The History of Cystic Fibrosis by Dr James Littlewood OBE

Edited and produced by Daniel Peckham

 

 

 

 

1953 di Sant’Agnese PA. Bronchial obstruction with lobar atelectasis and emphysema in cystic fibrosis of pancreas. Pediatrics 1953; 2:178-190. [PubMed]
This paper describes the classical right upper lobe collapse so characteristic of CF and notes bronchoscopy was usually not effective in expanding the collapsed lobe (however, only rigid bronchoscopes were available at that time). Of 211 children with CF 10% presented with collapse of one or more lobes. In the discussion there was still a lingering suggestion that vitamin A deficiency “may contribute but not a major cause”.

Harry Shwachman agreed that atelectasis worsens the prognosis but also noted “The hypothesis suggesting an imbalance of the autonomic nervous system which may affect many systems and organs is attractive”. So there was still no clear explanation for the various manifestations of the condition; some suspected the autonomic nervous system. With regard to the association of the pancreatic lesions and the pulmonary complications, di Sant’Agnese concludes that “a satisfactory understanding of this problem has not yet been attained” which seemed to sum up the situation.

 

 

1957 White R Jr, Dent JH, Derbes VJ. Asthmatic states caused by mucoviscidosis. J Louisiana St Med S 1957; 109:299-302. [PubMed]
Thirty eight of 66 children with CF from New Orleans had some degree of wheezing. The authors comment “It has been the common experience of mature pediatricians that administration of epinephrine in such circumstances has led to prompt, albeit transient, alleviation”. The mechanical factors that cause impairment of pulmonary function in asthma – bronchospastic contraction, edema of the mucous membrane and excessive secretion and retention of mucus, are present both in CF and asthma. The authors' message from their paper being - “it is the responsibility of all physicians who treat wheezing children to exclude this disorder (i.e. cystic fibrosis)”.

 

 

1970 Holsclaw DS, Grand RJ, Shwachman H. Massive haemoptysis in cystic fibrosis. Pediatrics 1970; 75:829-838. [PubMed]
First report dealing primarily with 29 episodes of haemoptysis – a serious complication as 13 of the 19 patients died within six months. Treatment was with transfusions and supportive care and surgical resection in one patient (also reported by Lenvitsky S, et al, JAMA 1970; 213:125-127).


Arterial embolisation had not been described as yet and the technique certainly improved the prognosis - for example Stern RC et al, (Am Rev Resp Dis 1977; 117:825) had no deaths in 38 patients although 48% had recurrent episodes. Also a series of 13 patients treated by bronchial artery embolisation was reported from Shwachman’s unit (Fellows KE et al, J Pediatr 1979; 95:959-963 below).

 

 

1979 Fellows KE, Kon Taik Khaw, Schuster S, Shwachman H. Bronchial artery embolisation in cystic fibrosis; technique and long term results. J Pediatr 1979; 93:959-963. [PubMed]
This technique was first reported in other diseases (Wholey MH et al, JAMA 1976; 236: 2501) and in two patients with CF in a series of 104 with various conditions (Remy J et al, Radiology 1977; 122:33). In this present series major bleeding ceased in 12 of the 13 patients with CF although five had minor recurrences. The authors advised the procedure should be limited to life-threatening episodes (also Holsclaw DS et al, 1970; Stern et al, 1977 both above)

 

 

Flume PA, Yankaskas JR, Ebeling M, Hulsey T, Clark LL. Massive hemoptysis in cystic fibrosis. Chest 2005; 128:729-738. [PubMed]
Massive hemoptysis is a serious complication in CF patients, occurring more commonly in older patients with more advanced lung disease. Nearly 1 in 100 patients will have this complication each year. There is an attributable mortality to the complication and considerable morbidity, resulting in increased health-care utilization and a measurable decline in lung function.

 

 

2006 Vidal V. Therasse E. Berthiaume Y. Bommart S. Giroux MF. Oliva VL. Abrahamowicz M. du Berger R. Jeanneret A. Soulez G. Bronchial artery embolization in adults with cystic fibrosis: impact on the clinical course and survival. J Vasc Intervent Radiol 2006; 17:953-958 [PubMed]
Although bronchial artery embolization (BAE) is effective in the acute control of recurrent or major hemoptysis in adults with cystic fibrosis, outcomes after embolization are not well known. Of 297 patients with cystic fibrosis hospitalized from 1990 to 2004, 30 patients (mean age, 26.7+/-9.2 years) presented with major or persistent hemoptysis that required 42 BAE sessions. These patients were compared with a control group of 27 patients without hemoptysis requiring embolization who were matched for age, sex, and forced expiratory volume in 1 second (FEV1). Hemoptysis stopped within 24 hours after BAE in 96.6% of patients (n=29), and there were no major complications. The change in the slope of FEV1 after the BAE or matching date was significantly worse in the embolization group (P=.0007). At last follow-up, nine and one patients, respectively, had undergone lung transplantation in the BAE and control groups (P=.002). The 5-year survival rates without lung transplantation were 31% and 84%, respectively, in the BAE and control groups (hazard ratio, 5.95; P=.002). Sixty-two percent of patients were free of hemoptysis 5 years after BAE. The number of collateral arteries was the only factor associated with the risk of death or recurrent hemoptysis (P=.001). Despite the effectiveness of embolization in controlling recurrent or major hemoptysis, adults with cystic fibrosis who have undergone BAE for hemoptysis are at much higher risk of respiratory function aggravation, death, and the need for lung transplantation than those who have not undergone BAE for hemoptysis. They are more likely to die or to undergo lung transplantation than to present with recurrent major hemoptysis.

 

This is useful extensive experience of treating haemoptysis in people with CF. As to be expected the patients with haemoptysis had more severe chest involvement and generally a worse prognosis but the procedure was successful and free of major complications with regard to the controlling the bleeding.

 

 

2011 Pestana Knight EM, Novelli PM, Joshi SM. Cerebral and systemic infarcts after bronchial artery embolization. Pediatr Neurol 2011; 45:324-327. [PubMed]
A 17-year-old girl with cystic fibrosis developed hemoptysis and underwent bilateral bronchial artery embolization with 300-500 mum and 500-700 mum microsphere particles. Afterwards, she was delirious and complained of headache, had altered mental status and general hyperreflexia. Her left fifth digit was painful and cyanotic. Neuroimaging demonstrated multiple embolic infarcts in the cerebellum, thalamus, and cerebral hemispheres. She was heterozygous for a prothrombin 20210A mutation. Her functional neurologic recovery was complete.

This is the first pediatric case of cerebral and systemic embolism after bronchial artery embolization. Although this complication is not predictable, the authors suggest it should be suspected in patients with underlying chronic lung disease who develop acute neurologic signs after bronchial artery embolization, because these patients are prone to anomalous arterial-arterial shunt formation. Bronchial artery embolization with microspheres constitutes an effective, safe procedure for controlling hemoptysis. However, this was an alarming and previously unreported complication of pulmonary artery embolisation treatment of haemoptysis. The more usual occasional complication is embolisation of the spinal arteries with the risk of paralysis.

 

 

 

Gao Z, Wood-Baker R, Harle R, Muller K, Hauser J, Reid DW. "Bong lung" in cystic fibrosis: a case report. J Med Case Rep 2010; 4:371. [PubMed]
Marijuana or "bong" lung has been described recently. Subjects typically develop large peripheral paraseptal lung bullae and are predisposed to spontaneous pneumothoraces.
A 23 year old man with CF developed large peripheral paraseptal lung bullae and was predisposed to spontaneous pneumothoraces related to using marijuana.

A "Bong" is a water pipe, bubbler or moof filtration device used for smoking cannabis or other inhaled substances. The condition would be worth considering in patients who had problems with recurrent pneumothoraces.

 

 

 

 

 

1966 Paxton DG, Scott EP. Pneumothorax: An unusual complication in fibrocystic disease. Am J Dis Child 1966; 111:311-312.[PubMed]
The authors did not find previous reports of pneumothorax in the American literature – only in text books. However, prior to this report there had been sporadic reports of pneumothorax in CF in the literature from 1947 (Fanconi G, Metaxas-Buhler M. Helv Paediat Acta 1947; 2:289-295). Also Doershuk (1964) had one example in 96 patients.
This present report is of sudden onset of left pneumothorax in a 12 year old girl with CF whose chest showed “far advanced changes” at the age of 7.5years (figure 1). With a tube and drainage the lung expanded in 2 days (figure 2); she was discharged in 6 days but died 4 months later from her pulmonary disease.


Pneumothorax is a complication which occurs in those with more advanced chest damage and is now very rare in children with CF. For example in the 2004 UK CF Registry there were no children reported as having pneumothorax and only one in an adult with cystic fibrosis.

Fig. 1: Massive left sided pneumothorax.

Fig. 2: Air resolved in 2 days with tube and drainage.

 

2006 Hafen GM. Ukoumunne OC. Robinson PJ. Pneumothorax in cystic fibrosis: a retrospective case series. Arch Dis Child 2006; 91:924-925.[PubMed]

Pneumothorax is a known complication in cystic fibrosis (CF), associated with poor outcome. Records of CF patients with pneumothorax at the Royal Children's Hospital, Melbourne between 1990 and 2004 were reviewed, and the characteristics, sputum culture results, lung function, treatment, and outcome for the 11 patients who had pneumothoraces were described.

 

Although a small series, this is a useful report as pneumothorax is now rare in children with CF.

 

 

2010 MacDuff A, Tweedie J, McIntosh L, Innes JA. Pneumothorax in cystic fibrosis: prevalence and outcomes in Scotland. J Cyst Fibros 2010; 9:246-249.

A total of 22 episodes of pneumothorax occurred in 20 patients in 3 Scottish CF centres over a 12 year period. 2 patients died as a result of the pneumothorax. 16 pneumothoraces were treated by insertion of an intercostal drain and 8 by observation. 8 patients suffered a prolonged air leak. 5 patients were treated with pleurodesis. Pneumothorax was associated with a small decline in lung function which persisted for at least 1year. Pneumothorax can present a challenge to treat in adult CF. However successful outcomes can be achieved even in cases of prolonged air leaks. Current national guidelines help in selecting optimal pleural interventions.

 

A recent account of experience with pneumothoraces is welcome and as the adult population increases in relation to children, it is likely that the increase in this complication will continue. Pneumothorax is now very rare in the children with CF as evidenced by virtually no instances in children recorded in the recent UK Annual Patient Registry reports.

 

 

2010 Gao Z, Wood-Baker R, Harle R, Muller K, Hauser J, Reid DW. "Bong lung" in cystic fibrosis: a case report. J Med Case Rep 2010; 4:371. [PubMed]
Marijuana or "bong" lung has been described recently. Subjects typically develop large peripheral paraseptal lung bullae and are predisposed to spontaneous pneumothoraces. A 23 year old man with CF developed large peripheral paraseptal lung bullae and was predisposed to spontaneous pneumothoraces related to using marijuana.

A "Bong" is a water pipe, bubbler or moof filtration device used for smoking cannabis or other inhaled substances. The condition would be worth considering in patients who had problems with recurrent pneumothoraces

 

 

 

 

2001 Sood N. Paradowski LJ. Yankaskas JR. Outcomes of intensive care unit care in adults with cystic fibrosis. Am J Resp Crit Care 2001; 163:335-338. [PubMed]
Mechanical ventilation has been discouraged in CF because of poor outcomes, but improved survival and the availability of lung transplantation have increased the indications for care of CF patients in the intensive care unit (ICU). We studied the outcomes of all CF patients admitted to the University of North Carolina Hospitals Medical ICU from January 1990 through December 1998. Seventy-six patients, ranging in ages from 17 to 45 yr (mean: 27 yr), and of whom 53% were female, had 136 admissions for exacerbations of CF with respiratory failure (RF, n = 65), hemoptysis (n = 33), antibiotic desensitization (n = 30), pneumothorax (n = 3), or other reasons (n = 5). Eighty-six percent of the patients with hemoptysis and all of those with desensitization and pneumothorax were alive 1 yr after ICU discharge. Of the 42 patients with RF, 37 (88%) required assisted ventilation. Twenty-three (55%) of the patients with RF survived to ICU discharge and 19 (45%) died. Seventeen (40%) of the patients with RF received lung transplants and 14 were alive 1 yr later. Without transplantation, three (7%) of the patients with RF were alive and three (7%) were dead 1 yr later. Sex, body mass index, and respiratory bacteria did not correlate with survival. We conclude that ICU care for adults with CF who have reversible complications is appropriate and effective. Ventilatory support is appropriate for some transplant candidates.

 

This is a useful indication of the fate of people with CF admitted to an ICU in a major CF Centre at the present time. Undoubtedly the policy of not admitting to an ICU or ventilating people with CF in no longer valid.

 

 

2006 Slieker MG. van Gestel JP. Heijerman HG. Tramper-Stranders GA. van Berkhout FT. van der Ent CK. Jansen NJ. Outcome of assisted ventilation for acute respiratory failure in cystic fibrosis. Intens Care Med 2006; 32:754-758. [PubMed]
To assess outcome of assisted ventilation in cystic fibrosis (CF) patients with acute respiratory failure (ARF), to identify risk factors associated with poor outcome and to compare long-term outcome of CF children who were mechanically ventilated for ARF with unventilated CF controls. A retrospective cohort study in two large CF centres in the Netherlands. Thirty-one CF patients required assisted ventilation for ARF between January 1990 and March 2005. All five children (under 2 years of age) and seven adults (27%) survived. CF patients younger than 2 years old, who are ventilated because of ARF, have a good prognosis and their long-term outcome seems identical to unventilated CF controls. ARF in adult CF patients still is associated with high mortality, especially among patients with acute on chronic respiratory failure.

 

The resort to assisted ventilation has changed over the years now there is the possibility of transplantation; prior to the mid Eighties before the first successful transplantations ventilation was regarded as inappropriate.

 

 

2009 McDermott S. Barry SC. Judge EE. Collins S. de Jong PA. Tiddens HA. McKone EF. Gallagher CC. Dodd JD. Tracheomalacia in adults with cystic fibrosis: determination of prevalence and severity with dynamic cine CT. Radiology 2009; 252:577- 586. [PubMed]
To determine the prevalence and severity of tracheomalacia in adults with cystic fibrosis (CF) by using dynamic cine multidetector computed tomography (CT) and to correlate these findings with pulmonary function test (PFT) results and the severity of parenchymal lung disease. Tracheomalacia was demonstrated in 24 (69%) patients and no control subjects during forced expiratory maneuvers (P = .001) and in 10 (29%) patients and one (10%) control subject during coughing. There was no correlation between tracheal cross-sectional luminal reduction and either predicted FEV(1) or CT Bhalla score. Tracheomalacia depicted at dynamic cine multidetector CT is a highly prevalent finding in adults with CF.

 

Clinically tracheomalacia has been observed on occasion but the present study demonstrates how common is the condition. It is interesting that similar tracheal abnormalites occur commonly in CF pigs in particular some degree of maldevelopment of the tracheal cartilage.

 

2011 George PM, Banya W, Pareek N, Bilton D, Cullinan P, Hodson ME, Simmonds NJ. Improved survival at low lung function in cystic fibrosis: cohort study from 1990 to 2007. BMJ 2011; 342:d1008. [PubMed]
To evaluate the survival of patients with cystic fibrosis whose lung function has deteriorated to a forced expiratory volume in one second (FEV(1)) below 30% predicted in the recent treatment era and to explore factors associated with any change in survival. 276 patients (147 (53%) male) attending the Brompton whose FEV(1) was first observed to be less than 30% predicted between 1 January 1990 and 31 December 2003. The median survival improved from 1.2 years in the 1990-1 group to 5.3 years in the 2002-3 group, with a marked improvement in survival from 1994. The use of nebulised recombinant human DNase was significantly associated with a reduced risk of death (hazard ratio 0.59, 95% confidence interval 0.44 to 0.79). Significantly increased risks were associated with a body mass index under 19 (hazard ratio 1.52, 1.10 to 2.10), long term oxygen therapy (3.52, 2.49 to 4.99), and nebulised antibiotics (1.84, 1.05 to 3.22). The authors concluded that a marked improvement has occurred in the survival of patients with cystic fibrosis with an FEV(1) less than 30% predicted. Secondary analyses suggest that some of this improvement may be due to use of recombinant human DNase.

 

This is encouraging data from the UKs major adult CF centre showing a much improved survival for these severely affected patients, presumably related to improved treatment. For some years a survival;- in this study the authors suggest that the use of DNase may be a significant factor.

 

 

2013 Jones A. Bilton D. Evans TW. Finney SJ. Predictors of outcome in patients with cystic fibrosis requiring endotracheal intubation. Respirology 2013; 18:630-636. [PubMed]

Acute severe clinical deterioration of patients with cystic fibrosis (CF) may mandate endotracheal intubation. The benefits of intubation were evaluated by examining which pre-admission parameters were associated with intensive care unit (ICU) outcome and assessing the potential benefits of intubation for survivors in terms of time from ICU discharge to death. Thirty patients required intubation on 34 occasions (8 per 1000 admissions). Eleven patients died in ICU and 7 after ICU but not hospital discharge. Fifty-nine per cent of 22 patients intubated for pneumothorax and/or haemoptysis survived to hospital discharge. Of the twelve intubated for infective exacerbations, 33% survived to hospital discharge. Those who died after hospital discharge survived 447 days. There were no significant differences for survivors in reasons for intubation, colonizing organism, frequency of infective exacerbations, severity of illness or pulmonary physiology. Osteoporosis and a greater fall in body mass index over the 24 months prior were more frequent in non-survivors.

Experience at the Royal Brompton Hospital indicated patients with CF developing haemoptysis and/or pneumothorax should be admitted to ICU and intubated promptly, should this be required. Chronic disease markers may be more relevant prognostically than rates of hospitalization or forced expiratory volume in 1s decline which should not be bars to invasive ventilation.

 

 

2014 Fischer AJ. Singh SB. Adam RJ. Stoltz DA. Baranano CF. Kao S. Weinberger MM. McCray PB Jr. Starner TD. Tracheomalacia is associated with lower FEV1 and Pseudomonas acquisition in children with CF. Pediatr Pulmonol 2014; 49:960-70.[PubMed]
Tracheomalacia (TM) occurs in approximately 1 in 2,100 children. Because the trachea develops abnormally in animal models of cystic fibrosis (CF), the authors examined the prevalence and clinical consequences of TM in children with CF. TM was defined as dynamic collapse of the trachea, and the severity was recorded.
Eighty-nine percent of children with CF had at least one bronchoscopy (n=97/109). Fifteen percent of these children had TM described in any bronchoscopy report (n=15/97 16%), eight of these had meconium ileus (P=0.003) and all were pancreatic insufficient. Pseudomonas aeruginosa infection occurred 1.3 years earlier among children with TM (P=0.01). Life-threatening episodes of airway obstruction occurred in 3 of 15 patients with CF and TM, including one leading to death.
 
So tracheomalacia is significantly more common in infants and children with CF than in the general population and is associated with airway obstruction and earlier Pseudomonas acquisition.
Intractable expiratory wheeze poorly responsive to treatment related to tracheomalacia is a major problem in occasional CF infants. The findings of abnormal tracheal development, analogous to that recently described in CF animals, is obviously an explanation. Such infants may present a really difficult management problem and in the early years obviously require extra close supervision at a cystic fibrosis centre.


 

2014 Sheikh SI. McCoy KS. Ryan-Wenger NA. Patel A. Kirkby S. Lobectomy in patients with cystic fibrosis. Can Respir J 2014; 21:e63-6. [PubMed]
Some patients with cystic fibrosis develop severe but localized lung disease or recurrent hemoptysis/pneumothorax refractory to conventional medical therapies. The outcomes of lung resection in patients with CF and worsening localized lung disease or recurrent hemoptysis/pneumothorax refractory to conventional therapy (n=15) were evaluated by reviewing the medical records of all patients with CF followed at the CF Center at Nationwide Children's Hospital (Columbus, Ohio, USA), who underwent lobectomy over a 15-year period (1998 to 2012).
The median age of the 15 patients (93% Caucasian) was 20 years (range two to 41 years) and their mean forced expiratory volume in 1 s (FEV1) was 59.5% of predicted one year before surgery. Three patients died within two years after lobectomy; all three deaths occurred in patients with an FEV1 <40% of predicted before surgery. There were no significant changes in mean height, weight, body mass index, hospital admissions or antibiotic use over time. The mean FEV1 decreased over time. Compared with at surgery, decline in FEV1 in the year before surgery was -5.4% (P=0.024) and decline in the year after surgery was -1.3% (P=0.513); however, the difference in the rate of decline was not statistically significant. The authors concluded that in patients with CF and localised worsening bronchiectasis and/or recurrent hemoptysis/pneumothorax, lobectomy carried a significant risk of mortality, especially in patients with FEV1 <40% of predicted, and should only be considered when all other measures fail.
 
This experience in older patients differs significantly from the relatively good results for lobectomy for localised severe changes in children reported by many previous authors (see Topics -> Surgery for details of previous publications). It is not surprising that when there is extensive lung involvement in older patients lobectomy will be less beneficial as was the case in the present study.

 


McDermott S, Barry SC, Judge EP, Collins S, de Jong PA, Tiddens HA, McKone EF, G, Dodd JD. Tracheomalacia in adults with cystic fibrosis: determination of prevalence and severity with dynamic cine CT.  Radiology. 2009; 252(2):577-86. doi: 10.1148/radiol. 25220819 56. Epub 2009 Jun 9. [PubMed]
To determine the prevalence and severity of tracheomalacia in adults with cystic fibrosis using dynamic cine multi-detector computed tomography (CT) and to correlate these findings with pulmonary function test (PFT) results and the severity of parenchymal lung disease.    
Mean predicted forced expiratory volume in 1 second (FEV(1)) was 70.6% +/- 20.7, and mean Bhalla CT score was 41.8% +/- 13.6. In patients with CF, dynamic cine mean tracheal cross-sectional area reduction was 51.7% +/- 18.4 (range, 9%-89%) for forced expiratory manoeuvres and 68.8% +/- 11.7 (range, 18%-88%) for coughing (P = .001). Tracheomalacia was demonstrated in 24 (69%) patients and no control subjects during forced expiratory manoeuvres (P = .001) and in 10 (29%) patients and one (10%) control subject during coughing. For end-expiration images, mean tracheal luminal reduction was 16.1% +/- 14.0% (range, 0.0%-53.0%), with one patient demonstrating tracheal luminal reduction of more than 50%. There was no correlation between tracheal cross-sectional luminal reduction and either predicted FEV(1) or CT Bhalla score.
Tracheomalacia depicted at dynamic cine multidetector CT is a highly prevalent finding in adults with CF.
 
- The tendency to tracheomalacia in people with CF is well documented and at times clinically evident as a tendency to severe expiratory wheeze (Fischer AJ et al, 2014 [PubMed]). Similar tracheal abnormalities have been documented in animal CF models (Adam RJ et al. 2013.[PubMed]

 

 


2015 Diwakar A, Adam RJ, Michalski AS, Tamegnon MM, Fischer AJ, Launspach JL, Horan RA, Kao SC, Chaloner K, Meyerholz DK, Stoltz DA,. Sonographic evidence of abnormal tracheal cartilage ring structure in cystic fibrosis.  Laryngoscope. 2015 Oct;125(10):2398-404. doi: 10.1002/lary.25255. Epub 2015 Mar 30. [PubMed]

Tracheal cartilage ring structural abnormalities have been reported in CF mice and pigs. Whether similar findings are present in humans with CF is unknown.
Tracheal cartilage ring size and shape were measured in adults with (n = 21) and without CF (n = 18).
Ultrasonography was used in human subjects to noninvasively assess tracheal cartilage ring structure in both the sagittal and the transverse planes. Tracheal cartilage ring thickness was also determined from histological sections obtained from newborn non-CF and CF pigs. These values were compared with human data.
Human CF tracheas had a greater width and were less circular in shape compared to non-CF subjects. CF tracheal cartilage rings had a greater midline cross-sectional area and were thicker compared to non-CF rings. Maximal tracheal cartilage ring thickness was also greater in both newborn CF pigs and human adults with CF, compared to non-CF controls.
The authors’ findings demonstrate that structural differences exist in tracheal cartilage rings in adults with CF. Comparison with newborn CF pig data suggests that some of these changes may be congenital in nature.