Cystic Fibrosis (CF)


Pre-1930s

The very first description of a possible cystic fibrosis (CF) case was found in the medical literature in 1595 following the autopsy of a supposedly “bewitched” 11-year-old girl who had a “swollen hardened gleaming white pancreas” according to Pieter Pauw, Professor of Botany and Anatomy at Leiden (1564-1617).1 

Delving further back into history, Busch places the advent of CF around 3000 BC, listing migration, gene mutations, and changes in nutrition as potential causes. He describes a ceremonial tradition of licking the foreheads of newborns and children crosswise to ascertain if there was a salty taste present. In medieval times, an infant with a salty brow was labeled as “fascinated” or “bewitched,” meaning the child was cursed by witches, and they were doomed to die presumably soon.1-3 The folklore of this tradition was later captured in a quote by Rochholz found in the Almanac of Children’s Songs and Games from Switzerland, stating, “The child will soon die whose brow tastes salty when kissed.”1

In 1838, von Rokitansky detailed autopsy results from a premature infant with meconium ileus, leading to meconium peritonitis and ileal perforation.1 Landsteiner made the connection between CF and meconium ileus when he described pancreatic lesions in an infant diagnosed with meconium ileus.1

In 1888, the English physician, Dr. Samuel Gee, first described celiac disorder, a syndrome characterized by diarrhea, abdominal distention, malabsorption, slowed growth, and pale stools.1,4 Gluten was not identified as the causative factor of celiac disease until 1950; therefore, Gee described a similarity in symptoms between celiac disease and CF, detailing histological changes in the pancreas and lungs in several autopsied infants.1,4 

The 1930s

In the 1930s, several scientists published research on diseases that aligned with the characteristics of CF.1 Margaret Harper in Sydney, Australia studied congenital pancreatic steatorrhea and described 8 children who possibly had CF contributing to the condition based on clinical characteristics, 4 of whom demonstrated the typical pancreatic changes on autopsy.1,5

Blackfan and Wolbach denoted histological pancreatic lesions in 6 of 11 children with vitamin A deficiency. These lesions, characterized by “dilatation of the acini and ducts, inspissated secretion, atrophy of the acini, lymphoid and leukocytes infiltration to some degree and fibrosis,” were identical in all 6 cases, prompting Blackfan and Wolbach to suspect a separate “disease entity.”1,6

In 1936, Fanconi wrote about 2 children with celiac syndrome who had profound changes in the lungs and pancreas, confirming the associations made by Dr. Gee back in 1888.1

In 1938, Blackfan and May presented a case study of 35 infants with pancreatic lesions who also developed chronic lung infections.1,7

Cystic fibrosis was not recognized as a specific disease entity until it was described in the literature in 1938 by pathologist, Dr. Dorothy Andersen, as “cystic fibrosis of the pancreas” following examination of the autopsy findings of 49 children who died from malnutrition with a diagnosis of celiac disease.1,8 Twenty of these children were autopsied at her hospital, the Babies’ and Children’s Hospital at Columbia Presbyterian Medical Center in New York, while the remaining children were either autopsied by her colleagues or their autopsy results were already published in the literature.1 

Dr. Andersen identified histological abnormalities of the pancreas in these children that contributed to the CF disease process, including neonatal intestinal obstruction, respiratory complications, and other characteristics that defined CF as its own disease entity separate from celiac disease. She hypothesized that severe intestinal malabsorption caused pancreatic epithelial metaplasia, which explained the vitamin A deficiency found in 14 of the 49 infants. According to Dr. Andersen, this vitamin A deficiency increased the likelihood of developing respiratory illnesses and bronchiectasis.1 

Post-1930s

Following Dr. Andersen’s publication, researchers noted the genetic incidence of CF in families, prompting the discovery of a Mendelian autosomal recessive mode of inheritance for the disorder.1,9

Another pathologist, Dr. Sidney Farber, who worked at the Children’s Hospital in Boston, made the discovery that CF was a multiorgan disorder, coining the term “mucoviscidosis” in which thickened mucus impacts the pancreas as well as other organs. He stated, “The inspissation of altered secretions in the pancreatic acini is only a part of a generalized disorder of secretory mechanisms involving many glandular structures but exerting its greatest effect on the pancreas.”1,10

During an extreme heat wave in the summer of 1948, Dr. Paul di Sant’Agnese made an important observation among dehydrated children seeking medical care in a New York City emergency room that those with CF had abnormally low serum chloride values. He investigated his observation further in 1952, demonstrating that 2 teenagers with CF had significantly higher concentrations of salt in their sweat than controls.1,8 Dr. di Sant’Agnese also made the discovery that sulphadiazine and nebulized penicillin quickly assisted the recovery of children with CF who experienced life-threatening chronic pulmonary infections. Since this discovery, antibiotic use has become the foundational treatment in those with CF who have respiratory illnesses, and Dr. di Sant’Agnese is credited with advancing the treatment of CF.1

Following Dr. di Sant’Agnese’s discovery in 1952, researchers identified a sweat electrolyte defect in 1953. Diagnosing CF became easier with the standardized acceptance of the sweat test in 1959; however, this challenged the belief that CF was only a disorder of the mucus.11

This suspicion was later confirmed in 1983 when scientists determined that a defect in the chloride transport chain in conjunction with sodium reabsorption caused CF. In 1989, researchers discovered the genetic link to CF when gene sequencing identified defects in the CFTR gene, producing an abnormal cAMP chloride channel protein that contributes to the disruption of the chloride transport chain.11

References

  1. Littlewood JM. History of cystic fibrosis. In: Hodson M, Bush A, Geddes D, eds. Cystic Fibrosis. 3rd ed. Boca Raton, FL: CRC Press; 2007:3-19.
  2. Busch R. On the history of cystic fibrosis. Acta Univ Carol Med (Praha). 1990;36(1-4):13-15.
  3. Yu E, Sharma S. Cystic fibrosis. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2021. Accessed January 4, 2022.
  4. Lavrova TE. Klinicheskaia kartina tseliakii u deteĭ [Clinical picture of celiac disease in children]. Eksp Klin Gastroenterol. 2003;(6):40-45, 153. Russian.
  5. Harper MH. Congenital steatorrhoea due to pancreatic defect. Arch Dis Child. 1938;13(73):45-56. doi:10.1136/adc.13.73.45
  6. Blackfan KD, Wolbach SB. Vitamin A deficiency in infants: a clinical and pathological study. J Pediatr. 1933;3(5):679-706. doi:10.1016/S0022-3476(33)80022-9
  7. Blackfan KD, May CD. Inspissation of secretion, dilatation of the ducts and acini, atrophy and fibrosis of the pancreas in infants: a clinical note. J Pediatr. 1938;13(5):627-634. doi:10.1016/S0022-3476(38)80155-4
  8. Cystic fibrosis: history. National Jewish Health. Accessed January 4, 2022. 
  9. Andersen DH, Hodges RG. Celiac syndrome: genetics of cystic fibrosis of the pancreas, with a consideration of etiology. Am J Dis Child. 1946;72:62-80. doi:10.1001/archpedi.1946.02020300069004
  10. Farber S. Pancreatic insufficiency and the celiac syndrome. N Engl J Med. 1943;229(17):653-657. doi:10.1056/NEJM194310212291705
  11. Davis PB. Cystic fibrosis since 1938. Am J Respir Crit Care Med. 2006;173(5):475-482. doi:10.1164/rccm.200505-840OE

Reviewed by Hasan Avcu. MD, on 1/5/2022.

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