Kon Taik Khaw

Multiple mutations in highly conserved residues are found in mildly affected cystic fibrosis patients

We have identified three different point mutations in the coding region of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Each mutation segregates with the disease in two- or three-generation pedigrees and is not found on the normal chromosome of any documented cystic fibrosis carrier. One of the mutations is found in two independent families that contain at least one individual with a mild course of disease. All of these alterations replace charged amino acids with less polar residues and are found in the putative transmembrane sections of the molecule. The mutated amino acids are found to be conserved in both rodents and amphibians and lie in a region of CFTR that is believed to form a channel in the membrane. Although these alterations are rare, they provide important clues to functionally important regions of the molecule.

Bronchial artery embolization in cystic fibrosis; technique and long-term results.

Severe bronchial hemorrhage in 13 patients with cystic fibrosis was treated by catheter embolization of bronchial arteries. Indications were either excessive bleeding persisting for several days, or bleeding serious enough to interfere with pulmonary drainage and recurring over weeks or months. In follow-up ranging from one to 30 months, cessation of major bleeding was achieved in 12 of 13 patients (93%), although 5 of 13 patients (40%) did have recurrence of minor hemoptysis. No neurologic or other major complications were encountered. However, there are potential risks and this approach at present should be limited to patients with life-threatening bleeding and carried out only by experienced angiographers.

Selective Bronchial Arteriography in Patients with Cystic Fibrosis and Massive Hemoptysis

Massive hemoptysis is a potentially fatal complication of long-standing cystic fibrosis. Lobectomy may prevent a hemorrhagic death if the hemorrhage source can be identified and if involvement of the remaining lung tissue is mild. Selective bronchial arteriography was performed in six patients with cystic fibrosis to localize a lobar source of bleeding. Arteriographic findings correlated with bronchoscopic observations. Bronchial arteriography may be helpful when bronchoscopy cannot be done because of continuous hemorrhage or because the severity of the lung disease precludes general anesthesia, but it is not an adequate substitute for bronchoscopy in most patients.

Pneumothorax in cystic fibrosis: Management and outcome

We reviewed our experience over the past 12 years to determine the best method of management, to determine the morbidity and the physiologic outcome of medical vs surgical treatment of pneumothorax complicating CF, and to assess the influence of age, sex, and Shwachman scores on survival. Sixty-five patients, ages ranging from 5 to 32 years (mean 18 years). Shwachman scores ranging from 25 to 87 (mean 57), and a male-female ratio of 1:1, experienced 170 pneumothoraces, 93 first episodes, and 77 recurrences, requiring 211 trials of management. All methods of management except needle aspiration resulted in a fair rate of resolution (70 to 100%), but recurrence rates were high for observation (60%), needle aspiration (79%), trocar thoracotomy (63%), tetracycline sclerosis (86%), and silver nitrate sclerosis (43%). The recurrence rates were 12.5% for quinacrine sclerosis and 0% for parietal pleurectomy. Quinacrine sclerosis and parietal pleurectomy were the most effective methods of management. There was no significant difference in pulmonary function before pneumothorax and after pleural sclerosis or parietal pleurectomy. Age, sex, and severity of pulmonary disease were all independent variables influencing prognosis. Severity of disease, rather than the occurrence of a pneumothorax, appears to be the major cause of death. We recommend that quinacrine sclerosis should be considered for management of the first pneumothorax, and parietal pleurectomy if it fails.

Echocardiographic Assessment of Cor Pulmonale in Cystic Fibrosis

The early clinical recognition and assessment of cor pulmonale are frequently difficult. To evaluate the usefulness of echocardiographic measurement of right ventricular dimension and septal motion in assessing cor pulmonale, we studied 94 patients with cystic fibrosis of varying severity. There was a significant relationship between increasing right ventricular dimension index (RVDI) and (1) decreasing clinical score, vital capacity, forced expiratory volume in one second (FEV1), and maximal midexpiratory flow rate (MMFR); and (2) increasing residual volume and thoracic gas volume. There was no correlation between right ventricular dimension index and PaO2. These findings were supported by electrocardiogram and pathologic evidence of right ventricular involvement. Abnormal septal motion was observed more frequently in patients with severe obstructive airway disease as measured by decreased vital capacity, FEV1, and MMFR. The data show that there is echocardiographic evidence of mild right ventricular enlargement and/or hypertrophy much earlier in the course of cystic fibrosis than previously suspected and that the echocardiogram is a useful tool in the evaluation of cor pulmonale in patients with cystic fibrosis.

Hypersensitivity to pancreatic extracts in parents of patients with cystic fibrosis

Because immediate hypersensitivity reactions can occur in individuals exposed to powdered pancreatic extracts, 36 patients with cystic fibrosis and 51 patents of such patients wwer studied for evidence of sensitization. Sensitivity to the extracts as evidence by history and skin testing was infrequent in the children with cystic fibrosis. However, skin testing for immediate hypersensitivity with either crude pancreatic extracts or inactivated trypsin correlated well in their patents with a history of clinical symptoms. IgE mediation of these reactions in sensitized individuals was demonstrated by antigen-induced histamine release from leukocytes, passive transfer studies, and immediate response to inhalation challenge.

ECHOCARDIOGRAPHIC (ECHO) ASSESSMENT OF COR-PULMONALE IN PATIENTS (PTS) WITH CYSTIC FIBROSIS (CF)

The early clinical recognition and assessment of cor-pulmonale in CF pts is frequently difficult. Echo measurement of right ventricular characteristics may offer a noninvasive, portable means of quantifying cardiovascular changes in CF. Thirty CF pts aged 8 to 26 yrs. (mean 16.7:body surface area≥1M2) from the out-patient and ward service were studied. Clinical score (Shwachman and Kulczyki), standard pulmonary function tests, arterial blood gases and Echo were performed. The mean clinical score for the group was 54 (range 15-100), vital capacity (VC) 62% of predicted (25-108), residual volume (RV) 268% of predicted (55-520), functional residual capacity (FRC) 159% of predicted (72-269), forced expiratory volume (FEV1) 41% of predicted (8-105), mid-maximum expiratory flow rate (MMEFR) 21% of predicted (4-95) and PaO2 57 mmHg (30-83). There was a significant relationship between increase in Echo right ventricular diastolic dimension (RVDD), and (a) decreasing clinical score (p < .01), FEV1 (p<.01) and MMEFR (p<.01) and (b) increasing RV and FRC (p<.01). No significant correlation was noted between RVDD and PaO2. Interventricular septal reversal was present only in pts with severe lung disease. We conclude that changes in RVDD are related to the severity of the lung disease and reflect right heart involvement in CF.

LEFT VENTRICULAR DYSFUNCTION IN PATIENTS WITH CYSTIC FIBROSIS

To evaluate the possibility of left ventricular(LV)dysfunction in patients(pts) with cystic fibrosis(CF), we studied 80 ambulatory and hospitalized CF pts with a mean Shwachman-Kulczyki clinical score of 55(range 15-100)using standard pulmonary function tests, echocardiography (ECHO) and systolic time intervals (STI). ECHO measurements were made of LV internal dimensions at end-diastole(ED) and end-systole, LV posterior wall thickness(PWT) and septal thickness(ST). All values were indexed by body surface area. LV-ED volume (LVEDV) and LV ejection fraction(EF) were calculated. We observed an increase in PWT which was directly related to a decrease in clinical score(p<.0l) and mid-maximal expiratory flow rate (p< .05) and increased functional residual capacity (FRC)(p<.05). EF decreased significantly with increased FFC(p<.05). LV-EDV decreased with increased residual volume (RV)(p<.05) and total lung capacity(p<.05). When compared with age-corrected normal values, the ratio of the STIs, pre-ejection period and LV ejection time(PEP/LVET) increased with decreased clinical score(p<.05) and increased RV(p<.01) and FRC(p<.05). PEP/LVET also increased with increased PWT(p<.001), ST(p<.01) and indexed right ventricular dimension by ECHO(p<.001) and with decreased LVEDV(p<.05). These data showing increased PWT and PEP/LVET, and decreased EF suggest LV dysfunction with increasing severity of pulmonary involvement in pts with CF.

THE VECTORCARDIOGRAM (VCG) IN CYSTIC FIBROSIS (CF)

The VCG (Frank system) as an indicator of severity of pulmonary involvement was assessed in 75 patients (pts) with CF. The Shwachman-Kulczycki clinical score(CS), PaO2, right maximum spatial vector(RMSV) and standard pulmonary function tests were performed. The VCG horizontal loops(HL) were classified on the basis of configuration into four groups: normal, mild (increased anterior forces ± small rightward terminal forces), moderate (increased anterior forces with prominent rightward terminal forces or narrow antero-posterior loop) and severe (diminished anterior forces with marked rightward posterior loop displacement). The CS was similar in the normal and mild groups but progressively decreased in the moderate (p<.01) and severe (p<.05) groups. Mean PaO2 for the normal group was 68 mmHg (range 54-76), mild 66 mmHg(57-83), moderate 56 mmHg (48-80)(p<.05) and severe 44 mmHg(30-60)(p<.01). Vital capacity and forced expiratory volumes were significantly lower (p<.01) in the moderate and severe categories when compared to the normal and mild groups. The mean RMSV in the normal group was 0.8 mv(range 0.4-1.1), mild 1.1 mv(0.7-2.2) (p<.02),moderate 1.2 mv(0.7-2.9) (p<101) and in the severe 1.8 mv(0.8-2.7) (p<.01). During the 8 months the study was in progress, 7 pts died all of whom were in the moderate or severe categories, we conclude that there is a significant relationship between right heart involvement assessed by the HL of the VCG and the severity of CF determined by CS, PaO2 and some pulmonary tests.

AMANTADINE FOR THE PROPHYLAXIS OF INFLUENZA IN PATIENTS WITH CYSTIC FIBROSIS

From January to March 1973, amantadine or placebo was administered in a double-blind fashion to 153 patients with cystic fibrosis, to evaluate its prophylactic efficacy against the A2/England/72 strain of influenza and its toxicity in this group of patients. Influenza vaccine containing A2 (Hong Kong) antigens had been administered to 59 patients during the previous 4 months. Side effects were slightly less common in the control (23) than in the treated (32) group, and only two patients withdrew from the study because of them. Of 38 episodes of acute respiratory illness occurring during the 2 month study period, 21 were in patients receiving amantadine. Their severity was not significantly different in treated and control children. Sera from all patients were tested for antibodies to 5 influenza strains. Only 9 patients had evidence of A2/England/72 infection. Three of the 9 had received amantadine and 4 had received influenza vaccine. All 3 asymptomatic patients had received influenza vaccine. While the low incidence of influenza precluded an evaluation of the efficacy of amantadine, vaccination with A2 (Hong Kong) vaccine appeared to offer protection against illness caused by the A2/England/72 strain. Further serologic studies of the 38 patients with acute respiratory illnesses suggest that viral infections may be important causes of exacerbation of respiratory disease in patients with cystic fibrosis.