Prenatal diagnosis of cystic fibrosis in South Africa

Prenatal diagnosis of cystic fibrosis (CF) has been made possible by the finding that the activity of various enzymes derived from the microvillar membranes of the fetus is decreased in 2nd trimester amniotic fluid. Gamma-glutamyl transpeptidase, aminopeptidase M and the phenylalanine-inhibitable form of alkaline phosphatase (AP) have been found to be of most diagnostic use in this respect, the odds of the fetus being affected with CF being 28:1 if the AP test is positive. When couples have already had a child with CF, pregnancies are being monitored by these methods at the University of Cape Town.     

Clinical presentation of mild cystic fibrosis in a Serbian patient homozygous for the CFTR mutation c.1393-1G>A

We present a case of a 19-year old male with uncommon initial clinical cystic fibrosis (CF) presentation and a rare CFTR genotype, homozygote for c.1393-1G>A mutation (legacy name 1525-1G>A).     

Growth and nutrition in South African children with cystic fibrosis.

OBJECTIVES: To study nutritional status and its dietary correlates in a South African cystic fibrosis (CF) population. DESIGN: Cross-sectional survey. POPULATION: Thirty-eight children and adolescents attending the CF clinic at Red Cross War Memorial Children's Hospital, Cape Town. METHODS: Standard anthropometry and a 3-day weighted food record. RESULTS: Median percentage expected weight for height (WFH) was 93 (interquartile range 84-101). Sixteen per cent of patients were below the 5th percentile for height. The proportion of patients who were malnourished (WFH less than 90) was greater among those over 10 years of age (47% v. 14.3%, chi 2 = 4.33, P = 0.037). Sixty-eight per cent of patients consumed less than the recommended daily intake of energy. There was no correlation between WFH and energy intake. Fat intake represented 29.6% (interquartile range 27.5-33%) of daily energy intake. CONCLUSIONS: Young South African children with CF are growing well despite relatively low intakes of energy and fat. Greater attention needs to be given to overcoming malnutrition among older children.     

The frequency of the delta F508 mutation in the cystic fibrosis genes of 71 unrelated South African cystic fibrosis patients.

The common delta F508 mutation is present in approximately 70% of mutant cystic fibrosis (CF) genes of European and North American populations. The frequency of the delta F508 mutation has been established for two groups of South African CF subjects. The mutation was found to be present in 82% and 53% of CF genes of white and coloured (i.e. of mixed ancestry) subjects respectively. These findings assist in providing appropriate counselling to individuals who have a family history of CF and in defining laboratory strategies for the establishment of an efficient genetic service for cystic fibrosis.     

Cystic fibrosis. Part I. Frequency of the delta F508 mutation in South African families with cystic fibrosis.

Cystic fibrosis (CF) is a common autosomal recessive disorder among people of European origin. With the localisation of the gene locus to chromosome 7q31 and the identification of closely linked polymorphic markers in 1985, it became possible to offer prenatal testing to couples at risk of having CF children, provided a live affected individual from that family was available for investigation. The CF gene, named CFTR, was cloned and sequenced in 1989 and the most common CF-causing mutation, delta F508, identified. A search for this mutation has been carried out in 81 South African white CF families of European origin. Using the polymerase chain reaction (PCR) technique the frequency of delta F508 was found to be 0.81. This mutation was not found in the 1 negroid and the 1 Indian CF family investigated.     

Voriconazole therapy in children with cystic fibrosis

BACKGROUND: There is increasing evidence for the efficacy of the antifungal voriconazole, particularly in immunosuppression. We describe our experience of using voriconazole in children with CF. METHODS: We performed a retrospective case note review of children with CF treated with voriconazole in a single centre over an 18 month period. RESULTS: A total of 21 children aged 5 to 16 years (median 11.3) received voriconazole for between 1 and 50 (22) weeks. Voriconazole was used as monotherapy in 2 children with recurrent allergic bronchopulmonary aspergillosis (ABPA); significant and sustained improvements in clinical and serological parameters for up to 13 months were observed, without recourse to oral steroids. Voriconazole was used in combination with an immunomodulatory agent in a further 11 children with ABPA, with significant improvement in pulmonary function and serology. 8 children without ABPA but who had recurrent Aspergillus fumigatus isolates and increased symptoms also received voriconazole; this group did not improve with treatment. Adverse effects occurred in 7 children (33%: photosensitivity reaction 3, nausea 2, rise in hepatic enzymes 1, hair loss 1). CONCLUSIONS: Voriconazole may be a useful adjunctive therapy for ABPA in CF. Voriconazole monotherapy appears to be an alternative treatment strategy when oral corticosteroids may not be suitable.     

Airway remodelling in children with cystic fibrosis

Background

The relationship between airway structural changes and inflammation is unclear in early cystic fibrosis (CF) lung disease. A study was undertaken to determine changes in airway remodelling in children with CF compared with appropriate disease and healthy controls.

Methods

Bronchoalveolar lavage and endobronchial biopsy were performed in a cross‐sectional study of 43 children with CF (aged 0.3–16.8 years), 7 children with primary ciliary dyskinesia (PCD), 26 with chronic respiratory symptoms (CRS) investigated for recurrent infection and/or cough and 7 control children with no lower airway symptoms. Inflammatory cells, cytokines, proteases and matrix constituents were measured in bronchoalveolar lavage fluid (BALF). Reticular basement membrane (RBM) thickness was measured on biopsy specimens using light microscopy.

Results

Increased concentrations of elastin, glycosaminoglycans and collagen were found in BALF from children with CF compared with the CRS group and controls, each correlating positively with age, neutrophil count and proteases (elastase activity and matrix metalloproteinase‐9 (MMP‐9) concentration). There were significant negative correlations between certain of these and pulmonary function (forced expiratory volume in 1 s) in the CF group (elastin: r = −0.45, p<0.05; MMP‐9:TIMP‐1 ratio: r = −0.47, p<0.05). Median RBM thickness was greater in the CF group than in the controls (5.9 μm vs 4.0 μm, p<0.01) and correlated positively with levels of transforming growth factor‐β₁ (TGF‐β₁; r = 0.53, p = 0.01), although not with other inflammatory markers or pulmonary function.

Conclusions

This study provides evidence for two forms of airway remodelling in children with CF: (1) matrix breakdown, related to inflammation, proteolysis and impaired pulmonary function, and (2) RBM thickening, related to TGF‐β₁ concentration but independent of other markers of inflammation.Newborn infants with cystic fibrosis (CF) have structurally normal airways but, at the time of death or lung transplantation, there is severe airway destruction and extensive bronchiectasis.¹ It has been assumed that these structural airway wall changes have occurred secondary to infection and inflammation. In asthma, airway remodelling has been thought to follow chronic airway inflammation,² but recent evidence has challenged this assumption, suggesting instead that remodelling may be an independent parallel process.³ Whether remodelling in CF is secondary to infection and inflammation or a separate process is of potential importance; if the former, then treatment of infection and inflammation could preserve airway function. But if remodelling is a separate process, relating to some aspect of cystic fibrosis transmembrane regulator (CFTR) dysfunction, new therapeutic approaches to preserve airway function may be required.Neutrophilic inflammation within the airway lumen in CF is central to the pathophysiology of the disease and can occur within the first few months of life.⁴ However, most previous work on airway wall pathology has come from explanted lungs or at necropsy. Little is known about the nature of histological changes in the airway wall in children with relatively mild disease or early stage disease, and how these changes may relate to inflammation within the airway lumen.Investigation of airway remodelling in CF to date has attempted to establish alterations in airway components, cytokines and proteases that appear important in asthma. Although there may be airway smooth muscle hyperplasia in adult CF biopsies compared with controls,⁵ it is unclear whether there is thickening of the reticular basement membrane (RBM) and whether any of these changes are seen in the paediatric age group.^6,7 However, biopsy immunoreactivity against transforming growth factor‐β₁ (TGF‐β₁), a cytokine known to be pro‐fibrotic in vitro,⁸ appeared to be associated with a better clinical picture.⁷ Increased levels of matrix metalloproteinase‐9 (MMP‐9) have been found in sputum and bronchoalveolar lavage fluid (BALF) from children with CF.^9,10 Furthermore, increased breakdown products of airway matrix components have been found in urine¹¹ and sputum¹² of patients with CF, but with no clear relationship with pulmonary function.We have previously shown that infants with CF have impaired lung function at diagnosis, irrespective of current or previous respiratory problems,¹³ and that there is no catch‐up in lung function in the preschool years, despite intensive treatment in specialist centres.¹⁴ We therefore hypothesised that structural airway wall changes are present early in the course of CF and that, as with atopic asthma, they may not be directly related to infection or inflammation. To this end, we compared endobronchial biopsies and BALF from children with CF with those from disease and healthy control groups. We studied matrix degradation and thickening of the RBM and looked for relationships with markers of airway inflammation and infection.     

Renal impairment in children with cystic fibrosis

BackgroundDue to the improvement in life expectancy in cystic fibrosis (CF), co-morbidities such as renal function impairment may be more frequent.AimTo determine the prevalence of renal disease in children with CF and to identify associated risk factors.MethodsA single-center retrospective study analyzing the genetic, clinical and therapeutic characteristics of 112 children. The estimated glomerular filtration rate (GFR), microalbuminuria and lithiasic risk factors were assessed.ResultsThe median calculated GFR (Schwartz) was 123, 161 and 155 ml/min/1.73 m² in children aged 1, 6 and 15 years, respectively. The cumulative dose of aminoglycosides was not correlated to GFR. Microalbuminuria was present in 22/38 patients. Hyperoxaluria was observed in 58/83 patients and was associated with a severe genotype, pancreas insufficiency and liver disease. Hypercalciuria, hyperuricuria and hypocitraturia were identified in 16/87, 15/83 and 57/76 patients, respectively.ConclusionRenal impairment in CF has various presentations. There appears to be low levels of renal impairment in children with CF. However, the risk of oxalocalcic urolithiasis is enhanced, and GFR may be underestimated by the Schwartz formula. Further studies using measured GFR techniques are thus warranted.     

Growth in prepubertal children with cystic fibrosis, homozygous for the Delta F508 mutation.

BACKGROUND AND METHODS: In cystic fibrosis, growth and lung function have been identified as prognostic markers of both severity of pulmonary disease and survival. Cross-sectional studies in patients with cystic fibrosis (CF) including all genotypes have shown that in prepubertal patients with lifetime continuous care within a specialised CF centre, growth can normalise. No corresponding improvement in lung function has been found. We used a longitudinal design to determine whether normalisation of growth could be found in the genetic subgroup of prepubertal children with CF with the homozygous Delta F508 mutation, which is one of the known severe mutations. METHODS: Data of all children born after 1980 with the homozygous Delta F508 mutation, diagnosed in early childhood at the specialised centre of the Children's Hospital of Berne were systematically assessed up to the age of 11 years and retrospectively analysed. Follow-up data of height, weight and BMI were compared to the Swiss reference population using z-scores. The correlations between lung function parameters (FEV1, MEF50, VC) and age, as well as lung function parameters and growth indices, were calculated. Additionally, the same correlations were examined in a cohort with the same mutation born 10 years earlier. RESULTS: In the study, cohort growth (height, weight and BMI) was significantly below that of the normal Swiss population. A significant decline of lung function with age was also found, however, no association between lung function and growth could be seen. Compared to an earlier cohort, an improved growth over the last decade could be shown but no improvement on lung function could be detected. Lung function varied widely in both groups. CONCLUSION: In contrast to sequential cross-sectional studies of children with CF, the present longitudinal study of children with homozygous for the Delta F508 mutation failed to confirm normalisation of growth over time. However, compared to the data of children born in the previous decade, improved growth was observed.     

Outcomes of fundoplication in children with cystic fibrosis

Purpose

Children with cystic fibrosis (CF) have a high prevalence of gastroesophageal reflux disease (GERD). As GERD is associated with chronic respiratory symptoms and feeding problems, fundoplication is often performed in children with CF. Although the outcomes of fundoplication have been described across diverse pediatric groups, there is no published experience with CF.

Methods

The records of 25 children with CF who underwent fundoplication in our center were reviewed. Data on symptoms and diagnostic testing results as well as on complications related to fundoplication were collected. Nutritional parameters and pulmonary function were compared before and after fundoplication.

Results

There was no mortality associated with fundoplication, but 12% had complications that required a subsequent surgical procedure. Whereas 28% were able to discontinue their antireflux medications, 48% developed symptoms of recurrent GERD. Overall, there was no change in body mass index, body mass index percentile, or the slope of forced expiratory volume in 1 second (FEV₁) after fundoplication. Children who had an FEV₁ of less than 60% predicted at the time of fundoplication exhibited an improvement in FEV₁ slope compared to those with FEV₁ of 60% or more (+5.3% vs −8.6% per year, P = .004).

Conclusion

The complication rate of fundoplication is similar to what has been reported in large series in children without CF. There is a high rate of recurrent GERD and little apparent benefit for either nutritional or pulmonary outcomes. The observed difference on FEV₁ slope, in those with moderate-severe vs mild lung disease, highlights the need to thoroughly evaluate the role of fundoplication in children with CF.     

Changes in the parent cystic fibrosis questionnaire-revised (CFQ-R) with respiratory symptoms in preschool children with cystic fibrosis

IntroductionThe Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory score is a validated and widely used patient-reported outcome. This study aimed to establish changes in the score with acute respiratory events in preschool children with CF and to investigate its’ relationship with physiological outcomes.MethodsThe Parent CFQ-R, multiple breath washout test and spirometry were performed at six study visits over one year. The clinical status of participants, stable or symptomatic, was defined by the patient's physician. Linear regression and distribution-based statistical methods were used to examine the changes in the CFQ-R from the last stable visit and to investigate its relationship with physiological outcomes.ResultsThere were 272 stable and 115 symptomatic visits from 78 participants. The mean CFQ-R Respiratory score did not change between consecutive stable visits (-0.73, SD 20.4). The mean (SD) score deteriorated by 15.5 (20.7) points between stable and symptomatic visits and improved by 14.8 (20.1) points between symptomatic and stable follow-up visits. When a clinically important change is defined as 0.5SD change (10-points), the positive predictive value (PPV) was 45% and the negative predictive value (NPV) was 84%. For visits with a 10-point worsening in the CFQ-R Respiratory score and a 15% increase in LCI, the PPV was better (81%) than using either measure alone.ConclusionThe CFQ-R Respiratory score is responsive to acute respiratory events in preschool children with CF and its utility to monitor individual patients is improved when combined with LCI.     

Assessment of hyperinflation in children with cystic fibrosis.

BACKGROUND--Radiological estimates of hyperinflation are used in several clinical and radiographic scoring systems for cystic fibrosis, but it is not known if these estimates of hyperinflation are related to measured total lung capacity. METHODS--Comparison was made of independent clinical estimates of hyperinflation from chest radiographs with objective plethysmographic and radiographic measurements of total lung capacity in 25 children with cystic fibrosis. RESULTS--There was good agreement between plethysmographic and radiographic measurements. Clinical estimation correctly predicted the extremes of hyperinflation, but grading was no more than 50% accurate in all other groups. CONCLUSION--The degree of hyperinflation cannot be estimated by inspecting chest radiographs in many children with cystic fibrosis. This does not invalidate the scoring systems, but suggests that a better term than "hyperinflation" should be sought.     

Bacterial contamination in the environment of hospitalised children with cystic fibrosis

Pathogenic bacterial colonisation in Cystic Fibrosis patients is associated with a poor prognosis; thus, protective measures need to be taken to prevent their transmission. We studied the extent of contamination in the environment of hospitalised children with cystic fibrosis (CF) associated with specific activities.We assessed the levels of bacterial contamination in 432 air and surface samples collected from various locations in our CF centre over a three-month period: the bedrooms, corridor, communal showers, school, leisure centre and the respiratory functional explorations (RFE) unit. Staphylococcus aureus and Pseudomonas aeruginosa strains found in bedrooms and the RFE were compared with those found in patient expectorations using pulsed field gel electrophoresis.In all sampling locations, there were high levels of airborne contamination just after the presence of patients or nursing staff. In the bedrooms, the amount of S. aureus or P. aeruginosa in the air, at wake-up and after physiotherapy, were significantly higher than that after the bedroom had been cleaned. For P. aeruginosa, 33% of isolates were multiresistant to antibiotics; 50% of the colonised patients had the same P. aeruginosa strain in their sputum as in air taken from their bedroom. P. aeruginosa was detected in 23% of samples taken from the surfaces in the showers after patient washing. Very low levels of pathogenic bacteria were found in samples from the other locations.Overall, activities with the highest risk of contamination in the CF ward are physiotherapy and washing in the communal shower room. We therefore recommend to open windows after physiotherapy and to implement a strong decontamination after showers.     

Voriconazole pharmacokinetics and photosensitivity in children with cystic fibrosis

BackgroundA high incidence of adverse skin reactions following long-term oral administration of voriconazole in children with cystic fibrosis and allergic bronchopulmonary aspergillosis (ABPA). The aim was to study the pharmacokinetics of voriconazole in these patients and to determine a possible association between drug levels and adverse effects.MethodsMultiple venous blood samples were collected for HPLC determination of voriconazole concentrations and routine blood tests. Adverse events were recorded.ResultsNo significant correlation was found between incidence of photosensitivity and voriconazole serum levels in 6 of 8 children with ABPA. 80% of patients had trough voriconazole concentrations<1000 ng/mL and were highly variable.ConclusionsLong-term voriconazole therapy and greater sun exposure in Greece appear to play a major role in the occurrence of photosensitivity. Steady-state plasma drug concentrations were found to be highly variable and below the recommended therapeutic range in most patients, without any apparent negative influence on outcome.     

Predicting hypoxaemia during flights in children with cystic fibrosis

BACKGROUND: We have previously suggested that it is possible to predict oxygen desaturation during flight in children with cystic fibrosis and chronic lung disease by non-invasive measurement of oxygen saturation following inhalation of 15% oxygen--the pre-flight hypoxic challenge. This study reports on the results of measurements over 5 years. METHODS: The study comprised a pre-flight hypoxic challenge measuring oxygen saturation by finger tip pulse oximetry (SpO(2)) during tidal breathing of 15% oxygen in nitrogen and spirometric testing 1 month before the flight followed by SpO(2) measurements during intercontinental flights to and from holidays abroad with children in wake and sleep states. RESULTS: Pre-flight tests were completed on 87 children with cystic fibrosis. Desaturation of <90% occurred in 10 children at some stage during the flight, three of whom received supplementary oxygen. Using a cut off SpO(2) of 90%, the pre-flight hypoxic challenge correctly predicted desaturation in only two of these children. The sensitivity and specificity of the pre-flight hypoxic challenge were 20% and 99%, respectively, compared with 70% and 96% for spirometric tests (using a cut off for forced expiratory volume in 1 second (FEV(1)) of <50% predicted). Overall, pre-flight spirometric tests were a better predictor of desaturation during flight with the area under the Receiver Operating Characteristic (ROC) curve of 0.89 compared with 0.73 for the hypoxic challenge test. CONCLUSIONS: In this group of subjects pre-flight spirometric testing was a better predictor of desaturation during flight than the pre-flight hypoxic challenge.