MANAGEMENT OF CYSTIC FIBROSIS IN RUSSIA
Kashirskaya N.Y., Kapranov N.I.
Russian CF Centre, Research Centre for Medical Genetics RAMS,
The first cases of cystic fibrosis (CF) were described in the former USSR in 1967 in the Institute of Paediatrics AMN USSR. It was not until 1989 that two officially designated CF centres opened the first one in Moscow and the second one in St Petersburg. Moscow Centre opened its doors for the CF patients on November 5th 1990. However during this period there were several clinics in Russia, which studied and treated CF. At this time the first attempts were made to develop the appropriate protocol for treatment of CF patients in accordance with their clinical status. In spite of all these efforts the prognosis of identified cases of CF was very poor with an average life expectancy of around 14 years. Over the last 20 years there have been huge political changes with resulting changes in geographical demarcation. The former USSR has broken up into a number of countries. Some of them as the Ukraine, Byelorussia, Baltic Republics, Georgia and Armenia have developed recognised CF Centres of their own. In the South of the former USSR the situation with the treatment and diagnostic of CF is very poor. Russia itself has a population of approximately 150 million. Since 1989 42 regional CF centres were recognised in Russian Federation: Moscow, St.Petersburgh, Arkhangelsk, Astrakhan, Voronezh, Volgograd, Vladimir, Kaliningrad, N.Novgorod, Novosibirsk, Novokuznetsk, Jaroslavl, Kostroma, Omsk, Kazan, Saratov, Ekaterinburgh, Samara, Tomsk, Tula, Vladivostok, Stavropol, Krasnodar, Barnaul, Irkutsk, Ufa, Ulyanovsk, Chelyabinsk, Krasnoyarsk, Perm, Izhevsk, Volgograd, Rostov on Don, Syktivkar, Tyumen, Kemerovo, Khabarovsk, Essentuki, Saransk, Smolensk, Petrozavodsk).
A National newborn screening programme has just started in our country (since June 2006 – pilot study and since 1 January 2007 – all over Russia). We use twice repeated IRT tests and sweat test after second positive ITR test. Accurate sweat testing is available in about 50% of 83 geographical regions of Russia. We use the biochemical method, which was introduced by Gibson and Cooke. But the absence of reference laboratory complicates the control of the results of the sweat test. In several CF centres doctors use Macroduct or Nanoduct (Wescor, USA) or Sanasol (Sanasol Meditechnika, Hungary) – screening systems. For the neonatal screening programme in 2008 Ministry of Health has bought 51 Nanoduct systems and plans to buy more in 2009 so that all 78 Neonatal screening laboratories for 83 administrative regions in Russian Federation will have them. Only in St.Petersburg method of measuring the nasal transepitheial electric potential differences is used.
All together in Russia we have about 2000 diagnosed CF patients. There were several attempts to study the diversity of CF mutations in populations of the former USSR, especially in Russian population. In most cases these attempts were aimed at the search of the most common mutations of CFTR gene, beside deltaF508 deletion. Our results (776 pts) proved that mutations in exons 13, 20, 21 and 19 are probably the common mutations in the CFTR gene in Russia and that the spectrum and distribution of common mutations in Russian population is peculiar. In 1999 Thilo Dork and Milan Macek found a new mutation, which is frequent in populations of Eastern-and Western-Slavic descent. This mutation deletes approximately 21,1 kilobases, spanning introns 1 to 3 of the CFTR gene. The frequency of this CFTRdele2,3(21kb) mutation in Russia is 7,2% and it takes now a second place after deltaF508 (54,2%). The frequencies of other 11 mutations are reached more than 0,5%: 2143delT (2,1%), W1282X (2,0%), N1303K (1,9%), 3849+10kbC-T (1,9%), 2184insA (1,7%), G542X (1,3%), 1677delTA (0,8%), 3821delT (0,8%), R334W (0,7%), L138ins (0,6%) и 394delTT (0,5%). The most important is the fact that about 23% of CFTR gene mutations remain unknown.
There are several centres in Russia that perform prenatal diagnosis of CF: National Centre for Prenatal Diagnosis of CF in the Institute of Obstetrics and Gynaecology, St. Petersburg; Research Centre for Medical Genetics RAMS, Moscow; Institutes of Medical Genetics in Tomsk, Ufa, Rostov on Don.
PREIMPLANTATION GENETIC DIAGNOSIS
Preimplantation genetic diagnosis (PGD) is an alternative for prenatal diagnosis that makes it possible to perform the diagnosis of monogenic disorders at the preimplantation embryo level. Cystic fibrosis is one of the monogenic diseases for which PGD can be performed. Since 2006 in the Center for family planning and reproduction (Clinic “Mother and child”), Moscow, 8 cases of PGD were done. 79 blastomeres underwent embryo biopsy in 8 IVF+ICSI cycles. After PGD for CF mutations and PGS for common aneuploidies 19 of them were transfered and 4 clinical pregnancies were achieved (pregnancy rate - 50%). 5 healthy babies have been born already and there is one ongoing pregnancy. No misdiagnosis was recorded. In our case pregnancy rate was 50%s, half of all women that underwent their first PGD cycle achieved a birth or ongoing pregnancy.
In 1993, through the charitable organisation, the International Integrated Health Association, a link has been established between the Southampton (UK) and the CF clinic of the Research Centre for Medical Genetics in Moscow. Dr. Chris Rolles, the Paediatrician Consultant of the Southampton University Hospital, and his colleagues played an outstanding role in the creation and completion of all clinical and research collaborative projects during following 5 years. Before our link with Southampton the main problems were:
- lack of the consistent supply of the enteric coated enzymes. Our patients were still using large quantities of old forms of enzymes such as Pancreatin.
- because of this patients were advised to be on a low fat diet.
- lack of the consistent supply of antibiotics for exacerbations of chest infection especially for pseudomonas infections.
- our technique of physiotherapy was just simple percussion with postural drainage.
- children were seen only if they had acute exacerbations.
After 2 years of twinning with Southampton most Moscow patients with CF were using an optimal routine outpatient based service with regular follow up visits of patients every 3 months instead of being hospitalised. More then 50 patients from Moscow receive the regular courses of i.v. antibiotics at home. We are happy to say now that since 1999 due to the Mayer of Moscow and Children’s department of Moscow Health Committee Muscovites receive all the necessary treatment free of charge including inhaled antibiotics (Bramitob and TOBI). The main strategy of CF treatment for muscovites and Moscow region (about 220 CF patients including 40 adults, >18 years of age) is as follows now:
- Microspheric pancreatic enzymes and high protein diet without any fat restriction
- Vitamins, especially fat-soluble
- Antibiotics including Tobramycin and Colistin for inhalation
- Mucolitics (Dornasa-alfa and N-acetylcysteine)
- Treatment of CF complications.
Since 1995 patients with liver problems use Ursodesoxycholic acid regularly. In Russia we were the first to introduce surgical means of treatment for portal hypertension syndrome in CF patients with liver cirrhosis including partial splenectomy. In the future we hope to introduce modern methods of treatment of liver disorders including transjugular intrahepatic portal systemic shunt (TIPSS) and liver transplantation (partial). Unfortunately the situation in other regions of Russia is not so well as in Moscow and Moscow region. Due to Federal Programme all CF patients receive free of charge Dornasa-alfa. The money for other drugs comes from the Regional budgets and from time to time CF patients have problems with necessary drugs including pancreatic enzymes. Together with our colleagues from the Research Institute of Pulmonology from Moscow we found that 50% survival rate for CF patients in 2007 was 27,9 years, with 31,7% patients above 15 years.
We believe that education of the doctors in CF is probably the most important factor in success for patients. The aim of our Russian CF Centre now is to spread all our knowledge to the doctors all over Russia and former USSR republics. Since 1995 we organise National Russian CF Congress. It is taking place every second year now. The last 9th CF Symposium was organised in the countryside of Moscow on April 3-4th. Regularly our specialists visit regional CF centres with lectures and CF patients’ consultations. In 2008-2009 we visited more then 15 regional CF centres. We continue the help to our colleagues in former USSR republics. During last several years we visited Baku (Azerbaijan), Minsk (Byelorussia), Tbilisi (Georgia), Yerevan (Armenia), Kharkov (Ukraine), Kishinev (Moldova), Almaty (Kazakhstan). We invite CF doctors from these centres to Moscow for training. For the last 2 decades we have an opportunity to participate in the International scientific CF conferences including: Congresses of the European Cystic Fibrosis Society and the European Respiratory society; Annual North American Cystic fibrosis conferences; European Gasroenterology weeks, etc.
Unfortunately we don’t have a National Russian CF Parents’ Association yet but have about 12 regional CF parents’ associations that are united in the Organisation that plan to be registered as the Russian one. Anyway without National status CF Parents’ organisation plays an important role in improving the CF care in Russia. There is a lot of information on the Internet sites www.cfhelp.ru and www.cfcf.ru.