The Q359K/T360K mutation causes cystic fibrosis in Georgian Jews.

BACKGROUND: The Q359K/T360K mutation, described in Jewish CF patients of Georgian decent, is of questionable clinical significance. METHODS: Clinical records of patients with the Q359K/T360K mutation from three CF centers were studied for phenotypic expression and putative mechanism of dysfunction. Computer models of mutant CFTR were constructed. RESULTS: Nine patients (4 homozygous) of Georgian Jewish origin were included. Age at diagnosis was 9.4 (0.25-38.2) years, median (range). Sweat chloride was 106 ±â€¯13 meq/L, mean ±â€¯SD. Nasal Potential Difference performed in three, was abnormal. All had pulmonary symptoms since early childhood and bronchiectasis. Median FEV1 was 88 (40-121)%. Five had chronic mucoid P. aeruginosa. Homozygous patients were pancreatic insufficient. Enzyme supplementation was initiated at 3.8 (1-14.7) years, median (range). Structural models hint at possible interference of this mutation with transmembrane chloride transport. CONCLUSION: In our cohort, the Q359K/T360K mutation resulted in a severe CF phenotype, although with residual early CFTR function. The CFTR2 database should consider defining this mutation as CF-causing.

Microbial contamination of nebulizers in the home treatment of cystic fibrosis.

BACKGROUND: Home nebulizers are in widespread use in cystic fibrosis (CF) and other chronic pulmonary diseases. Bacterial contamination may be a source of respiratory tract colonization. OBJECTIVES: To investigate microbial contamination of home nebulizers in CF patients, compare with sputum cultures and relate to cleaning practices. METHODS: A total of 29 home nebulizers of CF patients were cultured. Families were interviewed regarding cleaning routines and patients had sputum cultures for bacteria and fungi. RESULTS: In total, 19/29 (65%) nebulizers were contaminated: 18 reservoir cups, 14 mouthpieces and five filters. Pseudomonas spp. were isolated from 10 nebulizers (35%) and all 10 had Pseudomonas aeruginosa airway infection although without genetic typing we could not be sure this was the same bacteria as that from their nebulizer unit. An additional 7/29 had Pseudomonas aeruginosa airway infection without a contaminated nebulizer (P=0.001). No nebulizers were contaminated with Aspergillus. Only 4/19 contaminated nebulizers (22%) had been cleaned after every use, compared with seven of the 10 (70%) uncontaminated nebulizers (P=0.017). Only 7/19 patients with contaminated nebulizers (37%) and 5/10 with clean nebulizers (50%) recalled receiving cleaning instructions (not significant). CONCLUSIONS: Home nebulizers are frequently contaminated, particularly when cleaning instructions are inadequate, and may be a source of airway infection or reinfection especially following contamination from a patient chronically colonized with P. aeruginosa. Simple oral and written cleaning instructions should be offered.

Computerised paediatric asthma quality of life questionnaires in routine care.

BACKGROUND: Asthma quality of life questionnaires are not readily incorporated into clinical care. We therefore computerised the Paediatric Asthma Quality of Life Questionnaire (standardised) (PAQLQ(S)) and the Paediatric Asthma Caregivers Quality of Life Questionnaire (PACQLQ), with a colour-coded printed graphical report. OBJECTIVES: To (a) assess the feasibility of the electronic questionnaires in clinical care and (b) compare the child's PAQLQ scores with the parent's score, physician's clinical score and spirometry. METHODS: Children with asthma were given a clinical severity score of 1-4 (increasing severity) and then completed the PAQLQ(S) electronically (scores 1-7 for increasing quality of life in emotional, symptoms and activity limitation domains) followed by spirometry and physician review. Parents completed the PACQLQ. Inclusion criteria required fluent Hebrew and reliable performance of spirometry. Children with additional chronic diseases were excluded. RESULTS: 147 children with asthma aged 7-17 years completed PAQLQs and 115 accompanying parents completed PACQLQs, taking 8.3 (4.3-15) and 4.4 (1.5-12.7) min, respectively (mean (range)). Graphical reports enabled physicians to address quality of life during even brief visits. Children's (PAQLQ) and parents' (PACQLQ) total scores correlated (r = 0.61, p<0.001), although the children's median emotional score of 6.3 was higher than their parents' 5.7 (p<0.001), whereas median activity limitation score was lower than their parents': 5.0 and 6.8, respectively (p<0.001). No correlation was found with physician's clinical score or spirometry. CONCLUSIONS: Electronic PAQLQs are easy to use, providing additional insight to spirometry and physician's assessment, in routine asthma care. Future studies must assess impact on asthma management.

Cystic fibrosis mutations with widely variable phenotype: the D1152H example.

D1152H is a type IV cystic fibrosis transmembrane regulator (CFTR) mutation associated with abnormal chloride gating. Although comprising 5-6% of mutations on genetic screening, clinical reports of cystic fibrosis (CF) are rare, suggesting that the disease is mild, atypical, or even absent. We describe our experience, which contrasts with this assumption, in a retrospective case series encompassing 91 CF patients (74 Jewish) aged 8 months to 56 years, from 2000-2005. Nine patients of varied Jewish ethnic origins were homozygous (2 patients) or compound heterozygous for D1152H with 11 of 182 potential alleles (6%). Five were diagnosed at age 33-49 years. Of 4 infants, 1 was diagnosed by prenatal screening, 1 had a prenatal dilated bowel, and 1 had pulmonary symptoms. Sweat chloride was 28-120 meq/l. Three adults had chronic mucoid Pseudomonas aeruginosa in sputum, and a forced expired volume in 1 sec (FEV1) of 20-55%. One was on bilevel positive airway pressure (BIPAP) ventilation. The infants had pulmonary symptoms that responded well to therapy. All 9 patients had good nutrition, 6 were pancreatic-sufficient, and 3 adults had subclinical pancreatic insufficiency. Three adults had recurrent pancreatitis. None had a bowel obstruction. Two of 3 adult males were fertile. Although asymptomatic at times, the D1152H mutation is associated with a broad clinical spectrum. This information is crucial for genetic counseling. Lung disease may be evident from infancy, and is severe in some adults, although all have outlived the median life expectancy of CF. Hopefully, with early diagnosis and therapy, prognosis can be good. A multicenter study of this mutation is warranted.

Nontuberculous mycobacteria in cystic fibrosis associated with allergic bronchopulmonary aspergillosis and steroid therapy.

Nontuberculous mycobacterial (NTM) infection, particularly due to Mycobacterium abscessus, is an emerging disease that can be relentlessly progressive, particularly in cystic fibrosis (CF) patients. The risk factors that were associated with this increasingly symptomatic infection in a group of CF patients were investigated. A total of 139 CF patients aged 2-52 yrs were reviewed. Sputum was cultured for NTM annually or whenever clinical deterioration was unexplained. In total, 12 patients (8.6%) had positive cultures and six (4.3%) met the criteria for NTM pulmonary disease (five with M. abscessus). Five had allergic bronchopulmonary aspergillosis (ABPA) compared with one out of 133 patients without NTM disease. Five had received systemic steroids (four as a treatment for ABPA) compared with only one out of 133 without NTM lung disease. All six NTM patients deteriorated markedly following mycobacterial infection, and forced expiratory volume in one second dropped 18-46%. Despite prolonged triple antibiotic therapy, M. abscessus was not eradicated, and four out of six did not return to baseline clinically. In conclusion, severe nontuberculous mycobacterial lung disease, particularly with Mycobacterium abscessus, is becoming a perplexing challenge in cystic fibrosis patients. Allergic bronchopulmonary aspergillosis and systemic steroids appear to be risk factors, although small patient numbers limit this to a descriptive observation. When pulmonary condition deteriorates, increased surveillance for mycobacteria would enable prompt diagnosis and treatment.

Trampoline use as physiotherapy for cystic fibrosis patients.

Physicians and physiotherapists who care for CF patients have recommended the use of trampolines as a physiotherapeutic tool for enhancing cardiopulmonary performance, encouraging sputum production, and improving general well-being. Despite some therapeutic and recreational benefits associated with trampoline use, papers in the general pediatric population mostly document an increased incidence of injuries, ranging from minor trauma to spinal cord injuries and even death. The aim of this review is to examine the accumulated published data regarding the use of trampolines, to assess their potential contributions and disadvantages for CF patients, and to define whether trampoline use should be recommended. An extensive search in the published medical literature retrieved approximately 60 articles that primarily dealt with trampolines, out of which only two dealt with CF. The preponderance of these articles are reports pertaining to injuries related to the use of trampolines, with only a few describing the medical, physiologic, and/or psychological benefits of trampolines. Based on the accumulated data, the presumed benefits of trampoline use for CF patients are not proven. Furthermore, the suggested benefits could be acquired using other types of exercise. Weighing the known risks of trampolines against the potential benefits that are not unique to this modality suggests that the use of trampolines for CF should not be recommended.

Urogenital abnormalities in male children with cystic fibrosis.

BACKGROUND: Congenital bilateral absence of the vas deferens (CBAVD) is presumed to occur prenatally and is present in over 99% of adult males with cystic fibrosis (CF). AIMS: To describe ultrasonic features in male children with CF. We aimed to describe urogenital anomalies, comparing pancreatic sufficient and insufficient CF patients. METHODS: Pelvic and scrotal ultrasonography were performed in 12 boys with CF aged 2-12 years and 16 age matched healthy controls. RESULTS: Nine patients had pancreatic insufficiency (PI): seven had two severe mutations and two had unknown mutations. Three boys were pancreatic sufficient (PS), two with splicing mutations (5T and 3849+10kb C-T respectively) and borderline sweat tests. Seminal vesicles were visualised in 5/12 patients and 8/16 controls, compared to non-visualisation reported in all adults with CBAVD. Testicular microlithiasis was found in 4/18 PI, 0/6 PS, and 0/32 control testes, compared to 0.6-1.4% in healthy males and 15% in CF adults; 7/18 PI, 4/6 PS, and 0/32 control testes were smaller than predicted for age. The epididymal head was non-homogeneous with cysts, hypo-, or hyper-echogenicity in 5/18 PI, 1/6 PS, and 0/32 control testes. CONCLUSIONS: Genital abnormalities may occur early in CF, but are less common than described in adults. They are found more often in pancreatic insufficient than in pancreatic sufficient CF patients. However, a positive finding, if present, may aid in the diagnosis of the latter. A larger longitudinal study is recommended to better define the onset and progression of urogenital abnormalities.

Reaching the diagnosis of cystic fibrosis--the limits of the spectrum.

BACKGROUND: Cystic fibrosis is the most common life-limiting autosomal recessive genetic disorder in Caucasians. Typically it is a multisystem disease diagnosed by increased chloride levels on sweat testing, with mortality due mainly to progressive respiratory disease. The clinical spectrum of CF has recently been much expanded. Genetic testing for mutant CF transmembrane regulator has revealed atypical cases where sweat test results are borderline or normal. In other patients, genetic mutations cannot be identified but abnormal CFTR function is shown using nasal potential difference measurement. OBJECTIVES: To highlight the diagnostic and therapeutic dilemmas in cases of atypical cystic fibrosis. METHODS: We reviewed patients with atypical CF and widely varying phenotype who are managed at Schneider Children's Medical Center of Israel. RESULTS: Two patients had severe lung disease but little expression in other organs. Accurate diagnosis was essential to enable aggressive therapy in a specialized center. Four other patients are in excellent general health but have symptoms limited to male infertility, heat exhaustion, pancreatitis or transient liver dysfunction, while lung disease is minimal. For these patients, careful counseling is needed to avoid unnecessary upheaval, inappropriately aggressive management, and the psychosocial implications of a CF diagnosis. These dilemmas have increased considerably in our center, as in others worldwide. CONCLUSION: It is our obligation as clinicians--at the level of both primary physician and referral center--to maintain an ever higher index of suspicion for CF, tempered by a rational program of counseling and management appropriate to the individual.

Severe allergic bronchopulmonary aspergillosis in an infant with cystic fibrosis and her asthmatic father.

An infant with cystic fibrosis and her asthmatic father were diagnosed as suffering from allergic bronchopulmonary aspergillosis (ABPA). Cystic fibrosis was diagnosed in the infant at 6 weeks of age, and gene mutations were W1282X/G542X. She was diagnosed definitively as suffering from ABPA at age 3.5 years, but had suggestive symptoms from age 11 months. This may be the youngest age described to date for ABPA. The child responded well to systemic steroid therapy, but remained steroid-dependent over the next 4 years. Treatment with itraconazole enabled a marked reduction in steroid dosage. The father was an asthmatic, and a heterozygote for the cystic fibrosis transmembrane regulator (CFTR) mutation W1282X. He had a normal sweat test, atopy, and moderate reversible airway obstruction. There was no proven exposure to Aspergillus in the home environment. The importance of considering the diagnosis of ABPA even in infancy, the therapeutic dilemmas, and the possible role of abnormal CFTR function in the development of ABPA are discussed.

Ethmoiditis-associated periorbital cellulitis.

Seventy-two children with periorbital cellulitis were followed prospectively during a 30-month study period. Twenty patients (28%) had mucopurulent rhinorrhea with obvious radiological ipsilateral opacity of the ethmoid sinuses. This group of patients, as opposed to patients with periorbital cellulitis and no associated ethmoiditis, is characterized by the following features: Higher incidence of temperature greater than 38.5 degrees C (16/20 vs 24/52. P less than 0.01) and elevated white blood count greater than 15,000 cells/mm3 on admission (10/20 vs 5/52. P less than 0.001). Delayed recovery (6.7 +/- 3.4 vs 3.4 +/- 1.6 days. P less than 0.001). Higher rate of recurrent periorbital cellulitis with associated ethmoiditis within 6 months of follow-up (5/20 vs 1/52. P less than 0.01). This ethmoiditis-associated serious form of periorbital cellulitis requires an aggressive treatment regimen and a prolonged follow-up.

Increased bronchial responsiveness to exercise and histamine after allergen challenge in children with asthma.

Nonspecific bronchial reactivity to exercise and histamine was measured in nine children with asthma before and within nine days after allergen inhalation. All patients developed an immediate fall in FEV1 of greater than or equal to 16% after allergen inhalation, and five children also developed a definite late asthmatic response with a fall in peak expiratory flow of greater than or equal to 14% after 3 to 8 hours. Mean postexercise fall in FEV1 (delta FEV1) of the whole group was significantly greater after allergen challenge compared with that of control subjects (29 +/- 6% and 16 +/- 4%; p = 0.013). There was no change in refractoriness to repeated exercise after allergen challenge. The mean provocation concentration of histamine causing a decrease in FEV1 of 20% of the whole group was less after allergen challenge compared with that of control subjects (0.47 +/- 0.18 and 0.62 +/- 0.13), but this was not statistically significant (p = 0.19). Of the five children with late allergen reactions, all demonstrated increased histamine sensitivity, and all four children who developed definite exercise-induced asthma also demonstrated increased sensitivity to exercise. Of the four children without late allergen reactions, none demonstrated increase histamine sensitivity, but two of the three children with definite exercise-induced asthma demonstrated increased sensitivity to exercise. It may be that sensitivity to exercise is more easily affected by nonspecific reactivity than sensitivity to histamine. It is concluded that increased bronchial responsiveness to both exercise and histamine occur after allergen provocation in patients with asthma.

Treatment of status epilepticus with thiopentone sodium anaesthesia in a child.

A 4-month-old infant was admitted to the Pediatric Intensive Care Unit with Pneumococcal meningitis. A few hours after admission he developed intractable convulsions that could not be stopped with phenytoin, phenobarbitone and a continuous drip of diazepam. Thiopentone sodium anaesthesia was induced for 24 h terminating the status epilepticus. The clinical course, correlary EEG findings, treatment protocol and blood levels of the drugs given are described in detail.

Intracranial pressure in central nervous system infections and cerebral ischaemia of infancy.

Intracranial pressure was continuously monitored in 23 patients aged between 24 hours and 20 months. Fourteen had severe infections of the central nervous system (CNS) and 9 sustained prolonged cerebral ischaemia. The intracranial pressure measured at catheter placement was not a reliable indicator of the intracranial pressure that developed during the course of the disease. The mean maximal intracranial pressure in infants with CNS infection (57.4 +/- 25.8 mmHg) was significantly higher than in infants with cerebral ischaemia (34.6 +/- 17.6 mmHg). Mortality in CNS infections (36%) was closely correlated with the degree of increased intracranial pressure, while mortality in cerebral ischaemia (67%) was not. Continuous monitoring of intracranial pressure enables treatment to be started early so that intracranial pressure can be reduced and adequate cerebral perfusion pressure maintained. This may help to reduce morbidity and mortality.