Akanli L, Lowenthal DB, Gjonaj S, Dozor AJ. Plasma and red blood cell zinc in cystic fibrosis. Pediatr Pulmonol 2003; 35:2-7.https://pubmed.ncbi.nlm.nih.gov/12461732/

Fig. 1 Leyla Akanli healthcare ascension.org

Sixteen of 51 (31%) patients had low RBC zinc levels compared to 4 of 40 (10%) with low plasma zinc concentrations (P < 0.01). Thirteen of 38 patients (34%) in whom both values were obtained had low RBC zinc concentrations compared to 4 of 38 (11%) with low plasma zinc levels (P < 0.022). Neither low RBC nor plasma zinc levels correlated with nutritional status or lung function. In conclusion, about one third of patients with CF had low RBC zinc levels. Plasma zinc concentrations may not adequately reflect overall zinc status. This deficiency did not appear to be related to either nutritional status or lung function. The significance of low RBC zinc in CF is unknown. Studies on zinc keep appearing but the significance of a low plasma or red cell zinc level remains obscure.

Dr Leyla Alkali (fig.1) is a pediatric pulmonologist affiliated with the Division of Pediatric Allergy, Immunology and Pulmonary Children’s Hospital at Loma Linda Medical Center, Loma Linda University, Loma Linda, California 92354, USA. lakanli@ahs.llumc.edu

Ballmann M, Junge S, von der Hardt H. Low-dose methotrexate for advanced pulmonary disease in patients with cystic fibrosis. Respir Med 203; 97:498-500. [PubMed]

Fig. 1a Manfred Ballman

In the year before starting with low dose methotrexate (MTX), FEV1% decreased (median: 10% FEV1; range 9-15% P<0.005) after starting with MTX, FEV1% increased (median: 9% FEV1; range: 2-15% P<0.05). The IgG changed (median: -2 g/l; range: 0.2 to -7.3 g/l) in the first year with MTX.
The authors suggest that these preliminary data suggest a beneficial effect of MTX even in advanced pulmonary disease in CF patients.

– Subsequently there does not appear to have been any trials of methotrexate specifically for CF pulmonary disease, however there are reports of people with CF treated for various malignancies whose chest infections have improved significantly during treatment.  For example, Ruffles TJC et al. Osteogenic sarcoma in an adolescent with cystic fibrosis:successful treatment despite significant obstacles. Front Pediatr 2018 Sep 21;6:245. Full article with references on anti-tumorous chemotherapy and cystic fibrosis  https://pubmed.ncbi.nlm.nih.gov/30298123/

Dr Manfred Ballmann (Fig. 1a) is at the Paediatric Department, Medical School Hannover, Hannover, Germany.

Berge MT, Wiel E, Tiddens HA, Merkus PJ, Hop WC, de Jongste JC. DNase in stable cystic fibrosis infants: a pilot study. J Cyst Fibros 2003; 2:183-188[PubMed]

Fig. 1b Maartje Ten Berge St Antonius Ziekenhuis

The authors treated nine CF patients (aged 0.7-1.9 years) with nebulised rhDNase (2.5 mg) and NaCl 0.9% (10 ml) via jet nebulizer with cross-over once daily during 2-week treatment blocks. Measurements were performed at baseline and after treatment blocks and consisted of lung function tests (plethysmography and tidal rapid thoraco-abdominal compression technique), overnight pulse oximetry, and daily symptom scores. The DNase treatment and the different assessments were well tolerated by all children and their parents.
Lung function showed increased airway patency after treatment with rhDNase (P < 0.001), but not after NaCl 0.9%. This pilot study indicates that objective assessment of the effects of rhDNase is feasible in infants with CF who have little or no respiratory symptoms. The authors suggest that these results warrant a larger randomized placebo-controlled trial.

– This small but detailed study showed definite short term benefit from inhaled rhDNase even in infants. At least one large paediatric centre in the UK tries CF infants on rhDNase as soon as they are able to inhale it. It would seem logical to use rhDNase at an early stage as a number of studies have shown there is some degree of airways obstruction and hyperinflation in most CF infants even before they become infected.

It was not surprising that the use of rhDnase gradually increased in young infants. By 2021, according to the CF Foundation Patient Registry, 43.6% of infants less than 3yrs and 69.2% aged 3-5 years were taking regular rhDNase.

Dr Maartje Ten Berge (Fig.1b) is in the Department of Pediatrics, division of Respiratory Medicine, Erasmus MC–University Medical Center Rotterdam/Sophia Children’s Hospital, Netherlands.

Bateman ND, Fahy C, Woolford TJ. Nasal polyps: still more questions than answers. J Laryngol Otol 2003; 117:1-9. [PubMed]

Fig. 1c Neil Bateman met.nhs.uk

Nasal polyps are common, affecting one to four per cent of the population. Their cause, however, remains unknown and it is possible that it is not the same in all patients. They have a clear association with asthma, aspirin sensitivity and cystic fibrosis. Histologically they demonstrate large quantities of extracellular fluid, mast cell degranulation and an infiltrate of inflammatory cells, usually eosinophils. The authors believe that an endoscopic approach using a microdebrider facilitates accurate removal of polyps with preservation of normal anatomy.
This is a detailed review of polyps in general.

Dr Neil Bateman (Fig.1c) was in the Department of Otorhinolaryngology, Royal Hallamshire Hospital, Sheffield, UK. at the time of this publication – subsequently he became a consultant  ENT surgeon at Royal Manchester Children’s Hospital.

Button BM, Heine RG, Catto-Smith AG, Olinsky A, Phelan PD, Ditchfield MR,, Story I. Chest physiotherapy in infants with cystic fibrosis: to tip or not? A five-year study. Pediatr Pulmonol 2003; 35:208-213[PubMed]

Fig. 1d Brenda Button author’s photo

There has been controversy regarding the inclusion of postural drainage in the physiotherapy of asymptomatic infants with cystic fibrosis (CF). In this study Brenda Button and her colleagues compared the effectiveness of standard postural drainage chest physiotherapy (SPT) with a modified physiotherapy regimen without head-down tilt (MPT) in 20 young infants with CF. Patients receiving SPT had more days with upper respiratory tract symptoms than those on MPT (70 +/- 32.8 vs. 37 +/- 24.9 days; P = 0.04) and required longer courses of antibiotics (23 +/- 28.5 vs. 14 +/- 11.2 days; P = 0.05). Chest x-ray scores were similar at diagnosis but were worse at 2(1/2) years for those receiving SPT (P = 0.03). Forced vital capacity and forced expired volume in 1 sec (FEV(1)) at 5-6 years was lower for SPT than for MPT (P < 0.05). The authors concluded that MPT was associated with fewer respiratory complications than SPT in infants with CF.

Brenda Button (Fig. 1d) of the Department of Physiotherapy, Royal Children’s Hospital, Melbourne, Australia.  Subsequently senior clinician physiotherapist at the Albert Hospital . She works full time as the Respiratory Physiotherapy Stream Leader teaches undergraduate and postgraduate students in the clinical setting and supervises a number of Ph.D. and Masters students. Her work has been influential in most physiotherapists omitting the head down position in the physiotherapy recommendations for infants with cystic fibrosis.

Date H, Aoe M, Nagahiro I, Sano Y, Andou A, Matsubara H, Goto K, Tedoriya T, Shimizu N. Living-donor lobar lung transplantation for various lung diseases. J Thorac Cardiov Sur 2003; 126:476-481. [PubMed]

Fig 1e  Horishi Date ctsnet.org

This paper from Okayama Japan reports experience in living-donor lobar lung transplantation for patients with various lung diseases including restrictive, obstructive, septic, and hypertensive lung diseases. From October 1998 to March 2002, living-donor lobar lung transplantation was performed in 14 patients with end-stage lung diseases. Diagnoses included primary pulmonary hypertension (n = 6), idiopathic interstitial pneumonia (n = 2), bronchiolitis obliterans (n = 2), bronchiectasis (n = 2), lymphangioleiomyomatosis (n = 1), and cystic fibrosis (n = 1). Bilateral living-donor lobar lung transplantation was performed in 13 patients and right single living-donor lobar lung transplantation was performed for a 10-year-old boy with primary pulmonary hypertension.
All the 14 patients are currently alive with a follow-up period of 4 to 45 months. Although their forced vital capacity (1327 +/- 78 mL, 50.2% of predicted) was limited at discharge, arterial oxygen tension on room air (98.5 +/- 1.8 mm Hg) and systolic pulmonary artery pressure (24.8 +/- 1.6 mm Hg) were excellent. Forced vital capacity improved gradually and reached 1894 +/- 99 mL, 67.4% of predicted, at 1 year. All donors have returned to their previous lifestyles. The authors suggest that living-donor lobar lung transplantation can be applied to restrictive, obstructive, septic, and hypertensive lung diseases.

This type of procedure can be an alternative to conventional cadaveric lung transplantation for both pediatric and adult patients who would die soon otherwise. This is an interesting and impressive report from Japan with obvious success with this procedure of which there are few reports other than the work from Starnes group in San Diego in 2001 and subsequently.

Professor Hiroshi Date (Fig. 1e) is a cardiothoracic surgeon in the Department of Thoracic Surgery, Kyoto University, Japan

Dialer I, Hundt C, Bertele-Harms RM, Harms HK. Sonographic evaluation of bowel wall thickness in patients with cystic fibrosis. J Clin Gastroenterol 2003; 37:55-60. [PubMed]

Fig. 1b Irmela Dialer

Fibrosing colonopathy causing severe thickening of the colon wall was described in cystic fibrosis in 1994. It has been suggested that subclinical colon-wall thickening is a common feature in CF patients. In 83 CF patients and 31 controls transabdominal ultrasound was performed in the terminal ileum, cecum, ascending and descending colon. The relation of the measured wall thickness to age, sex, pancreatic enzyme intake, and intestinal diseases was analyzed.
In controls, mean wall thickness depending on gut region was 1.1 to 1.3 mm (SD 0.19-0.23). In CF patients, no evidence of severe thickening or stricture was found, but wall thickness was significantly higher than in controls in all measured regions (1.5-1.6 mm; SD 0.31-0.41). Patients with meconium ileus and distal intestinal obstruction syndrome had significantly increased thickness of the terminal ileum compared with patients without these complications. Neither the intake of high-strength enzymes nor enzyme dosage, age or sex were associated with wall thickness.

–  So the authors found no evidence that a subclinical stage of fibrosing colonopathy is prevalent among the CF patients. Slightly thickened gut walls in CF can be interpreted as an expression of glandular dysfunction in the CF intestine. This is a reassuring study failing to reveal significant bowel wall thickening in CF although slightly thicker bowel wall than in controls. The type of pancreatic enzyme preparations is not mentioned in the abstract.

Dr Irmela Dialer (fig. 1b) is at the Universities Kinderklinik und Kinderpoliklinik im Dr. von Haunerschen Kinderspital, Munich, Germany.

Drew J, Watson AR, Smyth A. Acute renal failure and cystic fibrosis. Archives of Disease in Childhood. 2003; 88:646. [PubMed] The authors, noticing the paucity of earlier reports of renal failure draw attention to a recent e-mail survey of members of the British Association for Paediatric Nephrology which revealed four cases of acute renal failure with combination antibiotic therapy in CF patients (three of four with ceftazidime and gentamicin). They suggest the increased incidence points to the need for increased vigilance when gentamicin and cephalosporin combinations are used to treat exacerbations, particularly if there is a potentially dehydrating state or pre-existing renal anomaly.

Further work was published confirming the occurrence of renal failure in CF and the relationship to the use of intravenous gentamicin (Bertenshaw C et al. Thorax 2007; 62:541-545.[PubMed]; Smyth A et al. Thorax 2008; 63:532-535.[PubMed]).

Frangolias DD, Ruan J, Wilcox PJ, Davidson AG, Wong LT, Berthiaume Y, Hennessey R, Freitag A, Pedder L, Corey M, Sweezey N, Zielenski J, Tullis E, Sandford AJ. Alpha 1-antitrypsin deficiency alleles in cystic fibrosis lung disease. Am J Resp Cell Mol 2003; 293:390-396.[PubMed] The conclusions of this detailed study were that alpha1-AT genotype is not a major contributor to the variability of pulmonary disease severity in cystic fibrosis.

Gibson RL, Emerson J, McNamara S, Burns LL, Rosenfield M, Yunker A, Hamblett N, Accurso F, Dovey M, Hiatt P, Konstan MW, Moss R, Retsch-Bogart G, Wagener J, Waltz D, Wilmott R, Zeitlin PL, Ramsey B. Significant microbiological effect of inhaled tobramycin in young children with cystic fibrosis. Am J Resp Crit Care Med 2003; 167:841-849. [PubMed]

Fig 1c. Ronald Gibson Seattle Childen’s

This trial of 300 mg tobramycin for inhalation twice daily in 21 children less than 6 years for early Pseudomonas infection was stopped as there was a significant microbiological effect in all the treated patients. There was no P. aeruginosa (PA) present in the 8 tobramycin-treated children but in only 1 of 13 in the placebo group had the infection cleared. The authors concluded that 28 days of tobramycin solution for inhalation, 300 mg twice daily, is safe and effective for significant reduction of lower airway Pseudomonas density in young children with CF.

This study from a leading N. American centre seemed to eventually convince many clinicians that early treatment of PA was effective in eradicating the organism as  first suggested in our letter to the Lancet from Leeds in 1985 nearly 20 years earlier (Littlewood et al, 1985. above) and later confirmed in Copenhagen in 1991 in a clinical trial (Valerius et al, 1991. above). We have found the delay in adopting early eradication treatment of PA by many centres difficult to understand in view of the mass of evidence supporting the obvious deleterious effect of chronic PA infection on patients’ ultimate health and even survival.

– There are certain treatments where the beneficial effect is so obvious and different t from previous experience that to wait for controlled trials to satisfy Cochrane reviewers denies many children the benefits of a very important treatment which may have favourable long term effects of their health and even survival. Early eradication of P. aeruginosa in one such treatment.

Dr Ronald Gibson (fig. 1c) is Director of the CF Clinical Centre at Seattle Children’s Hospital and  extensively involved in CF clinical care and research

Gilljam M. Chaparro C. Tullis E. Chan C. Keshavjee S. Hutcheon M. GI complications after lung transplantation in patients with cystic fibrosis. Chest. 2003; 123:37-41. [PubMed]
Lung transplantation is now available for many patients with cystic fibrosis (CF) and end-stage lung disease. While pulmonary graft function is often considered the major priority following transplantation, the nonpulmonary complications of this systemic disease also continue. GI complications after lung transplantation were common in patients with CF, and the authors advised that attention should be paid to the risk for DIOS in the early postoperative period. Prevention and early medical treatment are important in order to avoid acute surgery. Close collaboration with the CF clinic, in order to diagnose and treat CF-related complications, is recommended. The gastrointestinal aspects of treatment may receive insufficient attention if there are serious respiratory problems.

– This report of extensive experience from Toronto of patients after lung transplantations documents this advice and records experience of 27 of 75 patients. The present writer is aware of an instance where failure to give enzymes in the post operative period resulted in intestinal obstruction then complications with resulting fluid and parenteral nutrition eventually leading to fatal systemic candida infection.

Johnson C, Butler SM, Konstan MW, Morgan W, Wohl ME. Factors influencing outcomes in cystic fibrosis: a center based analysis. Chest 2003; 123:20-27. [PubMed]

Fig 2. Charlie Johnson

The analysis was conducted using data from the Epidemiologic Study of Cystic Fibrosis from 1995 through 1996. Within-site rankings tended to be consistent across the three age groups. Patients who were treated at higher ranking sites had more frequent monitoring of their clinical status, measurements of lung function, and cultures for respiratory pathogens. These patients also received more interventions, particularly courses of IV antibiotics for pulmonary exacerbations. There were substantial differences in lung health across different CF care sites. Frequent monitoring and increased use of appropriate medications in the management of CF were associated with improved outcomes.

This study by Dr Charlie Johnson (fig. 2) and colleagues confirmed the value of collecting data in a registry and analysis of that data to yield valuable information. Their findings reinforce the value of more frequent monitoring and interventions in achieving better clinical outcomes.

Jørgensen IM,Johansen HK, Frederiksen B, Pressler T, Hansen A, Vandamme P, Høiby N, Koch C. Epidemic spread of Pandoraea apista, a new pathogen causing severe lung disease in cystic fibrosis patients. Pediatr Pulmonol 2003; 36:439-446. [PubMed]
Pandoraea apista must be added to the increasing list of pathogens capable of causing chronic lung infection in cystic fibrosis (CF) patients. It is most likely that this strain of P. apista was transmissible among patients with CF, leading to spread of infection from the index patient to 5 other patients exposed during participation in winter camps and/or hospitalization. All patients developed chronic infection with high levels of antibodies, and 4 patients had a downhill course of lung disease.

P. apista must therefore be considered a new and sometimes important pathogen for CF patients and one of the increasing number of unusual organism which are significant pathogens for people with CF. Cohort isolation prevented further spread of P. apista in the CF center. Such reports from large CF centres such as Copenhagen are useful for clinicians who subsequently encounter such organisms.

Kollberg H, Carlander D, Olesen H, Wejaker PE, Johannesson M, Larsson A. Oral administration of specific yolk antibodies (IgY) may prevent Pseudomonas aeruginosa infections in patients with cystic fibrosis. Pediatr Pulmonol 2003; 35:433-440[PubMed]

Fig 3. Hans Kollberg

Immunotherapy with specific egg-yolk antibodies (IgY) may be an alternative to antibiotics for the prevention of Pseudomonas (PA) infections. Patients with CF gargled daily with an IgY-antibody preparation, purified from eggs of hens immunized with Pseudomonas bacteria. These patients were compared to a group who did not gargle with the preparation. Both groups had their first colonization with PA eradicated by antibiotics. The basic treatment for CF was essentially the same in both groups.
In the initial study, the period between the first and second colonization with PA was significantly prolonged for the treated vs. the control group. In the prolonged study, the treated group had only 2.5 sputum cultures positive for PA per 100 months of observation, and none of these patients became chronically colonized with PA. No adverse events were reported. In the control group, 13.7 cultures per 100 months of observation were positive for PA, and 5 (24%) patients became chronically infected with PA. This feasibility study shows that antipseudomonal IgY has the potential to effectively prevent PA colonization without any severe adverse effects.

Professor Hans Kollberg (fig. 3) from Uppsala has been attending CF meetings for many years. I first remember him giving a paper on the state of CF in Sweden at the 1980 Toronto CF conference. He has published 79 papers since 1964 many on a wide variety of CF topics. He has been developing this particular treatment for some years and it now seemed to be showing definite promise. Certainly one of the “long distance” CF doctors!!
Further report of this IgY treatment (Nilsson et al, 2007 below) where 10 year progress is reported; a multicentre trial was planned and started with European funding in 2011. There has been no specific publication relating to this trial up to 2018 but quite a number of publications on egg yolk antibodies (IgY) and their application in human and veterinary health  (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7106195/)

The most recent publication from Hans Kollberg himself appears to be a presentation at a Joint Event on 22nd Edition of International Conference on Immunology and Evolution of Infectious Diseases & 12th Edition of International Conference on Tissue Engineering and Regenerative Medicine during May 10-11, 2018 Frankfurt, Germany. (Journal HIV & Retro Virus Extended abstract Vol 5 Iss 1 2019).      The abstract is as follows –  “Phase III: The study was finished in June 2017. Totally 144 countable patients had been included. The results will be ready in spring 2018. All patients have gargled more than 250.000 times and no adverse events have been reported”    “Conclusion: Hopefully the now running double-blind, randomized phase III study will give results as expected and Anti-PA IgY might be registered and physicians will be able to give anti-PA IgY to all eligible CF patients”.

The final published data was a poster WS-12 5 at the 2019 ECFS meeting in Liverpool. This was  kindly sent to me by  Dr. rer. nat. Jutta Bend Mukoviszidose Institut gemeinnützige Gesellschaft für Forschung und Therapieentwicklung mbH In den Dauen 6  53117 Bonn.

Clinical study to evaluate an anti-Pseudomonas aeruginosa IgY gargling solution (EUDRACT 2011-000801-39) A. Schuster1, J. Bend2, N. Høiby3, P.E. Verde4, A. Rottmann4, A. Larsson5,the IMPACTT study group. 1Düsseldorf University Hospital, Department ofPaediatrics, Düsseldorf, Germany; 2Mukoviszidose Institut gGmbH, Bonn,Germany; 3Rigshospitalet, Department of Clinical Microbiology, Copenhagen,Denmark; 4Düsseldorf University Hospital, Coordination Center for ClinicalTrials, Düsseldorf, Germany; 5Uppsala University, Department of MedicalSciences, Uppsala, Sweden

Objectives: Prevention of chronic PA infection in CF patients is a major therapeutic goal. For this purpose, a novel approach has been developed: a gargling solution with egg yolk from specifically immunized hens containing IgY antibodies against PA. An open pilot study on anti-PA IgY gargling had shown promising results (Kollberg et al., 2003).
Methods: We performed a prospective, randomized, placebo-controlled,double-blind phase III multicenter study in CF patients, ≥5 years of age,who had had bronchopulmonary PA colonization within the last 3 years that had been successfully eradicated. The intervention to be evaluatedwas  argling every night, either with an anti-PA-containing IgY solution (active treatment, ACT), or with a solution containing unspecific IgY (placebo, PLAC). The primary endpoint was time from start of treatment to first recurrence of PA, upon 3-monthly study visits, with confirmatory analysis in the central microbiology laboratory. Study duration in each patient was 104 (±2) weeks max., or until detection of PA in bronchopulmonary secretions. N = 83 patients were analyzed in the ACT group, N = 81 patients in the PLAC group.
Results: Statistical analysis of the primary endpoint shows that the null hypothesis of no difference between treatment groups (p = 0.95) cannot be rejected. Median time to event was 105.14 weeks with ACT, whereas for PLAC the median lay beyond the study period. The PLAC group reacted with far less events than expected, while the ACT group results were in line with the anticipated outcome. Also, there was no treatment effect regarding secondary endpoints (FEV1, BMI, hospital days, school/work absenteeism, antibiotic use, exacerbations). Incidence of adverse events, most mild/ moderate, was similar in both groups.

Conclusion: Efficacy of regular gargling with anti-PA-IgY solution on prevention of PA-reinfection in CF patients could not be shown in our study. We are discussing an unspecific effect of IgY as shown experimentally.

A very disappointing conclusion after over 20 years of development.

Lenaerts C, Lapierre C, Patriquin H, Bureau N, Lepage G, Harel F, Marcotte J, Roy CC. Surveillance for cystic fibrosis-associated hepatobiliary disease: early ultrasound changes and predisposing factors. J Pediatr 2003; 143:343-350. [PubMed]

Fig 3a    Claude C Roy Wikipedia

To investigate routine ultrasonography (US) as an early marker and to identify risk factors for the development of cirrhosis and portal hypertension (PHT) in cystic fibrosis.  106 children with CF aged 5.9+/-2.3 years were followed for 10.4+/-0.2 years in a CF clinic. At enrollment, the US was normal, but biochemical and/or clinical disease was present in 10%. By the end of the study, 19 had developed US changes, eight with evidence of PHT. At the time of the initial US change, only 36.4% of those had, at the end of the study, either a heterogeneous or a nodular parenchyma, and only 50% of those with PHT had biochemical and/or clinical disease. Of the 30 patients treated with ursodeoxycholic acid for biochemical and/or clinical disease with (n=15) and without (n=15) associated US changes, PHT developed in six of the former and two of the latter. Univariate analysis and logistic regression showed that children with more severe disease in terms of forced expiratory volume in one second were at somewhat greater risk (P<.06) of PHT developing.

The authors concluded ultrasound was an early marker of liver disease and more severe CF disease, a predictor of progressive liver disease. They suggested a controlled trial should be done to assess isolated US-detected disease as an indication for UDCA.

Professor Claude Roy (1928-2015) is considered to be one of the founding fathers of paedaitric gastroenterology.  This is a record of experience and long follow up from Prof Claude Roy’s in Montreal centre where there is with extensive expertise in paediatric liver disease.

Lee TWR, Brownlee KG, Conway SP, Denton M, Littlewood JM. Evaluation of a new definition for chronic Pseudomonas aeruginosa infection in cystic fibrosis. J Cyst Fibros 2003; 2:29-34.[PubMed]

Fig 4. Tim Lee

The variable definition of chronic Pseudomonas infection in various publications was problem in comparing experience between CF centres. Patients with CF in Leeds were classified into four groups on the routine culture results over the previous 12 months as follows-

“Chronic” – more than 50% of cultures positive for Pseudomonas;
“Intermittent” – less than 50% of cultures were positive;
“Free”  –  previously had positive but clear for the past year
“Never” – patient has never had Pseudomonas.

Many previous studies used different definitions of chronic Pseudomonas infection making comparisons difficult. This “Leeds definition” was agreed by a number of experts including Niels Høiby and later confirmed as useful in a published study from Belgium (Proesmans M et al. Eur Respir J 2006; 27:937-943. [PubMed]). Subsequently the definitions have been quite widely adopted.

Dr Tim Lee (fig. 4) is now (in 2023) the Senior Paediatrician in the Leeds Regional Paediatric Unit which is now sited at the Leeds General Infirmary.  He is active in teaching and research and Head of Studies for the Postgraduate Programmes in Child Health, one of the largest Postgraduate Programmes within the School of Medicine. This is one of his earlier papers and must be one of the most frequently quoted in the CF literature!!

Li N, He B. Wang GF, Tang XY. A case report of cystic fibrosis and review of 16 cases of cystic fibrosis in Chinese patients. [Chinese] Chinese Journal of Tuberculosis & Respiratory Diseases 2003; 26:559-562. [PubMed].
A report a case of cystic fibrosis (CF) in a 14-year-old Chinese girl presenting with recurrent productive cough since birth with para sinusitis and otitis media was confirmed to have CF in Peking University First Hospital. Chest CT scan showed bronchiectasis, more severe in the right upper lobe. Sweat tests were taken three times, and the values of Na(+) and Cl(-) were (126.6 +/- 5.4) mmol/L and (108.9 +/- 3.3) mmol/L, respectively. The examination of the pancreas showed no remarkable cystic changes on CT scan and there was no pancreatic insufficiency.
Sixteen Chinese patients with CF reported from 1974 to 1999 were reviewed. Sixteen of the 17 patients (7 males and 9 females, aged from 6 months to 25 years) had clinical data available for analysis. Eleven of them had died, nine before the age of 13. They all suffered from frequent episodes of pneumonia, while 14 had malnutrition and 4 had jaundice. The diagnostic procedures included clinical features, sweat test and autopsy. Four of them had DNA screened and four kinds of novel mutations in the cystic fibrosis transmembrane conductance regulator gene were found.

So Chinese patients with CF show similar clinical manifestations to patients in the European and North American populations, but the CFTR mutations are different.

Majka L, Gozdzik J, Witt M. Cystic fibrosis-a probable cause of Frédéric Chopin’s suffering and death. J Appl Genet 2003; 44:77-84. [PubMed]

Fig. 4a Lucyna Majkaz     zhg.amued.pl

Frédéric Chopin – the great Polish composer and pianist-suffered from a chronic disease. Both during his life and after death physicians disagreed on the subject of Chopin’s diagnosis. His contemporaries accepted the diagnosis of a disease common in the 18th century-tuberculosis. Description of new clinical entities provoked new dilemmas in the 20th century.
The present authors believe the most tenable seems to be a diagnosis of cystic fibrosis. In this work they present F. Chopin’s case history and discuss pros and cons for cystic fibrosis as the cause of F. Chopin’s suffering and death.

There are many subsequent publications relating to a possible cause of Chopin’s death the latest being  Michal Witt et al.J Apple Genet 2018;59(4): 471-73.( https://pubmed.ncbi.nlm.nih.gov/30047032/)

Mirakhur A, Walshaw MJ. Autonomic dysfunction in cystic fibrosis. J R Soc Med 2003; 96 Suppl 43:11-17. [PubMed].
This a review of the various published work on the autonomic system in CF which has received attention over the years.

Olivier KN, Weber DJ, Wallace RJ Jr, Faiz AR, Lee JH, Zhang Y, Brown-Elliot BA, Handler A, Wilson RW, Schechter MS, Edwards LJ, Chakraborti S, Knowles MR. Nontuberculous Mycobacteria in Cystic Fibrosis Study Group. Nontuberculous mycobacteria. I: multicenter prevalence study in cystic fibrosis. Am J Resp Crit Care 2003; 167:828-834. [PubMed]
A prospective, cross-sectional study of the prevalence of NTM and clinical features of patients at 21 U.S. centers. Almost 10% of patients with CF who were 10 years or older were included (n = 986). The overall prevalence of NTM in sputum was 13.0% (range by center, 7-24%). Mycobacterium avium complex (72%) and Mycobacterium abscessus (16%) were the most common species. When compared with patients with CF without NTM, culture-positive subjects were older (26 vs. 22 years, p < 0.001), had a higher FEV1 (60 vs. 54%, p < 0.01), higher frequency of Staphylococcus aureus (43 vs. 31%, p < 0.01), and lower frequency of Pseudomonas aeruginosa (71 vs. 82%, p < 0.01). Molecular typing revealed that almost all patients within each center had unique NTM strains.

In summary, NTM are common in patients with CF, but neither person-to-person nor nosocomial acquisition explained the high prevalence. Older age was the most significant predictor for isolation of NTM. The clinical significance of NTM in CF is incompletely defined, but patients with these organisms should be monitored with repeat cultures.

Olivier KN, Weber DJ, Lee JH, Handler A, Tudor G, Molina PL, Tomashefski J, Knowles MR. Nontuberculous Mycobacteria in Cystic Fibrosis Study Group. Nontuberculous mycobacteria. II: nested-cohort study of impact on cystic fibrosis lung disease. Am J Resp Crit Care 2003; 167:835-840. [PubMed]

Fig 4b Kenneth Oliver eMedEvents

The prevalence of nontuberculous mycobacteria (NTM) is high (approximately 13%) in sputum of patients with cystic fibrosis (CF), but the impact on lung disease is unknown. The authors followed 60 incident NTM-positive and 99 culture-negative patients with CF for 15 months and assessed clinical impact of NTM by FEV1 and high-resolution computed tomography (HRCT) of the chest. Mycobacterium avium complex was seen in 75% of NTM-positive subjects. The annual rate of decline in FEV1 was not different among control versus NTM-positive subjects who did not, or did, meet American Thoracic Society microbiologic criteria for NTM disease (3 +/- 1, 3 +/- 2, and 5 +/- 2%, respectively). More subjects with three or more positive cultures for NTM had two or more characteristic findings on entry HRCT (60%, 9/15) as compared with subjects with two positive cultures or less (32%) or negative cultures (19%; p < 0.02). All subjects with three or more positive cultures and exit HRCTs (n = 6) showed progression of HRCT findings, whereas only 17% of subjects with two positive cultures or less had progression (p = 0.0006).

In summary, no significant short-term effect on FEV1 was detected in patients with multiple positive NTM cultures, but an abnormal HRCT was predictive of progression. Patients with CF and multiple positive NTM cultures, characteristic HRCT findings, and progression of HRCT changes should be monitored closely and considered for antimycobacterial therapy. These are two very useful papers for clinicians dealing with patients who have NTM infection.

Dr Kenneth Oliver (fig. 4b) is at The Cystic Fibrosis/Pulmonary Research and Treatment Center, the Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Parsons EP, Clarke AJ, Bradley DM. Implications of carrier identification in newborn screening for cystic fibrosis. Arch Dis Child Fetal & Neonat 2003; 88:F467-471. [PubMed]
A reassuring small study confirming that the dire psychological consequences of informing parents their infant to be a CF carrier predicted by some are not born out by this small study. Six months after disclosure to the parents, carrier identification of their infant was not perceived by parents to be problem. Also of course identifying the infant as a carrier has the potential for ensuring that only one of the parents is a carrier and also checking other blood relatives for carrier status if they so wish.

E P Parsons is at the Institute of Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff College of Medicine, Heath Park, Cardiff

Proesmans M, De Boeck K. Omeprazole, a proton pump inhibitor, improves residual steatorrhoea in cystic fibrosis patients treated with high dose pancreatic enzymes. Eur J Pediatr 2003; 162:760-763. [PubMed]

Fig. 4c Marijke Proesmans UZ Leuven

The results of 15 patients with confirmed steatorrhoea during the control evaluation were analysed. Median age was 8.7 years (range 3.5-15.9 years). Median daily lipase intake was 13,500 U/kg per day (range 10,000-22,000 U/kg per day). During treatment with omeprazole, median faecal fat loss (g fat/day) decreased from 13 g (quartiles 11.5-16.5 g/day) to 5.5 g (quartiles 4.9-8.1 g/day) (P<0.01). The same improvement was noted when fat absorption was calculated: 87% (quartiles 81-89%) without versus 94% (quartiles 90-96%) with omeprazole (P<0.001). So omeprazole improves fat digestion and absorption in cystic fibrosis patients with residual faecal fat loss despite maximal pancreatic enzyme substitution.

This is a small but useful study showing a definite improvement in absorption with acid suppression in patients with CF requiring more than the recommended doses of pancreatic enzymes.

Dr Marijke Proesmans (Fig 4c) is associate professor in the Faculty of Medicine, University of Leuven.

Robinson P, Carzino R, Armstrong D, Olinsky A. Pseudomonas cross-infection from cystic fibrosis patients to non-cystic fibrosis patients: implications for inpatient care of respiratory patients. J Clin Microbiol 2003; 41: 5741.[PubMed]

Fig 5. Phil Robinson

A 14-year-old boy with non-CF bronchiectasis secondary to chronic aspiration developed multiresistant Pseudomonas aeruginosa lower respiratory disease following several inpatient periods where accommodation and physiotherapy services were shared with CF patients known to be infected with the genetically identical strain of P. aeruginosa. Cross-infection with P. aeruginosa between CF patients and non-CF patients had not previously been described, and this finding raises significant issues relevant to the treatment of patients with non-CF suppurative lung disease.
Spread of a highly transmissible P. aeruginosa to a CF patient already chronically infected with P. aeruginosa had already been described from Liverpool (McCallum SJ et al. Lancet 2001; 358:558-560. above [PubMed]).

The spread of infection to non-CF patients from CF patients is a definite risk in hospital wards, particularly if there are immunocompromised patients mixing with CF patients who have chronic P. aeruginosa infection a situation. I have observed this on a paediatric ward on one occasion in the years before cross infection with P. aeruginosa was not considered to be a significant risk.

Dr Phil Robinson (figure 5) is Head of CF services and Respiratory Physician at the Royal Melbourne Children’s Hospital and a leading Australian authority on cystic fibrosis.

Saiman L, Marshall BC, Mayer-Hamblett N, Burns JL, Quittner AL, Cibene DA, Coquillette S, Fieberg AY Accurso FJ Campbell PW. Macrolide Study Group. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA 2003; 290:1749-56. [PubMed]

Fig 6. Lisa Saiman

This is the major CF Foundation multicentre study on azithromycin. The active group (n = 87) received 250 mg (if weight <40 kg) or 500 mg (if weight > or =40 kg) of oral azithromycin 3 days a week for 168 days; the placebo group (n = 98) received identically packaged tablets The azithromycin group had a significant mean 0.097-L (SD, 0.26) increase in FEV1 at day 168 compared with 0.003 L (SD, 0.23) in the placebo group. Participants in the azithromycin group had less risk of experiencing an exacerbation and at the end of the study weighed an average 0.7 kg more than participants receiving placebo.

So here was further evidence that azithromycin treatment was associated with improvement in clinically relevant end points and the authors advised the drug should be considered for patients with CF who are 6 years or older and chronically infected. Following this trial the product was licensed and by 2005 no less than 53.6% of patients on the US CF Foundation Patient Registry were taking azithromycin.

Professor Lisa Saiman’s (figure 6) primary research and clinical interests are in cystic fibrosis, healthcare-acquired infections and hospital epidemiology and multidrug-resistant organisms. Dr. Saiman is the director of the CF Referral Center for Synergy Studies in Multidrug-resistant Organisms isolated from Patients with CF. Attending Physician Hospital Epidemiologist, Morgan Stanley Children’s Hospital of New York-Presbyterian.

Saiman L, Siegel J. Cystic Fibrosis Foundation. Infection control recommendations for patients with cystic fibrosis: microbiology, important pathogens, and infection control practices to prevent patient-to-patient transmission. [Review] [395 refs] Infect Cont Hosp Ep 2003; 24(5 Suppl):S6-52.[PubMed]
Report of a Consensus Development Conference organised by the CF Foundation to which representatives from both USA and Europe were invited. The result is a very detailed paper full of information and nearly 400 references!

Simon-Bouy B, Satre V, Ferec C, Malinge MC, Girodon E, Denamur E, Leporrier N, Lewin P, Forestier F, Muller F. French Collaborative Group. Hyperechogenic fetal bowel: a large French collaborative study of 682 cases. Am J Med Genet 2003; Part A. 121A:209-213. [PubMed]
Hyperechogenic fetal bowel is detected in 0.1-1.8% of pregnancies during the second or third trimester. This 1997-1998 multicenter study in 22 molecular biology laboratories identified 682 cases of hyperechogenic fetal bowel detected by routine ultrasound examination during the second (86%) or third trimester. In 447 cases (65.5%), a normal birth was observed. Multiple malformations were observed in 47 cases (6.9%), a significant chromosomal anomaly was noted in 24 (3.5%), cystic fibrosis in 20 (3%), and viral infection in 19 (2.8%). In utero unexplained fetal death occurred in 1.9% of cases, toxemia in 1.2%, IUGR in 4.1%, and premature birth in 6.2%.

This study demonstrates that this ultrasound sign is potentially associated with medically significant outcomes. Having established that the bowel is hyperechogenic, recommended investigations should include a detailed scan with Doppler measurements, fetal karyotyping, cystic fibrosis screening, and infectious disease screening. After birth, newborns require paediatric examination because surgical treatment may be necessary. This should be combined with clear counseling of the parents. A very clear and practically useful paper from a large multicentre French study which indicates the significance of hyperechogenic bowel during pregnancy.

Dr Brigette Simon-Buoy is at  SESEP, Université de Versailles, Versailles, France.

Sheth S, Shea JC, Bishop MD, Chopra S, Regan MM, Malmberg E, Walker C, Ricci R, Tsui LC, Durie PR, Zielenski J, Freedman SD. Increased prevalence of CFTR mutations and variants and decreased chloride secretion in primary sclerosing cholangitis. Hum Genet 2003; 113:286-292. [PubMed].
This complex study concludes that the data indicate that there is an increased prevalence of CFTR abnormalities in primary sclerosing cholangitis (PSC) as demonstrated by molecular and functional analyses and that these abnormalities may contribute to the development of PSC in a subset of patients with inflammatory bowel disease.

Stratford FL, Pereira MM, Becq F, McPherson MA, Dormer RL. Benzo(c) quinolizinium drugs inhibit degradation of Delta F508-CFTR cytoplasmic domain. Biochem Bioph Res Co 2003; 300:524-530. [PubMed]
The results show, for the first time, that the benzo(c) quinolizinium compounds, MPB-07 and MPB-91, selectively inhibit degradation of the Delta F508 cytoplasmic domain protein. Studies using protease inhibitors demonstrated that both Delta F508 and wild-type proteins are substrates for cysteine proteases. The studies provide evidence that benzo(c) quinolizinium compounds protect a proteolytic cleavage site by direct binding to the first cytoplasmic domain of Delta F508-CFTR and this is a likely mechanism for increasing Delta F508-CFTR trafficking in intact cells.

Bob Dormer and Maggie McPherson continued their studies on the chemical correction of faulty CFTR.