Through Education and Collaboration to Better Care for Primary Imunodeficiencies in Albania and Kosovo

Primary immunodeficiency diseases (PIDs) also referred to as inborn errors of immunity (IEI) have long been neglected as medical conditions but are now recognized as a worldwide health problem. The rapid progress of research in this field has widened the gap between cutting-edge medical care in more developed western countries and the lack of appropriate diagnosis and treatment of these conditions in most countries, especially in those with poor socioeconomic conditions [1, 2]. Being in development, both Albania and especially Kosovo are good examples. The J Project physician education and clinical research collaboration program, however, resulted in a remarkable change in PID education and treatment in our countries over the past years and opened the way to the development of this previously neglected area of clinical medicine.

The J Project Albania (JPA)

Albania joined the J Project (JP) in 2009, and the very first meeting was organized in 2010 which was attended by 120 participants (Photo 1). At this inauguration meeting, we hosted the Albanian Minister of Health. Since then, JP meeting was held every year at different locations, mostly in Tirana, Albania. At each of these meetings, participation was growing both in number and diversity including pediatricians, immunologists, general practitioners, and other health professionals.

Photo 1.

Fist J Project meeting in Albania, year 2009

The JPA established the National Registry of Patients with IEI, and currently, the registry includes 262 patients. Of these, 132 belong to the primary immunodeficiency diseases (Table 1). All patients, except one case with CVID, are diagnosed below the age of 18. Ten children are diagnosed during the first year of life. Until now, there is no any screening program for immunodeficiency or De George syndrome.

Table 1.

Patients with IEI according to IUIS classification in Albania

	Inborn errors of immunity according to the IUIS classification (until December 2021)	Abs. number
1.	Immunodeficiency affecting cellular and humoral immunity	6
2.	combined immunodeficiencies with associated or syndromic features	17
3.	Predominantly antibody deficiencies	73
4.	Diseases of immune dysregulation	5
5.	Congenital defects of phagocyte number or function	4*
6.	Defects in intrinsic and innate immunity	4
7.	Autoinflammatory disorders	12
8.	Complement deficiencies	2
9.	Bone marrow failure	5
10.	Phenicopies of inborn errors of immunity	1
	Undefined PID	3
	Total registered patients	132
	Prevalence of PID per 105 inhabitants	2.86**

^*This number doesn’t include 130 patients with Cystic fibrosis

^**Selective Iga excluded from the total number of Pid patients

The immunologic service in Albania is part of the University Hospital Center of Tirana “Mother Theresa,” and it did clinical consultations of the patients in collaboration with the specialists of pediatric infectious diseases, hematology, pulmology, or other services where the patients are diagnosed. There is an immunologic lab, mainly for research work directed by the Academy of Science. The immunologic laboratory investigations are performed by the Central Laboratory of UHC “Mother Theresa.” Genetic investigations were done by joint projects or agreements between UHC and the other hospitals. Some of the patients are diagnosed in “Gaslini” hospital in Genoa, Italy, and the Acibadem hospital in Istanbul, Turkey, and mainly, the genetic examinations are analyzed at CENTOGENE, Rostock, Germany.

The only data that we have for vaccination complications are two cases. One with Bruton who developed vAPP (vaccine-associated poliomyelitis) after vaccination with OPV at the age of 4 months. The other child of 5 months old developed a fulminate fasciitis after BCG, in terrene of SCID (diagnosed post mortem).

The only center involved in the PID registry is the University Hospital Center”Mother Theresa” in Tirana, with its Department of Pediatrics and Central Laboratories.

The J Project Kosovo (JPK)

Primary immunodeficiency diseases have been brought to the attention of the medical authorities in Kosovo only in the past few years. For those familiar with the socioeconomic and medical care conditions in Kosovo, this is not surprising. With 31% of the population being 0–18 years old and with an average age of 29.5 years, Kosovo has the youngest population in Europe, but it also has the poorest child health indicators in the region. This country has the highest infant mortality rate in Europe with 15 deaths per 1000 live births which is nearly two times higher among children from Roma, Ashkali, and Egyptian communities reaching 26 per 1000 live births [3]. Child malnutrition continues to be a concern in Kosovo, and striking inequalities exist for children in the poorest households. Nearly 23% of children live in poverty, and 7% live in extreme poverty. Only one in three children between 6 and 36 months of age receives the minimum acceptable diet. Only 73% of children under 2 years of age are fully immunized. When it comes to the Roma, Ashkali, and Egyptian communities, the rate goes down to only 38%. Only 20% of household members rely on clean fuels and technology for cooking, heating, and lighting. Nearly 90% of households have access to clean drinking water, but 23% of the population still consumes water tainted with E. coli. Therefore, infective diarrhea and pneumonia continue to be the most common childhood diseases [3]. Kosovo also has a very low budget for health. With about $100 per capita per year, it is probably the lowest-income country in Europe. Importantly, almost half of this budget goes to salaries.

IEIs and other rare diseases still fall out of the attention of the health government and remain the problem for the patients and their families itself and the medical community. Although frequent infections, anemia, thrombocytopenia, inflammations, digestive tract problems, growth delay, and autoimmune diseases are indicative of IEIs, it was not possible before to confirm with laboratory tests. Therefore, the entire treatment was insufficient and focused on the treatment of complications.

While a specialized diagnostic lab for IEI is still missing in Kosovo, recent progress is promising, largely because of the implementation of the JP. From 2018 when a small group of enthusiastic doctors within the Pediatric Clinic became a member of the JP community, JPK has transformed into a movement numbering more than one hundred doctors, mostly pediatricians, family medicine specialists, and other concerned specialists. By promoting IEI diagnostics through research and collaboration, JPK has held annual meetings to discuss contemporary diagnosis and treatment for these diseases. Apart from four large annual events, two additional, smaller meetings were held in various regions to foster inclusiveness. One of these meetings was held during the COVID-19 pandemic in 2021. Hundreds of pediatricians, general physicians, immunologists, and other specialists attended these meetings, among them a number of colleagues from neighboring Albania and the Republic of North Macedonia, and on one occasion from the USA. As a result, the number of patients diagnosed with IEIs has increased (Fig. 1). While in 2018, only five patients were diagnosed with IEI, in 2022 we registered 17 patients. Over the years, the number of genetically confirmed diseases has also increased up to nine (Table 2).

Fig. 1.

a Increase in the number of patients through the years in Albania. b Increase in the number of patients through the years in Kosovo

Table 2.

Patients with IEI according to IUIS classification in Kosovo

Country	Center	Reported by	Inborn errors of immunity according to the IUIS classification ®											All	Population	Pts/103
			1	2	3	4	5	6	7	8	9	10	UD
Kosovo	Prishtina	Ismaili-Jaha V	1	4	8	0	4	0	0	0	0	0	0	17	1.935.000	0.88

JPK has been working closely with the Association of Kosovo Pediatricians’ Society and the Kosovo Association for Rare Diseases. Together, we managed to influence the policymakers within the Ministry of Health of the Republic of Kosovo to include the drugs for the treatment of IEI at the list of essential drugs and to establish a registry of patients. Since then, we have registered 17 patients (9 boys (52%) and 8 girls (48%). One of these patients who had—Telangiectasia passed away recently at the age of 7. The most common subcategory of IEI according to the IUIS classification was type 3 error representing primarily antibody deficiencies (8/17 or 47.06%). Type 2 and type 4 subcategories represented similar number of patients (4/14 each or 23.53% each). With a population of 1.935 million, Kosovo has a prevalence of confirmed IEIs of 0.88 (Table 2). The low prevalence of the IEI in Kosovo probably does not reflect the real frequency of these diseases in the country, but rather the need for more work to increase awareness. Additionally, the Ministry of Health has recognized the specialty of clinical immunology and has established a separate department to diagnose and treat immunodeficiency diseases within the University Clinical Center of Kosovo, the largest medical institution in the country. The Kosovo Government also covers the expenses of genetic testing. The JPK was supported from the Medical Chamber of Kosovo that accredited all JP programs. The JP program encouraged the families of the patients with IEI to organize themselves, and they are now important advocates within the country.

Advances have also been made in the treatment of patients with IEI. Two patients are receiving immunoglobulins, one of them with X-linked agamaglobulinemia and another with common variable immunodeficiency. One of the patients was treated with bone marrow transplantation in Turkey.

Abstract and Further Challenges

Both countries largely benefited from the association with the JP and should continue to actively participate in this program. On the national level, it increased awareness on PIDs and improved diagnosis and treatment. It also helped to shape national health politics and establish registries and subsidy medical treatment for the patients. The JP has also built cross-society cooperation and involved patients and the IEI community in this action. On the regional level, it helped both Kosovo and the Albania to build strong alliances with JP in the Balkans and coordinate professional collaboration. Members from our societies attended international meetings held in Western European countries, exchange ideas and experiences, and plan future activities. On the international level, we attended several JP meetings and participated at the biannual meetings of the European Society for Immunodeficiency. Several important documents were adopted and then implemented at these meetings. One of these documents, that advocates for free access to genetic testing for all patients, is the Antalya Declaration. We hope to help us to diagnose more patients and offer them up-to-date treatment earlier [4]. This will also help our countries to overcome the biggest difficulties, insufficient testing infrastructure, and lack of financial resources. Future challenges include raising awareness on IEIs, mobilizing health professionals, and increasing patient groups’ activity. We are devoted and eager to participate more actively in IEI-focused clinical research locally and in collaboration with foreign groups.

Author Contribution

VIJ and GKL designed this study and wrote the paper. All co-authors read the paper and approved its content.

Data Availability

Data used in this study are available on request.

Declarations

Ethics Approval

This publication was approved by the Research Ethics Committees of Kosovo.

Consent to Participate

All authors approved to participate in this study.

Consent for Publication

All authors approved the publication of the manuscript.

Conflicts of Interest

The authors declare no competing interests.