**1. Introduction**

Primary immunodeficiencies (PID) are genetic disorders of immunity whose incidence varies from 1:250 to 1:1,000,000 depending of disease and study population. Because of incomplete records of immunodeficiency in the world, is estimated that the prevalence of 1:5,000 to 1:100,000 (Geha *et al.,* 2007; Boyle & Buckley, 2007; Notarangelo,*et al.,* 2010). Thus, the PID is a important group to public health as other genetic diseases that rely government support in a neonatal screening program such phenylketonuria (PKU) with incidence of 1/15.000 (de Carvalho *et al.*, 2007) and congenital hypothyroidism, with incidence of 1/4.000 (American Academy of Pediatrics, 1993; Olivieri, 2009). The PID are classified in defective immune deficiency prevalent in predominantly antibody; combined immunodeficiencies, cellular immunodeficiencies, phagocyte defects, immune deficiencies associated with lymphoproliferative diseases, and deficiencies of complement system or secondary immunodeficiencies associated with other diseases. This classification is updated periodically by the International Union of Immunological Societies (IUIS), associated with the World Health Organization (WHO) (Geha *et al.,* 2007; Notarangelo,*et al.,* 2010).

This classification is progressively adjusting to the rapid evolution of the field. Many new phenotypes (e.g. hemophagocytosis, thrombotic purpura, herpes encephalitis, Mendelian susceptibility to mycobacterial infection, epidermodysplasia verruciformis, chronic mucocutaneous candidiasis, autoinflammatory disorders, and anhidrotic ectodermal dysplasia with immunodeficiency) have emerged as reflecting new PID.

Knowledge of PID is still deficient in many countries and within many countries, since doctors and health authorities are often poorly informed about their clinical presentations, diagnosis, importance and health impact of these diseases, and geographic factors that influence the release of same around the world (Sewell, 2006). Recent estimates of PID made by the European Parliament showed that approximately 1 in 800 to 10,000 people have PID that significantly affects your health, PID affect at least 10 million people worldwide, the true prevalence of PID in some forms of general population is estimated between 1 in 250 and 1 in 500, data comparable with type I diabetes (1 in 700) and multiple sclerosis (1 in

<sup>\*</sup> Corresponding Author

Primary Immunodeficiency Diseases in Latin America 359

overweight patients, however, a greater number of adults have been diagnosed as children grow and become adults (Bustamante *et al.,* 2008a). How healthy children have on average 6-8 mild respiratory infections, especially upper airway in first year of life and more than six episodes of otitis and gastroenteritis per year in the first three years of life, young children with high environmental exposure or with siblings who attend schools may exceed these averages by one to two years, the diagnosis of PID is often underestimated (Puck, 1997). But they may be observed in children with normal development, which may harbor latent PID or low impact on the immune system. Pediatrics specialize in PID ensure that half children are taken by parents to the doctor with a history of recurrent infections are normal, and other 50%, 30% have allergies, 10% other diseases and 10% PID (Grumach *et al.,* 1997). To aid diagnosis and reporting of PID, the American Red Cross and Jeffrey Model Foundation developed the 10 warning signs suspected for PID. For experts (Modell, 2007a; Modell, 2007b), these signs are considered extremely important, since the prognosis and therapeutic success depends upon prompt diagnosis, and most are performed in referral centers. However, some authors consider the 10 warning signs not sensitive or specific, since a third of patients do not present single warning sign (Aloi *et al.,* 2007). Once diagnosed with PID, the patient is referred to clinical immunologist who directs specific treatment, immunizations, and definitive and specific diagnosis. Thus, there is a gain in quality life of patients and their families, avoiding sequels, unnecessary suffering and high social cost. The therapeutic treatment these patients involve three basic tenets: reduce the exposure to the infectious agent, effective or prophylactic antimicrobial therapy, replacement of deficient immune functions (Garcia *et al.,* 2007). During the evaluation of PID is essential documentation of the patient's clinical history, frequency, duration and complications of infections, outbreaks of infection, microorganisms involved and response to treatment, and anatomical defects, allergic processes and metabolic disorders (Bonilla *et al.,* 2005). A detailed family history should be taken into consideration, since many PID are linked with X chromosome and the presence of children in maternal family with recurrent infections, or death in childhood due to severe infection indicates the possibility of PID. Initially, screening tests are indicated or initial and advanced testing as suspected PID (Sewell *et al.,* 2006). In general, immune assessment requires specialized laboratory and high financial cost, and it comes to pediatric patients, should be chosen methods that can be executed with low amount of blood (Oliveira & Fleisher, 2010). The diagnosis of some PID may be removed if they are used and selected screening tests such blood test for congenital neutropenia, leukocyte adhesion deficiency (LAD), severe combined immunodeficiency (SCID) and Wiskott-Aldrich Syndrome (WAS), or immunoglobulin's quantification in suspected predominantly antibody defects (Gill, 2002). The diagnostic criteria are divided into three categories, definite, probable and possible. In ensuring inclusion of patients with polymorphic variants in genes associated with PID and specific clinical and laboratory changes, the patient must meet all criteria characteristic of the disease (Conley *et al.,* 1999). The delay in diagnosis is often associated with limited access to specialized resources (Lindegren, 2004), is not unique to developing countries (Liang *et al.,* 2008), leading to large variation between numbers of cases (Stihem, 2004). In Finland, the common variable immunodeficiency (CVID) showed delay time diagnosis of 5 years in 2/3 of patients and 10 years in 1/3 these (Kainulainen *et al.,* 2001), in United Kingdom this delay was 6.2 years during 1989 to 1995, and decreased 3.5 years after implantation of government program to guide distribution of national guidance on recognition and diagnosis of PID, after a study

1000), although more than 200 PID have been discovered, some are more common than leukemia and lymphoma in children (Banks, 2010).

Initial efforts in classification of PID left WHO in 1970, where this first meeting was identified and classified 14 different entities, and in 2006, more than 100 types (Bonilla & Geha, 2006). Currently, they comprise more than 200 different types of genetic diseases that predispose the human host to recurrent infections, which may be associated with other disorders (Notarangelo *et al.,* 2010), but also to chronic and systemic inflammation, hypersensitivity reactions, autoimmunity, and cancer. Advances in biological sciences and biotechnology are now making possible for the first time, to systematically assess the actual impact of PID in human health, and this promises to revolutionize the way we look at these diseases.

Patients with PID have higher susceptibility to infection often accompanied by inflammatory disorders, hypersensitivity reactions, autoimmunity and cancer (Morimoto & Routes, 2008; Notarangelo 2010). The clinical presentation of patients is extremely broad, with asymptomatic individuals who have fulminating infection, which if not diagnosed and treated properly evolution to death (Chapel 2005; Bustamante *et al.,* 2008a). Patients with PID have consequence of delay diagnosis and treatment permanent damage of body. This involves disabling from attending school and/or work, reducing the number of people with productive capacity, increasing the number of people hospitalized with high cost to government, increased mortality rate in children and adults of working age (Yarmohammadi *et al.,* 2004; Bonilla *et al.,* 2005). The delay in diagnosis leads to pulmonary complications such bronchiectasis and irreversible change in the quality of life of patients and their families (Kainulainen *et al.,* 2001; Champi, 2002).

Although this delay in diagnosis of PID is evident in countries or disadvantaged regions, also occurs in developed countries after multiple hospitalizations of patients. Thus, is recommended research and education in PID, since the prognosis of many patients can be improved by early diagnosis and appropriate access to care and treatment (Bonilla *et al.,* 2005; Turvey & Bonilla, 2009). In medical terms, there are three important reasons for understanding the PID, first, a high index of suspicion and early diagnosis may lead to treatments that save lives or bring significant improvement in quality of life, secondly the discovery of genetic defects in immunity makes possible family counseling and prenatal diagnosis, and thirdly, the study of the pathophysiology of genetic and immunological defects provides important tools to understanding the regulation of the human immune system (Bustamante *et al.,* 2008b; Casanova *et al.,* 2008; Lee & Lau, 2009; Fried & Bonilla, 2009). In recent decades, no other field of immunology had so much progress in understanding how pathophysiology of primary immunodeficiencies. These developments have resulted not only in understanding of immunodeficiencies, but understanding of immune system in humans (Boufisha *et al.,* 2010). Patients with PID are considered not successful experiments of nature that brought many benefits to medicine in the installation of diagnostic protocols and rational treatment, location of targets for gene therapy and assessment of need for bone marrow transplantation and its benefits (Griffith *et al.,* 2009; Neven *et al.,* 2009; Pessach *et al.,* 2009; Kohn 2010). This knowledge was translated into association of specific defects of immunity with signs and symptoms that can establish correct diagnosis of disease, beyond the description of new immunodeficiency (Cassimos *et al.,* 2010). Since the PID diseases are congenital and hereditary character, children are

1000), although more than 200 PID have been discovered, some are more common than

Initial efforts in classification of PID left WHO in 1970, where this first meeting was identified and classified 14 different entities, and in 2006, more than 100 types (Bonilla & Geha, 2006). Currently, they comprise more than 200 different types of genetic diseases that predispose the human host to recurrent infections, which may be associated with other disorders (Notarangelo *et al.,* 2010), but also to chronic and systemic inflammation, hypersensitivity reactions, autoimmunity, and cancer. Advances in biological sciences and biotechnology are now making possible for the first time, to systematically assess the actual impact of PID in human health, and this promises to revolutionize the way we look at these

Patients with PID have higher susceptibility to infection often accompanied by inflammatory disorders, hypersensitivity reactions, autoimmunity and cancer (Morimoto & Routes, 2008; Notarangelo 2010). The clinical presentation of patients is extremely broad, with asymptomatic individuals who have fulminating infection, which if not diagnosed and treated properly evolution to death (Chapel 2005; Bustamante *et al.,* 2008a). Patients with PID have consequence of delay diagnosis and treatment permanent damage of body. This involves disabling from attending school and/or work, reducing the number of people with productive capacity, increasing the number of people hospitalized with high cost to government, increased mortality rate in children and adults of working age (Yarmohammadi *et al.,* 2004; Bonilla *et al.,* 2005). The delay in diagnosis leads to pulmonary complications such bronchiectasis and irreversible change in the quality of life of patients

Although this delay in diagnosis of PID is evident in countries or disadvantaged regions, also occurs in developed countries after multiple hospitalizations of patients. Thus, is recommended research and education in PID, since the prognosis of many patients can be improved by early diagnosis and appropriate access to care and treatment (Bonilla *et al.,* 2005; Turvey & Bonilla, 2009). In medical terms, there are three important reasons for understanding the PID, first, a high index of suspicion and early diagnosis may lead to treatments that save lives or bring significant improvement in quality of life, secondly the discovery of genetic defects in immunity makes possible family counseling and prenatal diagnosis, and thirdly, the study of the pathophysiology of genetic and immunological defects provides important tools to understanding the regulation of the human immune system (Bustamante *et al.,* 2008b; Casanova *et al.,* 2008; Lee & Lau, 2009; Fried & Bonilla, 2009). In recent decades, no other field of immunology had so much progress in understanding how pathophysiology of primary immunodeficiencies. These developments have resulted not only in understanding of immunodeficiencies, but understanding of immune system in humans (Boufisha *et al.,* 2010). Patients with PID are considered not successful experiments of nature that brought many benefits to medicine in the installation of diagnostic protocols and rational treatment, location of targets for gene therapy and assessment of need for bone marrow transplantation and its benefits (Griffith *et al.,* 2009; Neven *et al.,* 2009; Pessach *et al.,* 2009; Kohn 2010). This knowledge was translated into association of specific defects of immunity with signs and symptoms that can establish correct diagnosis of disease, beyond the description of new immunodeficiency (Cassimos *et al.,* 2010). Since the PID diseases are congenital and hereditary character, children are

leukemia and lymphoma in children (Banks, 2010).

and their families (Kainulainen *et al.,* 2001; Champi, 2002).

diseases.

overweight patients, however, a greater number of adults have been diagnosed as children grow and become adults (Bustamante *et al.,* 2008a). How healthy children have on average 6-8 mild respiratory infections, especially upper airway in first year of life and more than six episodes of otitis and gastroenteritis per year in the first three years of life, young children with high environmental exposure or with siblings who attend schools may exceed these averages by one to two years, the diagnosis of PID is often underestimated (Puck, 1997). But they may be observed in children with normal development, which may harbor latent PID or low impact on the immune system. Pediatrics specialize in PID ensure that half children are taken by parents to the doctor with a history of recurrent infections are normal, and other 50%, 30% have allergies, 10% other diseases and 10% PID (Grumach *et al.,* 1997). To aid diagnosis and reporting of PID, the American Red Cross and Jeffrey Model Foundation developed the 10 warning signs suspected for PID. For experts (Modell, 2007a; Modell, 2007b), these signs are considered extremely important, since the prognosis and therapeutic success depends upon prompt diagnosis, and most are performed in referral centers. However, some authors consider the 10 warning signs not sensitive or specific, since a third of patients do not present single warning sign (Aloi *et al.,* 2007). Once diagnosed with PID, the patient is referred to clinical immunologist who directs specific treatment, immunizations, and definitive and specific diagnosis. Thus, there is a gain in quality life of patients and their families, avoiding sequels, unnecessary suffering and high social cost. The therapeutic treatment these patients involve three basic tenets: reduce the exposure to the infectious agent, effective or prophylactic antimicrobial therapy, replacement of deficient immune functions (Garcia *et al.,* 2007). During the evaluation of PID is essential documentation of the patient's clinical history, frequency, duration and complications of infections, outbreaks of infection, microorganisms involved and response to treatment, and anatomical defects, allergic processes and metabolic disorders (Bonilla *et al.,* 2005). A detailed family history should be taken into consideration, since many PID are linked with X chromosome and the presence of children in maternal family with recurrent infections, or death in childhood due to severe infection indicates the possibility of PID. Initially, screening tests are indicated or initial and advanced testing as suspected PID (Sewell *et al.,* 2006). In general, immune assessment requires specialized laboratory and high financial cost, and it comes to pediatric patients, should be chosen methods that can be executed with low amount of blood (Oliveira & Fleisher, 2010). The diagnosis of some PID may be removed if they are used and selected screening tests such blood test for congenital neutropenia, leukocyte adhesion deficiency (LAD), severe combined immunodeficiency (SCID) and Wiskott-Aldrich Syndrome (WAS), or immunoglobulin's quantification in suspected predominantly antibody defects (Gill, 2002). The diagnostic criteria are divided into three categories, definite, probable and possible. In ensuring inclusion of patients with polymorphic variants in genes associated with PID and specific clinical and laboratory changes, the patient must meet all criteria characteristic of the disease (Conley *et al.,* 1999). The delay in diagnosis is often associated with limited access to specialized resources (Lindegren, 2004), is not unique to developing countries (Liang *et al.,* 2008), leading to large variation between numbers of cases (Stihem, 2004). In Finland, the common variable immunodeficiency (CVID) showed delay time diagnosis of 5 years in 2/3 of patients and 10 years in 1/3 these (Kainulainen *et al.,* 2001), in United Kingdom this delay was 6.2 years during 1989 to 1995, and decreased 3.5 years after implantation of government program to guide distribution of national guidance on recognition and diagnosis of PID, after a study

Primary Immunodeficiency Diseases in Latin America 361

of diagnostic centers and disinterest of private institutions in diagnosis of PID, regional variability access to educational program and establishment of diagnostic and treatment

**2. Difficulties in diagnosis, treatment and education of PID in Latin America** 

The main diagnostic centers in Argentina are located in Buenos Aires, and other centers are located in La Plata, Rosario, Cordoba and Mendoza. These centers are accessible and without cost to the community, provided that patients are referred by doctor. Private hospitals in Argentina offer only partial diagnosis, because no they have laboratories and professionals specialized in PID. Patients in Paraguay, Bolivia and Uruguay are also diagnosed and treated in Buenos Aires since these countries do not have adequate support. As their countries do not encourage their costs, or they do not have health insurance, this burden financially immunology centers in Argentina (Maceira *et al.,* 2010). Patients with PID who need IVIG are usually met in Buenos Aires, and treatment is not automatically continued in the pediatric patient who came into adults, it should be transferred from pediatric hospital to hospital for adults, interrupting treatment (Krasovec *et al.,* 2007). In Argentina, immunologists are not recognized experts by the Ministry of Health, and only two hospitals in Buenos Aires offer scholarships programs and post-graduate training in immunology funded by government agencies (Galicchio *et al.,* 2010; Condino-Neto

It is estimated that Brazil has 2,000 patients on treatment and approximately 20,000 patients with PID (Leiva *et al.,* 2007). Immunological diagnosis is supported by numerous centers located in São Paulo, Minas Gerais, Paraná, Rio Grande do Sul, Bahia and Rio de Janeiro (Grumach *et al.,* 1997; Leiva *et al.,* 2007). Centers located in southeast of country have specialized researchers, structure and molecular diagnostics. In Brazil, the federal government assists the movement of patients from regions without infrastructure to specialized centers, and coverage for certain screening tests of PID (Ocké-Reis & Marmor, 2010; Paim *et al.,* 2011). High costs and access to specialized laboratories are considered major problems by doctors for the diagnosis of PID (results available http://www.bragid.org.br/download/graphicos.pps), with strong educational, whose website presents PID centers throughout Brazil, journals, reviews and articles, case discussions, and announcements of meetings. This is supported by St. Jude's Hospital children and government agencies FAPESP and CNPq. Activities of this group include completion of first and second Summer School of PID by LAGID, implementation of Electronic Registration of Latin America Immunodeficiencies (http://imuno.unicamp.br:8080/) with installation of hardware in UNICAMP center computing support of ESID. The Federal University of São Paulo-UNIFESP, in partnership with Jeffrey Modell Foundation and Baxter International, created the first Jeffrey Modell Diagnostic Center for PID in Latin America; with goal of enabling physicians perform diagnostic, treatment and education of patients and PID cases reported in Brazil and Latin America. Patients with PID who need IVIG in Brazil receive government financial support, and not institutions or private health insurance, where patients should be initially admitted for diagnostic and treatment center. In Brazil, there are numerous funding agencies to residency

center (Pickett *et al.,* 2008; Condino-Neto *et al.,* 2011; Leiva *et al.,* 2011).

**2.1 Argentina** 

*et al.,* 2011).

**2.2 Brasil** 

conducted between 1996 to 2002 (Seymour *et al.,* 2005). To be assured diagnostic quality indicators should be generated which include patient registration data, which together form the field and field set and its variables called record. These cases are based registry designed to improve patient care, but are useful for studying diseases. An example is early records of 368 patients with chronic granulomatous disease (GCD) by American Foundation for Immunodeficiencies started in 1993, allowing a calculation of incidence of the disease for USA born in 1/200.000 (Winkelstein *et al.,* 2000). In 1997, this study has been expanded to Common Variable Immunodeficiency (CVID), Wiskott-Aldrich Syndrome (WAS), Severe Combined Immunodeficiency (SCID), Leukocyte Adhesion Deficiency (LAD), DiGeorge Syndrome, Hyper-IgM Syndrome (HIGM) (Winkelstein *et al.,* 2003) and X-Linked Agammaglobulinemia (XLA) (Winkelstein *et al.,* 2006), showing concern in development systems of records, population data for estimating incidence, prevalence and characteristics of disease. These data are important to maintain epidemiological studies and research and design of new clinical trials, reducing mortality, increasing survival and improved quality of life. In Europe, this service is performed by European Society for Immunodeficiency-ESID non-governmental organization that aims, to facilitate exchange of information between doctors, nurses, researchers, patients and their families, promote research into causes, mechanisms and treatment of PID (Sewel *et al.,* 2006; de Vries, 2006; Guzman *et al.,* 2007; Gathmann *et al.,* 2009). This group was established in 1993, Society in 1994, and receives data from 66 specialized centers in 26 European countries. In 2005 record showed amount of 10,000 patients from 26 countries with prevalence of 4-47/1.000.000, and the European internet-based patient and research database for primary immunodeficiencies results in 7,047 patients with PID in 30 countries (Knerr *et al.,*2008) and 7430 patients from 39 countries have been documented in the ESID database (Gathmann *et al.,* 2009).

In Latin America in 1993, was created the Latin American Group for Immunodeficiencies (LAGID) to study the prevalence of PID in different regions of Latin America and promote awareness of these diseases. There are also databases online with identification of mutations locus in specific cases of PID that are established by ESID and extended by others researchers. This was initiated in 1995 to collect data in Bruton's tyrosine kinase mutations (BTK) in XLA (Lindegren *et al.,* 2004). This occurred in Brazil, through the creation of Brazilian Group of Primary Immunodeficiencies (BRAGID), which through information campaigns, increased the number of 314 cases in 2000 to 536 cases in 2004 with Southeast region responsible for 70% total cases. Another relevant factor in understanding the epidemiology of PID is introduction of specialized care networks. In England there is the National Specialist Advisory Group Comissionary (NSCAG) of National Health System (NHS), which tracks PID complex cases, such the Great Ormond Street Hospital (Jones & Gaspar, 2000) and Newcastle General Hospital (Slatter & Gennery, 2010).

Several international initiatives are currently underway to promote awareness PID and increase number of diagnosis and registration of PID (http://www.primaryimmune.org/ resources/resources.htm) (Modell, 2007a; Modell, 2007b; Pickett *et al.,* 2008). Considering the increasingly frequent recognition of these diseases and their valuable contribution to understanding human immune system and mechanisms of defense against infections (more frequent medical care in worldwide) (Alcais *et al.,* 2009), it is essential establish the frequency and type in population (Casanova & Abel, 2007; Ballow *et al.,* 2009). The lack of proper diagnosis and treatment are the main problems in patients with PID in Latin America. These are related to lack of proper training of pediatrics, leading to misdiagnosis or late diagnosis, lack of proper screening, lack of government resources to implementation of diagnostic centers and disinterest of private institutions in diagnosis of PID, regional variability access to educational program and establishment of diagnostic and treatment center (Pickett *et al.,* 2008; Condino-Neto *et al.,* 2011; Leiva *et al.,* 2011).
