The History of Cystic Fibrosis by Dr James Littlewood OBE

Edited and produced by Daniel Peckham



In past years there were more studies on cardiac complications, particularly cor pulmonale when lung involvement was early and severe affecting most children and adolescents in the years before they died. The first report on cardiovascular manifestations of CF appeared in 1952 when the first few children survived for long enough to develop such complications (Nadas AS et al. Pediatrics 1952; 10:319-327. above).

As survival increases and people with CF can be expected to reach middle age and beyond it is timely that attention in again being given to the cardiac implications of many years of pulmonary disease and also perhaps to inherent cardiac abnormalities related to the CF.

In the early years of heart-lung transplantation in the Eighties, the so-called domino procedure, the heart from the CF recipient of the donor heart-lungs would be donated to a heart transplant recipient. It is interesting that the non-CF heart transplant recipients who received hearts from people with CF had a relatively good long term survival (76% at 5 years) - in fact better than patients who received hearts from non-CF patients (65% at 5 years) (Anyanwu AC et al. J Heart Lung Transplant 2002; 21:971-975.[PubMed]). This suggests that the heart from a severely affected person with CF who is a candidate for a heart lung transplant nevertheless appears to be suitable for use as a donor organ.



1951 Royce SW. Cor pulmonale in infancy and early childhood; report on 34 patients with special reference to the occurrence of pulmonary heart disease in cystic fibrosis of the pancreas. Pediatrics 1951; 8:255-274. [PubMed]
This paper by Stephen Royce of California and the subsequent publication by the paediatric cardiologist Alexander Nadas (Nadas et al, 1952 below) are early reports of cor pulmonale in children with CF who now were surviving for sufficient time for the cardiovascular problems secondary to severe lung disease to become evident. Seventy percent of children who died of chronic lung disease showed evidence of cor pulmonale at autopsy. Over half died in severe right sided heart failure and not surprisingly, therapy of the secondary heart problems was usually unsuccessful although understandably the complication received considerable attention as more children survived for longer periods.



1952 Nadas AS, Cogan G, Landing BH, Shwachman H. Studies in pancreatic fibrosis: cor pulmonale; clinical and pathologic observations. Pediatrics 1952; 10:319-327. [PubMed]
Alexander Nadas (1913 - 2000) of Harvard was described as the father of paediatric cardiology. This is another early report of cardiac complications in eight of 45 children aged six months to 17 years (17% of the patients); one died in right heart failure, the rest showed electrocardiographic changes of right ventricular hypertrophy. The authors suggested that cardiac complications may be an increasing problem with the efficiency of antibiotic treatment and increasing survival and this proved to be the case (also Royce, 1951 above).


1959 Holman RL, Blanc WA, Andersen D. Decreased aortic atherosclerosis in cystic fibrosis of the pancreas. Pediatrics 1959; 24:34-39. [PubMed]
At autopsy 21 non-CF control patients had four times the incidence of aortic atheroma (average percentage of the intimal surface involved with fatty streaks) than did 18 patients with CF aged six to 13 years.

The reasons were unknown and the authors did not think the simple explanation of fat malabsorption was the whole reason as other children dying from chronic malnutrition do not have this decreased incidence of atheroma. (also Moss TJ et al. J Pediatr 1979; 94:32-37. [PubMed]



2005 O'Mahony M. Skehan S. Gallagher C. Percutaneous stenting of the superior vena cava syndrome in a patient with cystic fibrosis. Irish Med J 2005; 98:85-86. [PubMed]              Superior vena cava (SVC) obstruction commonly occurs in the setting of malignancy. Cases of benign SVC obstruction are being seen more frequently with the use of long-term central venous lines. This is the case particularly in Cystic Fibrosis (CF). This report concerns the successful use of intravascular stenting to treat this distressing condition in the setting of thrombotic occlusion of the SVC in a patient with CF. This report is one of an increasing number of reports of complications associated with the use of totally implantable venous access devices.



2006 Montgomery GS, Sagel SD, Taylor AL, Abman SH. Effects of sildenafil on pulmonary hypertension and exercise tolerance in severe cystic fibrosis-related lung disease. Pediatr Pulmonol 2006; 41:383-385. [PubMed]
Cystic fibrosis (CF) patients with advanced lung disease are at risk for developing pulmonary vascular disease and pulmonary hypertension, characterized by progressive exercise intolerance beyond the exercise-limiting effects of airways disease in CF. This report concerns a patient with severe CF lung disease who experienced clinically significant improvements in exercise tolerance and pulmonary hypertension without changing lung function during sildenafil therapy.

Sildenafil has been reported to have a favourable effect on the DF508 mutation although no clinical trial had been reported by 2014. Here the drug is used to treat pulmonary hypertension which is common in severe CF lung disease.



2006 Garwood S, Flume PA, Ravenel J. Superior vena cava syndrome related to indwelling intravenous catheters in patients with cystic fibrosis. Pediatr Pulmonol 2006; 41:683-687. [PubMed]

Three patients with CF had superior vena cava syndrome (thrombosis in the large vein entering the heart) due to the presence in the vessel of a foreign body i.e. the implantable venous access device.

Although these devices proved to be a major overall advance since their introduction in the mid-Eighties, a variety of complications have been reported particularly if the devices are not cared for by experts – these include infection and various vascular clotting problems even paradoxical embolisation (Espiritu JD, Kleinhenz ME. Mayo Clin Proc 2000; 75:1100-1102. [PubMed]). Experience at CF centres shows that this particular complication is not rare and most have experienced one or two cases.



2008 Ghayyda SN, Roland D, Cade A. Seat belt associated central line fracture-a previously unreported complication in cystic fibrosis. J Cyst Fibros 2008; 7:448-449. [PubMed]                  It is not routine practice to advise on seating position within the car in relationship to the seatbelt placement over the anterior chest wall. Line failure due to direct pressure from a seatbelt worn to prevent injury in the sudden deceleration involved during a motor vehicle accident (MVA) has not been described previously in the CF literature This report concerns the case of an 8 year old child who fractured her Vascuport(R) line secondary to seatbelt trauma following a road traffic accident. Children and adults with CF should be advised to sit in the car on the side that places the shoulder strap of the seatbelt on the opposite side to the TIVAD line.


This is a useful practical report which will help to prevent an unusual complication not previously reported.



2009 Hull JH, Garrod R, Ho TB, Knight RK, Cockcroft JR, Shale DJ, Bolton CE. Increased augmentation index in patients with cystic fibrosis. Eur Resp J 2009; 34:1322-1328. [PubMed]
Increased large artery stiffness occurs in a range of inflammatory conditions indicating an ageing of the vasculature and additionally being an independent risk factor for cardiovascular events. Augmentation index (AIx) is increased in adults with CF, in the presence of a normal blood pressure and independent of diabetic status. Fix was related to the systemic inflammatory status.

These findings have implications for management and require further exploration so that cardiovascular health can be maintained.

As more adults are studied new findings arise. This contrasts with a previous report that there was a reduction in atheroma in patients with CF.



2011 Labombard a F, Policier A, Alewife M, Caravel C, Ribault V, Laurans M, Guillot M, Bergot E, Grollier G, Milliez P, Zalcman G, Saloux E. Myocardial strain assessment in cystic fibrosis. J Am Soc Echocardiog 2011; 24:1037-1045. [PubMed]
The aim of this work was to evaluate myocardial strain analysis as a tool for the early detection of left ventricular functional changes in patients with cystic fibrosis. A total of 42 consecutive patients (mean age, 24 +/- 7.5 years; 52% men) diagnosed with cystic fibrosis and referred for echocardiographic cardiac function assessment were prospectively enrolled. A group of healthy age-matched and gender-matched volunteers (n= 42) formed the reference population for echocardiographic comparisons. Left ventricular ejection fraction was conserved in both groups but was significantly lower in the cystic fibrosis group. Cardiac function assessment using Doppler tissue imaging parameters revealed that both systolic and diastolic measurements differed between the two groups: mitral peak systolic and diastolic velocities, as well as septal and lateral wall strain rates, were decreased in patients with cystic fibrosis, as was longitudinal strain of both the septal and lateral walls. The authors concluded that using strain measurements, subclinical changes in left ventricular function were found in patients with cystic fibrosis. These parameters were correlated with the degree of pulmonary involvement severity. These findings have potentially significant clinical implications for the outcomes and follow-up of patients with cystic fibrosis, meriting further studies.



2012 Takemoto CM. Venous thromboembolism in cystic fibrosis. Pediatr Pulmonol 2012; 47:105-112. [PubMed].
The incidence of venous thromboembolism (VTE) is increasing in the pediatric population. Individuals with cystic fibrosis (CF) have an increased risk of thrombosis due to central venous catheters (CVCs), as well as acquired thrombophilia secondary to inflammation, or deficiencies of anticoagulant proteins due to vitamin K deficiency and/or liver dysfunction. CVC-associated thrombosis commonly results in line occlusion, but may develop into serious life-threatening conditions such as deep venous thrombosis (DVT), superior vena cava syndrome or pulmonary embolism (PE). Post-thrombotic syndrome (PTS) may be a long complication. Local occlusion of the catheter tip may be managed with instillation of thrombolytics (such as tPA) within the lumen of the catheter; however, CVC-associated thrombosis involving the proximal veins is most often is treated with systemic anticoagulation. Initial treatment with heparin is a standard approach, but thrombolytic therapy, which may carry higher bleeding risks, should be considered for life and limb threatening episodes of VTE. Recommended duration of anticoagulation with low molecular weight heparin (LMWH) or warfarin ranges from 3 to 6 months for major removable thrombotic risks; longer anticoagulation is considered for recurrent thrombosis, major persistent thrombophilia, or the continued presence of a major risk factor such as a CVC. While CVCs are the most common risk for development of VTE in children, studies have not demonstrated a clear benefit with routine use of systemic thromboprophylaxis. The incidence and risk factors of VTE in CF patients are reviewed and principles of diagnosis and management will be summarized.


A useful review of an uncommon but potentially serious complication in people with CF.

Dr Takemoto is Associate Professor of Pediatrics at The Johns Hopkins Hospital.



2013 Eaden J. Peckham D. Myocardial infarction in an adult with cystic fibrosis and heart and lung transplant. Multidscip Respir M 2013; 8:37. [PubMed]

We present a case of myocardial infarction in a 19 year old female with cystic fibrosis who had a heart and lung transplant performed at the age of four years old. She presented atypically with a one day history of severe, intermittent, central, sharp chest pain, radiating to her back and down her left arm. A coronary angiogram showed proximal stenosis of the left anterior descending artery and right coronary artery. She was treated with percutaneous coronary intervention, involving drug eluting stents to the left anterior descending artery (LAD) and the right coronary artery (RCA).


In this study the authors discuss the pathophysiology, investigations and treatment of cardiac transplant vasculopathy. Although complete reversal of LAD and RCA stenosis was achieved, routine follow-up with coronary angiography and careful control of cardiac risk factors will be important to identify and reduce future restenosis and adverse cardiac events


2013 van Doorn CS. De Boo DW. Weersink EJ. van Delden OM. Reekers JA. van Lienden KP. Permanent cortical blindness after bronchial artery embolization. Cardiovasc Intervent Radiol 2013; 36:1686-9. [PubMed]

A 35-year-old female with a known medical history of cystic fibrosis had a massive haemoptysis. CTA depicted a hypertrophied bronchial artery to the right upper lobe and showed signs of recent bleeding at that location. Bronchial artery embolization (BAE) was performed with gelfoam slurry, because pronounced shunting to the pulmonary artery was present. Immediately after BAE, the patient developed bilateral cortical blindness. Control angiography showed an initially not opacified anastomosis between the embolized bronchial artery and the right subclavian artery, near to the origin of the right vertebral artery. Cessation of outflow in the bronchial circulation reversed the flow through the anastomosis and allowed for spill of embolization material into the posterior circulation. Unfortunately the cortical blindness presented was permanent.



2013 Chan BK. Rupasinghe SN. Hennessey I. Peart I. Baillie CT. Retained central venous lines (CVLs) after attempted removal: an 11-year series and literature review. J Pediatr Surg 2013; 48:1887-91. [PubMed]

This paper documents the incidence and management of retained CVLs in a tertiary pediatric surgical centre with access to interventional cardiology services. Children with retained CVLs were identified from departmental morbidity and mortality records over an 11-year period. The 11-year incidence of retained CVL was 0.3% (n=10; median duration in-situ 66.5 {range 47-146} months). The underlying pathology in 8 was cystic fibrosis. Antegrade transfemoral snare retrieval was successful in 6 of 7 attempts. In the remaining 3, a conservative approach was adopted following consultation with the family. None of the 4 with retained CVL developed complications (median follow-up 7.5 {range 1-53} months). The literature describes 38 pediatric index cases (including 10 from the current series). Seventeen (49%) were managed conservatively either intentionally or by default after failed endovascular removal attempt (n=4). No complications directly attributed to retained CVLs have been reported (median follow-up 40 {range 1-120} months). Reported morbidity associated with endovascular retrieval includes: procedural failure 30%, line embolization 8%, and intra-operative thrombo-embolism 8%.


The authors observed that literature regarding management of retained CVLs is anecdotal. Although uncommon, the complication should feature in consent for removal of CVLs. Conservative management carries long-term risks of infection, thrombosis, and even migration, albeit unquantified over a child's lifetime. Endovascular retrieval is feasible with appropriate expertise.



Wormser B. 50 Years Ago in The Journal of Pediatrics: Cor Pulmonale in Cystic Fibrosis of the Pancreas. J Pediatrics 2015; 167(5):1080.  26603710

(Discussing - Moss AJ, Harper WH, Dooley RR, Murray JF, Mack JF. J Pediatr 1965;67:797-807)

Moss etal published their work 19years after the medical community first recognized the phenomenon of pulmonary hypertension in patients with cystic fibrosis. This squeeze of the pulmonary vasculature had been attributed to hypoxemia and cor pulmonale, its sequelae, had been recognized as a major cause of death for patients with cystic fibrosis.This study aimed to improve the ability to detect pulmonary hypertension and cor pulmonale for prognostic purposes. This included an evaluation of the noninvasive technology available at the time. Their study of 21 stable patients with cystic fibrosis indicated that none of the available techniques (which included electrocardiogram, vectorcardiogram, chest radiograph, and vital capacity) could reliably predict the presence of cor pulmonale. This left only cardiac catheterization, the gold standard both then and now.Over the next 50years, our understanding of pulmonary hypertension in cystic fibrosis and other chronic pulmonary diseases has progressed, yielding an understanding of the chronic systemic inflammation and pulmonary vascular bed remodeling that occurs in these patients to create the phenomenon of pulmonary hypertension. We have created new means of examining our patients' hearts with noninvasive techniques such as Doppler echocardiography 1 and cardiac magnetic resonance imaging. Our treatment goals have evolved with our diagnostic technology and today, our studies of pulmonary hypertension in cystic fibrosis reflect that shift. Current research focuses on the outcomes of patients with pulmonary hypertension following lung transplantation. Recent analyses of the United Network for Organ Sharing registry modernized our knowledge by demonstrating that patients with severe pulmonary hypertension still have lower survival rates than those with mild hypertension, but that the existence of pulmonary hypertension does not affect post-transplant survival. 2 In the next 50years, the success of gene therapy and new medications already being tested will aim to make the discussion of pulmonary hypertension in patients with cystic fibrosis a vestige of medical history.

1. Belle-van Meerkerk G., Cramer M.J., Kwakkel-van Erp J.M., Nugroho M.A., Tahri S., de Valk H.W., et al: Pulmonary hypertension is a mild comorbidity in end-stage cystic fibrosis patients. J Heart Lung Transplant 2013; 32: pp. 609-6142. Hayes D., Tobias J.D., Mansour H.M., Kirkby S., McCoy K.S., Daniels C.J., et al: Pulmonary hypertension in cystic fibrosis with advanced lung disease. Am J Respir Crit Care Med 2014; 190: pp. 895- 905


- An interesting review of the changing approach to pulmonary hypertension in people with CF.