who the patient was initially trained by.

Adequacy of inhaler technique was determined according to the manufacturerâ&#x20AC;&#x2122;s recommendations using placebo devices. For MDI, the patients were required to shake the inhaler before use, remove the cap, breathe out away from the inhaler, put the inhaler in the mouth and press the inhaler while taking a slow, deep breath in, and hold their breath for ~10 seconds after removing the MDI from their mouth. For Accuhaler technique, the patients were required to open the Accuhaler correctly for exposure of the mouthpiece, press the lever down until it stopped, exhale (completely) away from the mouthpiece, place lips around the mouthpiece and breathe in steadily through the Accuhaler, remove from lips and hold breath for ~10 seconds afterwards. For Turbuhaler technique, the patients were required to unscrew and remove the cap. While holding the Turbuhaler upright, they should have twisted the coloured grip as far as it would go and then twisted it all the way back again until a click was heard, exhaled totally away from the mouthpiece, put the mouthpiece between their teeth, closed lips around and breathe in forcefully and deeply, and then remove the Turbuhaler from their mouth before breathing out. Part of the inhaler technique assessment was ensuring that the patients using inhaled corticosteroids rinsed their mouth after use of their device.

This information was analysed to compare MDI and DPI techniques, to assess whether the techniques were adequate or inadequate according to the guidelines given by the pharmaceutical company,

SARJ VOL. 23 NO. 1 2017

5

ORIGINAL RESEARCH

MDI v. DPI On comparing the overall inhaler technique of the MDI v. the DPI, the use of the MDI was found to be inferior. Of the patients, 179 were using DPIs and 175 were using the MDI. A total of 154 patients were using both devices. The MDI and DPI techniques were found to be 45% and 79% adequate, respectively (p<0.001). Inadequate technique was associated with poor co-ordination and incorrect use of the device (Fig. 1). Information about prior device usage and switching from one device to another because of difficulty in using a particular inhaler was not obtained during this study.

Initial training given Seven areas of initial training were compared for both the MDI and DPI. A marked inadequacy of inhaler technique was observed in patients whose initial MDI training was performed by family members (n=19), general practitioners (n=49), hospital staff, i.e. nursing staff dispensing medication (n=9), pharmacy staff (n=20) and self (n=4) (p<0.05) (Fig. 2). Similarly, inadequate technique was seen in the DPI group when taught by family members (n=7), general practitioners (n=17), hospital staff (n=5) and pharmacy staff (n=14) (p<0.001) (Fig. 3). The study revealed that initial training of both MDI (73 patients) and DPI (132 patients) in a non-pulmonology or pulmonology practice showed 100% adequacy. This may be related to the time available for training of the patients or the availability of suitably trained staff.

Duration of use There was no correlation between adequacy of the MDI or DPI and the duration of use of the inhaler, whether used for <1 year or >10Â years, as seen in Figs 4 and 5.

Adequacy, %

*

*

*

Family

GP

*

*

80 60 40 20 0

Hospital Pharmacy

Self

Specialist

Us

Fig. 2. MDI technique and initial training given. (*p<0.05) Inadequate

Adequate 100

Adequacy, %

Results

Inadequate

Adequate 100

*

*

Family

GP

*

*

*

80 60 40 20 0

Hospital Pharmacy

Self

Specialist

Us

Fig. 3. DPI technique and initial training given. (*p<0.001) Adequate

Inadequate

100 80

Adequacy, %

and to evaluate whether the duration of therapy was a marker for good or poor technique.

The statistical technique used was to test the hypothesis of the difference of proportions in two independent populations. The null hypothesis was that the proportions were equal in both populations, whereas the alternative hypothesis was chosen appropriately for each case. Appropriate use of z-statistics and Student t-statistics was allowed for as well.

60

6

15

21

0

16

1

13

1

>5

<10

4

21

7

40 20

5

8

12

11

8

7

18

1 <1

1

>1

<5

5

10

>10

Duration of inhaler use (years)

Accuhaler v. Turbuhaler With respect to DPI use, we collected a record of the patients using the Accuhaler (104 patients) and Turbuhaler (71 patients). In a study Adequate

Fig. 4. MDI technique and duration of use.

100

Inadequate

80

80

Inadequate Inadequate

60 40 20

Adequate Adequate

DPI

Fig. 1. Adequacy of MDI and DPI technique (p<0.001).

6 SARJ VOL. 23 NO. 1 2017

3

5

2

23

14

<5

5

Inadequate

5

3

5

3

60 40

21

11

2 20

11

5

35

20 0

0 MDI

Adequacy, %

Adequacy, %

100

11

Adequate

<1

1

>1

>5

Duration of inhaler use (years)

Fig. 5. DPI technique and duration of use.

<10

10

>10

ORIGINAL RESEARCH

41%

28% 59%

Adequate

Accuhaler

72%

Turbuhaler

Fig. 6. DPI percentage use comparing the Accuhaler and Turbuhaler. conducted in 2008, it was found that the Accuhaler was associated with a lower rate of incorrect handling than the Turbuhaler.[4] We included a sub-study comparing the Accuhaler and Turbuhaler, looking at percentage use between the two devices (Fig. 6) and technique inadequacies for both the DPI devices (Figs 7 and 8), in order to determine if this was still the case.

Of the patients using a DPI, 59% used the Accuhaler and 41% used the Turbuhaler. Although the percentage of Accuhaler users was considerably higher, the percentage of inadequate inhaler technique in the Accuhaler group was 28%, while the percentage of inadequate inhaler use in the Turbuhaler group was lower at 10% (p<0.001).

Discussion

In this urban-based, pulmonologist private practice population, we documented overall suboptimal inhaler technique use. However, DPI devices fared better than MDI devices. The reasons for this are uncertain, as the assumption would be that the same level of training was given to all patients. A possible explanation may be that patients are able to better train themselves using the DPI device, as a similar proportion used DPIs (n=179) and MDIs (n=175). There was no correlation between the duration of inhaler use and the technique used for the inhaler. Patients trained in a specialist and pulmonology practice showed superior technique to other groups in the study. This may simply relate to adequate time provided for training, together with teaching provided by staff educated in this area. In comparing two DPI devices, the Turbuhaler and Accuhaler, it was found that the Accuhaler was more widely used (68% Accuhaler v. 32% Turbuhaler).

The patients’ Turbuhaler technique (90% adequate) was superior to Accuhaler technique (72% adequate). The reasons for the superiority of the use of the Turbuhaler are not clear and cannot be ascertained from the study.

However, Sanchis et al.[5] reinforced the fact that no drug is effective until delivery to the site of action, and regular inhaler technique monitoring and training need to be performed, irrespective of the device type used or how long the patient has been using the medication.

The most likely reason for inhaler technique being so poor relates to inadequate training. It is suspected that the teachers themselves, including non-specialist doctors, nursing staff and pharmacists, do not know the correct technique for using different inhaler devices.

Another reason could relate to the time available to doctors, nursing

Inadequate

Fig. 7. Adequacy of the Accuhaler technique (p<0.001).

10% Adequate Inadequate 90%

Fig. 8. Adequacy of the Turbuhaler technique (p<0.001). staff and pharmacists to check the patient’s inhaler technique and to provide necessary corrective measures.

The situation may be improved by incorporating training on the use of the inhaler devices as a part of continuing medical education for medical, pharmacy and nursing students, as well as doctors.

The importance of regular monitoring of inhaler technique must be emphasised at all levels of healthcare. We would encourage the manufacturers of these devices to champion the drive to make sure their inhaler devices are used appropriately across all spheres of medicine.

Conclusion

Suboptimal use of inhalers for the management of obstructive lung disease remains a serious obstacle to the adequate management of these patients. This study highlights a significant opportunity for improving the control of obstructive lung disease by utilising improved training methods at the prescription level.

1. Van Blydenstein SA, Nqwata L, Banda NPK, Ashmore P, Wong ML. Factors affecting compliance and control of asthma in patients attending the Respiratory Outpatient Department, Chris Hani Baragwanath Academic Hospital. S Afr Respir J 2015;21(4):9195. https://doi.org/10.7196/sarj.2015.v21i4.43 2. Mash B, Rhode H, Pather M, et al. Quality of asthma care: Western Cape Province, South Africa. S Afr Med J 2009;99(12):892-896.

3. Fanta CH. Asthma. New Engl J Med 2009;360(10):1002-1014. https://doi.org/10.1056/ nejmra0804579 4. Khassawneh BY, Al-Ali MK, Alzoubi KH, et al. Handling of inhaler devices in actual pulmonary practice: Metered-dose inhaler versus dry powder inhalers. Respir Care 2008;53(3):324-328.

5. Sanchis J, Corrigan C, Levy ML, Viejo JL. Inhaler devices – from theory to practice.

Respir Med 2013;107(4):495-502. https://doi.org/10.1016/j.rmed.2012.12.007

SARJ VOL. 23 NO. 1 2017

7

ORIGINAL RESEARCH

Outcomes of resectable pulmonary aspergilloma and the performance gap in a high tuberculosis prevalence setting: A retrospective study S R Masoud,1 MD, MMed; E M Irusen,1 MB ChB, FCP (SA), PhD; C F N Koegelenberg,1 MB ChB, MMed (Int), FCP (SA), FRCP (UK), Cert Pulm, PhD; L J du Preez,2 MB ChB, DA (SA), FCS (SA), FCA (SA); B W Allwood,1 MB ChB, MPH, FCP (SA), Cert Pulm (SA), PhD Division of Pulmonology, Department of Internal Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Academic Hospital, Cape Town, South Africa 2 Cardiothoracic Surgery, Department of Surgery, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Academic Hospital, Cape Town, South Africa 1

Corresponding author: S R Masoud (salcolmx@gmail.com)

Background. Pulmonary aspergillomas develop in patients with underlying structural lung diseases. The mainstay of therapy is surgery.

Objectives. To assess treatment and clinical outcomes following diagnosis of potentially resectable pulmonary aspergilloma at the Tygerberg Hospital (TBH) between January 2013 and December 2015.

Methods. This was a retrospective analysis conducted at TBH. Patients were followed up between 6 and 29 months following diagnosis to analyse outcomes.

Results. Fifty-nine patients presented for surgery. The mean (SD) age was 44.5 (8.8) years. Thirty-six (61.0%) were male and 13 (22.0%) were HIV-positive. A previous history of pulmonary TB was identified in 83.1% of the patients. One or both upper lobes were involved in 58 patients (98.3%) and haemoptysis was the most frequent symptom, occurring in 56 patients (94.9%). Nine patients (15.3%) were considered unfit for surgery. As of June 2016, 23 (46.0%) of the remaining 50 patients had undergone surgery and 3 (6.0%) had died before surgery was performed. The median time from multidisciplinary discussion to surgery was 190 days (interquartile range 134 - 351). Twenty patients (87.0%) underwent lobectomy and 3 (13.0%) had pneumonectomy. There was no postoperative mortality. One patient developed bleeding, persistent air leak and aspiration pneumonia postoperatively. Three patients were hospitalised for >7 days postoperatively.

Following surgery, only two patients reported ongoing respiratory symptoms by day 90.

Conclusion. Less than half of the patients accepted for lung resection at TBH underwent surgery. Waiting times were long (>1 year in 25%) and were associated with mortality. Barriers to prompt surgery are complex, but should be addressed urgently.

S Afr Respir J 2017;23(1):8-13. DOI:10.7196/SARJ.2017.v23i1.154

Aspergillus is a ubiquitous fungus that causes a variety of clinical syndromes in the lung. Aspergilloma, which is the most common and best-recognised form of pulmonary involvement consists of masses of fungal mycelia, inflammatory cells, fibrin, mucus, and tissue debris, usually developing in preformed lung cavities.[1] The true incidence of aspergilloma is not known. In a study of 544 patients with pulmonary cavities secondary to tuberculosis (TB), 22% had radiological evidence of aspergilloma.[2] The natural history of aspergilloma is variable. In the majority of cases, the lesion remains stable; however, in ~10% of cases, it may decrease in size or resolve spontaneously without treatment.[3,4] An aspergilloma may be asymptomatic for years, although some patients experience minor haemoptysis. Severe haemoptysis may occur, with associated mortality rates between 2 and 14%.[5-10] Radiologically, an aspergilloma is classically a mobile, intracavitary mass surrounded by an air crescent, but it may also be an immobile ball, an irregular spongelike opacity containing air spaces, or even a network of fungal strands within cavities.[11] Medical treatment of aspergillomas with antifungal agents may be useful in preventing or treating life-threatening haemoptysis, and is considered the standard care for complex aspergilloma, also known as chronic cavitating pulmonary aspergillosis.[12] Bronchial artery

8 SARJ VOL. 23 NO. 1 2017

embolisation is frequently used as a temporising measure in patients with life-threatening haemoptysis; however, relapse occurs in ~50% of patients.[13,14] Surgical resection is the definitive treatment for patients with adequate pulmonary reserve and should be considered in all patients with severe haemoptysis. It has the benefits of prevention of lifethreatening haemoptysis, eradication of the pyogenic component and probable prolongation of life.[15-21] Although surgical resection is considered curative, it is not possible in every patient, for a variety of physiological and technical reasons. Such reasons may include poor physical condition, severe comorbidity, poor pulmonary reserve, extensive lung involvement or inability to localise the bleeding site.

Furthermore, the thoracic surgical expertise needed to perform lung resection is often limited or unavailable in low- and middle-income countries such as South Africa (SA), where aspergillomas are most common. The purpose of our study was to retrospectively review all cases of aspergilloma accepted for surgical resection at our tertiary hospital between January 2013 and December 2015, to assess outcomes.

Methods

Participants were retrospectively included in the study if they were: (i) at least 18 years old; (ii) diagnosed with pulmonary aspergilloma;

ORIGINAL RESEARCH and (iii) presented at a multidisciplinary forum at Tygerberg Hospital (TBH) between January 2013 and December 2015 for possible lung resection based on the European Respiratory Society’s guidelines.[22,23] In order to be presented for surgical resection at this forum, local protocol requires that the patient must have debilitating and/or severe and potentially life-threatening symptoms necessitating the surgery (for example, major haemoptysis or intractable pain), and in addition all patients should be deemed amenable to surgical resection by the attending pulmonologist.

Data for identified cases were collected from encounters in the chronological registers up to the end of May 2016. The hospital medical records were searched both manually and electronically for documents in hard copy and in digital format, respectively. Ethical approval for the study was obtained from the Stellenbosch University research ethics committee (ref. no. S15/07/158).

The data were captured and coded in Microsoft Office Excel 2016 (USA) before analysis using STATA 14 statistical software (StataCorp, USA). Continuous data were tested for normality using histogram plots and the Shapiro-Wilk test. For normally distributed data, means and standard deviations (SDs) were reported, while medians and interquartile ranges (IQRs) were reported for data that were not normally distributed. For categorical data, frequencies and proportions were reported.

For all estimations, 95% confidence intervals (CIs) were reported.

All significance tests for comparisons were two-sided and carried out with an alpha value of 0.05. The t-test and Mann-Whitney U-test were used for comparisons between numerical data, whereas the χ2 test and Fisher’s exact test were used for categorical variables.

Results

Between January 2013 and December 2015, 59 patients with pulmonary aspergilloma were presented to a weekly multidisciplinary forum at TBH for possible lung resection. Almost all the patients (98%) were recruited. The patients had a mean (SD) age of 44.5 (8.8) years, (range 27.4 - 66.3 years). Most patients were male (61%), and resided within the city of Cape Town municipality (52.5%) or the neighbouring Cape Winelands, a peri-urban municipality (44.1%) (Table 1). Thirteen patients (22%) were HIV-positive.

A previous history of pulmonary TB was reported in 83% of patients, and the majority (95%) of the patients presented with major haemoptysis requiring admission, while a minority (14%) reported chest pain and coughing, with or without haemoptysis. All patients presented to the forum were subjected to chest radiography, computed tomography (CT) of the chest and spirometry, and 75% underwent cardiopulmonary exercise testing as part of the workup for possible lung resection. Seventeen percent of the patients were categorised as having simple aspergilloma on CT and the remaining as complex aspergilloma according to criteria by Belcher and Plummer. [15] Most patients (89.9%) had involvement of a single lobe, and the majority (98.3%) had involvement of the upper lobes of either lung, with approximately equal involvement of the left upper (50.9%) and right upper lobes (47.5%) (Table 1). Eleven patients reported ongoing respiratory symptoms 90 days after the multidisciplinary discussion.

Nine patients (15.3%) were found to be unfit for surgery owing to poor lung function and high surgical risk. The characteristics of these

Table 1. Demographic characteristics Characteristic

n (%)*

Age (years), mean (SD)

44.5 (8.8)

Sex Male

36 (61.0)

Female

23 (39.0)

Residence City of Cape Town

31 (52.5)

Cape Winelands

26 (44.1)

Other

2 (3.4)

Symptoms Haemoptysis

56 (94.9)

Chest pain

8 (13.6)

Cough

4 (6.8)

Weight loss

2 (3.4)

Shortness of breath

3 (5.1)

Lobar involvement LUL

27 (45.8)

RUL

25 (42.4)

RUL + LUL

1 (1.7)

LUL + LLL

2 (3.4)

RUL + LLL

3 (5.1)

LLL

1 (1.7)

Type of disease Simple

10 (17.0)

Complex

49 (83.0)

Previous history of TB

49 (83.0)

HIV status Negative

41 (69.5)

Positive

13 (22.0)

Unknown

5 (8.5)

FEV1 (L/s), mean (SD)

1.83 (0.72)

Predicted % of FEV1, mean (SD)

59.3 (19.5)

DLCO (mL/min/mmHg), mean (SD)

16.1 (5.1)

Predicted % of DLCO, median (IQR)

57.1 (50.2 - 71.0)

VO2 max (mL/min/kg), mean (SD), n=44

22.6 (5.8)

Surgery Performed

23 (39.0)

Not performed

24 (40.7)

Unfit for surgery

9 (15.3)

Died prior to surgery

3 (5.1)

DLCO = diffusion capacity for carbon monoxide; FEV1 = forced expiratory volume in the first second; LLL = left lower lobe; LUL = left upper lobe; RLL = right lower lobe; RUL = right upper lobe; VO2 max = maximum oxygen uptake. *Unless otherwise specified.

SARJ VOL. 23 NO. 1 2017

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ORIGINAL RESEARCH patients are summarised in Table 2. They were relatively older than patients found fit for surgery (median age 47.6 v. 44.0 years) with significantly worse lung physiology.

The mean (SD) forced expiratory volume in the first second (FEV1) and the mean (SD) diffusion capacity for carbon monoxide (DLCO) of those unfit for surgery were 1.03 (0.37) L/s and 11.4 (3.6) mmol/min/mmHg, respectively, whereas those for surgically fit patients were 1.98 (0.67)Â L/s and 17.0 (4.9) mmol/min/mmHg, respectively. One of the patients required embolisation for recurrent haemoptysis 20 months after the discussion, while the remaining eight were lost to follow-up.

The 50 patients accepted for surgery were electively booked for the procedure with a median duration of 99 days (IQR 92 - 113) before their surgery appointment. Twentythree of them (46%) had had surgery by June 2016. There were no significant differences in the characteristics of those who underwent surgery and those who did not (Table 3).

Surgery was delayed in the majority of cases, with the median time from presentation to surgery being 190 days (IQR 134 - 351) among those who underwent surgery. Only three patients had surgery on the appointed day. The reason for delay or lack of surgery was not identified in the majority of patients. The identified reasons for delay among those who had surgery included miscommunication (n=1), hospital bed shortage (n=1), missed appointment (n=1) and lack of theatre time owing to competing emergency procedures (n=1).

Among those who did not undergo surgery, the identified reasons for delay included loss to follow-up (n=12), miscommunication (n=1), withdrawal of consent (n=2) and lack of transport (n=1). One patient developed myocarditis due to systemic lupus erythematosus and another developed active pulmonary TB. Three patients died from unknown causes before undergoing surgery.

Among those who did not undergo surgery, five remained symptomatic as at June 2016.

Table 2. Comparison between the surgically fit and unfit patients Characteristic

Surgically fit (n=50), n (%)*

Surgically unfit (n=9), n (%)*

p-value

Age (years), median (IQR)

44.05 (37.00 49.78)

47.63 (45.95 53.47)

0.066

Sex, male

31 (62)

5 (56)

0.715

City of Cape Town

21 (42)

5 (56)

Cape Winelands

27 (54)

4 (44)

48 (96)

8 (89)

Residence

Haemoptysis

0.847

Lobe involvement

0.371 0.127

LUL

25 (50)

2 (22)

RUL

20 (40)

5 (56)

RUL + RLL

2 (4)

0

LUL + LLL

0

1 (11)

RUL + LLL

1 (2)

0

LLL

2 (4)

1 (11)

Type of disease, complex

40 (80)

9 (100)

0.141

HIV-positive

11 (22)

2 (22)

0.605

FEV1 (L/s), mean (SD)

1.98 (0.67)

1.03 (0.37)

0.0001

Predicted % FEV1, mean (SD)

63.3 (17.3)

37.2 (16.6)

0.0006

DLCO, mean (SD)

17.0 (4.9)

11.4 (3.6)

0.0027

Predicted % DLCO, mean (SD)

61.4 (16.1)

43.8 (9.5)

0.0014

VO2 max (mL/min/kg), mean (SD)

23.4 (5.7)

17.9 (4.2)

0.0161

*Unless otherwise specified.

10 SARJ VOL. 23 NO. 1 2017

Among those who underwent surgery, 18 (78.3%) had resection of a single lobe, 2 (8.7%) had double lobectomy and 3 (13.0%) had pneumonectomy. There was no reported postoperative mortality.

One patient, however, developed bleeding, persistent air leak and aspiration pneumonia postoperatively, which required mechanical ventilation and an extended hospital stay.

Three further patients were hospitalised for >7 days postoperatively. Following surgery, only two patients reported ongoing respiratory symptoms by day 90. Microscopy of specimens from 22 of the resected lung sections identified fungal elements in 17 patients (73.9%) (Table 4).

Discussion

We found that in a selected population with symptomatic and potentially resectable aspergillomas, only 47% under went surgery. Resection of the involved lung is regarded as the most appropriate management strategy when the diagnosis of symptomatic aspergilloma is made and the patient is suitable for operation, [24,25] with non-operative treatment having a limited role in such patients. In the context of massive haemoptysis, the risk-benefit assessment favours a surgical approach, with an observed 5-year survival of 84% of subjects receiving lung resection, compared with 41% for those who do not,[10,26] with some authors observing the development of invasive aspergillosis in 20% of nonsurgically treated cases. [4] In the absence of massive haemoptysis, the indication for prophylactic surgical resection is less clear, with most authors suggesting observation of asymptomatic patients, and surgery only if symptoms develop.[27] All our patients required surgical resection for symptomatic disease, yet the factors responsible for delays and lack of operations appeared complicated and multifactorial. On average, patients were given appointment dates at a median of 3 months after the multidisciplinary discussion, but waited twice as long for their surgery, while over a quarter of patients waited more than a year for their operation. We were unable to identify any unique predictors for the lack of surgical intervention, and there were no differences in geographical location, HIV status, respiratory physiology or the site of aspergillomas in the lung between those who underwent surgery

ORIGINAL RESEARCH and those who did not. We were therefore unable to identify any systematic patient factors that could act as barriers to surgery.

The factors responsible for delay in surgery and non-operation were probably the result of both institutional and personal factors, although in the majority of cases no reason was identified, with high rates of loss to follow-up. In our context, institutional factors such as shortage of thoracic surgical lists, and non-availability of hospital beds for elective thoracic surgical cases, play a significant role in delaying elective surgical procedures. The high rate of loss to follow-up is of concern, and it is unclear to what extent patient and clinical factors played a role. In cases where a reason for delay was identified, a wide range of reasons were given, including abatement of symptoms, miscommunication, lack of transportation to hospital, hospital bed shortage, refusal to consent, loss to followup, clinical worsening and lack of theatre time due to emergency procedures. Personal factors as a reason for loss to follow-up are more difficult to assess, and it is not clear to what extent patient frustration with the hospital system was responsible. When performed, surgery appeared relatively safe with no reported mortality, and was well tolerated with few complications, in keeping with multiple contemporary studies where mortality rates of <1% were reported.[17-21] Without surgery, mortality was high (5.1%) and comparable to previous studies.[6-10] Our study population was relatively young and predominantly male. Pulmonary tuberculosis (TB) was the most common identified underlying lung disease in our study population in keeping with high incidence of the condition in the general population. TB is said to have the highest incidence among the 25 - 34 year age group, and to be twice as common in men in the Cape Town Metropolis.[28,29] Additionally, the low number of older patients in our study was likely due to selection bias, as older patients would have been less likely to be candidates for lung resection owing to greater surgical risk for a variety of reasons.

Previous TB was, unsurprisingly, identified as the most likely underlying disease in our study population, owing to the extremely high background incidence of TB in our country.[30] In some studies, >50% of patients with TB developed pulmonary cavities following treatment, and 10 - 30% of these cavities are estimated to be complicated by chronic

pulmonary aspergillosis, with the cavity size significantly associated with increased risk of developing aspergillosis.[31] The proportion of patients with HIV in our study is comparable with the ~19% prevalence of HIV in the general population of SA. [32] Remarkably, aspergillosis is unusual in patients with AIDS,[33] which contrasts with the relatively high frequency of aspergillosis in most other seriously immunocompromised patients. For example, up to 70% of patients with leukaemia have pulmonary aspergillosis after 30 days of neutropenia.[34] Nevertheless, the risk of developing TB is estimated to be between 26 and 31 times greater in people

infected with HIV, making them susceptible to the development of aspergillomas.[35,36] Unsurprisingly, upper lobectomy was the most common surgical procedure performed.

This is consistent with both the usual distribution of residual tuberculous cavities and the reported literature.[10,22,36,37] Study limitations Firstly, it was a retrospective cohort, and thus depended exclusively on existing clinical records. Therefore, a number of variables of interest were not consistently identified, and some data were not uniformly captured by all clinicians over the 3-year period. Secondly,

Table 3. Comparison between those resected and those not resected Characteristic

Resected (n=23), n (%)*

Not resected (n=27), n (%)* p-value

Age (years), median (IQR)

46.6 (40.5 - 49.8)

41.9 (32.6 - 49.8)

0.1995

Sex, male

15 (65.2)

16 (59.3)

0.665

City of Cape Town

11 (47.8)

16 (59.3)

Cape Winelands

12 (52.2)

9 (33.3)

Haemoptysis

22 (97.7)

26 (96.3)

Chest pain

3 (13.0)

5 (18.5)

Cough

1 (4.3)

1 (3.7)

Weight loss

0

1 (3.7)

Shortness of breath

0

1 (3.7)

Residence

0.383

Symptoms

0.908

Lobe involvement

0.903

LUL

11(47.8)

14 (51.9)

RUL

10 (43.5)

10 (37.0)

LUL + LLL

1 (4.3)

1 (3.7)

LLL

0

1 (3.7)

RUL + LLL

1 (4.3)

1 (3.7)

Type of disease

0.670

Simple

4 (17.4)

6 (22.2)

Complex

19 (82.6)

21 (77.8)

Previous history of TB

17 (73.9)

23 (85.2)

HIV-positive

5 (21.7)

6 (22.2)

0.956

FEV1 (L/s), median (IQR)

1.86 (1.63 - 2.13)

1.88 (1.51 - 2.42)

0.7099

Predicted % FEV1, median (IQR)

56.1 (51.2 - 73.0)

65.5 (49.1 - 76.6)

0.4331

DLCO, median (IQR)

16.2 (14.4 - 20.6)

16.0 (14.8 - 18.1)

0.8269

Predicted % DLCO, mean (SD)

59.6 (55.7 - 72.3)

58.6 (51.8 - 71.4)

0.6138

VO2 max (mL/min/kg), median (IQR)

23.8 (21.6 - 28.2)

22.0 (19.2 - 25.6)

0.6484

*Unless otherwise specified.

SARJ VOL. 23 NO. 1 2017

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ORIGINAL RESEARCH

Table 4. Surgical outcomes for patients undergoing surgery Characteristic

n (%)*

Days to surgery, median (IQR)

190 (134 - 351)

Extent of resection Lobectomy

18 (78.3)

Bi-lobectomy

2 (8.7)

Pneumonectomy

3 (13.0)

Complications Extended stay

4 (17.4)

Persistent air leak

1 (4.3)

Bleeding

1 (4.3)

Pneumonia Histology, fungal elements present

1 (4.3) 17 (73.9)

*Unless otherwise specified.

information on patient follow-up was not routinely documented or standardised for the majority of patients, and was obtained at non-standardised intervals. Finally, selection bias on the part of the attending physicians was possible, as only cases thought likely to be operable were presented at the multidisciplinary forum. To try to minimise these biases, we included all patients presented at the forum during the defined period, and created a standardised data extraction form for use on all patients.

Study strengths Some of the study strengths were the â&#x20AC;&#x2DC;real worldâ&#x20AC;&#x2122; approach, i.e. not within the context of a controlled trial, which perhaps allowed a more insightful assessment of current usual practice over time.

Similarly, the original data were collected by people other than the investigators, and were therefore independent of any specific hypothesis, diminishing observer bias. In addition, patients were presented in a multidisciplinary forum, which minimised the risk of errors in diagnosis.

Conclusions

Lung resection surgery remains the mainstay of therapy for pulmonary aspergilloma, yet in our context, less than half the patients fit for surgery underwent the operation, and waiting times were long (>1 year in 25%) and were associated with mortality, highlighting the need for a patient-centred approach. Barriers to prompt surgery are complex, but should be addressed urgently.

Acknowledgements. We would like to acknowledge the Department of Biostatistics at Stellenbosch University, particularly Mr Chivanse, for his contribution in analysing the data.

1. Ayman OS, Pranatharthi HC. The clinical spectrum of pulmonary aspergillosis. Chest 2002;121(6):1988-1999. https://doi.org/10.1378/chest.121.6.1988 2. British Thoracic and TB Association. Aspergilloma and residual tuberculous cavities: The results of a resurvey. A report from the Research Committee of the British Thoracic and TB Association. Tubercle 1970;51(3):227-245. https://doi.org/10.1016/00413879(70)90015-2 3. Gefter WB. The spectrum of pulmonary aspergillosis. J Thorac Imaging 1992;7(4):5674. https://doi.org/10.1097/00005382-199209000-00009

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4. Rafferty P, Biggs B, Crompton GK, Grant IW. What happens to patients with pulmonary aspergilloma? Analysis of 23 cases. Thorax 1983;38(8):579-583. https:// doi.org/10.1136/thx.38.8.579 5. Faulkner SL, Vernon R, Brown PP, Fisher RD, Bender HW. Hemoptysis and pulmonary aspergilloma: Operative versus nonoperative treatment. Ann Thorac Surg 1978;25(5):389-392. https://doi.org/10.1016/s0003-4975(10)63570-9 6. Glimp RA, Bayer AS. Pulmonary aspergilloma: Diagnostic and therapeutic considerations. Arch Intern Med 1983;143(2):303-308. https://doi.org/10.1001/ archinte.1983.00350020129023 7. Garvey J, Crastnopol P, Weisz D, et al. The surgical treatment of pulmonary aspergillomas. Thorac Cardiovasc Surg 1977;74(4):542-547.

8. Daly RC, Pairolero PC, Piehler JM, Trastek VF, Payne WS. Pulmonary aspergilloma.

Results of surgical treatment. J Thorac Cardiovasc Surg 1986;92(6):981-988.

9. Karas A, Hankins JR, Attar S, et al. Pulmonary aspergillosis: An analysis of 41 patients. Ann Thorac Surg 1976;22(1):1-7. https://doi.org/10.1016/s0003-4975 (10)63943-4 10. Jewkes J, Kay PH, Paneth M, et al. Pulmonary aspergilloma: Analysis of prognosis in relation to haemoptysis and survey of treatment. Thorax 1983;38(8):572-578. https:// doi.org/10.1136/thx.38.8.572 11. Tuncel E. Pulmonary air meniscus sign. Respiration 1984;46(1):139-144. https://doi. org/10.1159/000194682 12. Denning DW, Cadranel J, Beigelman-Aubry C, et al. Chronic pulmonary aspergillosis: Rationale and clinical guidelines for diagnosis and management. Eur Res J 2016;47(1):45-68. https://doi.org/10.1183/13993003.00583-2015 13. Swanson KL, Johnson CM, Prakash UBS, McKusick MA, Andrews JC, Stanson AW. Bronchial artery embolization: Experience with 54 patients. Chest 2002;121(3):789795. https://doi.org/10.1378/chest.121.3.789 14. Corr P. Management of severe hemoptysis from pulmonary aspergilloma using endovascular embolization. Cardiovasc Intervent Radiol 2006;29(5):807-810. https:// doi.org/10.1007/s00270-005-0329-0 15. Belcher JR, Plummer NS. Surgery in broncho-pulmonary aspergillosis. Br J Dis Chest 1960;54(4):335-341. https://doi.org/10.1016/s0007-0971(60)80067-8 16. Walsh TJ, Anaissie EJ, Denning DW, et al. Treatment of aspergillosis: Clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2008;46(3):327-360. https://doi.org/10.1086/525258 17. Lejay A, Falcoz PE, Santelmo N, et al. Surgery for aspergilloma: Time trend towards improved results? Interact Cardiovasc Thorac Surg 2011;13(4):392-395. https://doi. org/10.1510/icvts.2011.265553 18. Chen QK, Jiang GN, Ding JA. Surgical treatment for pulmonary aspergilloma: A 35-year experience in the Chinese population. Interact Cardiovasc Thorac Surg 2012;15(1):77-80. https://doi.org/10.1093/icvts/ivs130 19. Kim YT, Kang MC, Sung SW, Kim JH. Good long-term outcomes after surgical treatment of simple and complex pulmonary aspergilloma. Ann Thorac Surg 2005;79(1):294-298. https://doi.org/10.1016/j.athoracsur.2004.05.050 20. Pratap H, Dewan RK, Singh L, et al. Surgical treatment of pulmonary aspergilloma: A series of 72 cases. Indian J Chest Dis Allied Sci 2007;49(1):23-27.

21. Brik A, Salem AM, Kamal AR, et al. Surgical outcome of pulmonary aspergilloma.

Eur J Cardiothoracic Surg 2008;34(4):882-885. https://doi.org/10.1016/j. ejcts.2008.06.049 22. Brunelli A, Charloux A, Bolliger CT, et al. ERS/ESTS clinical guidelines on fitness for radical therapy in lung cancer patients (surgery and chemoradiotherapy). Eur Respir J 2009;34(1):17-41. https://doi.org/10.1183/09031936.00184308 23. Von Groote-Bidlingmaier F, Koegelenberg CFN, Bolliger CT. Functional evaluation before lung resection. Clin Chest Med 2011;32(4):773-782. https://doi.org/10.1016/j. ccm.2011.08.001 24. Babatasi G, Massetti M, Chapelier A, et al. Surgical treatment of pulmonary aspergilloma: Current outcome. J Thorac Cardiovasc Surg 2000;119(5):906-912. https://doi.org/10.1016/s0022-5223(00)70085-7 25. Massard G, Roeslin N, Wihlm JM, et al. Pleuropulmonary aspergilloma: Clinical spectrum and results of surgical treatment. Ann Thorac Surg 1992;54(6):1159-1164. https://doi.org/10.1016/0003-4975(92)90086-j 26. Passera E, Rizzi A, Robustellini M, et al. Pulmonary aspergilloma. Clinical aspects and surgical treatment outcome. Thorac Surg Clin 2012;22:345-361. https://doi. org/10.1016/j.thorsurg.2012.04.001 27. Kousha M, Tadi R, Soubania O. Pulmonary aspergillosis: A clinical review. Eur Respir Rev 2011;20(121):156-174. https://doi.org/10.1183/09059180.00001011 28. Nyabadza F, Winkler D. A simulation age-specific TB model for the Cape Town metropole. S Afr J Sci 2013;109(9/10):1-7. https://doi.org/10.1590/sajs.2013/20120106 29. Austin JF1, Dick JM, Zwarenstein M. Gender disparity amongst TB suspects and new TB patients according to data recorded at the South African Institute of Medical Research laboratory for the Western Cape Region of South Africa. Int J Tuberc Lung Dis 2004;8(4):435-439.

ORIGINAL RESEARCH 30. World Health Organization (WHO). Global TB Report 2014. Geneva: WHO, 2014:171.

31. De Vallière S, Barker RD. Residual lung damage after completion of treatment for multidrug-resistant TB. Int J Tuberc Lung Dis 2004;8(6):767-771.

32. The Joint United Nations Programme on HIV/AIDS (UNAIDS). Fact Sheet 2015.

UNAIDS Rep 2015;1-8.

33. Denning DW, Follansbee SE, Scolaro MM, Norris SS, Edelstein HH, Stevens DA. Pulmonary aspergillosis in the acquired immunodeficiency syndrome. N Engl J Med 1991;324(10):654-662. https://doi.org/10.1056/nejm199103073241003 34. Schwartz RS, Mackintosh FR, Schrier SL, Greenberg PL. Multivariate analysis of factors associated with invasive fungal disease during remission induction

therapy for acute myelogenous leukemia. Cancer 1984;53(3):411-419. https://doi. org/10.1002/1097-0142(19840201)53:3%3C411:aid-cncr2820530308%3E3.0.co;2-e 35. Getahun H, Gunneberg C, Granich R, Nunn P. HIV infection-associated TB: The epidemiology and the response. Clin Infect Dis 2010;50(S3):S201-207. https://doi. org/10.1086/651492 36. Selwyn P, Hartel D, Lewis V, et al. A prospective study of the risk of TB among intravenous drug users with human immunodeficiency virus infection. N Engl J Med 1989;320(9):545-550. https://doi.org/10.1056/nejm198903023200901 37. Denning DW, Riniotis K, Dobrashian R, Sambatakou H. Chronic cavitary and fibrosing pulmonary and pleural aspergillosis: Case series, proposed nomenclature change, and review. Clin Infect Dis 2003;37(S3):S265-S280. https://doi.org/10.1086/376526

SARJ VOL. 23 NO. 1 2017

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REVIEW

Vitamin D in respiratory diseases A Goolam Mahomed, MB BCh, FCP(SA), FCCP Department of Intensive Care, Sefako Makgatho Health Sciences University, Pretoria, South Africa Corresponding author: A Goolam Mahomed (akhtergm@telkomsa.net)

Vitamin D has traditionally been known for its role in bone homeostasis with its effects on calcium and phosphate absorption and secretion.

However, new evidence is emerging of its effects on a number of other cells, especially the immune system. This article reviews the role of vitamin D as it pertains to the respiratory tract and respiratory diseases.

S Afr Respir J 2017;23(1):14-18. DOI:10.7196/SARJ.2017.v23i1.156

Vitamin D belongs to a group of fat-soluble secosteroids and is required for intestinal absorption of calcium (Ca2+) and phosphate (PO43-). In humans, vitamin D is present as ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3), and both forms can be ingested from the diet and/or supplements. The body can also synthesise vitamin D from cholesterol when sun exposure is adequate, hence it has been nicknamed the ‘sunshine vitamin’.[1] Recently, interest has grown in the role of vitamin D in many non-skeletal medical conditions, including respiratory infection and lung function.[2] Emerging evidence indicates that vitamin D-mediated innate immunity is important in host defences against respiratory tract pathogens.[3] Observational studies suggest that vitamin D deficiency increases the risk of respiratory infections, incident wheezing illness in children and adults, and can cause asthma exacerbations. Vitamin D also modulates regulatory T-cell function and interleukin-10 (IL-10) production, which may increase the therapeutic response to glucocorticoids in steroid-resistant asthma.

History

In 1914, American researchers McCollum and Davis discovered a substance in cod liver oil which was later called ‘vitamin A’. In 1922, McCollum tested modified cod liver oil in which the vitamin A had been denatured. The modified oil cured rickets in sick dogs, so McCollum concluded the factor in cod liver oil that cured rickets was distinct from vitamin A. He called it vitamin D because it was the fourth vitamin to be named.[4] In 1923, American biochemist Harry Steenbock demonstrated that the irradiation of foodstuffs, especially milk, led to a cure for rickets. In 1932, an academic collaboration between Bourdillon, Rosenheim, King and Callow led to the isolation and characterisation of vitamin D and later in the 1930s, Windaus further clarified the chemical structure of vitamin D. By 1972, Holick had discovered that vitamin D was metabolised to two active forms, i.e. calcidiol and calcitriol.[5,6]

Recommended dietary allowance of vitamin D

The US Institute of Medicine (IOM) recommended dietary allowance of vitamin D is 400 international units (IU) per day for children younger than 1 year of age, 600 IU per day for children at least 1 year of age and adults up to 70 years, and 800 IU per day for older adults.

14 SARJ VOL. 23 NO. 1 2017

The US IOM concluded that serum 25-hydroxyvitamin D (25(OH)D) of 20 ng/mL or more would cover the requirements of 97.5% of the population.[7] The US Endocrine Society’s Clinical Practice Guidelines suggest that 400 - 1 000 IU/day may be needed for children aged <1 year, 600 - 1 000 IU/day for children aged ≥1 year, and 1 500 2 000 IU/day for adults aged ≥19 years to maintain 25(OH)D above the optimal level of 30 ng/mL.[8]

Sources of vitamin D

Sources of vitamin D include sun exposure, diet and supplements.

Vitamin D2 is obtained from ultraviolet irradiation of the yeast sterol, ergosterol, and remains the only pharmaceutical form of vitamin D approved by the US Food and Drug Administration. Vitamin D3 is synthesised in the skin and is present in oil-rich fish such as salmon, mackerel and herring. Both vitamin D2 and vitamin D3 are used in food fortification and supplements. The major foods fortified with vitamin D (D2 or D3) are milk, yoghurts, cheeses, orange juice and cereals. Vitamin D is metabolised in the liver to 25-hydroxyvitamin D3 (25(OH)D3), which is the best available indicator of vitamin D status. In the kidneys, 25(OH)D3 is metabolised to its active form, 1,25-dihydroxyvitamin D3, (1,25(OH)2D3). The levels of 1,25(OH)2D3 do not reflect vitamin D status as they are regulated by parathyroid hormone, Ca2+ and PO43- levels, and fibroblast growth factor 23.[7,8]

Physiology of vitamin D

Intestinal Ca2+ and PO43- absorption is regulated by 1,25(OH)2D3, and with severe vitamin D deficiency the efficiency of Ca2+ absorption decreases from 30 - 40 to 10 - 15%. Vitamin D deficiency also stimulates the parathyroid glands, leading to secondary hyperparathyroidism.

Secondary hyperparathyroidism maintains serum Ca2+ in the normal range at the expense of mobilising Ca2+ from the bone, and increases urinary PO43- loss, resulting in a decrease in serum PO43- level and an inadequate calcium-phosphate product (Ca2+ × PO43-). This results in a defect in bone mineralisation, which leads to rickets in children and osteomalacia in adults.[7,8]

Non-skeletal actions of vitamin D

The lung, brain, prostate, breast and colon tissues, among others, as well as immune system cells, express the vitamin D receptor (VDR) and responds to 1,25(OH)2D3, the active form of vitamin D, which

REVIEW is the ligand for the VDR receptor. In fact, cells without the VDR receptor are rare. In addition, some of these tissues and cells express the enzyme 25-hydroxyvitamin D-1α-hydroxylase, which is encoded by the CYP27B1 gene. Binding of 1,25(OH)2D3 to the VDR leads to the formation of a heterodimer with retinoid X receptor, which combines with vitamin D response elements (VDREs) that then regulate gene expression.[9] Directly or indirectly, 1,25(OH)2D3 controls >200 genes, including genes responsible for the regulation of cellular proliferation, differentiation, apoptosis and angiogenesis. It decreases cellular proliferation of both normal and malignant cells, and induces their terminal differentiation.[3] One practical application is the use of 1,25(OH)2D3 and its active analogues for the treatment of psoriasis.[2] 1,25(OH)2D3 is also a potent immunomodulator. Monocytes and macrophages exposed to a lipopolysaccharide or to Mycobacterium tuberculosis up-regulate the VDR gene and the 25-hydroxyvitamin D-1α-hydroxylase gene. Increased production of 1,25(OH) 2D 3 results in synthesis of cathelicidin, a peptide capable of destroying M. tuberculosis as well as other infectious agents. When serum levels of 25(OH)D3 fall below 20 ng/mL (50 nmol/L), the monocyte or macrophage is prevented from initiating this innate immune response.[3] 1,25-(OH)2D3 also inhibits renin synthesis, increases insulin production and increases myocardial contractility.[2]

Asthma and vitamin D levels

The majority of studies report an inverse association between serum 25(OH)D3 levels and asthma morbidity.[9] Vitamin D may play a causal role in asthma pathophysiology and vitamin D status may also impact on asthma therapy via a number of mechanisms, which include its antiviral properties, enhanced steroid responsiveness and down-regulation of atopy. It may also influence asthma by regulating the expression of disease-susceptibility genes. Biologically, there are data to suggest that 1,25(OH)2D3 can directly enhance secretion of the anti-inflammatory molecule IL-10 from regulatory T-cells derived from steroid-resistant individuals with asthma.[3] In vitro, 1,25(OH)2D3 regulates inflammatory responses in airway epithelial cells and airway smooth muscle cells, both of which may be targets of corticosteroid therapy.[3] The role of maternal vitamin D levels and their association with childhood wheeze and atopy is somewhat controversial. Hypponen et al.[10] found that vitamin D supplementation increased the risk of asthma in Finnish infants, but many recent studies have come to different conclusions. Wills et al.[11] found no evidence that maternal levels of vitamin D correlate with childhood atopy or asthma, but the Vitamin D Antenatal Asthma Reduction Trial (VDAART) study found that vitamin D supplementation during pregnancy led to decreased levels of asthma and wheezing.[12] In the Generation R Study, Gazibara et al.[13] found that maternal vitamin D levels did not correlate with asthma, but low levels of 25(OH)D3 at birth in infants were associated with higher airway resistance in childhood. In a recent meta-analysis of 15 prospective studies, Song et al.[14] suggested there may be a U-shaped association between maternal 25(OH)D3 levels and asthma, with the lowest risk of asthma at approximately 70 nmol/L of 25(OH)D3.

In the HUNT study of a cohort of 25 616 Norwegian adults, the authors showed that low vitamin D status was not significantly associated with incident asthma in most adults, but it may have increased risk in men without allergies.[15] In contrast, Korn et al.[16]

found that vitamin D deficiency and insufficiency were clearly associated with asthma, and also with poor control of asthma. A number of recent trials using vitamin D replacement therapy did not show improvement in asthma control. The Vitamin D Addon Therapy Enhances Corticosteroid Responsiveness in Asthma (VIDA) trial studied adult patients with symptomatic asthma and a serum 25(OH)D3 level of <30 ng/mL across nine academic medical centres in the USA. Oral vitamin D3 (100 000 IU once, then 4 000 IU/day for 28 weeks; n=201) or placebo (n=207) was added to inhaled ciclesonide (320 μg/d). Vitamin D3 did not reduce the rate of first treatment failure or exacerbation in adults with persistent asthma and vitamin D insufficiency.[17] Similarly, a trial of bolus-dose vitamin D3 supplementation did not influence exacerbation time for asthma or upper respiratory tract infections (URTIs) in adults with vitamin D deficiency.[18] A Cochrane meta-analysis recently showed that vitamin D supplementation does reduce the risk of severe exacerbations, and improves asthma symptom control in people with mild to moderate asthma.[19]

Vitamin D and chronic obstructive pulmonary disease

Low serum 25(OH)D3 levels have been associated with lower forced expiratory volume in 1 second (FEV1), impaired immunological control, and increased airway inflammation.[20,21] Many patients with chronic obstructive pulmonary disease (COPD) have a vitamin D deficiency, and therefore the effects of vitamin D supplementation may extend beyond preventing osteoporosis. In a recent study to determine if baseline 25(OH)D3 levels relate to subsequent acute exacerbation of COPD (AECOPD) in a cohort of patients at high risk for AECOPD, plasma 25(OH)D3 was measured at baseline in 973 participants on entry into a 1-year study designed to determine if daily azithromycin decreased the incidence of AECOPD. Relationships between baseline 25(OH)D 3 and AECOPD over 1 year were analysed with time to first AECOPD as the primary outcome and exacerbation rate as the secondary outcome. In this largely white (85%) cohort of North American patients with severe COPD (mean FEV1 1.12 L; 40% of predicted), the mean (SD) 25(OH)D3 was 25.7 (12.8) ng/mL. A total of 33.1% of participants were vitamin D insufficient (≥20 ng/mL - <30 ng/mL); 32% were vitamin D-deficient (<20 ng/mL), and 8.4% had severe vitamin D deficiency (<10 ng/mL). Baseline 25(OH)D 3 levels had no relationship to time to first AECOPD or AECOPD rates, and the authors concluded that in patients with severe COPD, baseline 25(OH)D 3 levels are not predictive of subsequent AECOPD. [22] In another study following 97 COPD patients at the Royal Free Hospital (UK), low 25(OH)D3 levels were not associated with frequent exacerbations and did not increase susceptibility to human rhinovirus infection. [23] In a randomised, single-centre, double-blind, placebo-controlled trial in Belgium, 182 patients with moderate to very severe COPD and a history of recent exacerbations were given 100 000 IU of vitamin D supplementation or a placebo every 4 weeks for 1 year. The primary outcome was time to first exacerbation. Secondary outcomes were exacerbation rate, time to first hospitalisation, time to second exacerbation, FEV1, quality of life, and death. Mean serum 25(OH)D3 levels increased significantly in the vitamin D group compared

SARJ VOL. 23 NO. 1 2017

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REVIEW with the placebo group. The median time to first exacerbation did not significantly differ between the groups, nor did exacerbation rates, FEV1, hospitalisation, quality of life, and death. However, a post hoc analysis in 30 participants with severe vitamin D deficiency (serum 25(OH)D3 levels <10 ng/mL) at baseline showed a significant reduction in exacerbations in the vitamin D-deficient group. [24] ViDiCO (Vitamin D Supplementation in Patients with Chronic Obstructive Pulmonary Disease), another recent study on vitamin D 3 supplementation in patients with COPD, found that supplementation protected against moderate or severe exacerbations, but not URTIs, in patients with baseline 25(OH)D3 levels of >50 nmol/L. [25] Vitamin D supplementation has also been suggested for improving physical performance, but a recent randomised trial did not show any benefits in this regard. [26] Although vitamin D deficiency may contribute to morbidity in COPD patients, a lack of vitamin D does not appear to contribute to excess mortality.[27]

Tuberculosis and vitamin D

The innate immune response is important in the defence against M. tuberculosis. Toll-like receptor triggering via vitamin D and cathelicidin is important in this response and may explain why black Americans, who are often vitamin D deficient, are more prone to contracting TB than are whites, and tend to have a more aggressive form of the disease.[28] Vitamin D deficiency has been linked to a higher prevalence of TB, and this may in part be explained by genetic polymorphisms of the VDR and seasonal variation in vitamin D levels, which have also been linked to susceptibility to TB.[29-33] The use of vitamin D as an adjunct to chemotherapy for TB has been tested in several clinical studies. Most of these studies have found beneficial effects, and a recent clinical trial in Pakistan, the SUCCINT (Supplementary Cholecalciferol in Recovery from Tuberculosis) study, showed accelerated clinical and radiographical improvement in those given supplemental high-dose vitamin D.[34] They also showed an improved immunological response, which was borne out by Coussens et al.[35] in another study.

Vitamin D, pneumonia and URTIs

Vitamin D regulates the production of the antimicrobial peptides cathelicidin and β-defensin-2 (βD2), which play an important role in the innate immune response to infection. Therefore, vitamin D may have a role in prevention and treatment of acute infections such as pneumonia.[36,37] Vitamin D deficiency in children has been strongly associated with the risk of acute lower respiratory tract infections (LRTIs) in a number of settings. In Ethiopia, for example, researchers found that 42% of children hospitalised for pneumonia had rickets, or severe vitamin D deficiency.[38] Associations between mortality and serum levels of 25(OH)D3, cathelicidin and βD2 were investigated in a prospective cohort of 112 patients admitted with community-acquired pneumonia during winter in New Zealand. Severe 25(OH)D3 deficiency (<30 nmol/L) was common in this population (15%), and was associated with a higher 30-day mortality rate compared with patients with sufficient 25(OH)D3.

These associations were not explained by differences in age, comorbidities or the severity of the acute illness. Neither cathelicidin nor βD2 levels predicted mortality, although there was a trend towards increased mortality with lower cathelicidin (p=0.053).

16 SARJ VOL. 23 NO. 1 2017

Neither cathelicidin nor βD2 levels correlated with 25(OH)D 3.

The authors concluded that 25(OH)D3 deficiency is associated with increased mortality in patients admitted to hospital with communityacquired pneumonia during winter.[39] In a prospective cohort study of 272 hospitalised community acquired pneumonia patients, 25(OH)D3, leukocytes, C-reactive protein, total cortisol, the Pneumonia Severity Index score and CURB-65 score were measured on admission.

Major outcome measures were intensive care unit (ICU) admission and 30-day mortality. A total of 143 (53%) patients were vitamin D deficient (<50 nmol/L), 79 (29%) patients were vitamin D insufficient (50 - 75 nmol/L), and 50 (18%) patients were vitamin D sufficient (>75 nmol/L). Vitamin D deficiency was associated with an increased risk of ICU admission and 30-day mortality independent of other factors.[40] There have been very few nutritional interventions aimed at the treatment or prevention of acute LRTIs published thus far. A randomised control trial in an area of high vitamin D deficiency in Afghanistan showed that one high dose of vitamin D3 combined with antibiotic treatment reduced the reoccurrence of pneumonia in children aged 1 - 36 months who had been hospitalised for pneumonia.[41] However, there are conflicting results from another randomised, placebo-controlled trial by the same group in the same area. Oral vitamin D3 (100 000 IU, n=1 524) was compared with a placebo (n=1 522) and given to children aged 1 - 11 months in Kabul, Afghanistan. There was no significant difference between the incidence of first or only pneumonia between the vitamin D and the placebo group. The authors concluded that quarterly bolus doses of oral vitamin D3 supplementation to infants were not an effective intervention to reduce the incidence of pneumonia in infants in this setting.[42] In a study published by Choudhary and Gupta,[43] short-term supplementation with oral vitamin D (1 000 - 2 000 IU per day for 5 days) had no beneficial effect on the resolution of severe pneumonia in under-5 children.

Vitamin D also modulates the innate response to respiratory viral infections.[44] Monthly high-dose vitamin D3 supplementation in elderly patients has been shown to reduce the incidence of acute respiratory tract infections.[45] In immunosuppressed patients and those with frequent respiratory tract infections, vitamin D supplementation has been shown to be of benefit.[46] In a recent meta-analysis of 25 randomised controlled trials, vitamin D supplementation was found to be a safe intervention, and it reduced the rate of acute respiratory tract infections, particularly in those who were initially vitamin D deficient. Those who were given daily or weekly doses benefited, but not those given bolus doses.[47]

Vitamin D and cystic fibrosis

Vitamin D deficiency is common in young children with cystic fibrosis, even in children with pancreatic sufficiency.[48] Higher levels of 25(OH)D3 are associated with lower rates of pulmonary exacerbations and, in adolescents, with better lung functions, as reflected by a higher FEV1.[49] Supplementation with vitamin D in patients with cystic fibrosis is a challenge because of poor absorption rates for vitamin D in these patients. In a recent pilot trial of vitamin D supplementation, higher doses of oral vitamin D were required to achieve adequate serum levels. The trial showed benefits of supplementation on quality of life, reduced inflammation and improved lung functions.[50]

REVIEW

Conclusion

Vitamin D deficiency is associated with a number of respiratory diseases, with notable effects on respiratory infections and lung function. Supplementation with vitamin D appears to improve many lung conditions. The evidence for vitamin D supplementation is not so clear-cut in obstructive airways disease such as COPD and asthma, but it is definitely beneficial in TB, and new evidence is mounting that it may be useful in patients with acute respiratory tract infections, particularly in individuals that are vitamin D deficient. Trials in patients with cystic fibrosis are at an early stage. The optimum route and dose for vitamin D supplementation still needs to be worked out, but recent analysis favours daily or weekly supplementation over bolus dosing. The genetic variability of the VDR may impact on outcomes. The development of new vitamin D analogues that target the inflammatory pathway without affecting calcium metabolism will be something for the future.[51] 1. Nair R, Maseeh A. Vitamin D: The ‘sunshine’ vitamin. J Pharmacol Pharmacother 2012;3(2):118-126. https://doi.org/10.4103/0976-500X.95506 2. Rosen CJ, Adams JS, Bikle DD, et al. The nonskeletal effects of vitamin D: An Endocrine Society scientific statement. Endocr Rev 2012;33(3):456-492. https://doi. org/10.1210/er.2012-1000 3. Hansdottir S, Monick MM. Vitamin D effects on lung immunity and respiratory diseases. Vitam Horm 2011;86:217-237. https://doi.org/10.1016/b978-0-12-3869609.00009-5 4. DeLuca HF. History of the discovery of Vitamin D and its active metabolites. Bonekey Rep 2014;479(3):1-8. https://doi.org/10.1038/bonekey.2013.213 5. Holick MF, Schnoes HK, DeLuca HF. Identification of 1,25-dihydroxycholecalciferol, a form of vitamin D3 metabolically active in the intestine. Proc Natl Acad Sci USA 1971;68(4):803-804 .

6. Holick MF, DeLuca HF, Avioli LV. Isolation and identification of 25-hydroxycholecalciferol from human plasma. Arch Intern Med 1972;129(1):56-61.

7. Holick MF. Vitamin D deficiency. N Engl J Med 2007;357(3):266-281. https://doi. org/10.1056/nejmra070553 8. Pramyothin P, Holick MF. Vitamin D supplementation. Guidelines and evidence for subclinical deficiency. Curr Opin Gastroenterol 2012;28(2):139-150. https://doi. org/10.1097/mog.0b013e32835004dc 9. Paul G, Brehm JM, Alcorn JF, et al. Vitamin D and asthma. Am J Respir Crit Care Med 2012;185(2):124-132. https://doi.org/10.1164/rccm.201108-1502ci 10. Hypponen E, Sovio U, Wjst M, et al. Infant vitamin D supplementation and allergic conditions in adulthood: Northern Finland birth cohort 1966. Ann N Y Acad Sci 2004;1037(1):84-95. https://doi.org/10.1196/annals.1337.013 11. Wills AK, Shaheen SO, Granell R, et al. Maternal 25-hydroxyvitamin D and its association with childhood atopic outcomes and lung function. Clin Exp Allergy 2013;43(10):1180-1188. https://doi.org/10.1111/cea.12172 12. Litonjua AA, Carey VJ, Laranjo N, et al. Effect of prenatal supplementation with vitamin D on asthma or recurrent wheezing in offspring by age 3 years: The VDAART randomized clinical trial. JAMA 2016;315(4):362-370. https://doi.org/10.1001/ jama.2015.18589 13. Gazibara T, den Dekker HT, de Jongste JC et al. Association of maternal and fetal 25-hydroxyvitamin D levels with childhood lung function and asthma: The Generation R study. Clin Exp Allergy 2016;46(2):337-346. https://doi.org/10.1111/ cea.12645 14. Song H, Yang L, Jia C. Maternal vitamin D status during pregnancy and risk of childhood asthma: A meta-analysis of prospective studies. Mol Nutr Food Res 2016. (epub ahead of print) https://doi.org/10.1002/mnfr.201600657 15. Mai X-M, Langhammer A, Camargo CA, Chen Y. Serum 25-hydroxyvitamin D levels and incident asthma in adults. The HUNT Study. Am J Epidemiol 2012;176(12):11691176. https://doi.org/10.1093/aje/kws235 16. Korn S, Hubner M, Jung M, Blettner M, Buhl R. Severe and uncontrolled adult asthma is associated with vitamin D insufficiency and deficiency. Respir Res 2013;14(1):25. https://doi.org/10.1186/1465-9921-14-25 17. Castro M, King TS, Susan J, Kunselman SJ, et al. Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels.

The VIDA randomized clinical trial. JAMA 2014;311(20):2083-2091. https://doi. org/10.1001/jama.2014.5052

18. Martineau AR, MacLaughlin BD, Hooper RL, et al. Double-blind randomized placebo-controlled trial of bolus-dose vitamin D3 supplementation in adults with asthma (ViDiAs). Thorax 2015;70(5):451-457. https://doi.org/10.1136/ thoraxjnl-2014-206260.101 19. Martineau AR, Cates CJ, Urashima M, et al. Vitamin D for the management of asthma. Cochrane Database Syst Rev 2016;2016(9):CD011511. https://doi. org/10.1002/14651858.CD011511.pub2 20. Janssens W, Bouillon R, Claes B, et al. Vitamin D deficiency is highly prevalent in COPD and correlates with variants in the vitamin D-binding gene. Thorax 2010;65(3):215-220. https://doi.org/10.1136/thx.2009.120659 21. Heulens N, Korf H, Janssens W. Innate immune modulation in chronic obstructive pulmonary disease: Moving closer toward vitamin D therapy. J Pharmacol Exp Ther 2015;353(2):360-368. https://doi.org/10.1124/jpet.115.223032 22. Kunisaki KM, Niewoehner DE, Connet JE. Vitamin D levels and risk of acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012;185(3):286-290. https://doi.org/10.1164/rccm.201109-1644oc 23. Quint JK, Donaldson GC, Wassef N, et al. 25-hydroxyvitamin D deficiency, exacerbation frequency and human rhinovirus exacerbations in chronic obstructive pulmonary disease. BMC Pulm Med 2012;12(1):28. https://doi.org/10.1186/14712466-12-28 24. Lehouck A, Mathieu C, Carremans C, et al. High doses of vitamin D to reduce exacerbations in chronic obstructive pulmonary disease: A randomized trial. Ann Intern Med 156(2):105-114. https://doi.org/10.7326/0003-4819-156-2-20120117000004 25. Martineau AR, James WY, Hooper RL, et al. Vitamin D supplementation in patients with chronic obstructive pulmonary disease (ViDiCO): A multicentre, doubleblind, randomised controlled trial. Lancet Respir Med 2015;3(2):120-130. https:// doi.org/10.1016/s2213-2600(14)70255-3 26. Berk SM, Edgington BD, Rector TS, Kunisaki KM. Supplemental vitamin D and physical performance in COPD: A pilot randomized trial. Int J COPD 2013;8:97-104. https://doi.org/10.2147/copd.s40885 27. Holmgaard DB, Mygind LH, Titlestad IL, et al. Serum vitamin D in patients with chronic obstructive pulmonary disease does not correlate with mortality – results from a 10-year prospective cohort study. PLOS ONE 2013;8(1):e53670. https://doi. org/10.1371/journal.pone.0053670 28. Liu PT, Stenger S, Li H, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 2006;311(5768):1770-1773. https:doi.org/ 10.1126/science.1123933 29. Powe CE, Evans MK, Wenger J, et al. Vitamin D-binding protein and Vitamin D status of black Americans and white Americans. N Engl J Med 2013;369(21):1991-2000. https://doi.org/10.1056/nejmoa1306357 30. Holick MF. Bioavailability of vitamin D and its metabolites in black and white adults.

N Engl J Med 2013;369(21):2047-2048. https://doi.org/10.1056/nejme1312291 31. Wilkinson RJ, Llewelyn M, Toossi Z, et al. Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: A case control study. Lancet 2000;355(9204):618-621. https://doi. org/10.1016/s0140-6736(99)02301-6 32. Martineau AR, Nhamoyebonde S, Oni T, et al. Reciprocal seasonal variation in vitamin D status and tuberculosis notifications in Cape Town, South Africa. Proc Natl Acad Sci USA 2011;108(47):19013-19017. https://doi.org/10.1073/pnas.1111825108 33. Realegeno S, Modlin RL. Shedding light on the vitamin D-tuberculosis-HIV connection. Proc Natl Acad Sci USA 2011;108(47):18861-18862. https://doi. org/10.1073/pnas.1116513108 34. Salahuddin N, Ali F, Hasan Z, et al. Vitamin D accelerates clinical recovery from tuberculosis: Results of the SUCCINT study (Supplementary Cholecalciferol in Recovery from Tuberculosis). A randomized, placebo-controlled, clinical trial of vitamin D supplementation in patients with pulmonary tuberculosis. BMC Infect Dis 2013;13(1):22. https://doi.org/10.1186/1471-2334-13-22 35. Coussens AK, Wilkinson RJ, Hanifa Y, et al. Vitamin D accelerates resolution of inflammatory responses during tuberculosis treatment. Proc Natl Acad Sci USA 2012;109(38):15449-15454. https://doi.org/10.1073/pnas.1200072109 36. Gunville CF, Mourani PM, Ginde AA. The role of vitamin D in prevention and treatment of infection. Inflamm Allergy Drug Targets 2013;12(4):239-245. https:// doi.org/10.2174/18715281113129990046 37. Youssef DA, Miller CWT, El-Abbassi AM, et al. Antimicrobial implications of vitamin D. Dermato-Endocrinol 2011;3(4):220-229. https://doi.org/10.4161/derm.3.4.15027 38. Muhe L, Lulseged S, Mason KE, Simoes EA. Case-control study of the role of nutritional rickets in the risk of developing pneumonia in Ethiopian children.

Lancet 1997;349(9068):1801-1804. https://doi.org/10.1016/s0140-6736(96)12098-5

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REVIEW 39. Leow L, Simpson T, Cursons R, Karalus N, Hancox RJ. Vitamin D, innate immunity and outcomes in community acquired pneumonia. Respirology 2011;16(4):611-616. https://doi.org/10.1111/j.1440-1843.2011.01924.x 40. Remmelts HH, van der Garde EM, Meijvis SC, et al. Addition of vitamin D status to prognostic score improves the prediction of outcomes in community-acquired pneumonia. Clin Infect Dis 2012;55(11):1488-1494. https://doi.org/10.1093/cid/ cis751 41. Manaseki-Holland S, Qader G, Masher MI, et al. Effects of vitamin D supplementation to children diagnosed with pneumonia in Kabul: A randomised controlled trial.

Trop Med Int Health 2010;15(10):1148-1155. https://doi.org/10.1111/j.13653156.2010.02578.x 42. Manaseki-Holland S, Maroof Z, Bruce J, et al. Effects on the incidence of pneumonia of vitamin D supplementation by quarterly bolus dose to infants in Kabul: A randomised controlled superiority trial. Lancet 2012;379(9824):1419-1427. https:// doi.org/10.1016/s0140-6736(11)61650-4 43. Choudary N, Gupta P. Vitamin D supplementation for severe pneumonia â&#x20AC;&#x201C; a randomized controlled trial. Indian Pediatr 2012;49(6):449-454. https://doi. org/10.1007/s13312-012-0073-x 44. Zdrenghea MT, Makrinioti H, Bagacean C, et al. Vitamin D modulation of innate immune responses to respiratory viral infections. Rev Med Virol 2017;27(1):e1909. https://doi.org/10.1002/rmv.1909.

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45. Ginde AA, Blatchford P, Breese K, et al. High-dose monthly vitamin D for prevention of acute respiratory infection in older long-term care residents: A randomized clinical trial. J Am Geriatr Soc 2016. (epub ahead of print) https://doi.org/10.1111/jgs.14679 46. Bergman P, Norlin AC, Hansen S, et al. Vitamin D3 supplementation in patients with frequent respiratory tract infections: A randomised and double-blind intervention study. BMJ Open 2012;13;2(6):e001663. https://doi.org/10.1136/ bmjopen-2012-001663 47. Martineau AR, Jolliffe DA, Hooper RL, et al. Vitamin D supplementation to prevent acute respiratory tract infections: Systematic review and meta-analysis of individual participant data. BMJ 2017;356(6583). (epub ahead of print) https://doi.org/10.1136/ bmj.i6583 48. Simoneau T, Bazzaz O, Sawicki GS, Gordan C. Vitamin D status in children with cystic fibrosis. Ann Am Thorac Soc 2014;11(2):205-210. https://doi.org/10.1513/ annalsats.201306-171bc 49. McCauley LA, Thomas W, Laguna TA, et al. Vitamin D deficiency is associated with pulmonary exacerbations in children with cystic fibrosis. Ann Am Thorac Soc 2014;11(2):198-204. https://doi.org/10.1513/annalsats.201208-068oc 50. Pincikova T, Paquin-Proulx D, Sandberg JK, FlodstrĂśm-Tullberg M, Hjelte L. Clinical impact of vitamin D treatment in cystic fibrosis: A pilot randomized, controlled trial.

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CASE REPORT

Interstitial lung disease-associated antisynthetase syndrome I Hassan, MB BCh, MMed (Int), FCP (SA), Cert Pulm (SA) Department of Intensive Care, School of Medicine, Sefako Makgatho Health Sciences University, Dr George Mukhari Academic Hospital, Ga-Rankuwa, South Africa Corresponding author: I Hassan (ismailhassan@mweb.co.za)

Interstitial lung disease (ILD) is one of the major extramuscular manifestations of polymyositis (PM) and dermatomyositis (DM).

Presentation of PM and DM with ILD is not uncommon, but its clinical and radiological features can be similar to other conditions and can be challenging to diagnose. The presence of anti-aminoacyl tRNA synthetase antibodies in the presence of ILD is diagnostic of antisynthetase syndrome. A delayed diagnosis can be associated with the progression of pulmonary involvement and potentially increased morbidity. Timely diagnosis leads to appropriable lifesaving treatment. We report on a patient with chronic respiratory symptoms who had positive anti-Jo-1 antibodies and presented in respiratory failure, requiring non-invasive ventilation.

S Afr Respir J 2017;23(1):19-21. DOI:10.7196/SARJ.2017.v23i1.157

Antisynthetase syndrome (ASS) is a subtype of inflammatory myositis (polymyositis and dermatomyositis), and presents with a constellation of other clinical features.[1-3] Acute dyspnoea in patients with the syndrome may be due to a spontaneous pneumomediastinum as a consequence of architectural distortion or vasculopathic lesions that result in alveolar and bronchial wall injury and subsequent air leaks.

Other causes of acute dyspnoea or respiratory compromise may be pulmonary embolus, muscle weakness and pneumonia.[4,5] Lung involvement may occur in the absence of muscular involvement. The anti-Jo-1 antibody was the first anti-ARS antibody to be discovered and is the most commonly reported autoantibody.

ILD-associated anti-aminoacyl tRNA synthetase (ARS) antibodies are the most prevalent manifestation of ASS.[4-6] We report a case of a patient with acute respiratory compromise in the setting of a positive anti-Jo-1 antibody, who was initially treated with non-invasive ventilation (NIV) and corticosteroids (CCSs), immune suppressants and a structured physiotherapy programme.

Case report

A 61-year-old female patient presented with sudden worsening of her chronic respiratory symptoms. She was misdiagnosed with asthma 6 years prior at another medical facility. Her medication included inhaled corticosteroids (ICSs), bronchodilators and methylxanthines.

She was a never-smoker and had previously worked as a domestic helper. There was a history of arthralgia for which she used nonsteroidal anti-inflammatory drugs and paracetamol. She reported no other symptoms. She had late inspiratory crackles on examination of the chest. The rest of her examination was unremarkable.

She had respiratory failure upon admission and was started on NIV delivered by continuous positive airway pressure/pressure support (CPAP/PS), with a positive end expiratory pressure (PEEP) of 8 cm H2O and pressure support of 15 cm H2O. She was successfully weaned off NIV by day 10 to nasal prongs delivering 2 L/min.

Serological tests for myositis are shown in Table 1. The patientâ&#x20AC;&#x2122;s creatinine kinase was normal. There was no evidence of myositis.

A diagnosis of ASS and ASS ILD was made. The lung function

test (spirometry) depicted a mixed pattern with a restrictive and obstructive picture (Fig. 1), as seen in Table 2. The carbon monoxide diffusion was markedly reduced. The X-ray of the hands (Fig. 2), chest X-ray (CXR) (Fig. 3) and computed tomography (CT) scan of the chest (Fig. 4) are shown.

The patient had a favourable response to the NIV, pulse methylprednisolone 1 g daily for 3 days and antibiotics. After the acute episode, she was started on azathioprine and CCSs. During this time she underwent physiotherapy. At subsequent visits 4 weeks and 8 weeks later, she had an improvement in her 6-minute walk test from 200 m to 400 m and her dyspnoea rating (assessed with the Borg scale) measured 4/10.

Discussion

The ASS syndrome is diagnosed and characterised by the presence of aminoacyl tRNA antibodies (anti-ARS antibodies) accompanied by any one of the features listed in Table 3. The frequency of these associations is also shown in Table 3.[2-4] The ASS comprises various Table 1. Serological tests for myositis Myositis profile

Results for case patient

Anti-Mi-2

Negative

Anti-Ku

Negative

Anti-PM-Sc1100

Negative

Anti-PM-Sc175

Negative

Anti-Jo-1

Positive

Anti-SRP

Negative

Anti-Pl-7

Negative

Anti-Pl-12

Negative

Anti-EJ

Negative

Anti-OJ

Negative

Anti-Ro-52

Positive

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CASE REPORT

Table 2. Spirometry results depicting a mixed pattern with a restrictive and obstructive picture Parameter

Pred

Pre

%Pred

Post

%Pred

%Diff (2/1)

VCmax (L)

2.59

0.76

29

0.75

29

–1

IC (L)

1.85

0.31

17

-

-

-

ERV (L)

0.75

0.45

60

-

-

-

FVC (L)

2.50

0.52

21

0.75

30

-

FEV1

2.09

0.51

24

-

-

46

FEV1%VCmax (%)

77.32

66.96

87

-

-

-

PEF (L/s)

5.72

3.48

61

2.75

48

-

FEF25 (L/s)

5.14

3.34

67

2.75

54

–21

FEF50 (L/s)

3.48

2.03

58

2.67

77

–20

FEF75 (L/s)

1.22

-

-

1.57

128

31

F1V1 (L)

-

0.70

-

-

-

-

PIF (L/s)

-

1.60

-

1.88

-

18

Pred = predicted value; Pre = pre-bronchodilator; %Pred = percentage predicted; Post = post-bronchodilator; %Diff = percentage difference; VCmax = maximum vital capacity; IC = inspiratory capacity; ERV = expiratory reserve volume; FVC = forced vital capacity ; FEV1 = forced expiratory volume in the first second; FEV1%VCmax = percentage of VCmax exhaled during FEV1; PEF = peak expiratory flow; FEF25 = forced expiratory flow at 25% of FVC; FEF50 = forced expiratory flow at 50% of FVC; FEF75 = forced expiratory flow at 75% of FVC; FIV1 = forced inspiratory volume in the first second; PIF = peak inspiratory volume.

10

Table 3. Clinical findings in patients with ASS and positive tRNA synthetase antibodies %

Interstitial lung disease

69

Myositis

90

Symmetrical inflammatory arthritis

5

Fever, weight loss

11

Raynaud’s phenomenon

17

Mechanic’s hands

17

combinations of ILD. This may present with usual interstitial pneumonia, nonspecific interstitial pneumonia, organising pneumonia or diffuse alveolar damage. The prevalence of these patterns varies, e.g. in a temporal sequence and some features may be more prominent than others. ASS syndrome affects women more than men, and the peak incidence is between the ages of 35 - 65 years. The mean age at presentation is 30 years.[1-5] Respiratory symptoms may have an insidious onset or may be severe in the form of acute respiratory distress syndrome (ARDS).

NIV instituted early may obviate the need for invasive mechanical ventilation.[6] Although the patient tested negative in this case, the pl-7 and antipl-12 seem to be more frequently associated with the presence of fibrosis in the absence of myositis.[3,4,6] Patients with new-onset and unclear ILD may not display signs of myositis or skin disease in the beginning. The lack of correlation between muscle and pulmonary symptoms often leads to a delayed diagnosis. The underlying CT pattern has no influence on disease progression or prognosis.[2,6] The anti-RO52/SSA antibody (a marker for Sjögren syndrome) may occur together with the anti-Jo-1 antibody, as in the case described, and is associated with particularly severe ILD.[7]

20 SARJ VOL. 23 NO. 1 2017

1 2

8

Flow (L/s )

Feature

6 4 2 0

1

2

3

4

5

6

–2 Fig. 1. Lung function test (spirometry) depicting a mixed pattern with a restrictive and obstructive picture.

A combination of drug treatment with a well-structured physiotherapy programme directed at resistance training and inspiratory muscle strength, over a period of several weeks, has an impact on overall wellbeing and symptom improvement. Physiotherapy can be beneficial in improving deconditioned muscles, but has no benefit in reversing fibrosis.[8,9] Patients are able to do more with improved physical strength and with a greater understanding of the condition and how to manage it.[5,8,9] This is evident from the improvement in the distance covered and dyspnoea rating during the 6-minute walk test.

Treatment is usually with CCSs and immunosuppressive agents.

Mycophenolate mofetil has been used with success in some instances.

Whether more aggressive therapy in PM/DM patients presenting with ILD really leads to better outcomes is still an open debate. What is clear is that a high index of suspicion in this case led to a diagnosis.[5,8,9] The timely and appropriate treatment with NIV prevented the deterioration during the acute setting.[1,6,8,9]

CASE REPORT

Fig. 2. X-ray of hands – no joint erosion seen.

Fig. 4. CT scan showing reticulation, traction bronchiectasis fibrosis with some ground-glass appearance and architectural distortion.

Fig. 3. CXR – coarse reticular pattern consistent with ILD. We suggest that in the appropriate clinical context, patients with multisystem involvement presenting with arthralgias, Raynaud’s phenomenon, myositis and lung involvement should be assessed for the ASS. A negative test for antinuclear antibodies (ANA) does not exclude the ASS syndrome. Frequent screening failures in the ANA test are not uncommon because the target antigen is mainly cytoplasmic in location. The routine screening for anti-Jo-1 antibody is recommended.

1. Douglas WW, Tazelaar HD, Hartman TE, et al. Polymyositis-dermatomyositisassociated interstitial lung disease. Am J Respir Crit Care Med 2001;164(7):1182-1185. http://dx.doi.org/10.1164/ajrccm.164.7.2103110

2. La Corte R, Naco LM, Locaputo A, Dolzani F, Trotta F. In patients with antisynthetase syndrome the occurrence of anti-Ro/SSA antibodies causes a more severe interstitial lung disease. Autoimmunity 2006;39(3):249-253. https://doi. org/10.1080/08916930600623791 3. Viancsa A, Csipo I, Nemeth J, Devenyi K, Gergely L, Danko K. Characteristics of interstitial lung disease in SS-A positive inflammatory myopathy patients. Rheumatol Int 2009;29(9):989-994. https://doi.org/10.1007/s00296-009-0884-9 4. Won HJ, Soon Kim D, Keun Lee, et al. Two distinct clinical types of interstitial lung disease associated with polymyositis-dermatomyositis. Respir Med 2007;101(8):17611769. https://doi.org/10.1016/j.rmed.2007.02.017 5. Fischer A, du Bois R. Interstitial lung disease in connective tissue disorders. Lancet 2012;380(9842):689-698. http://dx.doi.org/10.1016/S0140-6736(12)61079-4 6. Park IN, Jegal Y, Kim DS, et al. Clinical course and lung function changer of idiopathic nonspecific interstitial pneumonia. Eur Respir J 2009;33(1):68-76. https://doi. org/10.1183/09031936.00158507 7. Kokosi M, Riemer EC, Highland KB. Pulmonary involvement in Sjögren syndrome.

Clin Chest Med 2010;31(3):489-500. https://doi.org/10.1016/j.ccm.2010.05.007 8. Guglielmi S, Merz TM, Gugger M, Suter C, Nicod LP. Acute respiratory distress syndrome secondary to antisynthetase syndrome is reversible with tacrolimus. Eur Respir J 2008;31:213-217. https://doi.org/10.1183/09031936.00014707 9. Hervier B, Meyer A, Dieval C, et al. Pulmonary hypertension in antisynthetase syndrome: Prevalence, aetiology and survival. Eur Respir J 2013;42(5):1271-1282. https://doi.org/10.1183/09031936.00156312

SARJ VOL. 23 NO. 1 2017

21

BREATH-TAKING NEWS

No benefit of long-term oxygen therapy in moderate hypoxaemia in COPD There are established benefits of 24-hour supplemental oxygen in patients with chronic obstructive pulmonary disease (COPD) and severe hypoxaemia having resting oxygen saturation ≤88% or PO2 ≤55 mmHg (7.3 kPa), or ≤59 mmHg (7.9 kPa) with signs of rightsided heart strain or polycythaemia. Supplemental oxygen has typically also been provided to the far larger group of people with normal resting oxygen levels that fall during exertion or persons of COPD with moderate resting hypoxaemia, but no benefits of this have ever been established.

The recent Long-Term Oxygen Treatment Trial (LOTT study), which was a USA-based multi-centre randomised trial published in the New England Journal of Medicine, is the largest study of longterm oxygen therapy to date. The LOTT study sought to address this practice and evaluate clinically relevant patient outcomes in daily life.[1] The unblinded study was funded by the National Institutes of Health (USA) and recruited 738 participants with COPD (73% males) at 42 centres who had either (i) mild-to-moderate hypoxaemia at rest (oxygen saturation of 89 - 93%) or (ii) normal resting oxygen saturation that fell to 80 - 90% during a 6-minute walk test. They were randomly assigned to receive either long-term supplemental oxygen or no oxygen.

The supplemental oxygen was prescribed at 2 L O2/min continuously (at least 15 hours/day) in participants with resting hypoxaemia (57%) and as an adjusted oxygen dose during exercise and 2 L O2/min during sleep in participants with exertional hypoxaemia only (43%). They were followed for up to 6 years (median 1.5 years).

22 SARJ VOL. 23 NO. 1 2017

Patients receiving oxygen had no improvement in the primary outcome (rate of first hospitalisation or time to death after diagnosis, hazard ratio 0.94), quality of life, exercise capacity or COPD exacerbations compared with patients who did not receive supplemental oxygen.

The authors concluded that ‘among patients with COPD who have a resting SpO2 of >88%, long-term supplemental oxygen therapy does not result in longer survival than no oxygen therapy, regardless of whether the patients have exercise-induced desaturation.’

The study calls into question the current practice of routinely treating moderately hypoxaemic COPD patients with supplemental oxygen, and the tremendous expense incurred by state-funded institutions and private insurers.

This trial has far-reaching consequences for both the medical fraternity and funders in the practice of this often-used, expensive and unhelpful treatment, as this study showed.

S Sinha Roy Pulmonology Fellow, Division of Pulmonology, Department of Medicine, Stellenbosch University and Tygerberg Academic Hospital, Cape Town, South Africa 1. The Long-Term Oxygen Treatment Trial Research Group, A randomized trial of longterm oxygen for COPD with moderate desaturation. N Engl J Med 2016;375(17):16171627. https://doi.org/10.1056/NEJMoa1604344

S Afr Respir J 2017;23(1):22. DOI:10.7196/SARJ.2017.v23i1.155

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

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[1]

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

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

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

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

1 1

SARJ VOL. 23 NO. 1 2017

23

NEW

Antistatic Chamber

small, solid and effective

NEW aluminium Aspen is proud to announce the launch of an innovative new antistatic holding chamber, as an addition to our respiratory portfolio.

VORTEX® inhalation aid is suitable in providing: (1) • High lung deposition, low throat deposition • High dosage consistency • Disinfectable, ergonomic SmartTouch masks Description (2)

Indication (2)

VORTEX® with a mouthpiece

VORTEX® with mouthpiece and baby mask ‘Ladybug’

To be used in conjunction with medication sprays or "metered dose inhalers" in the treatment of respiratory tract diseases.

VORTEX® with mouthpiece and child mask ‘Frog’

Nappi Code

SEP (Excl VAT)

SEP (Incl VAT)

216379001

R 267,27

R 304,69

216375001

R 291,66

R 332,50

216376001

R 291,66

R 332,50

The NEW VORTEX® aluminium chamber inhalation aid!

Attach. Breathe. Relax.

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

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

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

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

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

For full prescribing information, please refer to the package inserts approved by the Medicines Regulatory Authority.

All adverse events should be reported by calling the Aspen Medical Hotline number or directly to GlaxoSmithKline on +27 11 745 6000.

ZAF/FP/0004/15a A19615 04/16

26622 Vortex A4 Journal ad 22.04.16 11.57 .indd 1

2016/04/22 11:58 AM

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