Cystic Fibrosis – A journey through time from the Middle Ages to the modern era

Cystic fibrosis (CF) is a life-threatening, progressive, inherited condition that causes severe damage to the body, mainly to organs of the respiratory and digestive system. It is estimated that more than 70,000 people worldwide have CF, with the average life expectancy being 44.4 years [1].

Cause and symptoms of cystic fibrosis

CF is caused by cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations [2, 3]. There are more than 2000 different mutations that can cause CF. These mutations affect the movement of salt and water in and out of the cells responsible for producing sweat, mucus, and digestive fluids. Normally, these fluids are thin and slippery, whereas, in people with CF, these fluids are thick and sticky — clogging ducts, tubes, and passageways in the body, affecting the lungs, pancreas, liver, intestines, and digestive system. People with CF experience multiple symptoms that vary depending on the severity of the disease. Some people are asymptomatic or experience mild symptoms until adolescence or adulthood. Symptoms might include salty sweat, frequent chest infections that could lead to respiratory failure, cough, shortness of breath, malnutrition, and exercise intolerance. Other CF-related diseases include male infertility, diabetes, liver, and bone disease.

Diagnosis and treatment of cystic fibrosis

CF is an autosomal recessive disease, meaning two copies of the affected gene are needed ­– one from each parent – to inherit the disease. Even if the parents do not have CF themselves, they could be carriers of the disease. Being a carrier means that someone has one copy of the genetic mutation. There is an estimation that 1 in 26 people are carriers of a CF-causing mutation, regardless of ethnicity [4]. Because of its prevalence, carrier screening, a genetic test that informs individuals whether they carry a gene for a certain genetic condition such as CF, is recommended for every couple considering pregnancy by international organizations such as the American College of Obstetricians and Gynecologists and the American College of Medical Genetics [5]. Additionally, most countries with a high prevalence of CF include the most common mutations of the CFTR gene in their newborn screening tests. Alternatively, CF can be diagnosed at any age with a sweat chloride test or a genetic test [6].

Unfortunately, there is no cure for CF, but there are some treatment options that can ease the symptoms and limit complications. Amongst the currently most used CF treatments are antibiotics to prevent infections, anti-inflammatory medications to lessen swelling and clear the airways, inhaled mucus-thinning drugs, medication to reduce the mucus in the body, and pancreatic enzyme supplements. A personalized fitness plan can also help people with CF increase their energy levels and lung function and a personalized dietary plan can help them avoid malnutrition [3]. In some serious cases of malnutrition, a feeding tube may be placed to increase calorie intake. For people experiencing more severe symptoms, treatment options include several surgical interventions such as bowel surgery to treat bowel blockages. Liver, pancreas, and lung transplants can be considered when severe CF-related diseases affect these organs.

Cystic fibrosis through the centuries

CF has been a challenge to understand since before the disorder was named. CF has been burdening people, especially children, since the Middle Ages, but it wasn’t until 1938 that the disease was given a name and was properly identified, which opened the door to characterizing it and finally coming up with ways of treating it. Below is a brief travel through time with important milestones that led to the discovery, better understanding, and improved treatment of CF.

B.C.: Cystic fibrosis in the Middle Ages

• CF references can be traced back to the Middle Ages. In medieval Europe, children who had CF symptoms were believed to be victims of witchcraft or cursed, and were condemned to die [7].

15^th-18^th century: First mentions of “bewitched” children in literature

• The curse became folklore and was immortalized in an Irish expression sometime in the 15^th century: “Woe to the child who tastes salty from a kiss on the brow, for he is cursed and soon will die”.

• It wasn’t until 1606 that a reference to CF appeared in a book. Written by medical professor Juan Alonso de Fontecha of the University of Alcalá de Henares in Spain, it stated: “When rubbing the forehead of the “bewitched” children, your fingers will taste salty” [8].

• The first believed accurate medical description of CF was made around 1595 by Pieter Pauw, a professor of botany and anatomy at Leiden University, in the Netherlands. Professor Pauw performed an autopsy on a “bewitched” girl and described in detail his findings, which included a “shinny pancreas” with cirrhosis, amongst others. He attributed the death to the pancreas but all his observations led to CF, which was still unknown at the time.

• The second medical description was in 1673 by Georg Seger who was treating a 3-year-old girl presenting with symptoms of CF in Poland. Later, an autopsy was performed on the girl by surgeon Bartholomaus Taubenheim, who also reported severe damage to the pancreas.

• A few years later, in 1677, a third case was published in a book by a professor of medicine in Amsterdam, Gerardus Leonardus Blasius, where he reported in detail the presence of a cirrhotic pancreas of an autopsy he performed on a young boy [9].

• In 1752, a Swiss anatomist and naturalist named Nils Rosen von Rosenstein published a book that consisted of various cases of pediatric diseases he had seen. In the same book, he mentions 12 different cases of children presenting symptoms of CF, which include delayed growth and swollen hands and abdomen. All children had a hardened pancreas during autopsy and he gave the disease the name “fluxus coeliacus”.

19^th century

• In 1835, pathologist Carl von Rokitansky performed a fetal autopsy and discovered intestinal perforation and meconium, the earliest stool of an infant, in the membrane that lines the abdominal cavity [10]. This is believed to be the first ever reported case of meconium ileus, a bowel obstruction that occurs when the meconium is thicker and stickier than normal which subsequently blocks the ileum, a part of the small intestine. The vast majority of infants with meconium ileus have CF and it is now considered to be a pathognomic symptom of CF [11].

• The second reported case of meconium ileus was reported in 1850 in Vienna by pediatrician Alois Bednar, while he was performing an autopsy on a newborn [9].

• In 1849, Frédéric Chopin, a famous Polish composer and pianist, died in Paris with the suspected cause of death being tuberculosis [12]. At the time of his death, he was treated by Dr. Jean Cruveilhier who was considered a specialist in tuberculosis and pathology. Even though Dr. Cruveilhier stated “tuberculosis of the lungs and larynx” on Chopin’s death certificate, he noted in other records that his death was caused by a disease not previously encountered. With today’s knowledge about CF, many signs including family history and childhood symptoms point towards a genetic disease, specifically CF. Chopin had two sisters who both died prematurely exhibiting the same symptoms as Chopin, such as respiratory problems, recurrent gastrointestinal disturbances, fatigue, delayed development, and food intolerance.

20^th century: The era of developments

• In 1936, pediatrician Guido Fanconi von Grebel published an article describing the disorder where, for the first time, the term “cystic fibrosis” was used [13]. In addition to using the term “cystic fibrosis” first, Dr Fanconi made significant contributions to medicine through his accurate descriptions of many disorders, with the most notable one being Fanconi anemia which bears his name [30].

• In 1938, pathologist Dr. Dorothy Andersen published a paper where she coined the term “cystic fibrosis of the pancreas”. In her article, she went on to describe in detail the symptoms of the disease, along with the histology of the pancreas, and distinguished CF from other diseases that presented similar symptoms, such as celiac disease [14]. Her article earned her a place in medical history as the person who discovered CF and opened the door for proper research on this unknown disease, which was finally differentiated and officially named.

• In 1946 Dr. Dorothy Andersen co-published another paper with Dr. Richard G. Hodges concluding that CF is a genetic disease and suggesting an autosomal recessive inheritance pattern, based on evidence [15]. In the same year, penicillin and synthetic antibiotics were used to treat CF patients with repetitive respiratory infections. The study was published by Dr. Dorothy Andersen and Dr. Paul di Sant’Agnese but the findings did not have the expected results [16].

• In 1948, during a heatwave in New York, Dr. Paul di Sant’Agnese noticed that his CF patients were notably losing salt in their sweat and published a paper on these sweat abnormalities. This observation was also the first time CF was correlated with salty sweat despite the folklore about salty kisses. The paper of Dr. Paul di Sant’Agnese is considered a milestone in CF history as his technique for measuring salt loss opened the door for the development of the sweat test in 1959 by Gibson and Cooke. This accessible and accurate method for diagnosing CF is still used today [17].

• In 1958, Canadian doctor Douglas N. Crozier went against standard dietary suggestions of the time and discovered that when giving his patients a fat-rich diet and supplementing with high doses of pancreatic enzymes, he could improve nutritional status and lengthen survival. This was considered yet another big breakthrough but his results were not published until 1974 [18]. Following the publication of his results, the dietary criteria of the time completely changed and further studies commenced to improve the nutritional supplementation with pancreatic enzymes. One of the major changes that followed was the size of the supplement capsules. Microspheres with an acid-resistant coat replaced large capsules. The coat prevented the capsule from being dissolved in the stomach, allowing it to reach the intestines before activation, increasing its effectiveness and improving the nutritional status of the patients with the use of a smaller dose. [19].

• In 1981, Dr. Michael Knowles presented his findings on abnormal epithelial function [20] helping Professor Paul Quinton to research further the sweat ducts of people with CF and finally explain the altered mucus viscosity seen with the disorder [21].

• In 1989, the gene responsible for causing CF, CFTR, was discovered and mapped. CFTR was the first disease-causing gene to be identified, which highlights the critical impact the disorder held [22]. The linking of the CFTR gene to the disorder was one of the most significant breakthroughs in the field of human genetics and the driving force that led to the decision to map the entire genome. This discovery led to a major improvement in the diagnosis of CF as an accurate, definite, and prompt way of diagnosing CF was finally introduced, sparing children the diagnostic struggle while suffering irreversible symptoms [23].

• By 1991, some countries had already started implementing routine newborn CF screening programs even though many organizations had concerns about whether the benefits outweighed any potential harm such as over-treatment with antibiotics to presymptomatic patients [24].

• In 1993, the first attempt to use adenovirus-mediated gene transfer as a treatment was performed and showed promising results by correcting the defect in the epithelial airway, a characteristic of CF [25]. This milestone study would eventually open the door to gene therapy treatment, a technique that aims to repair or reconstruct mutated genes, in patients with CF.

21^st century: The era of treatment breakthroughs

Organizations such as the European Cystic Fibrosis Society (ECFS) have established clinical trial networks for a collaborative approach to coordinate a more worldwide research between major, as well as minor, CF centers for the benefit of all CF patients [26]. Since the discovery of the CFTR gene, over 2000 mutations causing CF have been identified, which are divided into categories based on the impact they impose on the function of the CFTR gene. The severity and symptoms of CF can vary greatly depending on the CF-causing mutation or the combination of mutations. CF patients who perform comprehensive genetic testing for all or most known CFTR mutations can have more options and guided treatment based on the latest guidelines.

Gene therapy has been the most promising research for finding a cure for CF [27]. Gene therapy for CF will not be able to fix any organ damage that has already happened but could reduce the symptoms, prevent any further damage, and improve the quality of life of an individual with CF. The earlier CF is diagnosed, which nowadays can be achieved even prenatally, the earlier gene therapy can be implemented, which could result in a better prognosis for the affected person. There are two potential gene therapy methods to treat CF. The first one is the non-integrating method that delivers a piece of DNA with a correct copy of the CFTR gene to an affected person’s cell. This is not a permanent solution, thus it will need to be repeated once every few months, but it has limited side effects and assists in providing the missing information to create normal CFTR protein. The second gene therapy method is integrating gene therapy that delivers a piece of DNA with a correct version of the CFTR gene to an affected person’s cell to be integrated with their genome, “repairing” the CF-causing mutation. This method, even though it has a permanent effect, can have significant side effects such as an increased risk of cancer. Scientists are working to perfect this method and make it a safe cure for CF.

Conclusion

The path to treating and curing CF is an evolving journey with many challenges. Even decades ago, most children with CF did not survive into adulthood. Advancements in medicine since the second half of the 20^th century have enabled people with CF to live into their 40s and beyond, managing for the first time to lift the number of adults living with CF higher than the number of children living with CF [28]. CF is a disease that brought the scientific world together, and many institutions and research centers around the world continue to work to advance their knowledge of a disease that was once considered a curse, to discover new and ambitious perspectives for innovative drug development and treatment options, and to improve the prognosis and quality of life of affected individuals.

References

[1] Dickinson, Kimberly M., & Joseph M. Collaco “Cystic fibrosis.” Pediatrics in Review, vol. 42, no. 2, 1 Feb. 2021, pp. 55–67. https://doi.org/10.1542/pir.2019-0212.

[2] National Heart, Lung, and Blood Institute. “Cystic Fibrosis – Causes.” www.nhlbi.nih.gov, 21 Nov. 2023, https://www.nhlbi.nih.gov/health/cystic-fibrosis/causes.

[3] Cystic Fibrosis Foundation. “About cystic fibrosis.” Cystic Fibrosis Foundation, 2022, https://www.cff.org/intro-cf/about-cystic-fibrosis

[4] Westemeyer, Maggie et al. “Clinical experience with carrier screening in a general population: support for a comprehensive pan-ethnic approach.” Genetics in Medicine 22, 1320–1328 (2020). https://doi.org/10.1038/s41436-020-0807-4.

[5] Deignan, Joshua. L et al. (2023). “Updated recommendations for CFTR carrier screening: A position statement of the American College of Medical Genetics and Genomics (ACMG).” Genetics in Medicine, 25(8), 100867. https://doi.org/10.1016/j.gim.2023.100867.

[6] National Heart, Lung and Blood Institute. “Cystic fibrosis Diagnosis.” www.nhlbi.nih.gov, 21 Nov. 2023, https://www.nhlbi.nih.gov/health/cystic-fibrosis/diagnosis.

[7] Yu, Elaine and Sandeep Sharma. “Cystic Fibrosis.” StatPearls, StatPearls Publishing, 8 Aug. 2022. PMID: 29630258. https://pubmed.ncbi.nlm.nih.gov/29630258/.

[8] Quinton Paul M. “Physiological basis of cystic fibrosis: a historical perspective.” Physiological Reviews, 1999 Jan;79(1 Suppl):S3-S22. doi: 10.1152/physrev.1999.79.1.S3. PMID: 9922374. https://journals.physiology.org/doi/full/10.1152/physrev.1999.79.1.S3.

[9] Navarro, Salvador. (2016). “Historical compilation of cystic fibrosis.” Gastroenterología Y HepatologíA, 39(1), 36–42. https://doi.org/10.1016/j.gastre.2015.12.006

[10] Ortega, Maria. Moreno., et al. (2021) “Diving into Cystic Fibrosis History: Major Milestones”. EC Pulmonology and Respiratory Medicine, 10.8: 55-60. https://ecronicon.net/assets/ecprm/pdf/ECPRM-10-00844.pdf.

[11] “Meconium Ileus.”  Seattle Children’s Hospital. https://www.seattlechildrens.org/conditions/meconium-ileus/

[12] Majka, Lucyna et al. “Cystic fibrosis–a probable cause of Frédéric Chopin’s suffering and death.” Journal of Applied Genetics, vol. 44,1 (2003): 77-84. https://pubmed.ncbi.nlm.nih.gov/12590184/.

[13] Barben, Jürg. “First description of cystic fibrosis.” Journal of Cystic Fibrosis, 20(1), (2021) 183. https://doi.org/10.1016/j.jcf.2020.08.008.

[14] Lopez, Mari Arini. “History of cystic fibrosis.” Rare Disease Advisor, Jan. 2022, https://www.rarediseaseadvisor.com/hcp-resource/history-of-cystic-fibrosis/

[15] Andersen, Dorothy H. and Richard, G. Hodges (1946). “Celiac syndrome. V. Genetics of cystic fibrosis of the pancreas with a consideration of etiology.” American Journal of Diseases of Children, 72(1), 62-80. https://doi.org/10.1001/archpedi.1946.02020300069004.

[16] Di Sant’agnese, P. E. A., and D. H. Andersen “Celiac syndrome; chemotherapy in infections of the respiratory tract associated with cystic fibrosis of the pancreas; observations with penicillin and drugs of the sulfonamide group, with special reference to penicillin aerosol.” American journal of diseases of children, (1911) vol. 72 (1946): 17-61. https://pubmed.ncbi.nlm.nih.gov/20994054/.

[17] Chernick, Victor. (1998). “Test for the concentration of electrolytes in cystic fibrosis of the pancreas utilizing pilocarpine by iontophoresis, by Lewis E. Gibson and Robert E. Cooke, Pediatrics; 1959;24:545–549.” Pediatrics (1998) 102 (Supplement_1): 230–231. https://doi.org/10.1542/peds.102.s1.230.

[18] Crozier, D. N. (1974). “Cystic fibrosis: a not-so-fatal disease.” Pediatric Clinics of North America, 21(4), 935–950. https://doi.org/10.1016/s0031-3955(16)33069-3.

[19] Brady, Mary, Sue, et al. (1992). “Effectiveness of entertic coated pancreatic enzymes given before meals in reducing steatorrhea in children with cystic fibrosis.” Journal of the American Dietetic Association, 92(7), 813–817. https://doi.org/10.1016/s0002-8223(21)00735-5.

[20] Knowles, M., et al. “Increased bioelectric potential difference across respiratory epithelia in cystic fibrosis.” The New England Journal of Medicine, vol. 305,25 (1981): 1489-95. doi: 10.1056/NEJM198112173052502. PMID: 7300874. https://www.nejm.org/doi/10.1056/NEJM198112173052502?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed.

[21] Quinton, P. M. “Chloride impermeability in cystic fibrosis.” Nature, vol. 301,5899 (1983): 421-2. doi:10.1038/301421a0, https://www.nature.com/articles/301421a0.

[22] Tsui, L-C. et al., “Cystic fibrosis: analysis of linkage of the disease locus to red cell and plasma protein markers.” Cytogenetics and Cell Genetics, (1985) 39 (3): 238–239, https://doi.org/10.1159/000132144

[23] Farrell, Philip. M., et al. (2020). “The impact of the CFTR gene discovery on cystic fibrosis diagnosis, counseling, and preventive therapy.” Genes, 11(4), 401. https://doi.org/10.3390/genes11040401, https://www.mdpi.com/2073-4425/11/4/401.

[24] Farrell, Philip. M., et al. (2005). “Evidence on Improved Outcomes with Early Diagnosis of Cystic Fibrosis Through Neonatal Screening: Enough is Enough!” The Journal of Pediatrics, 147(3), S30–S36. https://doi.org/10.1016/j.jpeds.2005.08.012.

[25] Zabner, Joseph., et al. (1993). “Adenovirus-mediated gene transfer transiently corrects the chloride transport defect in nasal epithelia of patients with cystic fibrosis.” Cell, 75(2), 207–216. https://doi.org/10.1016/0092-8674(93)80063-k.

[26] Addy, Charlotte, et al. (2015). “Improvements in symptomatic treatment strategies for cystic fibrosis: delivering CF care in the 21st century.” Expert Opinion on Orphan Drugs, 4(1), 5–19, doi:10.1517/21678707.2016.1107473,

[27] Cystic Fibrosis Foundation. “Gene therapy for cystic fibrosis.” Cystic Fibrosis Foundation, www.cff.org, 2023, https://www.cff.org/Research/Research-Into-the-Disease/Restore-CFTR-Function/Gene-Therapy-for-Cystic-Fibrosis/.

[28] “How long do patients with cystic fibrosis live?” cystic-fibrosis.com, 30 Jul. 2019, retrieved May 8, 2024, from https://cystic-fibrosis.com/life-expectancy.

[29] Russo, Melissa, L. “Cystic fibrosis: Carrier screening.” UpToDate, retrieved May 13, 2024, from https://www.uptodate.com/contents/cystic-fibrosis-carrier-screening.  

[30] Fresquet, José L. “Guido Fanconi (1892-1979).” Historia De La Medicina [In Spanish]. Feb. 2024, retrieved May 15, 2024, from https://www.historiadelamedicina.org/fanconi.html.