Cystic fibrosis in low and middle-income countries (LMIC): A view from four different regions of the world.

Cystic fibrosis (CF) has been shown to affect people all over the world. While life expectancy for people with CF has increased substantially, CF is still associated with death in infants and young children in many regions, particularly in low and middle-income countries (LMIC). These countries face significant challenges to promote CF diagnosis and improvements to CF care due to financial constraints and a significant burden of other diseases. In this review, we describe the status of CF diagnosis and care in different LMIC settings, from four different parts of the world (Brazil, South Africa, Israel and India). We highlight challenges and opportunities for CF practitioners in LMIC to improve CF care and outcomes. While early CF diagnosis is the key to optimising outcomes, newborn screening may not be feasible for countries with lower CF incidence and higher birth rates, such as India or South Africa. CF therapies and care in LMIC need to be adapted to available resources of these countries. Collaboration initiatives of the global CF community with LMIC may improve CF care in these countries. Most individuals with CF in LMIC are not benefiting from CFTR modulator treatments due to the prohibitive cost of these drugs.

Cough augmentation techniques for people with chronic neuromuscular disorders.

BACKGROUND: People with neuromuscular disorders may have a weak, ineffective cough predisposing them to respiratory complications. Cough augmentation techniques aim to improve cough effectiveness and mucous clearance, reduce the frequency and duration of respiratory infections requiring hospital admission, and improve quality of life. OBJECTIVES: To determine the efficacy and safety of cough augmentation techniques in adults and children with chronic neuromuscular disorders. SEARCH METHODS: On 13 April 2020, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, and ClinicalTrials.gov for randomised controlled trials (RCTs), quasi-RCTs, and randomised cross-over trials. SELECTION CRITERIA: We included trials of cough augmentation techniques compared to no treatment, alternative techniques, or combinations thereof, in adults and children with chronic neuromuscular disorders. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility, extracted data, and assessed risk of bias. The primary outcomes were the number and duration of unscheduled hospitalisations for acute respiratory exacerbations. We assessed the certainty of evidence using GRADE. MAIN RESULTS: The review included 11 studies involving 287 adults and children, aged three to 73 years. Inadequately reported cross-over studies and the limited additional information provided by authors severely restricted the number of analyses that could be performed. Studies compared manually assisted cough, mechanical insufflation, manual and mechanical breathstacking, mechanical insufflation-exsufflation, glossopharyngeal breathing, and combination techniques to unassisted cough and alternative or sham interventions. None of the included studies reported on the primary outcomes of this review (number and duration of unscheduled hospital admissions) or listed 'adverse events' as primary or secondary outcome measures. The evidence suggests that a range of cough augmentation techniques may increase peak cough flow compared to unassisted cough (199 participants, 8 RCTs), but the evidence is very uncertain. There may be little to no difference in peak cough flow outcomes between alternative cough augmentation techniques (216 participants, 9 RCTs). There was insufficient evidence to determine the effect of interventions on measures of gaseous exchange, pulmonary function, quality of life, general function, or participant preference and satisfaction. AUTHORS' CONCLUSIONS: We are very uncertain about the safety and efficacy of cough augmentation techniques in adults and children with chronic neuromuscular disorders and further studies are needed.

Exogenous lipoid pneumonia in children: A systematic review.

OBJECTIVES: To describe the clinical-radiological-pathological characteristics and treatment outcomes of children with suspected exogenous lipoid pneumonia (ELP). DESIGN: Systematic review. We searched electronic databases and reference lists published between 1967 and 2018, restricted to non-accidental cases. RESULTS: Forty-four studies including 489 participants aged 1 day to 17 years from 13 countries were included. Cultural, medical, and behavioural rationale for oil-use was described. The clinical-radiological presentation varied widely. Diagnostic certainty was deemed highest if ELP was confirmed on bronchoalveolar lavage/frozen section lung biopsy with documented extracellular lipid on cytological staining and/or fat analysis. Non-tuberculous mycobacteria infection was identified in six studies: Mycobacterium fortuitum/chelonei, Mycobacterium smegmatis and Mycobacterium abscessus. Treatment comprised supportive therapy, corticosteroids, stopping oil, therapeutic lung-lavage and surgical resection. Outcomes were reported inconsistently. CONCLUSION: Paediatric ELP resulting from cultural and medical practices continues to be described globally. Preventive interventions, standardized reporting, and treatment efficacy studies for cases not averted, are lacking. Protocol registration: PROSPERO CRD42017068313.

Acute flaccid paralysis in South African children: Causes, respiratory complications and neurological outcome.

AIM: To describe the causes, clinical presentation and neurological outcome of acute flaccid paralysis in children. METHODS: A retrospective study in a tertiary paediatric hospital in South Africa. Data on clinical presentation, respiratory complications and long-term neurological outcomes of children presenting with acute flaccid paralysis were collected. Logistic regression analysis was applied to determine predictors for the need of mechanical ventilation. RESULTS: The study included 119 patients, 99 of whom had Guillain-Barré syndrome (GBS); 47 patients (39.5%) required mechanical ventilation. Backward logistic regression analysis revealed that bulbar dysfunction (P < 0.001), autonomic dysfunction (P = 0.003) and upper limb paralysis (P = 0.038) significantly predicted the need for mechanical ventilation. EuroQol-5D scores of self-care problems and usual activities after discharge significantly declined over time. CONCLUSIONS: In this large series from Africa, GBS was the main cause of acute flaccid paralysis in children and was associated with significant morbidity. Other causes of acute flaccid paralysis mimicking GBS were not uncommon and should be excluded in this setting.

Fighting to Breathe and Fighting for Health-Related Quality of Life: Measuring the Impact of Being Dependent on Technology for Breathing on the Child and Their Caregiver.

BACKGROUND AND OBJECTIVE: Medical advancement has enabled children to survive congenital airway anomalies, rare diseases and critical illnesses with medical technology including tracheostomies and long-term ventilation to support breathing. This study aimed to assess (1) the validity of the EQ-TIPS and EQ-5D-Y-3L in children dependent on technology and (2) the impact of caring for these children on the EQ-5D-5L and CarerQoL. METHODS: Caregivers of children aged 1 month to 18 years completed the EQ-TIPS or EQ-5D-Y-3L, Pediatric Quality of Life Inventory (PedsQL) and Paediatric Tracheostomy Health Status Instrument (PTHSI) to reflect the child's health. In addition, caregivers self-completed the EQ-5D-5L and CarerQoL. Reports of problems on EQ dimensions were compared across age groups with the Fisher's exact test. Spearman and Pearson's correlation coefficients and Kruskal-Wallis H-test were used to explore the association between caregiver and child scores, concurrent validity, and known-group validity of the EQ-TIPS and EQ-5D-Y-3L. RESULTS: Responses from 144 caregivers were collected, 66 for children aged 1 month to 4 years completing EQ-TIPS and 78 for children aged 5-18 years completing EQ-5D-Y-3L. The EQ-TIPS showed a higher report of no problems for social interaction for children aged 1-12 months (p = 0.040) than the older age groups, there were however no differences in the level sum score (LSS) or EQ Visual Analogue Scale scores between the age groups. The EQ-5D-Y-3L showed a significantly less report of problems for mobility (p = 0.013) and usual activities (p = 0.006) for children aged 5-7 years compared with children aged 8-12 and children aged 13-18 years. Similarly, the 5-7 years of age group had a significantly lower EQ-5D-Y-3L LSS compared with the older groups (H = 12.08, p = 0.002). The EQ-TIPS and EQ-5D-Y-3L showed moderate-to-strong associations with the PedsQL. EQ-TIPS median LSS was able to differentiate between groups on the clinical prognosis with a better health-related quality of life (HRQoL) in those where weaning from technology is possible compared with those where weaning is not possible (H = 18.98, p = 0.011). The EQ-5D-Y-3L can discriminate between breathing technology, where those with only a tracheostomy reported better HRQoL (H = 8.92, p = 0.012), and between mild and moderate clinical severity (H = 19.42, p < 0.001). Neither the PedsQL nor the PTHSI was able to discriminate between these groups across the age range. Caregiver and child HRQoL scores showed moderate-to-strong associations. CONCLUSIONS: The EQ-TIPS and EQ-5D-Y-3L showed good validity in children dependent on the technology for breathing. The EQ-TIPS and EQ-5D-Y-3L LSS were all able to differentiate between children with known clinical variables and outperformed both the PedsQL and PTHSI, making them preferable for intervention research. The caregiver scores are associated with the child HRQoL scores and thus a spill-over should be accounted for in any interventions targeting this cohort. It is recommended that future studies investigate the reliability and responsiveness of these measures in children dependent on technology for breathing.

Mechanical insufflation-exsufflation for people with neuromuscular disorders.

BACKGROUND: People with neuromuscular disorders (NMDs) may have weak respiratory (breathing) muscles which makes it difficult for them to effectively cough and clear mucus from the lungs. This places them at risk of recurrent chest infections and chronic lung disease. Mechanical insufflation-exsufflation (MI-E) is one of a number of techniques available to improve cough efficacy and mucus clearance. OBJECTIVES: To determine the efficacy and safety of MI-E in people with NMDs. SEARCH METHODS: On 7 October 2013, we searched the following databases from inception: the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL (The Cochrane Library), MEDLINE, and EMBASE. We also searched ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform for ongoing trials. We conducted handsearches of reference lists and conference proceedings. SELECTION CRITERIA: We considered randomised or quasi-randomised clinical trials, and randomised cross-over trials of MI-E used to assist airway clearance in people with a NMD and respiratory insufficiency. We considered comparisons of MI-E with no treatment, or alternative cough augmentation techniques. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial eligibility, extracted data, and assessed risk of bias in included studies according to standard Cochrane methodology. The primary outcome was mortality throughout follow-up or at six months follow-up. MAIN RESULTS: Five studies with a total of 105 participants were found to be eligible for inclusion in this review. All included trials were short-term studies (two days or less), measuring immediate effects of the interventions. There was insufficient detail in the reports to assess methods of randomisation and allocation concealment. All five studies were at a high risk of bias from lack of blinding. The studies did not report on mortality, morbidity, quality of life, serious adverse events or any of the other prespecified outcomes. One study was a randomised cross-over trial conducted over two days, in which investigators applied two interventions twice daily in randomly assigned order, with a reverse cross-over the following day. Four studies applied multiple interventions for cough augmentation to each participant, in random order. One study reported fatigue as an adverse effect of MI-E, using a visual analogue scale. Peak cough expiratory flow (PCEF) was the most common outcome measure and was reported in four studies. Based on three studies, MI-E may improve PCEF compared to an unassisted cough. All interventions increased PCEF to the critical level necessary for mucus clearance. The included studies did not clearly show that MI-E improves cough expiratory flow more than other cough augmentation techniques. Based on one study, which was at risk of assessor bias, the addition of MI-E may reduce treatment time when added to a standard airway clearance regimen with manually assisted cough. MI-E appeared to be as well tolerated as other cough augmentation techniques, based on three studies which reported comfort visual analogue scores. AUTHORS' CONCLUSIONS: The results of this review do not provide sufficient evidence on which to base clinical practice as we were unable to address important short- and long-term outcomes, including adverse effects of MI-E. There is currently insufficient evidence for or against the use of MI-E in people with NMDs. Further randomised controlled clinical trials are needed to test the safety and efficacy of MI-E.

Home ventilation in low resource settings: Learning to do more, with less.

Long-term ventilation (LTV) in children at home, especially invasive ventilation, is not widely available nor practised in low-resource settings (LRS). Barriers to providing LTV include underdeveloped pediatric critical care services, limited expertise in pediatric LTV, limited capacity to screen for sleep-disordered breathing (SDB) and high cost of LTV equipment and consumables. Additional challenges encountered in LRS may be unreliable electricity supply and difficult socioeconomic conditions. Where LTV at home has been successfully implemented, caregivers and families in LRS must often take full responsibility for their child's care as professional home-based nursing care is scarce. Selecting suitable children and families to offer LTV in LRS may therefore face difficult ethical decisions when families are disempowered or incapable of providing 24-h care at home. Early caregiver participation and hands-on training in tracheostomy care and LTV equipment is key to success, irrespective of the caregiver's level of education. The use of overnight oximetry, mobile phone technology, spirometry, and clinical evaluation are simple tools that can aid recognition and monitoring of children needing LTV. As children survive longer supported by LTV, engaging with adult services at an early stage is important to ensure suitable pathways for transition to adult care are in place. Building capacity and expertise in pediatric LTV in LRS requires targeted training of health professionals in related disciplines and advocacy to policymakers and funders that LTV in appropriately selected circumstances is worthwhile, life-changing, and cost-saving.

Clinical and Experimental Determination of Protection Afforded by BCG Vaccination against Infection with Non-Tuberculous Mycobacteria: A Role in Cystic Fibrosis?

Mycobacterium abscessus is a nontuberculous mycobacterium (NTM) of particular concern in individuals with obstructive lung diseases such as cystic fibrosis (CF). Treatment requires multiple drugs and is characterised by high rates of relapse; thus, new strategies to limit infection are urgently required. This study sought to determine how Bacille Calmette-Guérin (BCG) vaccination may impact NTM infection, using a murine model of Mycobacterium abscessus infection and observational data from a non-BCG vaccinated CF cohort in Sydney, Australia and a BCG-vaccinated CF cohort in Cape Town, South Africa. In mice, BCG vaccination induced multifunctional antigen-specific CD4+ T cells circulating in the blood and was protective against dissemination of bacteria to the spleen. Prior infection with M. abscessus afforded the highest level of protection against M. abscessus challenge in the lung, and immunity was characterised by a greater frequency of pulmonary cytokine-secreting CD4+ T cells compared to BCG vaccination. In the clinical CF cohorts, the overall rates of NTM sampling during a three-year period were equivalent; however, rates of NTM colonisation were significantly lower in the BCG-vaccinated (Cape Town) cohort, which was most apparent for M. abscessus. This study provides evidence that routine BCG vaccination may reduce M. abscessus colonisation in individuals with CF, which correlates with the ability of BCG to induce multifunctional CD4+ T cells recognising M. abscessus in a murine model. Further research is needed to determine the optimal strategies for limiting NTM infections in individuals with CF.

ß-adrenergic sweat test in children with inconclusive cystic fibrosis diagnosis: Do we need new reference ranges?

BACKGROUND: Investigating inconclusive cystic fibrosis (CF) diagnosis in children is difficult without advanced cystic fibrosis transmembrane conductance regulator (CFTR) function tests. This study investigated the utility of beta (ß)-adrenergic sweat test to exclude CF in participants with inconclusive diagnosis (CF suspects) in South Africa. METHODS: ß-adrenergic sweat test and sweat chloride tests (SCT) were performed simultaneously in CF suspects and adult controls (healthy, CFTR heterozygotes and CF). Cholinergic and ß-adrenergic induced sweat rate was measured by evaporimetry (transepithelial water loss [TEWL]: g H2 O/m2 /h) following intradermal injections. Next-generation sequencing of CFTR was performed in CF suspects. CF diagnosis was defined by genotype. RESULTS: Thirty-seven controls (10 healthy, 14 CF, 13 CFTR heterozygotes) and 32 CF suspects (26 children; 6 adults) were enrolled. Six were excluded from formal analyses due to ß-adrenergic sweat test failure. In adults, evaporimetry was superior to SCT for diagnosis of CF with ß-adrenergic:cholinergic ratio TEWL ≤ 0.05 achieving 100% sensitivity and specificity. Twenty-two CF suspect children (age range: 3.4-15.6 years) completed ß-adrenergic sweat testing of which none had CF confirmed by genotyping: ß-adrenergic:cholinergic ratio > 0.05 successfully excluded CF in all but one child who was CFTR heterozygous. Median peak ß-adrenergic TEWL and ß-adrenergic:cholinergic ratio in CFTR negative and CFTR heterozygous children was significantly lower than adult controls. CONCLUSION: ß-adrenergic sweat test is more accurate than SCT for excluding CF in children with inconclusive diagnosis. Established reference ranges for ß-adrenergic sweat test may not be suitable for children due to lower ß-adrenergic sweat secretion compared to adults.

Global disparities in cystic fibrosis outcomes prior to CFTR modulators: A CF registries cohort study in South Africa and Canada.

BACKGROUND: Outcomes of cystic fibrosis (CF) differ between low-middle income and high-income countries, but comparative data are lacking. We compared South African (SA) and Canadian CF outcomes to explore what disparities existed prior to access of CFTR modulators in Canada. METHODS: A cross-sectional study of SA and Canadian CF registries data for period 1 January to 31 December 2018. CF registry data were harmonised between countries to compare lung function and nutrition outcomes. Poor nutrition was defined as BMIz-score < -1 in children and < 18.5 kg/m2 in adults. Standardised mean difference (SMD) >10 was considered significant. RESULTS: After excluding Canadians on CFTR modulators and lung transplant recipients, data on 4049 Canadian and 446 SA people was analysed. Compared to Canada, people in SA were younger (median age 15.8 years vs. 24.1 years: SMD 52) with fewer males (47.8% vs 54.2%; SMD 12.5) and White (70.9% vs. 93.3%; SMD 61.3). Class I-III CFTR mutation frequency was similar in SA (n = 384, 86.1%) and Canada (n = 3426, 84.9%). After adjusting for age, gender, diagnosis age, genotype, P.aeruginosa infection and pulmonary treatments, FEV1pp was 8.9% lower (95% CI 6.3% to 11.4%) and poor nutrition 1.7-fold more common (OR 1.70; 95% CI 1.19-2.41) in SA compared to Canada. CONCLUSION: Lung function and nutrition was significantly lower in SA compared to Canada. Global disparities in CF outcomes between high and low-middle income countries are likely to widen as CFTR modulators are rapidly scaled up in only high-income countries.

Low incidence of pulmonary hypertension in children with suspected obstructive sleep apnea: A prospective observational study.

OBJECTIVES: Pulmonary hypertension (PH) secondary to obstructive sleep apnea (OSA) is an uncommon but serious perioperative risk factor in children undergoing surgery for adenotonsillar hypertrophy. Routine pre-operative echocardiography is commonly requested if severe OSA is suspected. We investigated the incidence of PH in children with suspected OSA and explored the association between PH and OSA severity. METHODS: A prospective study of children aged 1-13 years with suspected OSA admitted for overnight oximetry (OO) and echocardiography at a pediatric referral hospital in Cape Town, South Africa from 2018 to 2019. OSA severity was defined by McGill Oximetry Score (MOS): MOS 1-2 (mild-moderate) and MOS 3-4 (severe). PH was defined as mean pulmonary arterial pressure (mPAP) ≥20 mmHg estimated on echocardiographic criteria. Children with congenital heart disease, underlying cardio-respiratory or genetic disorders, and severe obesity were excluded. RESULTS: One hundred and seventy children median age 3.8 years (IQR 2.7-6.4) were enrolled and 103 (60%) were female. Twenty-two (14%) had a BMIz >1.0 and 99 (59%) had tonsillar enlargement grade 3/4. One hundred and twenty-two (71%) and 48 (28%) children had mild-moderate and severe OSA, respectively. Echocardiographic assessment for PH was successful in 160 (94%) children of which eight (5%) had PH with mPAP 20.8 mmHg (SD 0.9): six with mild-moderate OSA and two with severe OSA. No significant difference in mPAP and other echocardiographic indices was observed in children with mild-moderate (16.1 mmHg; SD 2.4) and severe OSA (15.7 mmHg; SD 2.1). Similarly, no clinical and OSA severity differences were observed in children with and without PH. CONCLUSION: PH is uncommon in children with uncomplicated OSA and there is no association of PH with severity of OSA measured by OO. Routine echocardiographic screening for PH in children with clinical symptoms of OSA without co-morbidity is unwarranted.

Mucoepidermoid carcinoma of the bronchus in two children: Case reports.

Childhood mucoepidermoid carcinomas (MEC) of the bronchus are rare. They present with non-specific symptoms and signs making diagnosis delayed. We present two children with bronchial MEC managed in a tertiary children's hospital in Cape Town, South Africa. The first was a 11-year male with recurrent haemoptysis and the second child was a 6-year female with recurrent unifocal pneumonia. Chest CT scan and bronchoscopy with biopsy confirmed the diagnosis. Both patients underwent treatment, including surgery and are doing well. It is important to exclude endobronchial lesions when children present with recurrent respiratory symptoms, since early diagnosis will enable lung-sparing treatment.

Trends in cystic fibrosis survival over 40 years in South Africa: An observational cohort study.

INTRODUCTION: Temporal trends in cystic fibrosis (CF) survival from low-middle-income settings is poorly reported. We describe changes in CF survival after diagnosis over 40 years from a South African (SA) CF center. METHODS: An observational cohort study of people diagnosed with CF from 1974 to 2019. Changes in age-specific mortality rates from 2000 (vs. before 2000) were estimated using multivariable Poisson regression. Data were stratified by current age < or ≥10 years and models controlled for diagnosis age, sex, ethnicity, genotype, and Pseudomonas aeruginosa (PA) infection. A second analysis explored the association of mortality with weight and forced expiratory volume in 1 s reported as z-scores (FEV1z-scores) at age 5-8 years. RESULTS: A total of 288 people (52% male; 57% Caucasian; 44% p.Phe508del homozygous) were included (median diagnosis age 0.5 years: Q1, Q3: 0.2, 2.5); 100 (35%) died and 30 (10%) lost to follow-up. Among age >10 years, age-specific mortality from 2000 was significantly lower (adjusted hazard ratio [aHR]: 0.14; 95% confidence interval [CI]: 0.06, 0.29; p < 0.001), but not among age <10 years (aHR: 0.67; 95% CI: 0.28, 1.64; p = 0.383). In children <10 years, Caucasian ethnicity was associated with lower mortality (aHR 0.17; 95% CI: 0.05, 0.63), and longer times since first PA infection with higher mortality (aHR: 1.31; 95% CI: 1.01, 1.68). Mortality was sevenfold higher if FEV1z was <-2.0 at age 5-8 years (aHR: 7.64; 95% CI: 2.58, 22.59). CONCLUSION: Overall, CF survival has significantly improved in SA from 2000 in people older than 10 years. However, increased risk of mortality persists in young non-Caucasian children, and with FEV1z <-2.0 at age 5-8 years.

Clinical correlations to distinguish severe from milder forms of obstructive sleep apnoea syndrome using overnight oximetry for prioritising adenotonsillectomy in a limited-resource setting.

BACKGROUND: In resource-poor settings with limited surgical services, it is essential to identify and prioritise children with severe and very severe obstructive sleep apnoea syndrome (OSAS) to expedite surgery. McGill's Oximetry Score (MOS) has been validated against polysomnography for OSAS and is affordable and easy to use. AIMS: The aim of this study was to assess the correlation of tonsillar size and clinical symptoms with MOS grade 3 or 4, to identify who requires overnight oximetry and who to prioritise for adenotonsillectomy. METHODS: Children with suspected OSAS were recruited from the otolaryngology clinic at the Red Cross War Memorial Children's Hospital. Demographics, symptom screening scores (SSS), patient characteristics, overnight oximetry (OO), echocardiography and MOS scores (graded 1-4) were recorded. Multivariate modified-Poisson regression models were used to examine correlations of patient characteristics 'with grade 3 or 4 MOS. RESULTS: One-hundred-and-three children were analysed, 38% were female, and median (IQR) age was 3.8 (2.5-5.3) years. Increased tonsil size was associated with a 60% increased risk of grade 3 or 4 MOS, risk ratio (RR) 1.59, 95% CI 1.10-2.29 (p = 0.014). Children with witnessed apnoeic events during sleep had 1.3 times increased risk of MOS Grade 3 or 4, RR 1.31, 95% CI (p = 0.033). A significant correlation was shown with grade 3 or 4 MOS, RR 1.15, 95% CI 1.03-1.27 (p = 0.010) by combining tonsillar size with the following symptoms: apnoeic events; struggling to breathe during sleep and needing to stimulate the child to breathe. CONCLUSION: Identifying children with suspected OSAS who require overnight oximetry can be performed using a simple 3-question screening tool: witnessed apnoeic events, struggling to breathe and the need to shake them awake to breathe. This is more precise with an additional clinical finding of grade 3 or 4 tonsils. These children should have surgery expedited. Any child with a MOS 3 or 4 score on OO needs to have expedited surgery.

Factors associated with clinical progression to severe COVID-19 in people with cystic fibrosis: A global observational study.

BACKGROUND: This international study aimed to characterise the impact of acute SARS-CoV-2 infection in people with cystic fibrosis and investigate factors associated with severe outcomes. Methods Data from 22 countries prior to 13th December 2020 and the introduction of vaccines were included. It was de-identified and included patient demographics, clinical characteristics, treatments, outcomes and sequalae following SARS-CoV-2 infection. Multivariable logistic regression was used to investigate factors associated with clinical progression to severe COVID-19, using the primary outcome of hospitalisation with supplemental oxygen. RESULTS: SARS-CoV-2 was reported in 1555 people with CF, 1452 were included in the analysis. One third were aged <18 years, and 9.4% were solid-organ transplant recipients. 74.5% were symptomatic and 22% were admitted to hospital. In the non-transplanted cohort, 39.5% of patients with ppFEV1<40% were hospitalised with oxygen verses 3.2% with ppFEV >70%: a 17-fold increase in odds. Worse outcomes were independently associated with older age, non-white race, underweight body mass index, and CF-related diabetes. Prescription of highly effective CFTR modulator therapies was associated with a significantly reduced odds of being hospitalised with oxygen (AOR 0.43 95%CI 0.31-0.60 p<0.001). Transplanted patients were hospitalised with supplemental oxygen therapy (21.9%) more often than non-transplanted (8.8%) and was independently associated with the primary outcome (Adjusted OR 2.45 95%CI 1.27-4.71 p=0.007). CONCLUSIONS: This is the first study to show that there is a protective effect from the use of CFTR modulator therapy and that people with CF from an ethnic minority are at more risk of severe infection with SARS-CoV-2.

The Management of Asymptomatic Congenital Pulmonary Airway Malformation: Results of a European Delphi Survey.

Consensus on the optimal management of asymptomatic congenital pulmonary airway malformation (CPAM) is lacking, and comparison between studies remains difficult due to a large variety in outcome measures. We aimed to define a core outcome set (COS) for pediatric patients with an asymptomatic CPAM. An online, three-round Delphi survey was conducted in two stakeholder groups of specialized caregivers (surgeons and non-surgeons) in various European centers. Proposed outcome parameters were scored according to level of importance, and the final COS was established through consensus. A total of 55 participants (33 surgeons, 22 non-surgeons) from 28 centers in 13 European countries completed the three rounds and rated 43 outcome parameters. The final COS comprises seven outcome parameters: respiratory insufficiency, surgical complications, mass effect/mediastinal shift (at three time-points) and multifocal disease (at two time-points). The seven outcome parameters included in the final COS reflect the diversity in priorities among this large group of European participants. However, we recommend the incorporation of these outcome parameters in the design of future studies, as they describe measurable and validated outcomes as well as the accepted age at measurement.

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.

BACKGROUND: Pneumocystis 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. METHODS: 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 Pneumocystis jirovecii. A control group of children with viral lower respiratory tract infections were investigated with PCR for PCP. RESULTS: 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. CONCLUSION: Real-time PCR is more sensitive than IF for the detection of P. jirovecii 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.

Cystic fibrosis in South Africa: spectrum of disease and determinants of outcome.

INTRODUCTION: Little is known about cystic fibrosis (CF) in low- to middle-income settings. This study aimed to describe the spectrum and outcomes of CF in South Africa (SA) from the recently established SA CF registry (SACFR). METHODS: Demographic, diagnosis and clinical data were extracted from the SACFR. Cross-sectional univariable and multivariable regression analysis of best forced expiratory volume in 1 s (FEV1; age≥6 years) and nutrition (all ages) in 2018 was conducted to investigate factors associated with severe lung disease (SLD; FEV1 ≤3.0 z-score) and undernutrition. RESULTS: By December 2018, ancestry of 447 individuals included in the SACFR was Caucasian (315; 70%), mixed (87; 19%) and black African (41; 9%). Median diagnosis age was 7.6 months (IQR 2.7-37.1). Genotype was p.Phe508del homozygous (220; 49%); p.Phe508del heterozygous (144; 32%) and neither p.Phe508del or unknown Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) variant in 83 (19%); the second most frequent CFTR variant was 3120+1G>A, common in black Africans. Median age of patients in 2018 was 14.7 years (IQR 7.4-24.4). SLD was independently associated with chronic methicillin-resistant Staphylococcus aureus (MRSA) (adjusted odds ratio( aOR) 16.75; 95% CI 1.74-161.50), undernutrition (aOR 5.20; 95% CI 2.23-12.13) and age (aOR 2.23 per 10 years; 95% CI 1.50-3.31). Undernutrition was associated in univariable analysis with low weight at diagnosis, non-Caucasian ancestry, chronic P. aeruginosa infection and lower socioeconomic status. CONCLUSION: Interventions targeting MRSA infection and nutrition are needed to improve CF outcomes in SA. Most people with CF in SA are eligible for highly effective CFTR modulator therapy.

Clinical characteristics of SARS-CoV-2 infection in children with cystic fibrosis: An international observational study.

BACKGROUND: The presence of co-morbidities, including underlying respiratory problems, has been identified as a risk factor for severe COVID-19 disease. Information on the clinical course of SARS-CoV-2 infection in children with cystic fibrosis (CF) is limited, yet vital to provide accurate advice for children with CF, their families, caregivers and clinical teams. METHODS: Cases of SARS-CoV-2 infection in children with CF aged less than 18 years were collated by the CF Registry Global Harmonization Group across 13 countries between 1 February and 7 August 2020. RESULTS: Data on 105 children were collated and analysed. Median age of cases was ten years (interquartile range 6-15), 54% were male and median percentage predicted forced expiratory volume in one second was 94% (interquartile range 79-104). The majority (71%) of children were managed in the community during their COVID-19 illness. Out of 24 children admitted to hospital, six required supplementary oxygen and two non-invasive ventilation. Around half were prescribed antibiotics, five children received antiviral treatments, four azithromycin and one additional corticosteroids. Children that were hospitalised had lower lung function and reduced body mass index Z-scores. One child died six weeks after testing positive for SARS-CoV-2 following a deterioration that was not attributed to COVID-19 disease. CONCLUSIONS: SARS-CoV-2 infection in children with CF is usually associated with a mild illness in those who do not have pre-existing severe lung disease.