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.

Risk factors and outcomes of extubation failure in a South African tertiary paediatric intensive care unit.

Background: Extubation failure contributes to poor outcome of mechanically ventilated children, yet the prevalence and risk factors have been poorly studied in South African (SA) children. Objectives: To determine the prevalence, risk factors and outcomes of extubation failure in an SA paediatric intensive care unit (PICU). Methods: This was a prospective, observational study of all mechanically ventilated children admitted to a tertiary PICU in Cape Town, SA. Extubation failure was defined as requiring re-intubation within 48 hours of planned extubation. Results: There were 219 episodes of mechanical ventilation in 204 children (median (interquartile range (IQR)) age 8 (1.6 - 44.4) months). Twenty-one of 184 (11.4%) planned extubations (95% confidence interval (CI) 7.2% - 16.9%) failed. Emergency cardiac admissions (adjusted odds ratio (aOR) 7.58 (95% CI 1.90 - 30.29), dysmorphology (aOR 4.90; 95% CI 1.49 - 16.14), prematurity (aOR 4.39; 95% CI 1.24 - 15.57), and ventilation ≥48 hours (aOR 6.42 (95% CI 1.57 - 26.22) were associated with extubation failure. Children who failed extubation had longer durations of ventilation (231 hours (146.0 - 341.0) v. 53 hours (21.7 - 123.0); p<0.0001); longer duration of PICU (15 (9 - 20) days v. 5 (2 - 9) days; p<0.0001) and hospital length of stay (32 (21 - 53) days v. 15 (8 - 27) days; p=0.009); and higher 30-day mortality (28.6% v. 6.7%; p=0.001) than successfully extubated children. Conclusion: Extubation failure was associated with significant morbidity and mortality in our setting. Risk factors for extubation failure identified in our context were similar to those reported in other settings. Contributions of the study: This study provides novel data on the prevalence, risk factors and outcomes associated with extubation failure in a single-centre South African PICU. The results of this study may help identify high-risk groups for extubation failure within our local context, and forms a basis for practice improvement initiatives aimed at decreasing extubation failure rates and improving outcomes.

The Critical Care Society of Southern Africa guidelines on the allocation of scarce critical care resources during the COVID-19 public health emergency in South Africa.

Letter by Gopalan et al. on article by Singh and Moodley (Singh JA, Moodley K. Critical care triaging in the shadow of COVID-19: Ethics considerations. S Afr Med J 2020;110(5):355-359. https://doi.org/10.7196/SAMJ.2020.v110i5.14778); and response by Singh and Moodley.

Critical care triage during the COVID-19 pandemic in South Africa: A constitutional imperative!

Triage and rationing of scarce intensive care unit (ICU) resources are an unavoidable necessity. In routine circumstances, ICU triage is premised on the best interests of an individual patient; however, when increased demand exceeds capacity, as during an infectious disease outbreak, healthcare providers need to make difficult decisions to benefit the broader community while still respecting individual interests. We are currently living through an unprecedented period, with South Africa (SA) facing the challenges of the global COVID-19 pandemic. The Critical Care Society of Southern Africa (CCSSA) expedited the development of a triage guidance document to inform the appropriate and fair use of scarce ICU resources during this pandemic. Triage decision-making is based on the clinical odds of a positive ICU outcome, balanced against the risk of mortality and longer-term morbidity affecting quality of life. Factors such as age and comorbid conditions are considered for their potential impact on clinical outcome, but are never the sole criteria for denying ICU-level care. Arbitrary, unfair discrimination is never condoned. The CCSSA COVID-19 triage guideline is aligned with SA law and international ethical standards, and upholds respect for all persons. The Bill of Rights, however, does not mandate the level of care enshrined in the constitutional right to healthcare. ICU admission is not always appropriate, available or feasible for every person suffering critical illness or injury; however, everyone has the right to receive appropriate healthcare at another level. If ICU resources are used for people who do not stand to benefit, this effectively denies others access to potentially life-saving healthcare. Appropriate triaging can therefore be considered a constitutional imperative.

Non-invasive continuous positive airway pressure ventilation and high-flow nasal cannula oxygen therapy use in children without primary lung pathology: A prospective observational study

Background. Non-invasive nasal continuous positive airway pressure (nCPAP) and high-flow nasal cannula oxygen therapy (HFNC) are non-invasive ventilation (NIV) modalities appropriate for children in developing countries. There is minimal literature describing nCPAP and HFNC use in children with respiratory compromise secondary to non-pulmonary disease. Objectives. Th present study aimed to describe the characteristics and outcomes of children without primary lung pathology, who received nCPAP and HFNC during their admission to Red Cross War Memorial Children's Hospital, Cape Town, South Africa. Methods. This was a prospective observational study of routinely collected data, between August 2015 and January 2016. Primary and secondary outcome measures were NIV failure (progression to intubation and invasive ventilation) and paediatric intensive care unit (PICU) admission, respectively. Comparative statistics were conducted using Mann-Whitney U or t-tests. Data significantly associated with the primary and secondary outcomes on univariate analysis were entered into backward stepwise logistic regression models to determine independent predictive factors. Results. There were 31 cases of nCPAP and 1 case of HFNC use in 31 patients (median age 3.5 (interquartile range (IQR) 1.8 - 7.6) months). The majority (n=23; 71.9%) presented with primary diarrhoeal disease. There were 2 deaths (6.5%), 17 (53.1%) PICU admissions, and 5 (15.6%) cases received invasive ventilation (NIV failure). The median duration of hospital stay was 11.5 (IQR 6.0 - 17.5) days. Patients who failed NIV had lower admission SaO2 levels than those without treatment failure (95% (IQR 95 - 99) v. 100% (IQR 100 - 100); p=0.03). On multiple logistic regression, lower temperature (adjusted OR (aOR) 0.19; 95% confidence interval (CI) 0.05 - 0.78; p=0.02) and receiving inotropes in the emergency setting (aOR 23.05; 95% CI 1.64 - 325.06; p=0.02) were independently associated with PICU admission. Conclusion. nCPAP was used clinically for the management of children with respiratory compromise secondary to non-pulmonary illnesses, particularly diarrhoeal disease. Larger controlled clinical studies are needed to determine the effectiveness and utility of nCPAP in this population. HFNC was not commonly used, and this modality requires further investigation in this population

Rate of Pulmonary Function Decline in South African Children with Cystic Fibrosis

Background. Pulmonary function tests (PFTs) objectively measure the extent and progression of cystic fibrosis (CF) lung disease. The rate of lung function decline in developing countries has not previously been studied. Aim. To investigate the average annual rates of pulmonary function decline in South African children with CF from 1999 to 2006. Methodology: The medical records and best PFT over 3-monthly intervals of children attending the CF clinic at Red Cross War Memorial Children's Hospital; Cape Town; were retrospectively reviewed and analysed using the mixed model regression method. Results. A total of 1 139 PFT were recorded on 79 patients; with a median (interquartile range) of 14 (6 - 21) PFTs per patient. The mean (standard error) forced expiratory volume in 1 second (FEV1) at age 6 years was estimated at 73.83 (3.34) per cent predicted with an FEV1 decline of 0.23 (0.43)per annum. FEV1 at age 6 was affected by age at CF diagnosis; genotype; and year of birth. Rate of FEV1 decline was significantly affected by Pseudomonas aeruginosa colonisation and genotype. Conclusions. Although FEV1 at age 6 years was low compared with developed countries; the annual rate of FEV1 decline in South African children with CF was minimal; setting the scene for improved survival in this population

Guideline for the diagnosis, prevention and treatment of paediatric ventilator-associated pneumonia.

OBJECTIVE: Ventilator-associated pneumonia (VAP) has been poorly studied in South Africa, but is likely to be a significant problem, with resulting increased morbidity and mortality in the paediatric intensive care unit population. This guideline is intended to review the evidence and recommendations for prevention and management of VAP in children and to provide, where possible, clear advice to aid the care of these children, to limit costly and unnecessary therapies and--importantly--limit inappropriate use of antimicrobial agents, EVIDENCE: The Working Group was constituted. Literature on the aetiology, prevention and management of paediatric VAP is reviewed. RECOMMENDATIONS: Evidence-based clinical practice guidelines are provided for VAP diagnosis and prevention in South Africa. In addition, the current status of antimicrobial use has been reviewed and clear recommendations are set out.

Effects of intraoperative electron irradiation in the dog on cell turnover in intact and surgically-anastomosed aorta and intestine.

Adult dogs were subjected to laparotomy and intraoperative electron irradiation after division and reanastomosis of aorta or after construction of a blind loop of small intestine having a transverse suture line and an end-to-side anastomosis. Dogs received intraoperative irradiation of both intact and anastomosed aorta or intestine in doses of 0, 2000, 3000, or 4500 rad. Animals were sacrificed at seven days or three months following treatment. At 24 hours prior to sacrifice, dogs received 5 mCi tritiated thymidine intravenously. Irradiated and non-irradiated segments of aorta and small intestine, including intact and anastomotic regions, were analyzed for tritiated thymidine incorporation and were subjected to autoradiography. Incorporation studies showed diminution in tritiated thymidine uptake by irradiated portions of aorta and small intestine, in both intact and anastomotic regions. Autoradiograms revealed that irradiated areas of intact or anastomotic aorta or intestine had diminished labeling of stromal cells, suggesting a lowered cell proliferative capacity of irradiated tissue compared to non-irradiated portions. Inflammatory cells showed similar labeling indices in irradiated and non-irradiated tissues, both intact and surgically-manipulated, suggesting that irradiation does not significantly affect a subsequent local inflammatory response. Radiation-induced decreases in tritiated thymidine incorporation in irradiated aorta and small intestine were generally more marked at seven days than at three months following irradiation, suggesting that radiation-induced depression of cell turnover rates decreases with time. The presence of tritiated thymidine uptake after irradiation demonstrates the ability of intact and surgically-manipulated aorta and intestine to recover from radiation-induced damage.

Partial replacement of urinary bladder by autologous gallbladder.

In an effort to find a more suitable method of partial urinary bladder replacement for those patients with either a damaged or contracted bladder, the use of the autologous gallbladder was studied. The urinary bladders of 6 female dogs were partially resected, and the defective portions were replaced by autologous gallbladder transplants. After six weeks, the gallbladder mucosa showed evidence of squamous cell metaplasia progressing toward transitional cell epithelium with minimal necrosis. The muscular layer showed extensive granulation tissue and revascularization. No changes were detected in the upper urinary tracts. No mortality or detectable morbidity was associated with the procedure. It appears that the gallbladder may have a role to play in partial urinary bladder replacement.