The History of Cystic Fibrosis by Dr James Littlewood OBE

Edited and produced by Daniel Peckham

 

1838 Rokitansky C von. Sections-Protokoll und Gutachen. Wien, 4. April 1838 (als Anhang).
Karl Freiherr von Rokitansky (1804-1878) (figure 1) was a distinguished Viennese pathologist and described as a founder of modern pathological anatomy. He was one of the towering figures who made

 

Fig. 1: Karl Freiherr von Rokitansky. From Wikipedia.

the New Vienna School into a world medical centre in the second half of the nineteenth century. His contributions were fundamental to the establishment of pathology as a recognised science, and he himself performed more than 30,000 autopsies. He was one of the few who stood by the side of Semmelweis in the controversy over aseptic methods.

Rokitansky described the autopsy findings in a seven month gestation premature male fetus found in a box in a cemetery in Vienna in 1834 as follows - “Truncus foetus septimestris, in cujus abdomine intestinum ileum proxime valvulum coeci pariete convexo hiat foramina semen cannabis aequante tunicis intestine extus revolutis cincto in peritonaei cavum illincque meconium effudit”. - In the last part of the small bowel there was a small ileal perforation the size of a hemp seed and around the perforation there was yellow jelly-like meconium partially fast sticking to the outside of the bowel.

Death was considered due to peritonitis secondary to the ileal perforation. Although the report did not include microscopic description of the pancreas, it was macroscopically normal.
Although the histology of the pancreas was not recorded, this report has been considered to be an early or even the first description of meconium ileus in CF although it was later shown that meconium ileus can occur in non-CF infants (Rickham et al,1965 below).

Later it was the recognition of the changes in the pancreas, present in some of the many infants that came to autopsy, that led to the eventual recognition of “fibrocystic disease of the pancreas” as a specific entity by Dorothy Andersen in 1938 (below); on the other hand the changes in the pancreas are very variable in severity.

 

1905 Landsteiner K. Intestinal obstruction from thickened meconium. Zentralbl Allg Pathol 1905; 16:903-907.
This was the first description of an infant with meconium ileus to be accompanied by a description of the associated pancreatic histological changes. The pancreas showed an increase in inter and intra lobular connective tissue and round cell infiltration and markedly dilated ducts. Landsteiner suggested that lack of pancreatic secretion had caused the thickening of the meconium. He mentions another infant where the pancreas was normal but there was no secretion of bile.
The report is considered to be the first to suspect that microscopic changes in the pancreas could interfere with secretions and digestion of meconium and thus result in bowel obstruction.

Oppenheimer & Esterly, the distinguished N. American pathologists, regard this as the first report of meconium ileus (1975, below).

Karl Landsteiner (1868-1943) was a Viennese pathologist who worked first in Vienna then from 1922 in the United States. He described the blood iso-agglutinins in 1900 and the blood groups in 1901 for which he received the Nobel Prize in 1930.

 

1929 Kornblith BA, Otani S. Meconium ileus with congenital stenosis of the main pancreatic duct. Am J Path 1929; 5:249 - 261.
Stenosis of the proximal end of Wirsung’s duct (the main pancreatic duct) was found in an infant with meconium ileus who died aged five days. There was marked increase in the stroma of the pancreas; the acini were atrophic and many areas replaced by connective tissue. The main duct was extremely widened which suggested a congenital anomaly of duct development as a cause of the pancreatic fibrosis which was present.


Almost certainly CF in view of the pancreatic changes and the meconium ileus (Dodd, 1936 below; Landsteiner, 1905 above similar).

 

1936 Dodd K. Intestinal obstruction due to meconium ileus in a newborn infant. J Pediatr 1936; 9:486-491.
Katherine Dodd of Nashville notes that “from time to time there have appeared in the literature reports of obstruction due apparently to no tumour or congenital malformation of the gastrointestinal tract but to an accumulation of mucilaginous meconium in the tract itself”. There is usually no mention of meconium ileus even in the more complete textbooks. This infant had signs of intestinal obstruction, developed bronchopneumonia and died at 10 days. There was tenacious grey material in the ileum and colon. “The only other organ showing marked changes was the pancreas” which showed marked changes of interstitial pancreatitis, cellular infiltration and dilatation of some ducts and acini” – in fact was typical of cystic fibrosis.
A review of the literature revealed 21 similar reported cases – the five who recovered were well having passed a large meconium plug and they probably had “meconium plug syndrome” and not cystic fibrosis. The rest had fatal obstruction due to abnormal bowel contents. In 5 cases abnormalities were found in the pancreas where this was examined (Kornblith et al, 1929 above; Landsteiner, 1905 above).

Dodd suggested that the failure of pancreatic secretion or bile to reach the gastrointestinal tract during fetal and neonatal life was at least part of the cause of meconium ileus.

 

1936 Meltzer S. Meconium ileus. Canad Med Ass J 1936; 34:186.
A single case report by Sara Meltzer, a pathologist in Winnipeg – the second infant in the family to die of neonatal obstruction. Abnormal meconium was noted but pancreas was not examined and the infant died on the first day. She mentions a similar case report by Kornblith & Otani 1929 (above) where there was stenosis of the duct of Wirsung (the main pancreatic duct) also twins seen by Sydney Farber with occlusion of the pancreatic duct and pancreatic fibrosis (also Dodd, 1936 above).

 

1938 Burger P. Cas rare d’ileus du nouveau-ne par epaississement du meconium. (A rare case of ileus in the newborn with inspissation of meconium). Gynec et Obstet 1938; 37:176-177.
A case of neonatal intestinal obstruction with pancreatic changes at autopsy. Almost certainly meconium ileus attributed to some abnormality in the secretions of the liver or pancreas.

 

1948 Hiatt R, Wilson P. Celiac Syndrome VII. Therapy of meconium ileus, report of 8 cases with review of the literature. Surg Gynec Obstetr 1948; 87:317-327. [PubMed]
These were early days for paediatric surgery and there were very few specialist paediatric surgeons and anaesthetists. In this first report of survival of infants with meconium ileus the surgeons at the Babies Hospital, New York irrigated the bowel via an incision at the junction of the dilated bowel and the portion containing inspissated meconium, and then closed the bowel. The operation was successful in 5 of 8 cases – better results than expected and very good for the time.

Later Shwachman comments in 1955 that prior to this report the “the surgical correction of the obstruction was considered hopeless” and this was “the first important contribution to correction of this condition”.

 

1950 Glanzmann E, Berger H. Meconium ileus; clinical and anatomopathologic observations, and chemical analysis of the intestinal content in a case of fatal meconium ileus in a six-day old child. Ann Paediatr – Internat Rev Pediatr 1950; 175:33-48. [PubMed]
An early report describing abnormal composition of meconium in CF infant that is "so altered physically and chemically that ileus inevitably occurs". The meconium contained a protein which in contact with fatty material forms a gelatinous substance. The protein is present in only small amounts or absent in normal meconium.

 

1950 Rapoport S, Buchanan DJ. Composition of meconium: Isolation of blood group specific polysaccharides. Abnormal composition of meconium. I. Meconium ileus. Science 1950; 112:150. [PubMed]
Meconium was shown to consist largely of a mucopolysaccharide which demonstrated a very high amount of blood-group-specific activity (also Buchanan & Rapoport, 1952 below).

 

1952 Buchanan DJ, Rapoport S. Chemical comparison of normal meconium and meconium from a patient with meconium ileus. Pediatrics 1952; 9:304-310. [PubMed]
This is the first report of increased protein content in the meconium of an infant with meconium ileus when compared with meconium from three non-CF infants.

Normal meconium contained less nitrogen than the meconium from the CF infant with meconium ileus. This observation would eventually form the basis of the BM Meconium screening test for cystic fibrosis (also Green et al, 1958 below; Green & Shwachman, 1968 below; Schutt & Isles, 1968 below)

 

1954 Olim CB, Ciuti A. Meconium ileus: new method of relieving obstruction. Ann Surg 1954; 140:736-740. [PubMed]
Unusual success was reported with local rectal instillation of hydrogen peroxide in removing the inspissated meconium in two infants. Robert Gross, a paediatric surgeon, commenting on the paper was “so impressed with the authors’ report that I shall certainly try the technique”. Local instillation of hydrogen peroxide appeared to be a popular method of relieving bowel blockages and was recommended for severe constipation with obstruction. However, the method did not appear to become popular for treating meconium ileus and there at no further publications relating to the method.

 

1957 Bishop HC, Koop CE. Management of meconium ileus, resection, Roux-en-Y anastomosis and ileostomy irrigation with pancreatic enzymes. Ann Surg 1957; 50:835-36. [PubMed]
This was a major surgical advance in the management of meconium ileus where mortality at the time was still over 50%. After resection of the most dilated portion of the ileum an end-to-side proximal-to-distal ileo-ileal roux-en-Y anastomosis is performed and the free end of the distal ileum brought out onto the abdominal wall as an Ileostomy (figure 2). The stoma acts as a safety valve and can be used to instil fluids, drugs or detergents.
Later the surgeons at the Queen Elizabeth Hospital, London reported an improvement in survival from 30% to 70% after adopting this procedure (McPartlin et al, Arch Dis Child 1972; 47:207-210)

 

Fig. 2: Bishop - Koop procedure.

 

1958 Green MN, Clarke JT, Shwachman H. Studies in cystic fibrosis of the pancreas: protein pattern in meconium ileus. Pediatrics 1958: 21:635-641. [PubMed]
This study confirmed the presence of large amounts of protein in the meconium from patients with meconium ileus. The meconium of subsequent newborn siblings of known patients with CF was examined in a later study (Green & Shwachman, 1968 below).

 

1961 Elian E, Shwachman H, Hendren WH. Intestinal obstruction in the newborn infant; usefulness of the sweat electrolyte testing differential diagnosis. N Eng J Med 1961; 264:13-16. [PubMed]
The authors managed to perform pilocarpine iontophoresis sweat tests in the first four days of life in 37 babies- a difficult feat at this early age. Another six newborns with intestinal obstruction were tested – the four with CF were all sweat test positive and the two with negative sweat tests had respectively Hirschprung’s disease and ileal atresia.
So sweat tests were already positive in the newborn period in infants with CF but an experienced and skilful technician would be required to perform the investigation. If an urgent answer is required at the present time a check on the infant for the presence of CF mutations would be helpful in most instances.

 

1964 Wiser WC, Beier FR. Albumin in the meconium of infants with cystic fibrosis: a preliminary report. Pediatrics 1964; 33:115-118. [PubMed]
Although an unusual protein content in the meconium of infants with meconium ileus had been described by a number of authors (Glanzmann E, Berger H. Ann Paediat 1950; 175:33 above; Buchannan & Rapoport Pediatr 1952:9:304 above; Green M et al. Pediatr 1958; 21:635 above), the present study was to determine if meconium from infants with CF who did not have meconium ileus also had an abnormal protein content as perhaps this could be “used in a predictive manner” i.e. for neonatal CF screening.


In this study, using immunoelectrophoresis, the meconium from five infants with a family history of CF (Cases 1 – 5) was examined for increased protein. The three of these infants with CF (Cases 1,2,& 4) had obviously raised albumin levels which did not occur in the two unaffected infants (Cases3 & 5) nor in two healthy control infants (Cases 6 & 7) (figure 3).

 

Fig. 3: Electrophoresis of meconium in this study.

This study, from Salt Lake City, was the first to demonstrate increased albumin in the meconium of all CF infants and to suggest the finding could be used in a “predictive manner”.

Later Schutt & Isles (Arch Dis Child 1968; 43:178 below) from Bristol in the UK showed that the increased albumin could be recognised very simply by using the Albustix dipstick test designed for testing urine for albumin; this method eventually formed the basis of the BM Meconium test used in several neonatal CF screening studies during the Seventies (In Europe by Stephan U, et al. Pediatrics 1975; 55:35-38 below; in Wales by Ryley HC, et al. Arch Dis Child 1979; 54:92-97 below; in the UK by Evans et al, 1983 below).

 

1965 Rickham PP, Boeckman CR. Neonatal meconium obstruction in the absence of mucoviscidosis. Am J Surg 1965; 109:173 - 177. [PubMed]
Mr. Rickham, a paediatric surgeon from the Alder Hey Children's Hospital in Liverpool, UK, reported seven infants who, although having neonatal meconium obstruction did not appear to have cystic fibrosis. Five survived and subsequently had normal sweat tests and trypsin was present in their stools; although three did show some evidence of intestinal malabsorption. The three infants that died had normal pancreatic histology further confirming they did not have CF. Also they did not have positive sweat tests and had normal routine pancreatic histology which has been found in only a minority of infants who die of meconium ileus (Oppenheimer & Esterly Arch Pathol 1973; 96:149-154). Other examples of non-CF neonatal meconium obstruction have been reported (Dolan TF, Touloukian RJ. J Pediatr Surg 1974; 9:821-824; Shigemoto H, et al. J Pediatr Surg 1978; 13:475-479). The fact that five of Mr Rickham's patients survived with normal sweat tests confirms they did not have CF.

This was an important report as the presumption that an infant with meconium ileus definitely had CF on one occasion to my knowledge resulted in an incorrect diagnosis of CF – a situation overlooked for some 10 years. A child of 10 years who had been treated in the neonatal period for meconium ileus was subsequently treated as having cystic fibrosis. In an outpatient clinic a medical student asked the consultant paediatrician the result of the sweat test. It was eventually discovered, after a search through the notes, that the child had never had a sweat test performed to confirm the diagnosis. So a sweat test was performed which proved quite negative as did all the other tests for cystic fibrosis. So the diagnosis was reversed. Subsequently the parents took legal action against the paediatric consultant concerned.

 

1965 Holsclaw DS, Eckstein HB, Nixon HH. Meconium ileus. A 20-year review of 109 cases. Am J Dis Child 1965; 109:101-113. [PubMed]
Douglas Holsclaw (figure 22 in main text) who was a colleague of Harry Shwachman’s, reviewed experience since 1944 of 109 infants with meconium ileus from the Hospital for Sick Children, Great Ormond Street, London. The paediatric surgeons were Mr Herbert Eckstein and Mr Nixon. Half the infants with uncomplicated meconium ileus, 18% with a perforation and 24% with gangrene of a loop of bowel survived. Of those treated surgically 41% survived after primary anastomosis, compared with 72% after a Bishop-Koop procedure (Bishop & Koop, 1957 above). Only 25% of those with a double barrelled ileostomy survived. Only 20 of 46 survivors reached one year and only seven lived over five years – virtually all died of pulmonary complications. However, there seemed to be a steady improvement occurring as nine of the 10 most recent cases survived.
Douglas Holsclaw published extensively over subsequent years (Kaplan et al, 1968; Holsclaw et al, 1970; Holsclaw et al, 1971; Holsclaw & Keith, 1980; Holsclaw et al, 1980 all mentioned below)

 

1968 Green MN, Shwachman H. Presumptive tests for cystic fibrosis based on serum protein in meconium. Pediatrics 1968; 41:989-992. [PubMed]
An early suggestion for neonatal CF screening from detection of the increased protein in meconium, a finding which was first described by Buchanan & Rapoport, 1952 (above). Wiser & Beier, 1964 (above) had described raised albumin in the meconium of infants who did not have meconium ileus. Meconium from 49 infants with CF who were siblings of 196 people known to have CF were tested and only 4 gave a negative protein reaction (trichloracetic acid ring test and a slide agglutination test); 1600 control meconium specimens were all negative.

The test was suggested as screening test for CF with 90% reliability. The authors stated – “It is strongly recommended that mass surveys be undertaken only with accompanying facilities for the clinical investigation and treatment of the patients found”. This was very sound advice and lack of centre care for infants with CF detected eventually proved to be a main reason that a large UK Wales & West Midlands neonatal screening study in the Eighties failed to show benefit for the screened infants (Chatfield et al. 1991).

 

1968 Schutt WH, Isles TE. Protein in meconium from meconium ileus. Arch Dis Child 1968; 43:178-181. [PubMed]
A really memorable little cameo presentation by Dr Werner Schutt of Bristol at the UK Paediatric Research Society. The authors state “we have found a simple side room technique helpful in detecting the presence or absence of albumin in significant quantities in meconium”. Protein in meconium of 9 infants with meconium ileus was high at 70% compared with 9% in controls infants and 22% in other cases of neonatal obstruction.
The authors proposed, for the first time, a simple test using the Albustix, a urine dipstick test that turned blue in the presence of the albumin, to detect the increased albumin in the CF meconium. A solution of a few drops of water and a little CF meconium was mixed on a white tile, and the Albustix was laid on the tile with the tip in the solution. There was an impressive blue coloration when there was excess albumin present.
The authors observed that the test “Could provide the basis for a screening test” – which it did – the BM Meconium test! Wiser & Beier (above) were the first to describe the excessive amount of albumin in the meconium of CF infants who did not have meconium ileus (Pediatrics 1964; 33:115-118. above).

 

1969 Noblett HR. Treatment of uncomplicated meconium ileus by gastrografin enema. A preliminary report. J Pediatr Surg 1969; 4: 190-197. [PubMed]
A major milestone in the treatment of meconium ileus, the first being the surgical management described by Hiatt & Wilson in 1953 (above); then the Bishop Koop ileostomy (1957 above). This is the first reported use of diatrizoate maglumine (Gastrografin) enemas for meconium ileus. Later reported from Liverpool as effective in meconium ileus equivalent in older patients when given by mouth (O’Halloran et al, 1986 below).

 

1970 Wagget J, Johnson DG, Borns P, Bishop HC. The non-operative treatment of meconium ileus by gastrografin enema J Paediatr 1970; 77:407-411. [PubMed]
This report confirmed the successful use of gastrografin enemas in four infants with meconium ileus. Gastrografin enemas were carefully injected into the colon with a fine tube and syringe under fluoroscopic control over about 45 minutes. While there were dangers (a previous infant’s colon had perforated with use of a Foley catheter), the lack of surgical success and the very poor outlook with the current treatments were considered good reasons for trying this medical procedure (Also Wagget J, Bishop HC, Koop CE. Experience with gastrografin enema in the treatment of meconium ileus. J Pediatr Surg 1970; 5:649-654. [PubMed]).

 

1972 Cain ARR, Deall AM, Noble TC. Screening for cystic fibrosis by testing meconium for albumin. Arch Dis Child 1972; 47:131-132. [PubMed]
One of the earliest reports from the paediatricians in Newcastle and Ashington in the North of England of meconium screening using the Labstix (Ames) urine test strip for albumin as suggested by Werner Schutt et al 1968 (above). A small smear of meconium was mixed with few drops of water on a glass slide and the Labstix placed on the edge. In this study one infant with CF was detected in 6200 newborns among whom there were also 2 with meconium ileus – the expected incidence of around 1 in 2000 births.

 

1974 Prosser R, Owen H, Bull F, Parry B, Smerkinich J, Goodwin HA, Dathan J. Screening for cystic fibrosis by examination of meconium. Arch Dis Child 1974; 49:597-601. [PubMed]
Dr Prosser, a paediatrician from Newport in Wales, considered the BM Meconium screening test gave too many false negative results. In Wales 34,228 samples were examined over 4 years; 12 infants with CF were detected – only a 60% detection rate. The paper was generally quoted and accepted as showing BM meconium test was unsuitable for neonatal CF screening due to the unacceptable false negative rate. Also, at that time, the standard of treatment of most children with CF in the UK in general paediatric clinics was such that early diagnosis was of little advantage to most infants with CF in terms of long term survival.


Despite these discouraging observations, in one of the Leeds maternity units where I was responsible for the infants (St Mary’s in Leeds) we started BM screening for CF in 1975. We used the method continuously at St Marys and then at St James's, when the maternity services moved there, until a change to IRT was made in 1995. When the BM test was done in the laboratory (rather than by the overworked midwives on the wards!!) we achieved an acceptable false negative rate of only some 12% (Evans et al, 1981 below). However, the IRT test described by Crossly and Elliot in 1979 was far superior and a major advance in neonatal CF screening. (also Stephan et al, 1975 below for European experience with the BM Meconium test)

 

1975 Antonowicz I, Ishida S, Shwachman H. Studies in meconium: Disaccharidase activities in meconium from cystic fibrosis patients and controls. Pediatrics 1975; 56:782-787. [PubMed]
The enzymatic activities of disaccharidases in meconium from infants with CF and controls were found to be significantly increased in the infants with CF. The test was suggested as an alternative method for screening for CF or a method of interpreting borderline BM tests but the test did not become widely used and interest waned.

 

2000 Mak GZ, Harberg FJ, Hiatt P, Deaton A, Calhoon R. Brandt ML. T-tube ileostomy for meconium ileus: four decades of experience. J Pediatr Surg 200; 35:349-352. [PubMed]
A total of 20 of 23 patients had resolution of their meconium ileus after T-tube irrigation with n-acetylcysteine or pancreatic enzymes. Three patients required additional surgery to relieve persistent bowel obstruction. All patients had the T-tube removed within the first 8 weeks after surgery. Two patients required subsequent repair of an incisional hernia. There were otherwise no complications of this procedure, with an average follow-up of 11.5 years. In patients with uncomplicated meconium ileus unrelieved by contrast enema, the T-tube ileostomy is an effective and safe treatment.

Extensive experience of this technique used at Texas Children's Hospital since 1959.

 

2004 Li Z. Lai HJ. Kosorok MR. Laxova A. Rock MJ. Splaingard ML. Farrell PM. Longitudinal pulmonary status of cystic fibrosis children with meconium ileus. Pediatr Pulmonol 2004; 38:277-284. [PubMed]
The authors prospectively compared from diagnosis to 12 years of age 32 CF children with MI to 50 CF children without MI who were diagnosed during early infancy through neonatal screening. MI children showed significantly worse forced expiratory volume in 1 sec (FEV(1)), forced vital capacity (FVC), forced expiratory flow between 25-75% of FVC (FEF(25-75)), % predicted FEV(1), % predicted FEF(25-75), and total lung capacity (TLC). These differences were particularly apparent beginning at age 8-10 years. In conclusion, MI children have worse lung function and more obstructive lung disease than those without MI. Such abnormalities are accompanied by reduced lung volume. MI is a distinct CF phenotype with more severe pulmonary dysfunction.

 

2012 Carlyle BE, Borowitz DS, Glick PL. A review of pathophysiology and management of fetuses and neonates with meconium ileus for the pediatric surgeon.  J Pediatr Surg 2012; 47:772-781. [PubMed]
Meconium ileus is primarily associated with CF transmembrane (conductance) regulator mutations F508del, G542X, W1282X, R553X, and G551D, and modifier genes have been found to explain approximately 17% of the phenotypic variability. Mouse, pig, and ferret models for CF demonstrate neonatal bowel obstruction mimicking MI. Sonographic findings of hyperechoic masses and dilated bowel in a high-risk fetus are suggestive of MI. Less than 7% of low-risk fetuses with hyperechoic bowel will have MI. Contemporary series of noninvasive management with Gastrografin enema report success rates of 36% to 39%, significantly lower than historical values. The optimal surgical technique remains controversial, although primary anastomosis results in surgical complication rates between 21% and 31%, higher than those noted with delayed anastomosis. Pulmonary function for patients with CF and MI at 15 and 25 years old is similar to those without MI, although height and weight percentiles may be lower.

This review for pediatric surgeons presents an examination of the literature and synthesizes current information about the pathophysiology, prenatal diagnosis, non operative and operative management, postoperative management, and prognosis of the patient with CF and MI.