Cystic fibrosis (mucus and viscosity) or cystic fibrosis of the pancreas, is a genetic disease affecting all organs bear a glandular epithelium. That is a lethal genetic disease autosomal recessive most common in populations europoïde type, then it is very rare in African and Asian populations. It is linked to mutations in the CFTR gene on chromosome 7, resulting in a deterioration of the CFTR (acronym for cystic fibrosis transmembrane conductance regulator). It is an ion channel permeable to the chlorine whose function is to regulate the transportation of chlorine through cell membranes. His failure causes an increase in the viscosity of mucus and its accumulation in the respiratory and digestive tracts. The disease affects many organs, but attacks are predominant respiratory and represent the bulk of the disease. The clinical form most frequently associated respiratory disorders, digestive disorders and growth staturopondérale. D'chronic and progressive disease often expressed early from infancy even though there are crude forms of late diagnosis.
The diagnosis is based on the sweat test confirmed by identification of genetic mutations. The neonatal screening, widespread in France since 2002 allows a diagnosis and early management while genetic counseling allows a couple heterozygous known not to have another child sick. There is no cure, but advances in care have improved the quality and life expectancy of patients, and in France, life expectancy at birth is gone 7 years in 1965 to 47 years in 2005.
Known since the Middle Ages, the disease is scientifically described by the Swiss pediatrician Guido Fanconi in 1936. It is identified two years later by Dorothy Hansine Andersen as an entity pathological reaching the pancreas hence its historical name of cystic fibrosis of the pancreas. It retains that name in English: cystic fibrosis.
History of the description of the disease
Cystic fibrosis, scientifically described as a disease in 1936, was in fact already known for a long time. In the Middle Ages we knew the disastrous fate of the newborn whose mother noticed the "kiss salty," ie the salty taste left by a kiss on the forehead of children. Welsh cites an old adage folklore of Northern Europe: "Woe to the child in whom a kiss on the forehead has a salty taste. He is bewitched and soon must die. ". In 1606, the Spanish doctor Alonso y de los Ruyzes of Fonteca reported that the fingers moved on the foreheads of children bewitched have a salty taste. Rochholz in his almanac of 1857 wrote "The child died soon embraced whose front is salty. "According Busch One of the first medical descriptions of injuries encountered in pancreatic cystic fibrosis could be an autopsy report done by Professor Pieter Pauw, in Leiden in the Netherlands in 1595, in which he describes a patient miserable 11 years and assumed spell with a pancreas expanded, hard and white.
In the nineteenth century Viennese doctor Karel Rokitansky said in a fetus fatal case of peritonitis méconiale, which was later identified as a complication of ileus méconial, intestinal obstruction neonatal present in some children mucoviscidosiques described in 1905 by Landsteiner.
At the beginning of the twentieth century appear to be the first observations involving pulmonary disease, diarrhea and pancreatic anomaly with several cases in the same family. In 1912, Garrod describes families whose children are diarrhea and die fat lung infection. These descriptions focus mostly on digestive problems, steatorrhea and pancreatic disorders, and their authors are a form of celiac disease even if lung problems were also noted.
In 1936, in a thesis written in German and chaired by the Swiss pediatrician Guido Fanconi, that the disease was first described in children with suspected celiac disease, known as the "cystic fibrosis of the pancreas and bronchiectasis ". The CF was considered a distinct disease entity in 1938 by the American pediatrician Dorothy Hansine Andersen, a doctor at Babies' Hospital in New York, who published an article titled "Cystic fibrosis of the pancreas and its relations with celiac disease. In carrying out autopsies on infants she described the clinical and histologic characteristics of the disease, including neonatal intestinal obstruction, respiratory and digestive complications and specific histological lesions of the pancreas. It linked the disease to a deficiency in vitamin A and persisted to support this theory for many years although it did was never confirmed.
The term mucoviscidosis, created from the words "mucus" and "viscous" was first used in 1943 by Dr. Sydney Farber, head physician at Children's Hospital Boston, to correct the name used by Dorothy Andersen, focusing on the pancreas. Farber was convinced that the disease was due to a widespread viscous mucus. The term mucoviscidosis still widely used throughout the world, and particularly in France, and is sometimes preferred the English term cystic fibrosis.
The hereditary nature and mode of transmission recessive were suggested in 1945 by Dorothy Andersen and Hodges.
In the wake of a heat wave resulting in a state of prostration young patients at the Columbia hospital in New York in 1948 that Dr. Paul di Sant 'Agnese discovered in 1953 and describes electrolyte abnormalities in the sweat of patients (significant increase in chlorine, sodium and potassium less marked), to consider a specific diagnosis for the disease: the sweat test. Until then, the diagnosis could not be done before the combination of clinical signs and symptoms suggestive of pancreatic insufficiency and intestinal malabsorption. For decades the thermal stimulation has been used, during which children were entirely wrapped in bandages to stimulate sweating. The collection of sweat was performed using blotters. About the realisation difficult, the technique was later simplified by the method of iontophoresis the pilocarpine described in 1959 by Gibson and Cooke, then improved by Shwachman and standardized in children by Legrys. The sweat test became and remains to this day the most reliable test for diagnosis, apart from the genetic analysis that was not available until much later.
This is the beginning of 1980 that the pathophysiologic link was made between on the one hand the anomaly of the secretion of mucus, causing obstructions with glandular abnormalities histological and secondly the anomaly of sweat, resulting in secretions salt without histological abnormality. In 1981, Knowles et al. Discovered that the electric potential in the nasal mucosa of patients mucoviscidosiques were more electronegative than among healthy subjects, which they explained by a massive reabsorption of sodium leading to dehydration to the surface the epithelium. This discovery was the physiological link between the lungs, pancreas and sweat glands. The common link explaining the achievement of various organs was not the mucus itself, but electrolyte abnormalities. In 1983 Quinton, itself suffering from cystic fibrosis, showed that the chlorine impermeability he had found in sweat glands was the cause of the increase in electrolytes in the sweat. This was seen as a major step in understanding the disease.
It remained to locate and identify the gene whose mutation causes cystic fibrosis, a task made difficult because only the clinical symptoms, mode of transmission autosomal recessive and the anomaly of transporting chlorine was then known. In the absence of any knowledge about the defective protein, and thus chemical marker identified, the recent technical positional cloning - or reverse genetics, which identifies a gene without knowing the protein for which it encodes, was used. The method involves using statistical analyses of genetic linkage to determine the region of chromosome where the gene has a high probability of finding to the sequencing and study the genes expressed. The gene for cystic fibrosis is the first gene to be cloned only by analysis of bonds.
In 1985, Eiberg et al. Found a link between the enzyme paraoxinase (PON) and the CF gene by studying families with more than one child reaches. The same year, Tsui et al. Following studies on mice hybrids, located the gene on the long arm of chromosome 7 with a marker RLFP linked to both paraoxinase and cystic fibrosis.
In 1989, the gene involved in cystic fibrosis is isolated by teams Tsui Lap-Chi, Collins and Riordan. The genetic defect behind the disease is finally discovered, it is a mutation of a gene located on 7q31 and containing 27 exons, called cystic fibrosis (CF) encodes a protein called the cystic fibrosis transmembrane transmenbrane conductance regulator (CFTR), composed of amino acids 1480. This is just a little later they brought evidence that CFTR was indeed a canal chlorine. The discovery of the genetic abnormality permit thereafter adding genotyping protocol diagnosis, and consider therapy.
History of the assumption of the disease
In the years 1940, the disease was regarded as primarily a problem with a nutritional deficiency in vitamin A. The assumption is summarized mainly to a diet rich in proteins, intramuscular injections of vitamin A in high doses, extracts pancreatic and inhalation of penicillin. In 1945, Dorothy Andersen advises "a diet low in fat, rich in protein, with a free vegetables, fruits and sugar and starchy foods in moderate restriction. A supplementation of vitamin A is essential and complex pancreatic and vitamin B are added. ". She said that the diet must be started early to be effective. At that time the survival time is short, 64% of 28 patients in a series of the Mayo Clinic below the age of 7. The first antibacterial drugs, a sulfamidé marketed under the name of Prontosil, was available in 1934 and penicillin injectable form in 1944. Other antibiotics followed and eurrent a key role in the treatment of patients. To this date, the main pathogen was Staphylococcus aureus strains, and many were still sensitive to penicillin. In 1946 Di Sant Agnese and D. Andersen wrote that improving the prognosis during this decade is due to "an appropriate regime started quickly and continued on an ongoing basis, the use of sulphadiazine during the period of chronic cough and inhalation of penicillin. ".
In 1950, the plight of children affected is still regarded as hopeless but a few specialized centers in the care of CF see the day the USA and the UK. The drainage posture is then a traditional treatment of bronchiectasis the stage and in 1950 Young proposes to begin the diagnosis. The effect of bronchodilateurs is described in 1959. In 1955 Shwachman describes in detail a method of care which lays the foundations of modern processing: early diagnosis, treatment and active early lung infection and monitoring and maintaining the nutritional status. During this decade, other antibiotics are emerging. In 1951, while the Staphylococcus aureus bacterium is usually found, we note the increased frequency of Pseudomonas aeruginosa, attributed to prolonged antibiotic treatment, however, the benefit of aggressive antibiotic treatment is gradually becoming evident. In 1952 Shwachman reported the emergence of resistance of S. aureus and the terramycine writing that the aerosol penicillin and streptomycin are useful. In 1958 Shwachman Kulczycki and publish the first article summary from a large specialist centre in which they describe their clinical classification system and noted an improvement in the prognosis of children suffering and increased the frequency of survival to age adult. The mortality of children sick with an ileus méconial is then still above 50% but was greatly improved by a surgical method of ileostomy described in 1957 by Bishop and Koop. In 1955 that the objective evidence of the effectiveness of treatment with pancreatic enzymes is made by the team of Norman London.
In the years 1960, the creation of national organizations devoted to the disease allows a collaborative approach between the medical community and parents and patients. Thus the U.S. FC National Research Foundation (later to become the CF Foundation) was founded in 1955, the Canadian CF Foundation in 1959, the UK FC Research Foundation Trust in 1964 and the International Cystic Fibrosis Association in 1965 in Paris. The survival of patients remains very precarious, most dying during early childhood, childhood or adolescence, after years of painful chronic illness. The "Mist tent therapy" was a form of treatment popular in the USA in this period was to make the children sleep in a fine mist in order to reduce the viscosity of secretions and improve their respiratory. But its effectiveness was not recognized and treatment was discredited in the early 1970. Encouraging results from London however, in 1969 David Lawson is the first to suggest that antibiotic anti-staph continues to improve survival and in 1972 he wrote that "a more rapid diagnosis by a neonatal screening is improved essential because currently the diagnosis is made at the stage while pulmonary lesions are already present ". Margaret Means in 1972 also reported a halving of mortality among children under 5 years, rising from 14% to 6.5%, thanks to anti-staphylococcal antibiotics available since 1957. She writes that "a vigorous treatment and control of infection in early childhood can prevent most of these patients become inadequate respiratory Children".
In the years 1970, much progress is being made, especially in terms of medical and surgical care neonatal; ventilation newborn becomes possible and is gradually improving. This decade is marked by growing interest vis-à-vis chronic nutritional problems that appear with the extension of the survival of patients. The general attitude was restrictive and rigid, then recommended intakes of 30 to 40 grams of fat per day, 200 kcal / kg / day and 4 to 5 g protein / kg / day. 'Allan Diet "to improve the intestinal absorption and nutritional status of patients had proved its effectiveness, but proved too demanding and too costly to be used routinely. The pancreatic enzymes gastro-resistant appeared and there were major advances to a normal fat intake, and thus energy intake increased in most patients. In 1978 an article supporting the hypothesis that a good nutritional status is associated with a better prognosis seems. It was during this decade that describes a non-surgical treatment of ileus méconial by washing the Gastrografine, which describes the pathogenic role of Burkholderia cepacia whose dangerous and contagious entails radical changes in clinical practice and social habits of patients and we realized that the severity of infection P.aeruginosa and life are related, observation at the origin of Danish protocol of intravenous antibiothérapies 3 months. Progress is so important that the vision of doctors about the disease is gradually changing. In 1974 Crozier publishes an article titled "The cystic fibrosis - a fatal disease if not". In 1981 Norman announced that a new era begins and it is "time to stop using the term genetic disease most lethal".
In the years 1980, considerable scientific advances take place on understanding disease, but without much repercussion on the care of patients. In 1983 prenatal diagnosis is available for families with one child already affected. In 1984 an article by the Australian Peter Phelan is obvious that care in specialized centers are a major factor in the best survival observed in patients of New South Wales compared to those of England and Wales , Treated in paediatric services General. This observation was followed by the creation of many centres specializing in the care of cystic fibrosis, including the United Kingdom. The dramatic improvement observed after basic treatment consists of 2 weeks of intravenous antibiotic therapy, physiotherapy, nutritional support and adequate doses of pancreatic enzymes prompted many parents to these centres. The intravenous antibiotics became the cornerstone of the treatment of chronic infection with P. aeruginosa which affects virtually all patients. Faced with the degradation that inevitably follows the judgement of the antibiotic, the specialised centre of Copenhagen Danish introduced protocols cures quarterly systematic 2 weeks of intravenous antibiotics, leading to an improvement of the impressive survival of their patients. To improve the quality of life and reduce costs, salaries IV antibiotics at home are developed gradually. After an article of 1981 by Margaret Hodson in which she describes as atomizations twice daily gentamicin and carbenicilline help stabilize patients with infections P. aeruginosa recurrent, atomizations antibiotics are experiencing a renewed interest important. In 1985 Littlewood notes that atomizations of colomycine can eradicate infection P. aeruginosa and prevent its chronic until regarded as inevitable. A major advance for patients with terminal stage of the disease is the first heart-lung transplant performed in 1984 at Harefield the United Kingdom at Chapel Hill and the USA. Thereafter the translantation bi-lung became more popular. Of the living donors were used particularly the USA, because of a shortage of organ donors.
This decade also knows significant progress in nutrition. It becomes obvious that patients with a normal fat intake have a higher energy intake, improved nutritional status and a better growth. Another major advance is the emergence of new enzymes acid-resistant, Pancrease then Creon. It is gradually becoming evident to many practitioners that the restriction on fat is now rarely indicated if adequate doses of pancreatic extracts are made. In cases of malnutrition, while intravenous parenteral nutrition is proving to be a solution in the short term, its implementation is not easy and enteral nutrition, a nasogastric tube or gastrostomy, gradually takes the scale.
In early 1990, a wave of enthusiasm following the identification of the CFTR gene, some patients think that a cure was discovered. The animal models are created with mutant mice can be searched in vivo on the functioning of the gene. Studies on the replacement gene are undertaken and although progress is slow, Davies plans in 2001 that gene therapy will become a reality within 5 to 10 years. Pharmacological treatments alternative or complementary intended to improve the function CFTR are also under study. Specialized centres in the care of adults mucoviscidosiques appear. With the advent of medicine based on the facts, all processing, traditional or new, are coming under scrutiny. Antibiotics intravenous steroids and inhaled bronchodilator seems useful, mucolytique Pulmozyme is effective in improving lung function, P. aeruginosa can be eradicated by early treatment and chronic infection enjoys an inhaled antibiotic-long short and cures quarterly intravenous antibiotics. The oral steroids are too toxic for prolonged periods. Different techniques are also physiotherapy réevaluées leading in 2002 to a recommendation by the CF Trust. It highlights the risks of transmission of infectious agents such as Burkholderia cepacia and Pseudomonas aeruginosa between patients, leading to a loss of meetings and groups of patients, profoundly changing their social life.