SARJ Vol 23, No 2 (2017)

South African

Respiratory Journal VOLUME 23

|

NUMBER 2

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JUNE 2017

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

THE SOUTH AFRICAN

RESPIRATORY JOURNAL VOLUME 23 | NUMBER 2 | JUNE 2017

CONTENTS EDITORIAL 26

The tip of the iceberg: Alarming increase in the detection of MDR-TB K Dheda, A Esmail

29

NEWS

ORIGINAL RESEARCH

30

The prevalence and management of rifampicin-resistant tuberculosis among adults at Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa R M Narsing, A S Karstaedt, F Sahid

CASE REPORTS

35

A rare case of lymphangiomatosis D Parris, A van Niekerk, E Marais, I O Lawal, A Goga, A C Jeevarathnum, X Dearden, R J Green Dyspnoea on exertion in a child: A presentation of neuroendocrine hyperplasia of infancy A C Jeevarathnum, A van Niekerk, D Parris, X Dearden, A Goga, R J Green

42

BREATH-TAKING NEWS

44

PRODUCT NEWS

39

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

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EDITORIAL

The tip of the iceberg: Alarming increase in the detection of MDR-TB In this issue of SARJ, Narsingh et al.[1] highlight the alarming and burgeoning problem of multidrug-resistant tuberculosis (MDR-TB).[2] More recently, this has been supplanted by an increasing burden of extensively drug-resistant TB (XDR-TB),[3] and resistance beyond XDR-TB.[3] The problem of programmatically incurable TB and its spread, in our communities, from home-discharged index cases has recently been highlighted.[4] In their study, Narsingh et al.[1] found that almost 11% of patients assessed, had MDR-TB. Although there are several drawbacks to this estimate, including the study design, this highlights the alarming increase in the detection of MDR-TB in many of our urban centres. In 2014 almost 20 000 cases of MDR-TB were detected nationally.[5] The disease prevalence, given that 220 000 cases were tested, was ~8.5%.

These data and clinical observations in urban areas are discordant with the recent prevalence survey indicating a much lower rate of MDR-TB nationally. Nevertheless, this still represents an alarming burden of MDR-TB given that 50 - 60% of the MDR-TB caseload remains undetected.

Drug-resistant TB represents a serious threat to TB control for several reasons. The mortality, as demonstrated in this study, is surprising high; ~30 to 40% for MDR-TB and 60 to 70% for XDR-TB (prior to the use of bedaquiline).[5,6] This is worse than the mortality rates for many cancers. There is also considerable long-term morbidity due to chronic lung disease. If this were not enough, drug-resistant TB is already consuming almost 40 - 50% of the total National TB Programme budget,[7] which is not sustainable.

Drug-resistant TB is also a major threat to healthcare workers.

Indeed, Narsingh et al.[1] show that only ~50 - 60% of patients were isolated. Recent reports indicate that healthcare workers in KwaZuluNatal have a rate of drug-resistant TB almost six-fold higher than the general population, strongly suggesting that it is nosocomially contracted.[8] Drug-resistant TB in healthcare workers has also been reported in the Western Cape Province.[9] This highlights the poor infection control protocols and interventions that are available in our clinics and hospitals. Both the constitution of the country and the Occupational Health and Safety Act are openly being flouted.

How can we address this MDR-TB epidemic? Clearly, as the authors[1] point out, proper education of healthcare workers is important to ensure that patients are appropriately treated, However, first and foremost, we need to address the extremely high burden of TB itself. This requires eradication of poverty and overcrowding, addressing the socioeconomic inequalities in the country, addressing the epidemic of HIV that fuels TB, and also addressing other major drivers such as smoking, exposure to indoor air pollution, and the growing epidemic of type II diabetes.[2] Next we need to address the transmission of drug-resistant TB. Approximately 80% of the MDRTB burden is due to person-to-person spread. As 60 - 70% of the caseload remains undetected, transmission will not be addressed unless active case finding is adopted.[10] Recently it has been shown that molecular tools can greatly improve case detection when using a mobile van staffed by healthcare workers.[10] Innovative strategies are

26 SARJ VOL. 23 NO. 2 2017

also required to address transmission in congregate settings such as schools, churches, beer halls, and taxis.

We also need better diagnostic tests. There is a need to move towards ‘precision medicine’ for TB, where simultaneous multi-drug readouts are obtained so patients can be treated with bespoke therapy rather than the ‘kitchen sink’ approach that is currently being used. Wider access to newer and repurposed drugs, such as bedaquiline, delamanid, and linezolid are required. The issue of infection control to protect healthcare workers also needs urgent attention. Most importantly, we need to understand the pathogenesis of MDR and XDR-TB. More recent data suggest that, in contradiction to blaming the patient and healthcare workers, several other factors are important, including population-based pharmacokinetic (PK) variability, various mycobacterial-related factors including efflux pumps, and PK mismatch due to suboptimal penetration of drugs into tuberculous TB cavities.[3] If we do not understand and address these factors, we will continue to lose the precious new anti-TB drugs, which is already happening, given the increasing number of treatment failures being seen despite the use of bedaquiline.

Our national TB control programme, and the healthcare system as a whole, is akin to the Titanic, which is on course for a deadly collision.

Only the tip of the iceberg is visible but will anyone take heed? Evasive action is urgently needed, but can we respond in time?

K Dheda, A Esmail Division of Pulmonology, Department of Medicine & University of Cape Town Lung Institute, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa keertan.dheda@uct.ac.za 1. Narsing RM, Karstaedt AS, Sahid F. The prevalence and management of rifampicinresistant tuberculosis among adults at Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa. S Afr Resp J 2017. 2017;23(2):30-34. https://doi. org/10.7196/SARJ.2017.v23i2.151 2. Dheda K, Barry CE, Maartens G. Tuberculosis. Lancet 2016;387(10024):1211-1226. https://doi.org/10.1016/SO140-6736(15)00151-8 3. Dheda K, Gumbo T, Maartens G, et al. The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis. Lancet Respir Med 2017;5(4):291-360. https://doi. org/10.1016/S2213-2600(17)30079-6 4. Dheda K, Limberis JD, Pietersen E, et al. Outacomes, infectiousness, and transmission dynamics of patients with extensively drug-resistant tuberculosis and homedischarged patients with programmatically incurable tuberculosis: A prospective cohort study. Lancet Respir Med 2017;5(4):269-281. http://doi.org/10.1016/S22132600(16)30433-7 5. World Health Organization. Global tuberculosis report. Geneva: WHO, 2016.

6. Pietersen E, Ignatius E, Streicher EM, et al. Long-term outcomes of patients with extensively drug-resistant tuberculosis in South Africa: A cohort study. Lancet 2014;383(9924):1230-1239. https://doi.org/10.1016/S0140-6736(13)62675-6 7. Pooran A, Pieterson E, Davids M, Theron G, Dheda K. What is the cost of diagnosis and management of drug resistant tuberculosis in South Africa? PLoS ONE 2013;8(1): e54587. https://doi.org/10.1371/journal.pone.0054587 8. O'Donnell MR, Jarand J, Loveday M, et al. High incidence of hospital admissions with multidrug-resistant and extensively drug-resistant tuberculosis among South African health care workers. Ann Intern Med 2010;153(8):516-522. http://doi. org/10.7326/0003-4819-153-8-201010190-00008 9. Jarand J, Shean K, O'Donnell M, et al. Extensively drug-resistant tuberculosis (XDR-TB) among health care workers in South Africa. Trop Med Int Health 2010;15(10):1179-84. http://doi.org/10.1111/j.1365-3156.2010. 02590.x 10. Calligaro GL, Zijenah LS, Peter JG, et al. Effect of new tuberculosis diagnostic technologies on community-based intensified case finding: A multicentre randomised controlled trial. Lancet Infect Dis 2017;17(4): 441-450. http://doi.org/10.1016/S14733099(16)30384-X

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FROM THE EDITOR

Prof. Keertan Dheda receiving a certificate of commendation from Prof. Jess Mandel, Chair of the International Conference Committee, after the keynote address at the 2017 American Thoracic Society Conference.

Congratulations to Professor Keertan Dheda, who delivered the keynote address at the 2017 American Thoracic Society Conference in Washington, D.C., USA. The conference was attended by ~17 000 delegates. The keynote address, which recognises leading international scientific excellence in a particular field of pulmonary medicine, is an unopposed lecture of ~60 minutes, during which no

other parallel sessions or lectures are running. Four sets of keynote lectures were delivered during the conference, one of which was by Anthony S. Fauci, Director of the National Institute of Allergy and Infectious Diseases. A certificate of commendation was awarded to Prof. Dheda at the end of the lecture and the event was covered in the American local news.

SOUTH AFRICAN THORACIC SOCIETY ANNUAL GENERAL MEETING DATE: 24th August 2017 TIME: 17h40 – 18h40 VENUE: Canal Walk Conference Centre, Cape Town

SARJ VOL. 23 NO. 2 2017

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ORIGINAL RESEARCH

The prevalence and management of rifampicin-resistant tuberculosis among adults at Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa R M Narsing,1,3 MB BCh, FCP; A S Karstaedt,2,3 MB BCh, MMed; F Sahid,2,3 MB BCh, FCP Division of Pulmonology, Department of Internal Medicine, Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa Division of Infectious Diseases, Department of Internal Medicine, Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa 3 School of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

1 2

Corresponding author: R M Narsing (raj4065@yahoo.com)

Background. Early effective management of drug-resistant tuberculosis (TB) is important for the patient, and for infection control. The Xpert MTB/RIF (Cepheid, USA) assay detects Mycobacterium tuberculosis DNA and the presence of rifampicin resistance.

Objective. To assess the prevalence and initial management of rifampicin-resistant pulmonary TB (PTB), confirmed by the Xpert MTB/ RIF assay, in hospitalised adult patients.

Methods. This retrospective descriptive study assessed adult patients from March 2011 to February 2013. Data was obtained from the National Health Laboratory Service database and patient records. Management comprised the submission of additional confirmatory sputum tests, initiation of appropriate anti-TB drug therapy, patient isolation, and proper referral.

Results. The prevalence of rifampicin resistance was 10.6% (n=77) of 729 positive assays. The initial management was assessed for 70 patients with complete records. However, of these 70 patients, 12 patients had been discharged and 5 patients had died prior to receiving their results. The management of the total cohort, and of the 53 remaining inpatients, was analysed separately. The overall confirmatory sputum submission rates were 76%, 60%, 60% and 26% for TB microscopy, Line Probe Assay, TB culture, and drug-susceptibility testing, respectively, and 87%, 72%, 68% and 30%, respectively for the 53 remaining patients. Overall, 33% of patients received appropriate anti-TB treatment, 50% were isolated, and 49% were appropriately referred. For the 53 remaining patients, 43% received appropriate drug treatment, 66% were isolated, 64% were appropriately referred, and 19% were not referred. The inpatient mortality rate was 19%.

Conclusions. Rifampicin-resistant TB prevalence in-hospital was more than double the national rate. The initial management of patients with rifampicin-resistant PTB was substandard. Submission of paired sputum samples and educating healthcare professionals and healthcare users are of paramount importance to improve the management of drug-resistant TB. S Afr Respir J 2017;23(2):30-34. DOI:10.7196/SARJ.2017.v23i2.151

Tuberculosis (TB) causes a significant burden of disease worldwide, with ~9.6 million cases and 1.5 million deaths in 2014.[1] South Africa (SA) is ranked among the top six countries in the world as having the largest number of incident cases.[1,2] Mycobacterium tuberculosis (MTB) is the organism responsible for TB infection and has been treated successfully for many decades. The emergence of drugresistant TB has complicated the management of the disease. Multidrug-resistant tuberculosis (MDR-TB) is defined as resistance to the two most effective first-line drugs, isoniazid (INH) and rifampicin (RIF).[3] Of the new TB cases reported in 2013 and 2014, there were ~480 000 cases of MDR-TB annually,[1,2,4] with an estimated 6 900 cases in SA in 2014.[4] It was estimated that 3.3% of new TB cases were due to MDR-TB, whereas 20% of previously treated TB cases had presented with MDR-TB in 2014.[1] Risk factors for the development of MDR-TB include previous exposure to anti-TB treatment, incomplete treatment regimens, poor patient compliance, lack of availability of adequate medication, co-infection with HIV, social barriers, lack of patient access to care, poorly coordinated management strategies from healthcare institutions and inadequate guidelines.[5-11] In 2013, there were an estimated 2.1 million new HIV infections globally and 1.5 million new infections in the World Health

30 SARJ VOL. 23 NO. 2 2017

Organization (WHO) African region. [12] Patients who are coinfected with HIV and TB are more likely to have rapid progression to active TB disease, have a higher likelihood of MDR-TB, and higher mortality.[4,13-17] The incidence of HIV co-infection and TB is the highest in the African region, with about 80% of cases being co-infected.[2] In sub-Saharan Africa there was an estimated 70% co-infection rate of drug-resistant TB and HIV.[2,14] Gandhi et al.[18] demonstrated a 92% co-infection rate of MDR-TB and HIV in KwaZulu-Natal Province, SA. Resistance to RIF usually occurs due to point mutations of the rpoB gene,[3,19,20] with more than 95% of mutations responsible for the development of RIF resistance occurring in this gene.[3,21] In regions with a high probability of MDR-TB, such as sub-Saharan Africa, RIF resistance can be used as a reliable indicator for MDR-TB.[22] The WHO has endorsed the use of molecular testing for the rapid diagnosis of TB and drug resistance.[23] The Xpert MTB/RIF (Cepheid, USA) assay has been approved for use since December 2010. The assay detects MTB DNA and the presence of RIF resistance.[23] Studies reviewing the effectiveness of the Xpert MTB/RIF assay found a sensitivity of 95% and specificities of 94 - 98% with smear-positive sputum and sensitivities of 55% and 67% in smear-negative sputum.[24,25] The rapid

ORIGINAL RESEARCH result is an advantage when compared to the lengthier duration of conventional drug susceptibility testing (DST).[26] In 2011, the SA Department of Health released guidelines for the management of drug-resistant TB.[27] Following the result of RIFresistant MTB on the Xpert MTB/RIF assay, MDR-TB treatment should be initiated, confirmatory sputum specimens submitted, patients should be isolated and appropriately referred. Treatment should then be reviewed following laboratory confirmation of drug susceptibility.[27] A combination of five effective chemotherapeutic agents are recommended for the treatment of MDR-TB. [28] These include a fluoroquinolone (moxifloxacin or ofloxacin), a secondline aminoglycoside (kanamycin or amikacin), pyrazinamide, ethionamide and terizidone.[27] Commitment from both the patient and the healthcare professional is essential to treat TB and drugresistance effectively in affected communities. Local studies have shown that patient compliance, delay in initiation of treatment, loss to follow-up, poor contact tracing, and early mortality still remain hindering factors in current treatment strategies.[29-31] Ebonwu et al.[30] found that only 63% of patients were initiated on MDR-TB treatment in Gauteng Province in 2011.

This study aimed to describe the prevalence and initial management of hospitalised adult patients with RIF-resistant pulmonary TB (PTB), as diagnosed by the Xpert MTB/RIF .

Methods

Study setting Chris Hani Baragwanath Academic Hospital (CHBAH) is a tertiarylevel hospital with 702 adult medical beds that serves the community of Soweto and surrounding areas.

Study design This retrospective descriptive study, based on record review, assessed adult patients with RIF-resistant PTB during a two-year period from March 2011 to February 2013. The National Health Laboratory Service (NHLS) provided a list of all patients with a positive Xpert MTB/RIF assay result. Patients included in the study were older than 14 years and were admitted to the adult medical wards at CHBAH. The prevalence of RIF resistance was calculated by dividing the number of positive RIF-resistant Xpert MTB/RIF assays by the total number of positive Xpert MTB/RIF assays (i.e. RIF-sensitive and RIF-resistant) submitted by adult patients at CHBAH during the 2-year period. RIF resistance was further subdivided into MDR-TB (resistance to both RIF and INH), RMR (resistance to RIF only) and unclassified (patients without confirmatory test submission).

The management of patients was assessed based on submission of the confirmatory sputum samples (line probe assay (LPA), TB microscopy, TB culture, and DST), appropriate drug therapy (a fluoroquinolone, such as moxifloxacin or ofloxacin, a second-line aminoglycoside, such as kanamycin or amikacin, pyrazinamide, ethionamide, and terizidone), adequate isolation of patients with confirmed RIF-resistance, and referral to a designated drug-resistant TB care centre.

Data collection A list of patients who were >14 years old, and had RIF-resistant MTB confirmed by an Xpert MTB/RIF assay, was compiled and their

records were obtained from the CHBAH’s records department. Data from the NHLS database and the TB care centre at CHBAH were obtained to support information obtained from the patients’ hospital records. For patients with confirmed RIF-resistance, a name search was performed on the NHLS database to obtain all confirmatory sputum samples that were submitted. The data collection sheet used for the study recorded patient demographics, HIV status, CD4 count, antiretroviral therapy (ART), previous TB exposure, previous TB treatment completion, current anti-TB drug treatment, the time taken to obtain the MTB/RIF assay result, the submission and results of additional TB susceptibility tests, isolation of the patient, appropriate referral and hospital outcome. The data were then collated and entered on an Excel worksheet.

Permission to conduct this study was granted by the Human Research Ethics Committee at the University of the Witwatersrand (ref. no. M131033) and the Medical Advisory Committee at CHBAH. The National Manager of Academic Affairs and Research at the NHLS granted permission to access their result database.

Results

Prevalence of RIF-resistant TB Of the 729 positive Xpert MTB/RIF assays submitted, 77 were positive for RIF resistance. The prevalence of RIF-resistant PTB among patients who presented to CHBAH between March 2011 and February 2013, was 10.6%. Seven patients’ files could not be traced and therefore they were not included in further analysis. Of the 70 patients, 22 (31.4%) had RMR-TB, 19 (27.1%) had MDR-TB, and 29 (41.4%) patients had no other confirmatory test submitted and therefore the pattern of drug resistance could not be established.

Demographic characteristics, HIV co-infection and TB history Thirty-four patients (49%) were female. The mean (SD) age was 36 (10.2) years. Among 66 patients with known HIV-serostatus, 58 (83%) patients were HIV-positive and 8 (11%) patients were HIVnegative. Among the 51 (88%) patients who had their CD4 cell counts recorded, the mean CD4 cell count was 91 cells/μL. The median CD4 cell count was 43 cells/μL (interquartile range (IQR) 15 - 160). Thirtytwo (55%) HIV-positive patients were on ART prior to admission.

Forty-one (59%) patients had a history of previous TB, among whom 11 (26.8%) patients had more than one episode of TB. Four (9.8%) patients admitted to not completing their prescribed treatment regimen previously. Twenty-six (37%) patients were being treated for susceptible PTB at the time of hospitalisation (Table 1).

Management Of the 70 patients with RIF-resistant TB, 12 (17%) patients had been discharged and 5 (7%) patients had died. Therefore 53 (75.7%) patients were still in hospital when their Xpert MTB/RIF result was obtained. Table 2 displays the results of the management outcomes for the total cohort (N=70) and the subgroup (N=53) of patients who received their results in hospital.

Additional susceptibility testing It took on average 3.36 days (range: 1 - 10 days) from the date of admission to obtain the Xpert MTB/RIF result (Table 2). Overall, 42 (60%) patients had the LPA test submitted, to differentiate

SARJ VOL. 23 NO. 2 2017

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ORIGINAL RESEARCH Table 1. Prevalence of TB and baseline characteristics of study cohort (N=70) n (%)* Prevalence RMR

22 (3.02)

MDR-TB

19 (2.60)

Unclassified

29 (3.97)

Baseline characteristics Female

34 (49)

Age (years), mean (SD)

36 (10.2)

HIV-positive

58 (83)

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

43 (15 - 160)

CD4 cell count <100 cells/µL

37 (73)

ART

32 (55)

Previous history of TB infection

41 (59)

Discharged before results available

12 (17)

Time to obtain Xpert MTB/RIF assay result (days), mean (SD)

3.36 (2.28)

Duration of hospitalisation (days), median (IQR)

11 (6 - 18)

Inpatient mortality

13 (19)

TB = tuberculosis; RMR = rifampicin mono-resistance; MDR-TB = multi-drug resistant tuberculosis; SD = standard deviation; ART = antiretroviral therapy; IQR = interquartile range; MTB/RIF = rifampicin-resistant Mycobacterium tuberculosis. *Unless otherwise specified.

Table 2. Management outcomes for study cohort (N=70) and remaining inpatients (N=53)* n (%) Outcome

Study cohort (N=70)

Inpatients (N=53)

LPA

42 (60)

38 (72)

DST

18 (26)

16 (30)

TB culture

42 (60)

36 (68)

TB microscopy

53 (76)

46 (87)

No additional testing

20 (29)

11 (21)

Adequate drug treatment

23 (33)

23 (43)

Patients isolated

35 (50)

35 (66)

Patients appropriately referred

34 (49)

34 (64)

LPA = line probe assay; DST = drug susceptibility testing; TB = tuberculosis. *Management outcomes of 70 patients with rifampicin-resistant TB and the 53 patients still hospitalised on receipt of results.

between MDR-TB and RMR-TB. Of the sputum samples submitted, 53 (76%) and 42 (60%) patients had submitted sputum specimens for TB microscopy and TB culture, respectively. Eighteen (26%) patients had submitted sputum samples for DST. Of the 53 patients who received results in hospital, 38 (72%) patients had the LPA test, 46 (87%) and 36 (68%) patients had a TB microscopy and TB culture sent, respectively. DSTs were requested for 16 (30%)

32 SARJ VOL. 23 NO. 2 2017

patients. Twenty (29%) patients of the overall cohort had no further sputum tests requested.

Drug therapy Of the anti-TB drug therapy that was provided to patients, 23 were initiated on appropriate treatment for MDR-TB, representing 33% of the total cohort and 43% of the 53 remaining inpatients (Table 2).

Thirty-nine patients were kept on treatment for drug-susceptible TB. Isolation, referral and outcome It took an average of 4 days to isolate patients. The median duration of hospitalisation was 11 days (IQR 6 - 18). Half of the patients in the study cohort and 66% of the inpatients were isolated, respectively.

Appropriate referral was carried out for 34 patients, constituting 49% of the cohort and 64% of the 53 remaining patients.

Of the other 36 patients, 10 (14%) patients were not appropriately referred, 12 (17%) patients were discharged before their result became available, 1 (1.4%) absconded, and 13 (19%) patients died in hospital.

Discussion

Study of the initial inpatient management of patients diagnosed with RIF-resistant PTB is important for two main reasons. Firstly, for the patient’s benefit, it measures the time to diagnosis after hospitalisation, the submission of further sputum tests to define the extent of resistance to anti-TB drugs, early initiation of guideline-recommended therapy, and referral for supervision and management. Secondly, for the purpose of infection control to protect other patients and healthcare workers, it investigates patient isolation and initiation of effective treatment. Knowing the prevalence of RIF-resistant TB can strengthen the case for effective infection control in a given population.

The prevalence of RIF-resistance during the 2-year period was 10.6%. This was more than double the rate of 4.6% found in a national survey conducted in SA during the period 2012 - 2014.[32] The prevalence of RMR (3.02%) exceeded that of MDR-TB (2.60%), but the unclassified group (3.97%) was the largest due to a lack of submission of confirmatory tests. Since CHBAH is a referral centre for patients with complicated and non-resolving disease processes, it could be expected that the prevalence rates would be higher than the national average. The prevalence rate of RMR has doubled in new TB cases nationally, and in the Western Cape Province, since 2002.[32,33] Risk factors for the increase in prevalence were advanced HIV infection and previous TB treatment.[33] The recommended management strategy of confirmed RIF-resistant TB includes submission of confirmatory tests, initiation of MDRTB therapy, isolation, and referral to an appropriate health facility to continue management.[27] The confirmatory tests include sputum samples sent for TB microscopy and culture, LPA, and DST. Overall, our study revealed that 76%, 60%, 60% and 26% of TB microscopy, TB culture, LPA and DST samples were submitted, respectively.

A likely reason for the disjuncture between rates of submission for culture and DST is that the laboratory form requires the clinician to request DST separately from culture submissions, whereas many clinicians assume that susceptibility tests would be performed automatically. Two factors that may have contributed negatively to the overall results were patients who were discharged (17%) or had died (7%) before their result had become available. After these two

ORIGINAL RESEARCH factors had been taken into consideration, 72% had the LPA test, 68% had the TB culture submitted, and 30% had the DST requested, which still demonstrates a substantial deficiency in the submission of confirmatory tests despite having a confirmed result on MTB/RIF assay. In Zimbabwe, the submission rate of sputum samples for culture and DST at two healthcare centres was 70%, of which only half reached the laboratory and were processed.[34] Possible explanations for our results are that patients may have been transferred to the referral centre before a confirmatory specimen was submitted, the patient may no longer have been expectorating sputum, or the attending doctor may not have known the recommended protocol. Premature discharging of patients is a direct result of limited hospital beds and a high patient demand at our centre.[29] Patient tracing and continued surveillance would ensure that these patients receive the diagnosis and appropriate medical treatment, despite being discharged early.

Educating healthcare workers and encouraging sputum sample collection immediately after obtaining the result, can improve the rate of confirmatory tests submission and thus ensure accurate diagnosis and treatment. A better solution would be to send paired samples, whereby the laboratory would retain the second sputum sample for the supplementary and confirmatory tests, which would be triggered once the MTB/RIF assay detects RIF resistance.

A fundamental part of managing drug-resistant TB is the correct combination of therapeutic drugs. At the time of the study being conducted, the five essential drugs used during the intensive phase to treat MDR-TB were kanamycin or amikacin, moxifloxacin, ethionamide, terizidone, or cycloserine and pyrazinamide.[27] In our high-prevalence setting, the presence of RIF resistance may be used as a surrogate for MDR-TB; however due to the recent studies displaying an increase in RMR prevalence, [32-33] this may no longer be true. Nonetheless, each of the 70 patients from our study should have been initiated on MDR-TB treatment. The study revealed that <50% of the patients received appropriate drug treatment in hospital. Of the patients who were inadequately treated, 89% were kept on treatment for drug-susceptible TB. The regimen may not have been changed due to the patient being prematurely discharged (17%) or dying (7%) before their result became available, or possibly due to the patient being rapidly transferred to a dedicated centre for drug-resistant TB management.

Inadequate knowledge of the appropriate drug regimen by the treating doctors may have accounted for the reluctance to amend treatment. It is imperative that all healthcare providers that are faced with the challenge of TB and drug-resistance on a day-to-day basis become familiar with the appropriate drug-resistant treatment regimen.

It took an average of 3.36 days from the day of admission to confirm the presence of RIF-resistant PTB. The Xpert MTB/RIF assay was introduced for use as a point-of-care, rapid diagnostic assay in poor rural areas. Its use in the tertiary level hospital revealed a longer duration before obtaining the result, which was contrary to the intended rapid use of the assay. A delay in obtaining the result leads to a delay in appropriate treatment, and exposure of the hospital population to drug-resistant organisms. Possible explanations include a delay in obtaining a sputum sample from the patient, delays in transport, registration, or processing of the specimen by the laboratory, and sputum samples that may be lost in transit.[34] A contemporary investigation of the time to obtaining a result would be beneficial.

After patients who were discharged or had died before their result

became available were taken into account, 66% of the remaining 53 patients were isolated with a mean time of 4 days after being admitted.

The time taken to isolation corresponds to the duration of time taken to obtain the MTB/RIF assay result. Appropriately isolating patients with drug-resistant TB, while awaiting referral, will decrease the risk of further transmission in the hospital setting. Many hospitals have a limited number of isolation facilities, which are typically reserved for patients with a high clinical suspicion for, or confirmed, drugresistant TB. Appropriate referral forms an essential part of the management of drug-resistant TB. The referral centre will: ensure that patients have the correct confirmatory tests submitted and will review the results; prescribe correct drug therapy and will have adequate stock of drugs; screen for HIV and initiate and manage ART; monitor progress with resubmission of sputum specimens for testing to assess treatment success; manage adverse drug reactions; and have access to allied healthcare providers to discuss dietary advice, to manage psychological issues, and to perform hearing tests for those on aminoglycosides.

Of the 53 patients who received their results in hospital, 64% were appropriately referred, while 14% were not referred, with the remainder dying in hospital, and a single case absconded.

The mortality rate was 19%, which was comparable with the global estimate of 16% among patients with MDR-TB[4] and a local study[29] that demonstrated an inpatient mortality rate of 19% among patients diagnosed with PTB. A delay in obtaining the diagnosis, inappropriate drug therapy, and advanced HIV disease may have contributed to the overall mortality.

The prevalence of HIV and any RIF-resistant TB co-infection in this cohort was 83%, which is in keeping with global comparisons of 70 - 80%,[2,14] and corresponds with the high levels found in subSaharan Africa. Ghandhi et al.[18] demonstrated a rate of 92% with MDR-TB and HIV co-infection. Most of the patients had advanced immunosuppression.

Study limitations Owing to the lack of submission of the follow-up LPA and DST tests, a considerable proportion (40%) of the study population could not be assigned a specific resistance pattern. Although the NHLS system was searched by name for evidence of follow-up testing, the retrospective nature of the study did not allow us to trace patients who had not submitted tests, to ascertain details of further testing and appropriate care. Although the study design allowed for the description of prevalence and initial management at the beginning of the treatment programme, it did not incorporate patientsâ&#x20AC;&#x2122; adherence to treatment, adverse reactions, and long-term outcomes. The study only reviewed a single healthcare facility and therefore the results only pertain to a limited geographical area, which may not be fully representative of other regions in SA. The adequacy of records and untraceable records was another limitation to the study. The quality of information recorded within the inpatient hospital files was sufficient in most instances.

Conclusion

In conclusion, our results revealed that the prevalence of RIFresistant PTB in our setting was >10%. The study also showed that the overall management (including confirmatory tests, appropriate drug therapy, isolation, and referral) of patients with RIF-resistant

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ORIGINAL RESEARCH PTB was substandard and there are multiple areas that need to be improved upon. Submission of paired sputum samples and storage by the laboratory may improve the diagnostic yield of drug-resistant TB. Educating healthcare professionals regarding initial management and therapeutic regimens is of paramount importance to help control the scourge of this treatable disease.

Acknowledgements. Mr Tinyiko Ngobeni, health data analyst at the Corporate Data Warehouse for the National Health Laboratory Service, who compiled the list of Xpert MTB/RIF assays performed during the study period. Chris Hani Baragwanath Academic Hospital records office, for tracing of patients’ files. Honest Muchabaiwa, for his assistance regarding the overall data interpretation.

Author contributions. Design, analysis and interpretation – RMN, ASK, FS. Drafting and revision – RMN, ASK, FS. Approval of version to be published – RMN, ASK, FS. Funding. None.

Conflicts of interest. None 1. World Health Organization. Global Tuberculosis Report. Geneva: WHO, 2015. http:// apps.who.int/iris/bitstream/10665/191102/1/9789241565059_eng.pdf (accessed 27 July 2016).

2. World Health Organization. Global tuberculosis report. Geneva: WHO, 2014. http:// apps.who.int/iris/bitstream/10665/137094/1/9789241564809_eng.pdf (accessed on 24 March 2015).

3. Kalokhe AS, Shafiq M, Lee JC, et al. Multidrug-resistant tuberculosis drug susceptibility and molecular diagnostic testing. Am J Med Sci 2013;345(2):143-148. http://doi.org/10.1097/MAJ.0b013e31825d32c6 4. World Health Organization. Drug resistant TB surveillance & response supplement, Global Tuberculosis Report. Geneva: WHO, 2014. www.who.int/tb/publications/ global_report/gtbr14_supplement_web_v3.pdf (accessed on 24 March 2015).

5. Caminero JA. Multidrug-resistant tuberculosis: Epidemiology, risk factors and case finding. Int J Tuberc Lung Dis 2010;14(4):382-390.

6. Ormerod LP. Multidrug-resistant tuberculosis (MDR-TB): Epidemiology, prevention and treatment. Br Med Bull 2005;73-74(1):17-24. http://doi.org/10.1093/bmb/ldh047 7. Shamaei M, Marjani M, Chitsaz E, et al. First-line anti-tuberculosis drug resistance patterns and trends at the national TB referral center in Iran – eight years of surveillance. Int J Infect Dis 2009;13(5):e236-e240. http://doi.org/10.1016/j. ijid.2008.11.027 8. Sandman L, Schluger NW, Davidow AL, Bonk S. Risk factors for rifampinmonoresistant tuberculosis: A case-control study. Am J Respir Crit Care Med 1999;159(2):468-472. http://doi.org/10.1164/ajrccm.159.2.9805097 9. Nakiyingi L, Nankabirwa, H, Lamorde M. Tuberculosis diagnosis in resource-limited settings: Clinical use of GeneXpert in the diagnosis of smear-negative PTB: A case report. Afr Health Sci 2013;13(2):522-524. http://doi.org/10.4314/ahs.v13i2.46 10. Meyssonnier V, Bui TV, Veziris N, Jarlier V, Robert J. Rifampicin mono-resistant tuberculosis in France: A 2005-2010 retrospective cohort analysis. BMC Infect Dis 2014;14:18. https://doi.org/10.1186/1471-2334-14-18 11. Keugoung B, Fouelifack FY, Fotsing R, Macq J, Meli J, Criel B. A systematic review of missed opportunities for improving tuberculosis and HIV/AIDS control in Subsaharan Africa: What is still missed by health experts? Pan Afr Med J 2014;18:320. http://doi.org/10.11604/pamj.2014.18.320.4066 12. World Health Organization. Global update on the health sector response to HIV. Geneva: WHO, 2014. http://apps.who.int/iris/bitstream/10665/128494/1/9789241507585_eng. pdf?ua=1 (accessed on 19 May 2015).

13. Dean AS, Zignol M, Falzon D, Getahun H, Floyd K. HIV and multidrug-resistant tuberculosis: Overlapping epidemics. Eur Respir J 2014;44(1):251-254. http://doi. org/10.1183/09031936.00205413 14. Wells CD. Global impact of multidrug-resistant pulmonary tuberculosis among HIV-infected and other immunocompromised hosts: Epidemiology, diagnosis, and strategies for management. Curr Infect Dis Rep 2010;12(3): 192-197. http://doi. org/10.1007/s11908-010-0104-5

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15. Farley JE, Ram M, Pan W, et al. Outcomes of multi-drug resistant tuberculosis (MDRTB) among a cohort of South African patients with high HIV prevalence. PLoS ONE 2011;6(7):e20436. http://doi.org/10.1371/ journal.pone.0020436 16. Chung-Delgado K, Guillen-Bravo S, Revilla-Montag A, Bernabe-Ortiz A. Mortality among MDR-TB cases: Comparison with drug-susceptible tuberculosis and associated factors. PLoS ONE 2015;10(3):e0119332. http://doi.org/10.1371/journal. pone.0119332 17. Van den Hof S, Tursynbayeva A, Abildaev T, Adenov M, Pak S, Ismailov S. HIV and multidrug-resistant tuberculosis: Overlapping risk factors. Eur Respir J 2015;45(2):567-569. http://doi.org/10.1183/09031936.00131014 18. Gandhi NR, Andrews JR, Brust JC, et al. Risk factors for mortality among MDRand XDR-TB patients in a high HIV prevalence setting. Int J Tuberc Lung Dis 2012;16(1):90-97. http://doi.org/10.5588/ijtld.11.0153.

19. Traore H, Fissette K, Bastian I, Devleeschouwer M, Portaels F. Detection of rifampicin resistance in Mycobacterium tuberculosis isolates from diverse countries by a commercial line probe assay as an initial indicator of multidrug resistance. Int J Tuberc Lung Dis 2000;4(5):481-484.

20. Sougakoff W, Rodrigue M, Truffot-Pernot C, et al. Use of a high-density DNA probe array for detecting mutations involved in rifampicin resistance in Mycobacterium tuberculosis. Clin Microbiol Infect 2004;10(4):289-294. https://doi.org/10.1111/ j.1198-743X.2004.889.x 21. Kurbatova EV, Cavanaugh JS, Shah NS, et al. Rifampicin-resistant Mycobacterium tuberculosis: Susceptibility to isoniazid and other anti-tuberculosis drugs. Int J Tuberc Lung Dis 2012;16(3):355-357. http://doi.org/10.5588/ijtld.11.0542 22. World Health Organization. Global Tuberculosis Report. Geneva: WHO, 2012. http:// apps.who.int/iris/bitstream/10665/75938/1/9789241564502_eng.pdf (accessed 03 March 2013).

23. Theron G, Peter J, van Zyl-Smit R, et al. Evaluation of the Xpert MTB/RIF assay for the diagnosis of pulmonary tuberculosis in a high HIV prevalence setting. Am J Respir Crit Care Med 2011;184(1):132-140. http://doi.org/10.1164/rccm.201101-0056OC 24. Steingart KR, Sohn H, Schiller I, Kloda LA, Boehme CC, Pai M, Dendukuri N. Xpert® MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults.

Cochrane Database Syst Rev 2014;1(1):CD009593. http://doi.org/10.1002/14651858.

CD009593.pub3 25. Baker BJ, Holtom PD. Additional benefits of GeneXpert MTB/RIF assay for the evaluation of pulmonary tuberculosis among inpatients. Clin Infect Dis 2015;60(8):1287-1288. http://doi.org/10.1093/cid/civ006 26. Weyer K, Mirzayev F, Migliori G, et al. Rapid molecular TB diagnosis: Evidence, policy-making and global implementation of Xpert(R)MTB/RIF. Eur Respir J 2013;42(1):252-271. http://doi.org/10.1183/09031936.00157212 27. Department of Health, Republic of South Africa. Management of drug-resistant tuberculoisis policy guidelines. Pretoria: Department of Health, 2011.

28. Van Altena R, de Vries G, Haar CH, et al. Highly successful treatment outcome of multidrug-resistant tuberculosis in the Netherlands, 2000-2009. Int J Tuberc Lung Dis 2015;19(4):406-412. http://doi.org/10.5588/ijtld.14.0838 29. Edginton ME, Wong ML, Phofa R, Mahlaba D, Hodkinson HJ. Tuberculosis at Chris Hani Baragwanath Hospital: Numbers of patients diagnosed and outcomes of referrals to district clinics. Int J Tuberc Lung Dis 2005;9(4):398-402.

30. Ebonwu JI, Tint KS, Ihekweazu C. Low treatment initiation rates among multidrugresistant tuberculosis patients in Gauteng, South Africa, 2011. Int J Tuberc Lung Dis 2013;17(8):1043-1048. http://doi.org/10.5588/ijtld.13.0071 31. Nkosi D, Janssen S, Padanilam X, Louw R, Menezes CN, Grobusch MP. Factors influencing specialist care referral of multidrug- and extensively drug-resistant tuberculosis patients in Gauteng/South Africa: A descriptive questionnaire-based study. BMC Health Serv Res 2013;13:268. http://doi.org/10.1186/1472-6963-13-268 32. National Institute for Communicable Diseases. South African Tuberculosis Drug Resistance Survey 2012–2014, Sandringham, South Africa, http://www.nicd.ac.za (accessed 21 November 2016).

33. Mukinda FK, Theron D, van der Spuy GD, et al. Rise in rifampicin-monoresistant tuberculosis in Western Cape, South Africa. Int J Tuberc Lung Dis 2012;16(2):196202. http://doi.org/10.5588/ijtld.11.0116 34. Charambira K, Ade S, Harries AD, et al. Diagnosis and treatment of TB patients with rifampicin resistance detected using Xpert® MTB/RIF in Zimbabwe. Public Health Action 2016;6(2):122-128. http://doi.org/10.5588/pha.16.0005

CASE REPORT

A rare case of lymphangiomatosis D Parris,1 BSc, MB BCh, FCPaed, Dip Allergy; A van Niekerk,1 MB ChB, MMed; E Marais,2 MB ChB, MMed Anat Path; I O Lawal,3 MBBS; A Goga,1 MB ChB, DTM&H, DCh, MSc, MCh, MSc Epidemiology, FCPaed, PhD; A C Jeevarathnum,1 MB BCh, FCPaed, Dip Allergy, MMed, Cert Paed Pulm, European Respiratory Diploma; X Dearden,1 MB ChB, FCPaed, MMed, Dip Allergy; R J Green,1 PhD, DSc Department of Paediatrics and Child Health, School of Medicine, Faculty of Health Sciences, University of Pretoria, and Steve Biko Academic Hospital, Pretoria, South Africa 2 Department of Anatomical Pathology, School of Medicine, Faculty of Health Sciences, University of Pretoria, and Steve Biko Academic Hospital, Pretoria, South Africa 3 Department of Radiology, School of Medicine, Faculty of Health Sciences, University of Pretoria and Steve Biko Academic Hospital, Pretoria, South Africa 1

Corresponding author: D Parris (drdeniseparris@gmail.com)

Lymphangiomatosis is a rare disorder and the underlying aetiology is poorly understood. The diagnosis is difficult, and relies on various clinical, radiological and histological features. Therapy is diverse, with combinations of treatment required to achieve disease control. The prognosis is guarded, and currently a vast amount of work is being undertaken to understand the disease, and to find focused therapy.

We present a case of histologically, and radiologically proven lymphangiomatosis in a 4-year-old child who presented with nonspecific symptoms.

S Afr Respir J 2017;23(2):35-38. DOI:10.7196/SARJ.2017.v23i2.153

Lymphangiomatosis is thought to be an intrauterine anomaly that occurs during embryogenesis, with unchecked proliferation of lymphatic vessels.[1,2] Currently, no genetic, immunological or environmental factors have been identified in the pathogenesis of the disease. The clinical manifestations are diverse, and can occur as an isolated disorder, like a cystic hygroma, or can present with profound cardiovascular involvement, chylothoraces, and chylous pericardial effusions.[3] The diagnosis is made on a biopsy of the involved site, and demonstration of dilated lymphatic channels, with positive staining for D2-40 and CD-31 antigens.[4] Since the pathophysiology of the disease is poorly understood, therapy is largely experimental, with variable outcomes.[1,2,4,5]

Case report

A 4-year-old female child was referred with a left-sided chest mass, extending from the 3rd to the 6th rib laterally, and extending anteriorly over the mid-clavicular line. It was soft, non-tender, not pulsating, and 10 cm Ă&#x2014; 15 cm in size. She had developed a chronic cough, which was initially dry, but had become progressively more productive. There was no associated significant history.

Clinically, the child was well-grown, with no features of clubbing or anaemia. The mass was palpable over the left chest wall. The percussion note was stony-dull and breath sounds were markedly decreased over the left chest, in keeping with a pleural effusion. The rest of the examination was unremarkable.

Her laboratory evaluation revealed a mild anaemia. The HIV ELISA test result was negative. Both the Mantoux test, and the Gene-Xpert results for pulmonary tuberculosis were negative. There was no evidence of infection on blood screening. Erythrocyte sedimentation rate, renal functions, liver function tests, and thyroid function tests were all within normal limits.

Her pleural tap, under ultrasound guidance, was diagnostic for a chylothorax - both clinically, and on biochemical analysis of the pleural fluid (Table 1).

Table 1. Biochemical analysis of the pleural fluid Parameter

Value

pH

7.6

Colour

Milky

Total fat

5 g/dL (elevated)

Cholesterol

1.8 mmol/L (elevated)

Triglycerides

1.9 mmol/L (elevated)

Total protein

4 g/dL

Electrolytes

Equivalent to plasma

Glucose

4.8 mmol/L

Chylomicrons

Positive

Chest X-ray (CXR) revealed a massive left-sided effusion (Fig. 1) The cardiac assessment was normal, with no evidence of pulmonary hypertension or cor pulmonale. Her computed tomography (CT) scan (Figs 2A - 2D) demonstrated a left-sided effusion, with extensive destruction of the left lung. Multiple lytic lesions were visible in the spleen, and the vertebrae of T3 and T4. Lymphoscintigraphy of the chest demonstrated evidence of a lymphatic leak, but due to the extensive lymphatic involvement, the exact site was not delineated.

Owing to the progressive deterioration of the patientâ&#x20AC;&#x2122;s clinical condition, a pleural biopsy was performed under general anaesthesia, and this result was diagnostic. The biopsy findings were pathognomonic of diffuse pulmonary lymphangiomatosis (DPL). Variable amounts

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35

CASE REPORT

Fig. 1. Massive left-sided effusion (green arrow), with mediastinal shift (red arrows).

A

B

of fibrosis, with areas of focal haemorrhage, were demonstrated.

Aggregates of inflammatory cells, mainly small lymphocytes, were visualised. Diffuse and complex dilatation, with irregularity of lymphatic vessels, and lined by a single layer of endothelial cells, was recorded. The anastomosing spaces were filled with eosinophilic material and chyle. The cells stained positively for D2-40, and CD31 antigen (Figs 3A - 3D). This confirmed the diagnosis of DPL. Treatment with dietary modification, along with glucocorticoids, and propranolol, was implemented. The propranolol treatment was implemented at a starting dose of 0.5 mg/kg, and increased gradually, but was stopped owing to severe diarrhoea, vomiting, headache, and bradycardia. Propanolol treatment was stopped, but restarted a week later at 0.5 mg/kg. The drug was slowly increased to 1 mg/kg over the next 2 weeks, and was better tolerated. The effusion reaccumulated, despite the above therapy and repeat pleural drainage. A PleurX catheter was inserted, and the mother received extensive training with respect to the management of the catheter. At the time of publication of this manuscript, the patientâ&#x20AC;&#x2122;s diet was monitored by a dietician and she was she was being followed up at our clinic.

Discussion

C

D Fig. 2. Contrast scan of the lungs, vertebrae, and abdomen. (A) Extensive pleural effusion (red arrow) with lung consolidation, and cystic changes (green arrow). (B) Effusion with consolidation, trapped air (green arrow), and a soft tissue mass on the left (blue arrow). (C) Lytic lesions in the vertebrae (T3 and T4). (D) Extensive lytic lesions present in the spleen (purple arrow).

36 SARJ VOL. 23 NO. 2 2017

Lymphangiomatosis is a rare disorder. The underlying aetiology is poorly understood, but recent research suggests that vascular endothelial growth factor receptor-3 (VEGFR-3) may be involved in the development of lymphangiomatosis.[1] The process is thought to occur during embryonic growth.[1,6] There are currently no genetic, immunological, or environmental factors implicated in the causation of the disorder. The malformations may occur in utero as part of another syndrome. Syndromes commonly associated with lymphatic malformations include Noonan syndrome, Turner syndrome, and Down syndrome.[1,2] The disorder is characterised by masses of fluidfilled channels that can occur anywhere in the body, and may be either focal or diffuse.[7] The lymphatic malformations can present at any age. Typically, congenital malformations present as soft, spongy, non-tender masses.[1,8] In older children, the presentation is dependent on the site of the lesion, and the mass effect on adjacent structures. Infection, trauma, or bleeding into the malformation may result in rapid expansion of the lesion.

CASE REPORT

A

B Fig. 3. Immunochemical staining of the lung and pleural biopsy specimen.

(A) Histologically, the lung biopsy revealed an increase in the size and number of thin-walled channels lined by attenuated endothelial cells (H&E × 40). (B) The lung biopsy revealed an increase in the size and number of thin-walled channels lined by attenuated endothelial cells with lymphocytes visualised (H&E × 100). (C) Immunohistochemical staining (×200) with D2-40 antigen showing proliferation of the lymphatic channels, and strongly highlights the lining of the channels.

(D) The attenuated endothelial cells lining the anastamosing irregular lymphatic channels where strongly positive for anti-CD31, which is highly specific for vascular endothelium (arrow) (Immunoperoxidase and anti-CD31 × 200).

Clinically, patients may present with disfiguring lesions over the body or upper airway obstruction from lesions, involving the mouth, tongue, and trachea. Swallowing and speech may be affected with supraglottic lesions.[9] Lung lesions can cause marked airway compromise. Gastrointestinal involvement may result in severe weight loss, while splenic involvement causes severe abdominal pain. Bone involvement can lead to either bone overgrowth or bone loss, with an increased risk of pathological fractures.

This disease entity is known as Gorham-Stout syndrome, which is also referred to as vanishing bone disease.[10,11] Pulmonary lymphangiomatosis can have a varying clinical presentation, from being asymptomatic to profound respiratory failure.[1,2,7,12] The disease is more rapidly progressive in children, where the clinical features reported include chronic cough, recurrent respiratory tract infections, haemoptysis from vessel erosion, and chyloptysis.[1,3,12] Dyspnoea, chest pain, and chylous pleural effusions, are other associated features. The chylous effusions can be large, causing airway compromise.[13] Complications associated with DPL include compression of the adjacent chest wall, with lytic lesions in the bone.[13] Pneumothoraces have also been reported. Chylous pericardial effusions may produce cardiac tamponade, with hypotension.[5,12] Pulmonary hypertension and cor pulmonale are features of this disease. The chylous pleural effusions are a nidus for infection, with severe pneumonias occurring in already compromised respiratory patients. Disseminated vascular coagulation is a rare complication.[8,12] Chest radiographs are not diagnostic in DPL, but may reveal diffuse interstitial patterns, and pleural effusions. Contrasted computed

tomography (CT) scans demonstrate bilateral, smooth thickening of the interlobular septae and bronchovascular bundles, with patchy ground-glass opacities, as well as diffuse fluid accumulation in the mediastinum and hilar soft tissue. Unilateral or bilateral pleural effusions, with pleural thickening can also be observed. Not all the features may be present in a patient. These findings are not conclusive for DPL, but may allude to the possibility of the disease.[2,9,12,14] Lymphoscintigraphy or lymphangiography can be useful in outlining the lymphatic vessels, and in identifying the site of the lymphatic leak.

These investigations both require administration of a contrast media.

A simultaneous CXR, or CT scan, will outline the lymphatic anatomy.

The sensitivity of this investigation is low in DPL.[6,8,15] Bronchoscopy is of limited value, and most diagnoses of DPL are based on open lung biopsy followed by immunohistochemical staining.[4] Pulmonary function tests were shown to reveal both restrictive and obstructive patterns.[3,7] This investigation is difficult in the young child.

Treatment options are varied, and no single therapy has proven to be successful. For localised disease, surgical resection may be therapeutic.[9] For DPL, dietary modification with a low-fat diet, and medium-chain triglycerides, along with albumin infusions, has demonstrated little success.[12] Sclerotherapy using doxycyline as the sclerosing agent has resulted in improvement in some patients; however, this form of therapy requires multiple injections of doxycycline, and is of limited value in extensive disease.[16] Two commonly employed therapies include interferon alfa-2b (INF-2b) and glucocorticoids. Successful treatment was achieved in a 5-year-old boy who presented with a right-sided pleural effusion.

Thoracocentesis revealed a chylous effusion, and a chylothorax was confirmed on immunohistochemical analysis that demonstrated the positive CD31 and CD34 markers for vascular endothelial cells; some of the endothelia stained positive for the monoclonal antibody, D2-40. This is a confirmatory test for lymphangiomatosis. Wholebody MRI on the boy confirmed disseminated disease. PEGylated INF-2b, was administered weekly at a dose of 1.0 µg/kg. After the second dose of INF-2b, 1.8 L of chylous fluid was evacuated from the pleural space. The third dose of the drug was increased to 1.5 µg/kg.

The child’s clinical condition improved, and after 3 months of therapy, his lung function, exercise tolerance, chest radiographs, and bone lesions showed marked improvement. He experienced some minor side-effects, including headache, raised temperatures, and malaise. These side-effects were transient. He was on INF therapy for 9 months with no further disease progression, and improved quality of life.[1,17) Other drugs used include biphosphonates, thalidomide, and rapamycin.[1] Octreotide is a synthetic analogue of somatostatin, which is an endogenous hormone, has been used with some success in the reduction of chyle production within the lymphatic system; however, the side-effect profile has limited its clinical use.[18] More recently, propranolol and bevacizumab have been found to inhibit synthesis of vascular endothelial growth factor.[4,19,20) Both these drugs have demonstrated encouraging results. Propranolol was used in a 13-year-old boy, in whom the dosage of PEGylated INF2b was decreased as a consequence of marked side-effects, including depression. The effusion reaccumulated despite increasing the dose of PEGylated INF-2b. The volume of chylous fluid drained daily was >100 mL. Treatment with propranolol was commenced at 0.5 mg/kg/day, in three divided doses. The daily volume of chylous fluid declined slowly, allowing the INF-2b to be discontinued. He

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37

CASE REPORT received 10 months of daily propranolol, with improved quality of life, and decreased drainage of pleural fluid.[1,19] Bevacizumab was successfully used on a 40-year-old female, in whom the diagnosis of pulmonary lymphangiomatosis was delayed for 3 years. She presented with haemoptysis initially, and subsequent mediastinal masses, pleural masses, and splenic disease. Revision of her previous histology confirmed diffuse pulmonary lymphangiomatosis.

Intravenous bevacizumab, at a dose of 1 mg/kg, was administered intravenously every 3 weeks. The haemoptysis resolved, the blood haemoglobin levels stabilised, and the masses decreased in size; however, therapy was aborted after seven treatments, as the patient developed hypertension. The patient did not have further episodes of haemoptysis and, 10 months post cessation of bevacizumab, the masses had not increased in size.[1,20] Radiotherapy has been used for DPL where surgery is contraindicated, with poor results and the potential for lung fibrosis.[11] Only one case of successful lung transplantation has been reported.[15] Acknowledgements: Prof. R. Green for being an amazing project supervisor.

Author contributions: DP wrote the manuscript. EM (Department of Histopathology) prepared the slides. IOL (Department of Radiology) analysed the scans. AVN reviewed the patient with DP. RJG reviewed the manuscript.

Funding: None Conflicts of interest: None

1. Tazelaar HD, Kerr D, Yousem SA, Saldana MJ, Longston C, Colby T. Diffuse pulmonary lymphangiomatosis. Human Pathol 1993;24(12):1313-1322. https://doi. org/10.1016/0046-8177(93)90265-i 2. Faul JL, Berry GJ, Colby TV, et al. Thoracic lymphangiomas, lymphangiectasis, lymphangiomatosis, and lymphatic dysplasia syndrome. Am J Respir Crit Care Med 2000;161(3):1037-1046. https://doi.org/10.1164/ajrccm.161.3.9904056 3. Satria MN, Pacheco-Rodriguez G, Moss J. Pulmonary lymphangiomatosis. Lymphat Res Biol 2011;9(4):191-193. https://doi.org/10.1089/lrb.2011.0023 4. Ramani P, Shah A. Lymphangiomatosis: Histologic and immunohistochemical analysis of four cases. Am J Surg Path 1993;17(4):329-335. https://doi.org/10.1097/00000478199304000-00002

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5. Nakagawa T, Koizumi T, Oiwa K, et al. Sudden death of a 14-year-old girl with lymphangiomatosis. Gen Thorac Cardiovasc Surg 2016;64(2):116-119. https://doi. org/10.1007/s11748-014-0450-6 6. Bellini C, Villa G, Sambucetti G, et al. Lymphoscintigraphy patterns in newborns and children with congenital lymphatic dysplasia. Lymph 2014;47(1):28-39.

7. Zhao J, Wu R, Gu Y. Pathology analysis of a rare case of diffuse pulmonary lymhangiomatosis. Ann Transl Med 2016;4(6):114. https://doi.org/10.21037/ atm.2016.03.30 8. Fukahori S, Tsuru T, Asagiri K, et al. Thoracic lymphangiomatosis with massive chylothorax after tumor biopsy and with disseminated intravenous coagulation â&#x20AC;&#x201C; lymphoscintigraphy, an alternative minimally invasive imaging technique: Report of a case. Surg Today 2011;41(7):978-982. https://doi.org/10.1007/s00595-010-4383-0 9. Perkins JA, Manning SC, Tempero RM, et al. Lymphatic malformations: Review of current treatment. Otolaryngol Head Neck Surg 2010;142(6):795-803. https://doi. org/10.1016/j.otohns.2010.02.026 10. Yavasoglu I, Ă&#x2021;akiroglu U. Diffuse lymphangiomatosis: Gorham-Stout syndrome.

Intern Med 2014:53(1):75-76. https://doi.org/10.2169/internalmedicine.53.0987 11. Gordon KD, Mortimer PS. Progressive lymphangiomatosis and Gorhams's disease: Case report and clinical implications. Lymphat Res Biol 2011;9(4):201-204. https:// doi.org/10.1089/lrb.2011.0021 12. Kadakia KC, Patel SM, Yi ES, Limper AH. Diffuse pulmonary lymphangiomatosis.

Can Respir J 2013;20(1):52-54. https://doi.org/10.1155/2013/971350 13. Canil K, Fitzgerald P, Lau G. Massive chylothorax associated with lymphangiomatosis of the bone. J Pediatr Surg 1994;29(9):1186-1188. https://doi.org/10.1016/00223468(94)90796-x 14. Du MH, Ye RJ, Sun KK, et al. Diffuse pulmonary lymphangiomatosis: A case report with literature review. Chin Med J 2011;124(5):797-800. https://doi.org/10.3760/cma .j.issn.0366-6999.2011.05.033 15. James D. Chylothorax in infants and children. Pediatrics 2014:133(4):722-733. https:// doi.org/10.1542/peds.2013-2072 16. Burrows PE, Mitri RK, Alomari A, et al. Percutaneous sclerotherapy of lymphatic malformations with doxycycline. Lymphat Res Biol 2008;6(3-4):209-216. https://doi. org/10.1089/lrb.2008.1004 17. Ozeki M. Funato M. Clinical improvement of diffuse lymphangiomatosis with pegylated interferon alfa-2B therapy: Case report and review of the literature. Pediatr Hematol Oncol 2007;24(7):513-524. https://doi.org/10.1080/08880010701533603 18. Roehr CC, Jung A, Proquitte H, et al. Somatostatin or octreotide as treatment options for chylothorax in young children: A systematic review. Intens Care Med 2006;32(5):650-657. https://doi.org/10.1007/s00134-006-0114-9 19. Ozeki M, Fukao T, Kondo N. Propranolol for intractable diffuse lymphangiomatosis.

N Engl J Med 2011;364(14):1380-1382. https://doi.org/10.1056/nejmc1013217 20. Aman J, Thunnissen E, Paul MA, van Nieuw Amerongen GP, Vonk-Noordegraaf A. Successful treatment of diffuse pulmonary lymphangiomatosis with bevacizumab.

Ann Intern Med 2012;156(11):839-840. https://doi.org/10.7326/0003-4819-156-11201206050-00016 21. Kinnier CV, Eu JP, Davis RD, et al. Successful bilateral lung transplantation for lymphangiomatosis. Am J Transplant 2008;8(9):1946-1950. https://doi.org/10.1111/ j.1600-6143.2008.02340.x

CASE REPORT

Dyspnoea on exertion in a child: A presentation of neuroendocrine hyperplasia of infancy A C Jeevarathnum, MB BCh, FCPaed, Dip Allergy, MMed, Cert Paed Pulm, European Respiratory Diploma; A van Niekerk, MB BCh, MMed; D Parris, BSc, MB BCh, FCPaed, Dip Allergy; X Dearden, MB ChB, FCPaed, MMed, Dip Allergy; A Goga, PhD; R J Green, PhD, DSc Department of Paediatrics and Child Health, School of Medicine, Faculty of Health Sciences, and University of Pretoria and Steve Biko Academic Hospital, Pretoria, South Africa Corresponding author: A C Jeevarathnum (acjeevarathnum@gmail.com)

Neuroendocrine hyperplasia of infancy (NEHI) syndrome is a rare type of interstitial lung disease in children, the exact incidence of which is unknown. The diagnosis of NEHI syndrome can be made on particular geographical findings on a computed tomography scan in a patient with a suggestive clinical picture, after exclusion of more common disorders. The gold standard of diagnosis is lung biopsy with bombesin staining. There is no current treatment for NEHI syndrome and symptoms usually resolve with time. We present a case of biopsy-proven NEHI in an infant who presented with dyspnoea on exertion.

S Afr Respir J 2017;23(2):39-41. DOI:7196/SARJ.2017.v23i2.159

Neuroendocrine hyperplasia of infancy (NEHI) is a type of childhood interstitial lung disease (chILD) first described in 2005.[1] It is thought to be benign because it gradually resolves over time without treatment. Patients present with failure to thrive, tachypnoea, crackles and hypoxia.[1] Infant pulmonary function testing is suggestive of air trapping.[2] Lung-biopsy specimens indicate the presence of neuroendocrine cells in the terminal airways without other structural parenchymal disease.[3] Since the publication by Brody et al.[4] in 2010 the international literature has suggested that a diagnosis of NEHI syndrome can be made with confidence if the computed tomography (CT) scans have a particular geographical appearance in a patient who has a suggestive history and clinical findings. Patients with NEHI syndrome may incur significant morbidity with failure to thrive, and supplemental nutritional intervention is occasionally required.

Symptoms are thought to gradually improve over time; however, more recently it has been shown that patients with NEHI syndrome may experience exacerbations of their illness, with significant air trapping.[5]

The patientâ&#x20AC;&#x2122;s autoimmune screen and sweat tests were negative. His immune system displayed a partial mannan-binding lectin deficiency, with an absolute value of 201 ng/mL. The abnormalities in his immune profile could not explain his symptoms.

His chest X-ray (CXR) showed marked hyperinflation with nonspecific reticular opacities in the right middle lobe and the lingua region; however, these features were not striking. His cardiac echocardiogram was normal. The HRCT chest scan (Fig. 1) showed ground glass opacities predominantly in the right middle lobe and lingula area, with no noted bronchiectasis. The bronchoalveolar

Case report

A 14-month-old male was referred for assessment of difficulty in breathing. The symptoms were predominantly dyspnoea on exertion, with shortness of breath, tachypnoea, and visible recessions noted by the parents from 6 months of age. There was no cough or wheeze associated with the dyspnoea on exertion. There was no significant family history of asthma or cystic fibrosis.

Clinically, he displayed no evidence of chronic lung disease, with no chest wall deformity, plethora, cyanosis or clubbing. He was hyperinflated with a barrel-shaped chest. No tachypnoea was noted at rest. He became tachypnoeic on exertion with a respiratory rate of 40 bpm. However, oxygen saturations were maintained post exercise.

Severe sternal recessions were noted on exertion. There were no wheezes on auscultation at rest, or on exertion.

Fig. 1. Axial computed tomography chest scan depicting ground-glass opacities, predominantly in the right middle lobe, and lingula lesions (white arrows), which are characteristic of the geographical distribution associated with neuroendocrine hyperplasia of infancy (Courtesy of Prof.

A van Niekerk, Department of Paediatrics and Child Health, Steve Biko Academic Hospital)

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CASE REPORT lavage (BAL) ruled out an infective/inflammatory aetiology, but did not provide any additional diagnostic yield.

At this point, the most likely diagnosis was thought to be NEHI syndrome and the parents were counselled accordingly. A decision was then taken to proceed to a lung biopsy and undertake bombesin staining to confirm the diagnosis of NEHI after the parents sought confirmation of the diagnosis. The HRCT chest scan was in fact diagnostic and the lung biopsy was only undertaken because the parents sought histological confirmation. In retrospect, the diagnosis could have been made without lung biopsy confirmation. Fig. 2 depicts haematoxylin and eosin (H&E) staining, which shows nonspecific interstitial changes. Bombesin staining was positive (Fig. 3). The clinical picture, CXR and CT chest scan findings, together with bombesin staining on lung biopsy specimens, were thought to be consistent with the diagnosis of NEHI. The parents were counselled accordingly, and general measures including vaccinations, nutrition, and avoidance of environmental tobacco smoke were instituted. At the time of publication of this manuscript, the patient had not experienced any exacerbations relating to the NEHI syndrome

Discussion

NEHI syndrome forms part of the group of chILD diseases. The worldwide incidence of chILD in children is rare, estimated at 0.13 - 16.2 cases per 100 000.[6] NEHI syndrome forms a subset of these rare disorders. The true incidence of NEHI syndrome is unknown; although it is assumed to be very rare, its true incidence could be underestimated. Retrospective lung biopsy data reveal an incidence of 10 - 14% of lung biopsy specimens in paediatrics, as per biopsy specimens of patients submitted for workup of chILD.[2,7] The aetiology of NEHI syndrome is largely unknown. However, there is evidence of a heritable aspect to the syndrome. There are a number of familial cases of NEHI syndrome for which no genetic mutation has been found;[8] however, Young et al.[9] identified a previously unreported mutation in the NKX2.1 gene that may cause NEHI. NEHI presents in otherwise healthy infants within the first few months to a year of life.[1,8,10] The peak incidence is at 3.8 months of age.

There is a slight male predominance. Patients present with tachypnoea with or without recessions, even at rest, and there is always a chronic history of tachypnoea that may precede viral infections. Cough and wheeze are not prominent features of NEHI.[1,10] Certainly, tachypnoea seems to be the most common presenting feature, and one should be wary of NEHI syndrome in patients who present with tachypnoea as the only complaint.

On examination, patients are noted to be hyperinflated. There may be failure to thrive noted secondary to the increased work of breathing.

Clubbing is not a feature and has not been reported in patients with NEHI. The CXR might be normal or show features of hyperinflation with perihilar opacities.

The approach to diagnosis of a patient with suspected NEHI syndrome would follow a similar algorithm, as set out by the American Thoracic Society for the workup of a patient with suspected interstitial lung disease.[11] Firstly, more common causes, such as acute and chronic infections, asthma, cystic fibrosis, and primary immune deficiencies need to be ruled out. It is mandatory

40 SARJ VOL. 23 NO. 2 2017

that these patients have a formal cardiac evaluation to rule out congenital cardiac causes.

If the initial workup is non-contributory, a CT chest scan should be undertaken. This is by far one of the most important investigations in revealing the diagnosis. It is well known that the diagnosis of NEHI syndrome can be made without a lung biopsy in those patients with a suggestive clinical syndrome. The characteristic HRCT findings of a patient with NEHI syndrome include ground-glass opacities in the right middle lobe, lingula, as well as the medial aspects of the upper and lower lobes; this occurs in the absence of other parenchymal abnormalities.[4,8] These findings reduce the need for performance of lung biopsies in all patients who present with a suggestive syndrome.

In NEHI syndrome patients, pulmonary function testing (PFT) shows elevated functional residual capacity[2] and, although PFT may play a role in suggesting the diagnosis, it cannot be used as a diagnostic method.

BAL specimens in patients with NEHI are non-inflammatory. A case series pilot study of 41 patients in 2013 including patients with cystic fibrosis, NEHI, follicular bronchiolitis, and controls revealed patients with NEHI had the lowest BAL white-cell count, a higher percentage of alveolar macrophages, and lower levels of interleukin 1-β, macrophage inflammatory protein-1β, and interleukin-8 on BAL

Fig. 2. H&E lung biopsy staining showing non-specific inflammatory changes. (Courtesy of Dr Preea Pillay, Department of Anatomical Pathology, Ampath Laboratories)

Fig. 3. Bombesin staining of lung biopsy, showing significant positive neuroendocrine cells (arrow heads). (Courtesy of Dr Preea Pillay, Department of Anatomical Pathology, Ampath Laboratories)

CASE REPORT compared with other patients in the study. With further research and validation of data in this series, BAL specimens may well be considered diagnostic in time to come.[12] In some cases, where the typical features are not seen on a HRCT chest scan, a lung biopsy may be required to diagnose NEHI. The initial H&E stains may show mild inflammatory changes. The chromogranin A staining used in some pathology laboratories does not sufficiently stain neuroendocrine cells in NEHI and therefore should be avoided.

The hallmark of the lung-biopsy changes lies in bombesin staining and demonstration of pulmonary neuroendocrine cells.[2] There is no specific treatment of NEHI, and therefore treatment of patients with NEHI requires supportive measures including vaccinations, avoidance of environmental tobacco smoke, and provision of adequate nutrition. Steroids have shown little benefit in the management of patients.[1] Most patients with NEHI demonstrate gradual improvement over time without specific treatment of the disease. However, recently it has been shown that patients with NEHI also display exacerbations of the disease, with increased air trapping being a predominant feature.

Unfortunately, there is no conclusion on how to actively manage a patient with NEHI during an exacerbation.[5] In the case series which described these exacerbations, oxygen was used in one case, and Zithromax with prednisone in the other; both showed resolution over time.[12] As this syndrome gains more recognition in the international literature, management strategies during an exacerbation will probably be alluded to.

Acknowledgements: None.

Author contributions: ACJ wrote the manuscript. AVN reviewed the patient with ACJ. DP, XD, AG and RJG co-authored the manuscript.

Funding: None Conflicts of interest: None

1. Deterding RR, Pye C, Fan LL, Langston C. Persistent tachypnea of infancy is associated with neuroendocrine cell hyperplasia. Pediatr Pulmonol 2005;40(2):157-165. http:// doi.org/10.1002/ppul.20243 2. Kerby GS, Wagner BD, Popler J, et al. Abnormal infant pulmonary function in young children with neuroendocrine cell hyperplasia of infancy. Pediatr Pulmonol 2013;48(10):1008-1015. http://doi.org/10.3410/f.718045206.793480909 3. Young LR, Brody AS, Inge TH, et al. Neuroendocrine cell distribution and frequency distinguish neuroendocrine cell hyperplasia of infancy from other pulmonary disorders. Chest 2011;139(5):1060-1071. http://doi.org/10.1378/chest.10-1304 4. Brody AS, Guillerman RP, Hay TC, et al. Neuroendocrine cell hyperplasia of infancy: Diagnosis with high-resolution CT. Am J Roentgenol 2010;194(1):238-244. http:// doi.org/10.2214/AJR.09.2743 5. Houin PR, Deterding RR, Young LR. Exacerbations in neuroendocrine cell hyperplasia of infancy are characterized by increased air trapping. Pediatr Pulmonol 2016(51):E9E12. http://doi.org/10.1002/ppul.23347 6. Hime NJ, Zurynski Y, Fitzgerald D, et al. Childhood interstitial lung disease: A systematic review. Pediatr Pulmonol 2015;50(12):1383-1392. http://doi.org/10.1002/ ppul.23183 7. Deutsch GH, Young LR, Deterding RR, et al. Diffuse lung disease in young children: Application of a novel classification scheme. Am J Respir Crit Care Med 2007;176(11):1120-1128. http://doi.org/10.1164/rccm.200703-393OC 8. Vece TJ, Young LR. Update of diffuse lung disease in children. Chest 2016;149(3):836845. http://doi.org/10.1378/chest.15-1986 9. Young LR, Deutsch GH, Bokulic RE, Brody AS, Nogee LM. A mutation in TTF1/ NKX2.1 is associated with familial neuroendocrine cell hyperplasia of infancy. Chest 2013;144(4):1199-1206. http://doi.org/10.1378/chest.13-0811 10. Oâ&#x20AC;&#x2122;Connor MG, Wurth M, Young LR. Rare becomes more common: Recognizing neuroendocrine cell hyperplasia of infancy in everyday pulmonary consultations. Ann Am Thorac Soc 2015;12(11):1730-1732. http://doi.org/10.1513/AnnalsATS.201507422LE 11. Kurland G, Deterding RR, Hagood JS, et al. An official American Thoracic Society clinical practice guideline: Classification, evaluation, and management of childhood interstitial lung disease in infancy. Am J Respir Crit Care Med 2013;188(3):376-394. http://doi.org/10.1164/rccm.201305-0923ST. 12. Popler J, Wagner BD, Tarro HL, Accurso FJ, Deterding RR. Bronchoalveolar lavage fluid cytokine profiles in neuroendocrine cell hyperplasia of infancy and follicular bronchiolitis. Orphanet J Rare Dis 2013;8(1):175-184. http://doi.org/10.1186/17501172-8-175

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BREATH-TAKING NEWS

Allergy and infant feeding guidelines in the context of resourceconstrained settings The World Health Organization and the United Nations Children’s Fund both advise exclusive breastfeeding (EBF) in the first 6 months of life, despite the mother’s HIV status. There is indisputable evidence that EBF in the first 6 months of life has benefits for the overall health of child and mother. This strategy has proven benefits in reducing the incidence of infant otitis media, lower respiratory tract infections, gastroenteritis and vertical HIV transmission. Early introduction of solids has the potential to increase the incidence of obesity, anaemia, diarrhoeal illness, and eczema.

However, studies in high-income countries have shown that early introduction of allergenic foods, such as peanuts, egg, sesame, wheat, cow’s milk protein, prior to 6 months of age, has the potential to decrease the incidence of food allergies later in life. Early introduction of complementary foods, prior to 6 months of age, runs the risk of shortening the overall duration of breastfeeding.

In settings with a high burden of HIV and/or other infectious diseases and malnutrition, early introduction of complementary feeds may be detrimental to the overall health of the community. In these communities, families with high a incidence of atopy that might benefit from early introduction of allergenic foods, should be advised individually.

A C Jeevarathnum Paediatric Pulmonologist, University of Pretoria and Steve Biko Academic Hospital, Pretoria, South Africa

1. Levin M, Goga A, Doherty T, et al. Allergy and infant feeding guidelines in the context of resource-constrained settings. J Allergy Clin Immunol 2017;139(2):455458. https://doi.org/10.1016/j.jaci.2016.09.039

Dysbiosis and probiotics in the ICU Traditionally, clinicians have dichotomised bacteria into harmful pathogens and friendly commensals. With increasing recognition of the significance of the individuals’ microbiome, this traditional way of thinking has been somewhat challenged. The microbiome is the collection of commensal organisms living on and within each of us.

The impact of the microbiome on homeostasis and maintenance of our daily physiology is being recognised increasingly in the literature.

The intestinal microbiome is a complex entity that can be harmful if the equilibrium is disturbed - a process referred to as dysbiosis. Patients in the intensive care unit (ICU) are at particular risk of dysbiosis given the high rate of antibiotic use, dietary changes, and the stress of critical illness. This disruption is thought to potentiate a host of untoward effects. From another perspective, restoration of the microbiome in the form of probiotics is an avenue of much debate in recent literature.

Probiotics are defined as living microbes of human origin that offer beneficial health effects to the host when ingested in sufficient quantities.

Research on the use of probiotics is challenging, as interpretation requires the consideration of many confounding factors, including the dose and type of probiotic to name a few. Furthermore, there is no standardisation across studies that would render it easier to interpret these findings.

42 SARJ VOL. 23 NO. 2 2017

Nonetheless, some noteworthy conclusions have been made regarding probiotic therapy, which has shown: • 40 - 50% reduction in antibiotic-associated diarrhoea • 60% reduction in rates of Clostridium difficile infection • 20% reduction in overall ICU nosocomial infections • 40% reduction in operative site infections and sepsis • 25 - 40% reduction in the rate of ventilator-associated pneumonia • reduction in the severity and mortality of necrotising enterocolitis.

The increase in research efforts in this field is bound to identify other benefits of probiotic therapy. Currently the optimal probiotic agent and its ideal dose cannot be standardised as there is too much variation between studies, but this area would most likely be more defined in the near future.

A C Jeevarathnum Paediatric Pulmonologist, University of Pretoria and Steve Biko Academic Hospital, Pretoria, South Africa 1. Morrow LE, Wischmeyer P. Blurred lines: Dysbiosis and probiotics in the ICU. Chest 2017;151(2):492-499. https://doi.org/10.1016/j.chest.2016.10.006

BREATH-TAKING NEWS

Childhood asthma and the bacterial microbiota of the upper respiratory tract The bacterial microbiota of the lower airways have been implicated in the pathogenesis of asthma, the severity of asthma, and the response to therapy. Unfortunately, it is impractical to sample the lower airway routinely to further define the association between the microbiome of the lower airways and asthma. It is plausible that sampling of the upper airway is likely to reflect lower airway samples. Considering the united airway hypothesis, it is justified to conclude that the upper and lower airways share physiological and pathological response patterns.

Previous studies have alluded to the fact that there might be an association between childhood wheeze and colonisation of the upper respiratory tract with certain pathogens, including Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae.

Sampling of the lower airways involves bronchoalveolar lavage or bronchial brushings. Samples of the upper airway involve nasal and throat samples.

A recent cross-sectional study sampled 327 throat swabs and 68 nasal swabs from school-aged children, and looked at the correlation to childhood wheeze. The results were interpreted according to whether the children resided in a farming or non-farming area. Childhood wheeze was positively correlated to colonisation with a particular

taxonomic unit of Moraxella (odds ratio = 3.78; 95% confidence interval 2.02 - 7.05). The association was only present in children not residing on farms. There was no association between bacterial load and farming exposure, or asthma status.

The study illustrated an association between Moraxella and asthma status; however, it is difficult to tease out cause and effect. It is possible that asthma renders a favourable environment for colonisation with Moraxella, or Moraxella in non-farm resident children predisposes to inflammation and childhood wheeze. Further studies are needed in this field.

A C Jeevarathnum Paediatric Pulmonologist, University of Pretoria and Steve Biko Academic Hospital, Pretoria, South Africa 1. Depner M, Ege MJ, Cox MJ, et al. Bacterial microbiota of the upper respiratory tract and childhood asthma. J Allergy Clin Immunol 2017;139(3):826-834. https://doi. org/10.1016/j.jaci.2016.05.050

S Afr Respir J 2017;23(2):42-43. DOI:10.7196/SARJ.2017.v23i2.164

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

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

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

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

Reference

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

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

PHARMACOLOGICAL CLASSIFICATION: A.8.2 Anticoagulants.

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

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

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

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

L.ZA.GM.06.2014.1007

© Bayer HealthCare Pharmaceuticals June 2014

44 SARJ VOL. 23 NO. 2 2017

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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.

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