**3. Latin American group of immunodeficiency**

One of major problems of records diseases in underdeveloped countries has been limitation of diagnostic and treatment, and send reports of cases by physicians, resulting in overestimation in certain clinical centers in collection of samples, since most of these centers is reference to some types of PID, and lack of standardized definitions of cases makes it impossible to calculate rates of healthy population from this source, by only reporting positive cases without reference population data (Condino-Neto *et al.,* 2011).

The PID diagnosis is performed in immunology centers, usually located in major cities of Latin American countries, and the vast majority of pediatricians and general practitioners are not prepared to establish PID diagnosis. The medical community educator has a role in awareness of population and health professionals in PID. In 1997, the University of São Paulo, Brazil, 166 cases of PID were registered with frequency of predominantly humoral defects (60.8%), T cell defects (4.9%), combined T-and B-cell deficiencies (9, 6%), phagocyte disorders (18.7%) and complement deficiency (6%). During observed period, 13.8% of children died, primarily of recurrent infections. In comparison with other reports, was higher relative frequency of phagocyte and complement deficiency. This is the first report on PID over 15 year's observation (1981-1996) (Grumach *et al.,* 1997). In 1998, a Colombia study with 83 PID patients demonstrated most common disturbance was antibody deficiency (74,6%), followed abnormalities of unspecific mechanisms (13,3%), deficiencies of cell mediated immunity (9,6%), and mortality ratio was 6% especially in patients with cellular deficiency (Núñes, 1988).

In Antioquia, Colombia, between August of 1994 and July of 2002, 98 patients was registered with diagnosis of PID, with most frequent report antibodies deficiency (40,8%), followed by combined deficiencies (21,4%)(Montoya *et al.,* 2002). In Latin America, in 1993, immunologists from four Latin American countries (Argentina, Brazil, Chile, Colombia), created the Latin American Group for Immunodeficiencies (LAGID) to study the frequency of PID and promote knowledge by general practitioners and specialists in allergy and immunology, including Latin American countries, creating a record in each participating country. Currently, 14 countries belong to this group, which had record 3321 patients in 2004.

LAGID was implemented in 1993 with the mission to include several Latin American countries, spread the educational and awareness programs, establish PIDD registries, and

Primary Immunodeficiency Diseases in Latin America 365

Mucocutaneous Candidiasis. Representing diseases of immune dysregulation, Argentina reported 22 cases of Immunodeficiency with Hypopigmentation, followed by 14 cases of Brazil. Congenital defects of phagocytic number, function or both, Brazil reported 50 cases of cyclic neutropenia and 42 cases of Chronic Granulomatous Disease (CGD), and Argentina 46 cases. Brazil reported 50 cases of deficiency complement, followed by 13 reports of Argentina (Leiva *et al.,* 2007). Like others studies, predominantly antibody deficiency was the principal PID observed in Latin America, Australia (Baumgart *et al.,* 1997; Kirkpatrick et al., 2007), China (Zhao *et al.,* 2006; Wang *et al.,* 2011), Egypt (Reda *et al.,* 2009), French (CEREDIH, 2010), Hong Kong (Lam *et al.,* 2005), Iran (Aghamohammadi *et al.,* 2002; Farhoudi *et al.,* 2005; Rezaei *et al.,* 2006), Italy (Luzi *et al.,* 1983), Kuwait (Al-Herz, 2008), Netherland (Zegers *et al.,* 1994), Norway (Stray-Pedersen *et al.,* 2000), Poland (Bernatowska *et al.,* 1998), Republic of Ireland (Abuzakouk *et al.,* 2005), Spain (Matamoros *et al.,* 1997; Milá *et al.,* 2001), Swiss (Ryser *et al.,* 1998), Taiwan (Lee *et al.,* 2011), Thailand (Benjasupattananan *et al.,* 2009), Tunisia (Bejaoui *et al.,* 1997) and USA (Javier *et al.,* 2000; Stiehm, 2007), Studies in other countries reveled major number of granulocyte dysfunction in India (Verma *et al.,* 2008), and Combined T-and B-cell Immunodeficiency

On October 14, 2009, a group of experts from six Latin American countries (Argentina, Brazil, Chile, Colombia, Honduras and Mexico) and representatives of LASID meet in Cartagena de Indias in Colombia to discuss particular needs of each country about PID. Also this year, was created on-line Program Registration in Latin America (Registration of Society for Immunodeficiencies Latin American-LASID) in site http://deficiencia.unicamp.br:8080/, to provide information of PID epidemiology in Latin America. This meeting was held on 28 and 29 April in São Paulo, with the participation of 90 participants from Argentina, Brazil, Chile, Colombia, Honduras and Mexico, three faculty members from the USA and a faculty member of ESID. The online registration for Latin America was adapted from the record set ESID in Europe; Latin America is supported by Jeffrey Modell Foundation and National Council for Scientific and Technological Development (CNPq) of Brazil. From this date, 24 centers were enrolled in diagnosis, treatment and research, with more than 600 registered patients. In others countries, the online database network make good results in records of PID (Eades-Perner *et* 

The LAGID has published four reports and proceedings; the first two papers focused on the prevalence and characteristics of PID patients in Latin America (Zelazco *et al.,* 1998; Leiva *et al.,* 2007); the third and fourth summarized deficiencies in PID diagnosis and treatment in Latin America and described features of educational outreach program, immunology fellowship program, and laboratory network aimed at correcting these deficiencies (Condino-Neto *et al.,* 2011; Leiva *et al.,* 2011). From July 2009 to September 2010, the LAGID

In April 2011, the registry of Immunodeficiencies completed two years, with more than 1000 cases reported from 35 centers representing various Latin America countries. Recently, the Committee decided to hold LASID collaborative studies with the recorded data to better understand profile of prevalent PID, such XLA, HIgM, and CGD, filling out form and sending data to protocololasidxla@bragid.org.br or protocololasidhim@bragid.org.br or protocololasiddgc@bragid.org.br depending on PID. The group also offers financial education programs in PID, with projects submitted to e-mail info@imunopediatria.org.br.

in Turk (Shabestari *et al.,* 2007).

recorded 838 cases of PID.

*al.,* 2007; Guzman *et al.,*; 2007; Gathmann *et al.,* 2009),

promote annual scientific meetings with the participation of well-recognized international authorities in the PID field, This environment made possible the intensive interaction among Latin American doctors which in turn interacted with North American and European investigators resulting in a network, significant scientific development in Latin America, and the several resultant publications, starting with the clinical studies based on the LAGID registries

In order to encourage the registration of cases by LAGID, this sets out on its website (http://www.lagid.lsuhsc.edu) the objectives:


The first LAGID published a series of studies in 1998, recording instances of medical services totaling 1428 patients of eight countries (Argentina, Brazil, Chile, Colombia, Costa Rica, Mexico, Paraguay, Uruguay), concluding that predominantly antibody deficiencies were reported in 58% patients, followed by cellular and antibody immunodeficiencies associated with others abnormalities in 18%, immunodeficiency syndromes associated with granulocyte dysfunction in 8%, phagocytic disorders in 9%, combined cellular and antibody immunodeficiencies in 5%, and complement deficiencies in 2% of patients (Zelazko *et al.,* 1998).

In a second step, this same group published a second series of studies in 2007, documenting 3.321 cases of 12 Latin American countries (Argentina, Bolivia, Brazil, Chile, Colombia, Costa Rica, Ecuador, Mexico, Peru, Paraguay, Uruguay and Venezuela). The most common form of PID was predominantly antibody deficiency (53,2%), other well-defined PID syndromes such ataxia telangiectasia, Hyper IgE and Di George (22,6%), Combined T- and B-cell Immunodeficiency (9,5%), phagocytic disorders (8,6%), diseases of immune dysregulation (3,3%) and complement deficiencies (2,8%). All countries that participated in the first publication in 1998 reported increase in PID register cases, ranging between 10 and 80% (Leiva *et al.,* 2007).

In second LAGID record, Argentina recorded 852 cases of predominantly antibody deficiency, and Brazil 404 with predominates isothype deficiencies of light chain with normal numbers of B cells. Brazil reported 75 cases of Combined T-and B-cell Immunodeficiency and Argentina 69 cases. Like other well-defined syndromes, Argentina reported 60 cases of Di George Syndrome, 42 of Hyper IgE Syndrome and 40 of Wiskott-Aldrech Syndrome, Costa Rica 82 cases of DNA repair defects and Brazil 37 cases of Chronic

promote annual scientific meetings with the participation of well-recognized international authorities in the PID field, This environment made possible the intensive interaction among Latin American doctors which in turn interacted with North American and European investigators resulting in a network, significant scientific development in Latin America, and the several resultant publications, starting with the clinical studies based on the LAGID

In order to encourage the registration of cases by LAGID, this sets out on its website

3. Knowing the time that elapses between the onset of symptoms and diagnosis and measure whether this time can be shortened through the dissemination of knowledge

4. Create awareness in importance of PID in primary care physicians, educators from basic and clinical science and health authorities to decide how to allocate resources for

5. Promote research in various aspects of specific PID that would not be possible to settle

6. Disseminate the findings in field of Latin American PID to medical and international

The first LAGID published a series of studies in 1998, recording instances of medical services totaling 1428 patients of eight countries (Argentina, Brazil, Chile, Colombia, Costa Rica, Mexico, Paraguay, Uruguay), concluding that predominantly antibody deficiencies were reported in 58% patients, followed by cellular and antibody immunodeficiencies associated with others abnormalities in 18%, immunodeficiency syndromes associated with granulocyte dysfunction in 8%, phagocytic disorders in 9%, combined cellular and antibody immunodeficiencies in 5%, and complement deficiencies

In a second step, this same group published a second series of studies in 2007, documenting 3.321 cases of 12 Latin American countries (Argentina, Bolivia, Brazil, Chile, Colombia, Costa Rica, Ecuador, Mexico, Peru, Paraguay, Uruguay and Venezuela). The most common form of PID was predominantly antibody deficiency (53,2%), other well-defined PID syndromes such ataxia telangiectasia, Hyper IgE and Di George (22,6%), Combined T- and B-cell Immunodeficiency (9,5%), phagocytic disorders (8,6%), diseases of immune dysregulation (3,3%) and complement deficiencies (2,8%). All countries that participated in the first publication in 1998 reported increase in PID register cases, ranging between 10 and

In second LAGID record, Argentina recorded 852 cases of predominantly antibody deficiency, and Brazil 404 with predominates isothype deficiencies of light chain with normal numbers of B cells. Brazil reported 75 cases of Combined T-and B-cell Immunodeficiency and Argentina 69 cases. Like other well-defined syndromes, Argentina reported 60 cases of Di George Syndrome, 42 of Hyper IgE Syndrome and 40 of Wiskott-Aldrech Syndrome, Costa Rica 82 cases of DNA repair defects and Brazil 37 cases of Chronic

registries

about PID

(http://www.lagid.lsuhsc.edu) the objectives: 1. Knowing the frequency of different PID

in very small groups of patients

in 2% of patients (Zelazko *et al.,* 1998).

80% (Leiva *et al.,* 2007).

immune community

2. Compare the frequency of different PID by region and country

diagnosis and treatment of diseases in diverse groups

7. Facilitate the formation of support groups for parents and sponsors

Mucocutaneous Candidiasis. Representing diseases of immune dysregulation, Argentina reported 22 cases of Immunodeficiency with Hypopigmentation, followed by 14 cases of Brazil. Congenital defects of phagocytic number, function or both, Brazil reported 50 cases of cyclic neutropenia and 42 cases of Chronic Granulomatous Disease (CGD), and Argentina 46 cases. Brazil reported 50 cases of deficiency complement, followed by 13 reports of Argentina (Leiva *et al.,* 2007). Like others studies, predominantly antibody deficiency was the principal PID observed in Latin America, Australia (Baumgart *et al.,* 1997; Kirkpatrick et al., 2007), China (Zhao *et al.,* 2006; Wang *et al.,* 2011), Egypt (Reda *et al.,* 2009), French (CEREDIH, 2010), Hong Kong (Lam *et al.,* 2005), Iran (Aghamohammadi *et al.,* 2002; Farhoudi *et al.,* 2005; Rezaei *et al.,* 2006), Italy (Luzi *et al.,* 1983), Kuwait (Al-Herz, 2008), Netherland (Zegers *et al.,* 1994), Norway (Stray-Pedersen *et al.,* 2000), Poland (Bernatowska *et al.,* 1998), Republic of Ireland (Abuzakouk *et al.,* 2005), Spain (Matamoros *et al.,* 1997; Milá *et al.,* 2001), Swiss (Ryser *et al.,* 1998), Taiwan (Lee *et al.,* 2011), Thailand (Benjasupattananan *et al.,* 2009), Tunisia (Bejaoui *et al.,* 1997) and USA (Javier *et al.,* 2000; Stiehm, 2007), Studies in other countries reveled major number of granulocyte dysfunction in India (Verma *et al.,* 2008), and Combined T-and B-cell Immunodeficiency in Turk (Shabestari *et al.,* 2007).

On October 14, 2009, a group of experts from six Latin American countries (Argentina, Brazil, Chile, Colombia, Honduras and Mexico) and representatives of LASID meet in Cartagena de Indias in Colombia to discuss particular needs of each country about PID. Also this year, was created on-line Program Registration in Latin America (Registration of Society for Immunodeficiencies Latin American-LASID) in site http://deficiencia.unicamp.br:8080/, to provide information of PID epidemiology in Latin America. This meeting was held on 28 and 29 April in São Paulo, with the participation of 90 participants from Argentina, Brazil, Chile, Colombia, Honduras and Mexico, three faculty members from the USA and a faculty member of ESID. The online registration for Latin America was adapted from the record set ESID in Europe; Latin America is supported by Jeffrey Modell Foundation and National Council for Scientific and Technological Development (CNPq) of Brazil. From this date, 24 centers were enrolled in diagnosis, treatment and research, with more than 600 registered patients. In others countries, the online database network make good results in records of PID (Eades-Perner *et al.,* 2007; Guzman *et al.,*; 2007; Gathmann *et al.,* 2009),

The LAGID has published four reports and proceedings; the first two papers focused on the prevalence and characteristics of PID patients in Latin America (Zelazco *et al.,* 1998; Leiva *et al.,* 2007); the third and fourth summarized deficiencies in PID diagnosis and treatment in Latin America and described features of educational outreach program, immunology fellowship program, and laboratory network aimed at correcting these deficiencies (Condino-Neto *et al.,* 2011; Leiva *et al.,* 2011). From July 2009 to September 2010, the LAGID recorded 838 cases of PID.

In April 2011, the registry of Immunodeficiencies completed two years, with more than 1000 cases reported from 35 centers representing various Latin America countries. Recently, the Committee decided to hold LASID collaborative studies with the recorded data to better understand profile of prevalent PID, such XLA, HIgM, and CGD, filling out form and sending data to protocololasidxla@bragid.org.br or protocololasidhim@bragid.org.br or protocololasiddgc@bragid.org.br depending on PID. The group also offers financial education programs in PID, with projects submitted to e-mail info@imunopediatria.org.br.

Primary Immunodeficiency Diseases in Latin America 367

One of great difficulties encountered in developing countries for training professionals in PID is to awaken academic and professional interests, without compromising quality of life and survival of students and health professionals. Thus, different Latin American countries offer scholarships funded by educational institutions and other entities, governmental or private, with development of people involved and trained in specific areas of health. One of major problems seen in developing countries is the absence of jobs, which means that many students, just looking for graduate services that offer post-graduate scholarships, forgetting commitment they have with the community. Another problem in Latin America is formation of highly trained and qualified for certain areas of education and research, which are not absorbed by countries, end migrating to other parts of world. To resolve these problems, the Advisory Council LAGID determined availability of scholarships for doctors interested in area of clinical PID, as well doctors and teachers interested in immunology. The participating institutions were willing to participate in record LAGID, and grant applicants to submit personal statement, career development plan, and mentor involved with project statement of no conflict of financial interest and letters of recommendation. In this agreement, it was established that no country could be assigned more than two grants during period of two years, and beneficiaries of scholarship must publish report on its

One of the major problems encountered in developing countries is lack of proper training of physicians and pediatric regional variability in access to educational program and establishment of diagnostic and treatment center. Thus, education and training are needed for specialists, pediatricians, general practitioners from different countries and regions of Latin America, ensuring that they are able to recognize warning PID signs. This includes creation of Summer School, symposia and conferences of PID. These educational efforts should also be understood to medical students, nurses and general public. For that, programs are needed government and private funding, and network (Leiva *et al.,* 2011). In Brazil, the Jeffrey Modell Foundation, and Baxter pharmaceutical industry, created on April 29, 2009 at Federal University of São Paulo-UNIFESP, the first Jeffrey Modell Diagnostic Center for PID in Latin America, based in field of Immunology pediatric UNIFESP, with working points in different parts of the country. The Jeffrey Modell Diagnostic Center operates in front of medical education, diagnosis and records of PID and patient education (Modell, 2007a; Modell, 2007b). Other diagnostic centers sponsored by the Jeffrey Modell will be opened in Mexico, Argentina, Colombia and Chile. Advancing educational model for educational outreach in Latin America is observed in the Brazilian Group of Human Immunodeficiency (BRAGID) (http://www.bragid.org.br), whose number of registered doctors increased from 190 in 2002 to 2.500 in 2009, after creation of local seminars on dating PID. The BRAGID provides information on warning PID, different clinical presentation PID of and diagnostic laboratories. Offer clinical cases that can be discussed in Internet. This model is followed in Colombia, which has specialized site that shows warning PID signs, types of PID and use of IVIG. In other Latin American countries, government agencies related to areas of health are more concerned with control of infectious diseases, and most

**3.3 Scholarship program offer**

activities or clinical results or research (Leiva *et al.,* 2011).

**3.4 Creation of centers of education, diagnosis and treatment** 

professionals in the field of immunology work independently.

Those studies contributed with new insights on clinical presentation and impacted positively on the molecular diagnosis of PID. All together the Latin American experience shows that BCG complications is prevalent among SCID, T-cell deficiencies, and CGD patients; that fungal infections is highly prevalent among X-linked HIGM patients, and that ataxia-teleangiectasia is especially frequent in Mexico and Costa Rica. Currently Chile is building a new diagnostic center at University La Frontera that will interact with research centers in Argentina, Brazil, and Colombia. This strategy will strength even more the interaction among the several Latin American research centers.

Studies by LAGID showed numerous factors responsible for delay in diagnosis and treatment of patients with PID. Most pediatricians and family physicians in Latin America are not sufficiently trained to carry out the diagnosis of PID, there is a low amount of specialized installations for specific immunological tests, there is limited coverage for screening tests given by the government or private institutions, regional variability access to health and failure to comply with guidelines in certain countries and regions. To improve some of these aspects, diagnosis and treatment of patients with PID, experts from Latin America and the USA meet to discuss three specific programs, educational program (The L-Project), scholarships program and establishing of laboratory network to expand access to data (The Latin América Advisory Board on Primary Immunodeficiencies) (Leiva *et al.,* 2011; Condino-Neto *et al.,* 2011).
