The History of Cystic Fibrosis by Dr James Littlewood OBE

Edited and produced by Daniel Peckham

(* article not included in main text)

 

 

 

*1960 Blattner RJ. Ocular findings in cystic fibrosis of the pancreas. J Pediatr 1960; 57:287-9. [PubMed]

This is the first reference to ocular findings in PubMed. The next is by Bruce GM et al. 1960 which is abstracted below under Chloramphenicol

 


2015 Roberts R; Speight L; Lee J; George L; Ketchell RI; Lau D; Duckers J.  Retinal screening of patients with cystic fibrosis-related diabetes in Wales - a real eye opener.  J Cyst Fibros 2015; 14(2):282-4. [PubMed]
In the UK the National Screening Committee recommends annual retinal screening for all diabetic patients over the age of twelve years. Currently, patients on insulin therapy for Cystic Fibrosis-Related Diabetes Mellitus (CFRD) at the All Wales Adult Cystic Fibrosis Service, UK are invited for annual screening.  67 of the 228 (29%) patients attending the CF centre were receiving insulin therapy. Of the 43 who had retinal scans, 18 (42%) had evidence of retinopathy. Patients with retinopathy had a higher mean HbA1c (p=0.04), mean duration of diabetes and mean duration on insulin (p<0.001).
Almost half of the patients screened had evidence of retinopathy but over a third of the patients with CFRD did not attend screening appointments. Improving patient uptake of retinal scans will become increasingly important in an ageing CF population.
 

- A disappointing proportion of eligible patients attended for retinal screening particularly in view of the high percentage of retinopathy in those who did attend.

 

 

 

1923 Wilson JR, DuBois RO. Report of a fatal case of keratomalacia in an infant with postmortem examination. Am J Dis Child 1923; 26:431-446.
A female infant aged five months died 18 days after admission. She had been fed almost entirely on diluted condensed milk and was severely wasted. There was severe keratomalacia and eventually perforation of the left cornea. At autopsy microscopic examination showed extensive changes in many organs including the lungs, salivary glands and pancreas. There were inflammatory lesions in the lachrymal and salivary glands.
The pancreas (figure 12 in main text) showed keratinisation in certain ducts, many epithelial lined cyst like cavities, a marked inflammatory processes and extensive fibrosis. The lungs also showed keratinisation of the epithelium a marked peribronchitis, bronchiectatic cavities and abscesses. The authors observed - “To the mechanical effect of desquamated keratinized epithelium we are inclined to attribute the pancreatic cysts and bronchiectasis”.


This is an interesting paper as Dorothy Andersen, who described CF in 1938 (below), for many years considered the pancreatic lesions and intestinal malabsorption to be primary and the other systemic effects to be the result of the vitamin A deficiency which, for example, caused secondary squamous conversion of the lining respiratory epithelium. It seems almost certain that the present infant had CF with severe secondary vitamin A deficiency.

 

1931 Daffinee RW, Higgins HL, Mallory TB. Corneal ulcers and roughened conjunctivae associated with fat intolerance. N Engl J Med 1931; 204:1264-1267.
A white male infant aged six months had spots on his eyes noted by the mother also weight loss. He died of bronchopneumonia one month later and at one stage was excreting 40% of his dietary fat intake (70% of which was neutral fat). Autopsy showed almost complete atresia of the cystic duct and histologically “extremely marked disease of the pancreas” - practically all the acinar tissue had disappeared. The lungs showed multiple abscesses. Mallory, the author who was the pathologist, writes “in the later stages of the disease he had a definite pancreatic lack whatever the original cause may have been”.


There can be little doubt that this infant had CF although there are a number of reports suggesting that severe stenosis or even atresia of the pancreatic duct may the the primary cause of the clinical syndrome

 

1933 Blackfan KD, Wolbach SB. Vitamin A deficiency in infants. J Pediatr 1933; 3:679-706.
Kenneth Blackfan (1883-1941) was Associate Professor of Pediatrics at Johns Hopkins, then Professor of Pediatrics at Cincinnati and at Harvard from 1923 to 1941. He apparently ‘mentored’ both Louis Diamond and Sydney Farber. In 1941 he died of lung cancer at the age of 58 – at the height of his career. The Children's’ Hospital in Boston is on Blackfan Street - named after him.


This is an interesting account primarily of early vitamin A deficiency, in which there was considerable interest at the time, the vitamin having been discovered relatively recently in 1919. In 13 infants and young children, 11 of whom were eventually autopsied, vitamin A deficiency was reported. Epithelial metaplasia due to vitamin A deficiency was considered an important predisposing factor to infection by causing – “loss of protective powers of the epithelium due to diminished or absent mucus secretion and loss of ciliary motion”. Six of the 11 infants autopsied had extensive pancreatic lesions (later recognised as typical of CF), that the authors correctly attributed to inspissation of secretion in the ducts.
The authors noted that “The pancreatic lesions were all identical and presumably representing a disease entity. At first we regarded the pancreatic changes as the result of vitamin A deficiency (as did Dorothy Andersen for some years). As the same condition has been found scores of times without other evidences of vitamin A deficiency and since it is not constant even in vitamin A deficiency, we must consider the two are not necessarily connected”. The photomicrograph of pancreas (figure 1) is typical of the changes seen in CF for which Blackfan & May (1938 below) gave credit to Wolbach for the first clear description.

 

Fig. 1: Photomicrograph of pancreas. From the paper with permission.

The authors continue “The pancreatic lesion referred to is characterised by dilatation of acini and ducts, by inspissated secretion, atrophy of the acini, lymphoid and leukocyte infiltration of some degree and fibrosis. Our preliminary studies indicate that the pathogenesis of this striking pancreatic affection resides in the production of an abnormal secretion which inspissates and leads to distension and atrophy of ducts and acini. It is reasonable to assume that this pancreatic lesion, if extensive, may be responsible for failure to utilise fats and hence vitamin A in the presence of an adequate intake”.
The authors concluded that vitamin A deficiency was not infrequent and should be suspected without regard to the characteristic eye signs; histological evidence of vitamin A deficiency may appear in infants who appear to be receiving and adequate intake; they postulate that some factor or factors interfering with storage or utilisation of this vitamin lessens the availability of the supply essential for normal nutrition; certain diagnostic criteria to identify at an early stage are mentioned and vitamin A deficiency should be considered as a general systemic disease rather than as a local disease of the eye.

 

 

1995 Morkeberg JC, Edmund C, Prause JU, Lanng S, Koch C, Michaelsen KF. Ocular findings in cystic fibrosis patients receiving vitamin A supplementation. Graefe’s Arch Clin Exp Ophthalmol 1995; 233:709-713. [PubMed]
Only 26% of 35 patients examined in the Copenhagen clinic had normal vitamin A status as measured by serum retinol and light sensitivity but reduced contrast sensitivity. Conjunctival imprints showed dry eye in 42%; decreased tear stability in 49% and other abnormalities of low tear production (31%) and increased numbers of dying cells (23%). In fact 26% were considered to have the criteria for “keratoconjunctivitis sica”. The authors even suggested that the high incidence of dry eye could be a primary manifestation of CF.

These findings are more likely the result of suboptimal vitamin A status particularly as only 26% had normal vitamin A levels. In studies where vitamin A status is regularly monitored to maintain normal serum levels, only reduced contrast sensitivity is found (Ansari et al. 1999 below) and the cause of this is unexplained.

 

 

2008 Mrugacz M. Kasacka I. Bakunowicz-Lazarczyk A. Kaczmarski M. Kulak W. Impression cytology of the conjunctival epithelial cells in patients with cystic fibrosis. Eye 2008; 22:1137-1140. [PubMed]
Cystic fibrosis affects all secretory epithelia, including the eye, and belongs to the group of ocular surface epithelial diseases, termed keratoconjunctivitis sicca or dry eye syndrome. The aim of this study was to evaluate goblet cell population and conjunctival epithelial morphology in patients with CF. A total of 20 CF patients and 20 controls underwent conjunctival impression cytology. Impression cytology showed conjunctival squamous metaplasia and goblet cell loss in patients with CF. The reduced goblet cell numbers and squamous metaplasia may be indicative of a higher degree of epithelial damage of conjunctival epithelial cells in CF patients, and the presence of neutrophils is a strong sign for an inflammatory background of this disease.In view of the simple, noninvasive nature of impression cytology, this technique may prove to be an important tool for the diagnosis and monitoring of dry eye changes in CF patients.

These changes are described in a number of reports dealing with vitamin A status and still appear to be present even when the vitamin levels are normal. (Ansari EA et al. 1999[PubMed]).

 

 

 

 

 

1952 Wallenstein L, Snyder J. Neurotoxic reactions to Chloromycetin. Ann Int Med 1952; 36:1526-1528.
The first report of some of the serious side effects of chloramphenicol (the antibiotic first became available in 1951) in a 24 year-old patient (who did not have CF) with ulcerative colitis after 4 months continuous treatment with the antibiotic. The lady developed loss of vision, optic and peripheral neuritis but fortunately this settled when the drug was stopped. This is the first of a number of reports of chloramphenicol toxicity following prolonged use (Keith CG. Arch Dis Child 1966; 41:262-266; Harley RD et al. Trans Am Acad Ophthalmol Otolaryngol 1970; 74:1011-1031). Lasky MA et al. JAMA 1953; 151:1403-1404) reported a boy aged 14 with Staphylococcal endocarditis who had 6 g of chloramphenicol daily for 6 weeks and developed optic neuritis; later there was no recovery of vision.


The first reports of side effects in people with CF, who also required prolonged courses of antibiotics, was some 10 years later (Denning et al, 1963 below; Huang NN. J Pediatr 1966; 68:32-44 below).

 

1960 Bruce GM, Denning CR, Spalter HF. Ocular findings in cystic fibrosis of the pancreas: a preliminary report. Arch Ophthalmol 1960; 63:391-401.[PubMed]
The authors became aware of complaints referable to impaired vision and abnormal fundal appearances in their patients in the summer of 1958 and they report the eye findings in 27 patients. Definite impairment of vision was noted in 4 of 10 patients. Characteristic findings were “varying degrees of engorgement and edema of the disc marked in some instances by haemorrhages and in others by cystic changes in the macula”. All those affected had severe pulmonary involvement and raised gammaglobulin levels in the serum and spinal fluid. A later report failed to provide an explanation for the eye changes including chronic hypoxia, hypercapnia, right heart failure, increased intracranial pressure, a bleeding tendency or some disturbance of serum globulins (Soc Pediatr Res 1960; abstract 127). In 1963 the effects of chloramphenicol were reported (Denning et al, 1963 below).

 

Fig. 2: Carolyn Denning. From www.nlm.nih.gov/changingthefaceofmedicine

Dr Carolyn Denning (figure 2) was one of the leading CF paediatricians at that time working first in New York with Dorothy Andersen and later at St Vincent’s Hospital in New York. In the figure 1 she is examining the hand print of a person with CF on a “Shwachman plate” (see N Eng J Med 1956:255:999-1001 above).

I had the pleasure of visiting her unit in the late Eighties, having been encouraged to do so by Ron Tucker the then Director of the UK CF Trust; he was very keen that I should visit her. Carolyn Denning was the first woman to chair the National Cystic Fibrosis Foundation’s Medical Advisory Council and was one of the first to organize and initiate a multidisciplinary team approach to management of the disease – this was very apparent when visiting her and her team at St Vincent’s. A quote from the website “A Changing Face of Medicine” typifies her general approach - "My office visits," she says, "are conducted in a private setting with no interruptions by telephone or office personnel with a one-hour minimum allotted to each patient. I am realistic yet optimistic, stressing the importance of hope. I am current on research activities in the field as well as other important relevant events. I follow through on all matters pertaining to the patient and his office visit and I am available by telephone at all times. I put great stress on personal integrity, ethics and moral beliefs. As director of a large, multi-disciplinary group of health professionals, I have worked hard to choose people who share the same philosophy." It was good to see such an excellent team in action.

 

1963 Denning CR, Bruce GM, Spalter HF. Optic neuritis in chloramphenicol treated patients with cystic fibrosis. J Pediatr 1963; 63:878.
The first report of optic neuritis in four children with CF on long term chloramphenicol – a complication which had been reported first in 1952 by Wallstein & Snyder (1952 above) in a woman with inflammatory bowel disease who after five months developed optic neuritis and peripheral neuritis.

Later a number of reports in people with CF were reviewed by Harley RD et al (Trans Am Acad Ophthalmol Otol 1970; 74:1011-103.[PubMed]). Numbness and tingling of the peripheries preceded the ocular signs which appeared to be related to the total dose received. It was suggested that 25 mg/kg/day for not more than 3 months was relatively safe. Fortunately, visual acuity usually recovered soon after stopping the drug but may recur if treatment was resumed. (Also Huang N et al. J Pediatr 1966; 68:32-44.[PubMed]).

 

1966 Huang NN, Harley RD, Promadhattavedi V, Sproul A. Visual disturbances in cystic fibrosis following chloramphenicol administration. J Pediatr 1966; 68:32-44. [PubMed]
There were visual changes in nine (27%) of 33 patients with CF who had received chloramphenicol in total doses of 81-283 g. The authors mention another patient treated with 135 g of chloramphenicol over 4.5 months (Cocke JG, et al. J Pediatr 1966; 68:27). The authors state that although visual disturbances had been described in children with CF and advanced respiratory disease (Bruce GM et al. Arch Ophthalmol 1960; 63:391-401.[PubMed]) only advanced respiratory changes were present as an explanation; however, these authors later described four children with eye changes due to chloramphenicol (Denning et al. J Pediat 1963; 63:878. above) as did Huang et al. (3rd Interscience Conference Antimicrob Chemother 1963:79). Such patients with eye changes had always received prolonged treatment with chloramphenicol. The eye symptoms usually improved when the drug was stopped. Regular tests of vision were advised when the drug was used for prolonged periods.

 

 

970 Harley RD, Huang NN, Macri CH, Green WR. Optic neuritis and optic atrophy following chloramphenicol in cystic fibrosis patients. Trans Am Acad Ophthalmol Otolaryngol 1070; 74:1011-1031. [PubMed]
This is a review of the literature on chloramphenicol toxicity and experience with eye complications in cystic fibrosis. The authors considered that the peripheral numbness, tingling and cramps frequently preceded the ocular signs which were often sudden. Variable ocular signs were seen including both papilloedema and normal disks. Optic neuritis and visual loss were related both to dosage and duration of treatment. 25 mg/kg/day for not more than 3 months appeared to be safe. Fortunately, most patients’ visual acuity returned soon after stopping the drug.

 

 

*1987 Spaide RF, Diamond G, D'Amico RA, Gaerlan PF, Bisberg DS. Ocular findings in cystic fibrosis. Am J Opthalmol 1987; 103:204-10. [PubMed]

The authors examined 32 patients with cystic fibrosis, paying special attention to optic nerve performance and pupillary function. Decreased visual acuity occurred in nine of 64 eyes. Three of 17 patients (18%) who used chloramphenicol had bilaterally delayed P100 waves of the visual-evoked response of greater than 3 standard deviations. This was not found in patients who did not use chloramphenicol. Contrast sensitivity in patients with cystic fibrosis was decreased at every spatial frequency when compared to healthy controls. This decrease was noted in patients who did and did not use chloramphenicol, suggesting that chloramphenicol is not the only cause of decreased contrast sensitivity in cystic fibrosis.

With pharmacologic pupil testing the authors determined that patients with cystic fibrosis display a preganglionic oculosympathetic paresis that corresponded to the disease severity, as measured by the Shwachman score.

 

 

 

 

 

1963 Rubin LS, Barbero GJ, Chernick WS, Sibinga MS. Pupillary reactivity as a measure of autonomic balance in cystic fibrosis. J Pediatr 1963; 63:1120-1129.[PubMed]
There was considerable interest in possible abnormalities of the autonomic nervous system considered to be in some way related to the basic defect. The authors found significant differences in the pupillary reactivity between people with CF and controls. Holzel in Manchester had found normal levels of acetyl cholinesterase in various tissues and concluded any cholinergic over-stimulation was not due to absence of the hydrolysing enzyme (Holzel A et al. Lancet 1962; i: 822-823 above). Autonomic abnormalities were later confirmed by Davies et al, (N Eng J Med 1980; 302:1453-1456 below) and more recently were reviewed by Mirakhur A et al. (J R Soc Med 2003; 96 Suppl 43:11-17).


Although there was considerable interest in autonomic abnormalities this knowledge does not appear to have made any contribution to either the treatment or the understanding of the basic defect. There was a later reports of excessive finger wrinkling in people with CF when their fingers were immersed in warm water and this phenomenon has been related to autonomic function (Elliott, 1974 below).

(See "CNS" TOPIC for more on autonomic abnormalities)