Cystic fibrosis: What’s new in South Africa in 2019

Cystic fibrosis (CF) is one of the most common autosomal recessive  disorders worldwide. The incidence of CF depends on the prevalence of CFTR (cystic fibrosis transmembrane conductance regulator) gene  mutations in the population, which is determined by genetic diversity and ethnicity. Over 2 000 CFTR mutation variants, divided into six distinct functional classes, are now identified, but not all cause CF disease.  Advancements in the molecular diagnosis of CF and recognition of a wider spectrum of CF severity have led to recent revision of CF diagnostic nomenclature and criteria. Identifying which CFTR mutations people with CF carry is important, as novel treatments that target the specific CFTR  dysfunction at a molecular level are now available, and many new drugs are in the pipeline. These and other advancements in CF are comprehensively covered in the revised 5th edition of the South African Cystic Fibrosis Consensus Guidelines, published in 2017. In addition, the South African Cystic Fibrosis  Registry Initiative (SACFRI) was launched in April 2018. SACFRI is a multicentre public-private collaboration of CF healthcare  providers across South Africa (SA), which will prospectively collect data relating to CF diagnosis and  outcomes in SA. Local SA registry data are critical to understanding the epidemiology of CF in SA, and SACFRI willbe an important tool to identify and prioritise areas of CF care that require intervention

Adenovirus-associated pneumonia in South African children: Presentation, clinical course and outcome

Background. Viruses have emerged as important aetiological agents of childhood pneumonia.Objective. To investigate the clinical presentation, severity and outcome of adenovirus-associated pneumonia (AVP) in children.Methods. A retrospective analysis of AVP cases over 12 months was performed, including demographic, clinical course and outcome (death, persistent lung disease (PLD)) data.Results. Two hundred and six AVP cases (median age 12 months, interquartile range 6 - 24) were identified; 70 children (34.0%) were malnourished and 14 (6.8%) were HIV-infected. Twenty-nine children (14.1%) developed PLD, which was associated with hypoxia at presentation in 26 cases (89.7%; p=0.01) and necessitated admission to the intensive care unit (ICU) in 18 (62.1%; p<0.01); 18/206 children (8.7%) died. Admission to the ICU (odds ratio (OR) 8.3, 95% confidence interval (CI) 2.3 - 29.0) and a positive blood culture (OR 11.2, 95% CI 2.3 - 54.1) were independent risk factors for mortality.Conclusions. Adenovirus is a potential cause of pneumonia and PLD in young children in South Africa. ICU admission and a positive blood culture were associated with poor outcome

Overnight oximetry as a screening tool for moderate to severe obstructive sleep apnoea in South African children

Background. Obstructive sleep apnoea (OSA) is common in children yet  often overlooked, as symptom-based screening is unreliable. Polysomnography is regarded as the gold standard for the diagnosis of OSA, but is not widely available in South Africa (SA). Overnight oximetry is a validated screening tool for OSA.Objectives. To describe the impact and utility of overnight oximetry at a tertiary children’s hospital in SA.Methods. A retrospective descriptive study was conducted of patients screened for OSA by overnight oximetry at a paediatric referral hospital from December 2012 to December 2014. Clinical data were retrieved from the oximetry database and medical records. Recordings of ≥6 hours were considered adequate and included in the study. OSA severity was  determined using the McGill score. Details on management and outcome were documented.Results. Oximetry studies in 137 of 153 patients were suitable for analysis (88 males (64.2%), median age 31.4 months (interquartile range (IQR) 15.8 - 65.8). Adenotonsillar hypertrophy was common (n=97, 70.8%), and 65 children (47.4%) had two or more underlying OSA risk factors. McGill’s score classified patients as follows: no/mild OSA n=55 (40.1%), moderate OSA n=23 (16.8%), severe OSA n=23 (16.8%) and very severe OSA n=36 (26.3%). Male gender, adenotonsillar hypertrophy and a lower weight-for-age z-score (–1.3 v. –0.7; p=0.038) were associated with severe to very severe OSA. Seventy-eight children (56.9%) were referred for surgery, 33 (24.1%) receiving urgent surgery within a median of 6 days (IQR 4 - 12). In contrast, 59 children (43.1%) with suspected OSA did not require surgical intervention.Conclusions. Overnight oximetry is a simple low-cost tool to assess severity of OSA and prioritise appropriate OSA management in resource-constrained settings such as SA

Impact of fibrinolytics on the outcome of empyema in South African children

Background. Childhood pneumonia is common in all countries, and empyema is one of the commonest complications. The role of routine intrapleural fibrinolytics in the management of childhood empyema is not well established in low- and middle-income countries.Methods. We did a prospective observational study of children sequentially hospitalised with empyema between December 2006 and December 2011 in South Africa (SA). Intrapleural tissue plasminogen activator (TPA), administered according to a standard protocol, was introduced in September 2009. Outcomes in children treated with TPA after 2009 were compared with the historical cohort not treated with TPA who met the treatment criteria.Results. One hundred and forty-two children with empyema, median age 17 months (interquartile range 8 - 43), were admitted during the study period. Excluding children who did not have a chest tube inserted and those in whom fibrinolysis was contraindicated, there were 99 patients, 52 of whom received fibrinolytics. Clinical characteristics and empyema aetiology were similar in those who received fibrinolysis and those who did not. Eighteen children (38.3%) not treated with TPA required surgery v. 5 (9.6%) treated with TPA (relative risk 0.25; 95% confidence interval 0.1 - 0.6). The median duration of hospitalisation was similar in both groups. Complications occurred rarely and with a similar incidence in both groups. In-hospital mortality was low, with two deaths in each group.Conclusion. Intrapleural TPA resulted in a four-fold reduction in surgery. Fibrinolytics should be used for management of empyema in children in SA

Overnight oximetry as a screening tool for moderate to severe obstructive sleep apnoea in South African children

Background. Obstructive sleep apnoea (OSA) is common in children yet often overlooked, as symptom-based screening is unreliable. Polysomnography is regarded as the gold standard for the diagnosis of OSA, but is not widely available in South Africa (SA). Overnight oximetry is a validated screening tool for OSA.Objectives. To describe the impact and utility of overnight oximetry at a tertiary children’s hospital in SA.Methods. A retrospective descriptive study was conducted of patients screened for OSA by overnight oximetry at a paediatric referral hospital from December 2012 to December 2014. Clinical data were retrieved from the oximetry database and medical records. Recordings of ≥6 hours were considered adequate and included in the study. OSA severity was determined using the McGill score. Details on management and outcome were documented.Results. Oximetry studies in 137 of 153 patients were suitable for analysis (88 males (64.2%), median age 31.4 months (interquartile range (IQR) 15.8 - 65.8). Adenotonsillar hypertrophy was common (n=97, 70.8%), and 65 children (47.4%) had two or more underlying OSA risk factors. McGill’s score classified patients as follows: no/mild OSA n=55 (40.1%), moderate OSA n=23 (16.8%), severe OSA n=23 (16.8%) and very severe OSA n=36 (26.3%). Male gender, adenotonsillar hypertrophy and a lower weight-for-age z-score (–1.3 v. –0.7; p=0.038) were associated with severe to very severe OSA. Seventy-eight children (56.9%) were referred for surgery, 33 (24.1%) receiving urgent surgery within a median of 6 days (IQR 4 - 12). In contrast, 59 children (43.1%) with suspected OSA did not require surgical intervention.Conclusions. Overnight oximetry is a simple low-cost tool to assess severity of OSA and prioritise appropriate OSA management in resource-constrained settings such as SA.

Real-world disparities and ethical considerations with access to CFTR modulator drugs: Mind the gap!

The third Sustainable Development Goal (SDG), to ensure healthy lives and promote well-being for all at all ages, has particular relevance and implementation challenges amongst people living with rare diseases such as cystic fibrosis (CF). Although the treatment and projected outcome of CF has significantly improved with the advent of CF transmembrane conductance regulator protein modulator (CFTRm) therapy, there remains significant global inequality with regards to access to these life-saving and life-altering drugs. Elexacaftor, tezacaftor, and ivacaftor (ETI) triple combination therapy, first licensed in the United States in 2019, has rapidly become the standard of care for children aged 6 years and older in most high-income countries for individuals with CFTR variants responsive to ETI. Negotiated agreements for access to ETI are currently in place in North America,Europe, Israel ,Australia and New Zealand. However, less priority has been given to negotiate agreements for access to CFTRm in low-middle income countries(LMIC) with significant CF populations such as Central and South America, India, the Middle East, and Southern Africa. These countries and individuals living with CF are therefore effectively being left behind, in direct conflict with the stated principle of the 2030 SDGs. In this review, we highlight the current global inequity in access to CFTRm drugs and its impact on widening disparities between high-income countries and LMIC in CF outcomes and survival. We further discuss the reasons for this inequity and explore the ethical- and human rights-based principles and dilemmas that clinicians, families, governments, and healthcare funders must consider when prioritizing fair and affordable access to expensive CFTRm drugs. Lastly, we propose possible solutions to overcoming the barriers to accessing affordable CFTRm drugs in LMIC and illustrate with examples how access to drug therapies for other conditions have been successfully negotiated in LMIC through innovative partnerships between governments and pharmaceutical industries

Control of hyperbolic equations

The new analogs of Wendroff’s type inequalities for discontinuous functions are considered. The impulse influence on the behaviour of the solutions of hyperbolic equations with nonlinearities of the Lipschitz and H¨older types is investigated.Розглянуто новi аналоги нерiвностей Вендрофа для розривних функцiй. Дослiджено вплив iмпульсного збурення на поведiнку розв’язкiв гiперболiчних рiвнянь з нелiнiйностями як лiпшицевого так i гельдерового характеру.Рассмотрены новые аналоги неравенств Вендрофа для разрывных функций. Исследовано воздействие импульсных возмущений на поведение решений гиперболических уравнений с нелинейностями как липшицевого так и гельдерового характера

Pneumocystis pneumonia in South African children diagnosed by molecular methods

Background: Pneumocystis pneumonia (PCP) is an important cause of hospitalization and mortality in HIV-infected children. However, the incidence of PCP has been underestimated due to poor sensitivity of diagnostic tests. The use of polymerase chain reaction (PCR) for pneumocystis has enabled more reliable diagnosis. This study describes the incidence, clinical features and outcome of PCP in South African children diagnosed using PCR. Methods: A prospective study of children hospitalised in South Africa with suspected PCP was done from November 2006 to August 2008. Clinical, laboratory and radiological information were collected. Lower respiratory tract specimens were obtained for PCP immunofluorescence (IF), real- time PCR for pneumocystis, bacterial and mycobacterial culture. Nasopharyngeal aspirates were taken for immunofluorescence (IF), real-time PCR for pneumocystis and PCR for respiratory viruses. A blood specimen for bacterial culture and for cytomegalovirus PCR was taken. Children were followed for the duration of their hospitalisation and the outcome was recorded. Results: 202 children [median (interquartile range, IQR) age 3.2 (2.1– 4.6) months] were enrolled; 124 (61.4%) were HIV infected. PCP was identified in 109 (54%) children using PCR, compared to 43 (21%) using IF and Grocott staining (p < 0.0001). Most PCP cases (88, 81%) occurred in HIV-infected children. All 21 cases (19%) occurring in HIV- negative children had another risk factor for PCP. On logistic regression, predictive factors for PCP were HIV infection, lack of fever, high respiratory rate and low oxygen saturation whilst cotrimoxazole prophylaxis was protective (OR 0.24; 95% CI 0.1 to 0.5; p < 0.002). The case fatality of children with PCP was higher than those without PCP (32.1% versus 17.2%; relative risk 1.87; 95% confidence interval (CI) 1.11 – 3.15). Amongst HIV-infected children, a CD4 less than 15% was the only independent predictor of mortality. Conclusions: The diagnostic yield for PCP is more than 2.5 times higher on PCR than other detection methods. PCP is a very common cause of severe hypoxic pneumonia and is associated with high mortality in HIV-infected African infants

Clinical presentation and outcome of Tuberculosis in Human Immunodeficiency Virus infected children on anti-retroviral therapy

<p>Abstract</p> <p>Background</p> <p>The tuberculosis (TB) and human immunodeficiency virus (HIV) epidemics are poorly controlled in sub-Saharan Africa, where highly active antiretroviral treatment (HAART) has become more freely available. Little is known about the clinical presentation and outcome of TB in HIV-infected children on HAART.</p> <p>Methods</p> <p>We performed a comprehensive file review of all children who commenced HAART at Tygerberg Children's Hospital from January 2003 through December 2005.</p> <p>Results</p> <p>Data from 290 children were analyzed; 137 TB episodes were recorded in 136 children; 116 episodes occurred before and 21 after HAART initiation; 10 episodes were probably related to immune reconstitution inflammatory syndrome (IRIS). The number of TB cases per 100 patient years were 53.3 during the 9 months prior to HAART initiation, and 6.4 during post HAART follow-up [odds ratio (OR) 16.6; 95% confidence interval (CI) 12.5–22.4]. A positive outcome was achieved in 97/137 (71%) episodes, 6 (4%) cases experienced no improvement, 16 (12%) died and the outcome could not be established in 18 (13%). Mortality was less in children on HAART (1/21; 4.8%) compared to those not on HAART (15/116; 12.9%).</p> <p>Conclusion</p> <p>We recorded an extremely high incidence of TB among HIV-infected children, especially prior to HAART initiation. Starting HAART at an earlier stage is likely to reduce morbidity and mortality related to TB, particularly in TB-endemic areas. Management frequently deviated from standard guidelines, but outcomes in general were good.</p

Improved detection of Pneumocystis jirovecii in upper and lower respiratory tract specimens from children with suspected pneumocystis pneumonia using real-time PCR: a prospective study

<p>Abstract</p> <p>Background</p> <p><it>Pneumocystis </it>pneumonia (PCP) is a major cause of hospitalization and mortality in HIV-infected African children. Microbiologic diagnosis relies predominantly on silver or immunofluorescent staining of a lower respiratory tract (LRT) specimens which are difficult to obtain in children. Diagnosis on upper respiratory tract (URT) specimens using PCR has been reported useful in adults, but data in children are limited. The main objectives of the study was (1) to compare the diagnostic yield of PCR with immunofluorescence (IF) and (2) to investigate the usefulness of upper compared to lower respiratory tract samples for diagnosing PCP in children.</p> <p>Methods</p> <p>Children hospitalised at an academic hospital with suspected PCP were prospectively enrolled. An upper respiratory sample (nasopharyngeal aspirate, NPA) and a lower respiratory sample (induced sputum, IS or bronchoalveolar lavage, BAL) were submitted for real-time PCR and direct IF for the detection of <it>Pneumocystis </it><it>jirovecii</it>. A control group of children with viral lower respiratory tract infections were investigated with PCR for PCP.</p> <p>Results</p> <p>202 children (median age 3.3 [inter-quartile range, IQR 2.2 - 4.6] months) were enrolled. The overall detection rate by PCR was higher than by IF [180/349 (52%) vs. 26/349 (7%) respectively; p < 0.0001]. PCR detected more infections compared to IF in lower respiratory tract samples [93/166 (56%) vs. 22/166 (13%); p < 0.0001] and in NPAs [87/183 (48%) vs. 4/183 (2%); p < 0.0001]. Detection rates by PCR on upper (87/183; 48%) compared with lower respiratory tract samples (93/166; 56%) were similar (OR, 0.71; 95% CI, 0.46 - 1.11). Only 2/30 (6.6%) controls were PCR positive.</p> <p>Conclusion</p> <p>Real-time PCR is more sensitive than IF for the detection of <it>P. jirovecii </it>in children with PCP. NPA samples may be used for diagnostic purposes when PCR is utilised. Wider implementation of PCR on NPA samples is warranted for diagnosing PCP in children.</p