Consortium wants to improve diagnosis of primary immunodeficiency

The idea is to facilitate the exchange of ideas among the country’s leading resource centers and to conduct human resources training.

By Karina Toledo

Agência FAPESP – With the intention of improving the diagnosis and treatment of primary immunodeficiencies – a heterogeneous group of diseases related to more than 180 genetic defects that cause poor functioning of the immunological system – local scientists have created the Brazilian Consortium for Reference and Training in Primary Immunodeficiencies.

The group’s first meeting, which brought together four centers in the Northeast (Fortaleza, Natal, Recife, and Salvador), two in the Midwest (Brasília and Cuiabá), and seven in the Southeast (Belo Horizonte, Rio de Janeiro, Campinas, Ribeirão Preto, Botucatu, and two in São Paulo), was held on March 2 during the activities of the 2nd São Paulo Advanced School of Sciences in Primary Immunodeficiencies (ESPCA-PID), an event funded by FAPESP.

“The idea is to facilitate the exchange of ideas among these centers and to conduct human resources training. Additionally, we are going to organize the treatment offered in the Unified Health System (SUS), establishing a line of care for children with several levels of assistance,” explained Magda Carneiro-Sampaio, professor of Pediatrics at Universidade de São Paulo’s Medical School (FM-USP) and one of the creators of the consortium.

According to Carneiro-Sampaio, the professors invited to participate in the 2nd ESPCA-PID also helped define public policies regarding primary immunodeficiency patients.

One of the group’s first measures will be to disseminate, with the assistance of the Ministry of Health, a list of 12 signs that could indicate a primary immunodeficiency disease in an infant’s first year of life to primary-care pediatricians. The list includes serious or persistent infections, adverse reactions to vaccines with live viruses, congenital cardiopathies, persistent diarrhea, and a family history of immunodeficiency or sudden death by infection.

The list was originally published in Pediatric Allergy & Immunology magazine in 2011 by doctors from FMUSP. The creation of the list was coordinated by Carneiro-Sampaio; the list is the result of a FAPESP-funded study and the group’s 35 years of clinical experience.

“When the front-line doctors suspect a primary immunodeficiency, they should send the patient to one of the specialized centers so that diagnosis and treatment can occur. However, the main thing is to call the problem to the attention of doctors because the majority of children affected die without a diagnosis,” explained Carneiro-Sampaio.

It is estimated that primary immunodeficiency diseases affect one in 1,200 people worldwide. In Brazil, therefore, there should be approximately 165,000 carriers of these diseases, but only 3,000 cases have been diagnosed at present. Recently, the Pediatrics Department (Children’s Institute) and the Departments of Clinical Medicine and Dermatology at FMUSP published an article detailing 1,008 cases of well-defined primary immunodeficiency diseases, which could represent the greatest series in a single center ever published.

In the case of serious primary immunodeficiency diseases, which if untreated lead to death in infected individuals, it is estimated that 250 new cases emerge yearly in Brazil. The majority of these individuals die without being diagnosed.

“In order to reduce infant mortality in Brazil, which is still high, we cannot just invest in vaccination campaigns against polio and basic sanitation. That phase is over. Now is the time for diagnosing genetic diseases and improving neonatal assistance,” opined Carneiro-Sampaio.

With the diagnosis made, it is possible to treat patients with gamma globulin, the main substitution therapy for antibody deficiencies that has been broadly disseminated within the public health network. The recommendation for more serious cases is hematopoietic stem cell transplantation, a treatment that is currently offered by SUS at three centers in Brazil but will be expanded.

“Normally, we use umbilical cord cells stored in public stem cell banks, but in some cases, it is possible to use stem cells from siblings. It is a therapy with significant chances of a cure that allows children to have a normal life in the future,” commented Carneiro-Sampaio.

Pioneering initiative

Since 2001, the Brazilian Primary Immunodeficiency Group has been working to promote continuing education for doctors, dissemination of warning signs for these diseases, and the development of a network of laboratories and specialized centers nationwide to improve the diagnosis and treatment of primary immunodeficiency diseases. This group was created through the initiative of Beatriz Tavares Costa-Carvalho, from Universidade Federal de São Paulo (Unifesp). Today, the group has more than 4,000 doctors registered.

In 2007, the initiative gained the support of the Jeffrey Modell Foundation for Primary Immunodeficiency, one of the world’s most important resource centers in the area. This allowed for implementation of a Latin American Registry of Immunodeficiencies, coordinated by Professor Antonio Condino Neto, from the Immunology Department at USP’s Biomedical Sciences, which contains more than 4,000 cases. 

Neonatal tracking

In 2010, Brazil inaugurated a FAPESP-funded neonatal triage project on serious primary immunodeficiency diseases through the initiative of Condino Neto and in collaboration with Unifesp researchers. The objective is to improve diagnosis of a group of diseases known as Severe Combined Immunodeficiency Disease (SCID), so-named because they affect both the system of lymphocyte B production and T cells, leaving babies highly susceptible to infection. If untreated through medication or hematopoietic stem cells in the first year of life, the infirmity is 100% lethal. 

In the first stage of the project, held during Marília Pyles Patto Kanegae’s postdoctoral studies, approximately 2,000 babies born in hospitals within the complex of Unifesp hospital schools were examined, and two suspected cases were diagnosed.

"Currently, our project is in the second stage, going large scale. Through a partnership with APAE in São Paulo, we intend to submit 250,000 children per year to triage. Instead of conducting exams at USP, we will transfer equipment to the APAE laboratory. The cases detected will be handled in Unifesp’s Pediatrics Department,” explained Condino Neto.

In the second half of 2013, another neonatal tracking project will begin at Hospital das Clínicas, the hospital school of Universidade Federal de Minas Gerais, which is funded through a partnership between the Brazilian Ministry of Health and the U.S. Centers for Disease Control (CDC). 

“We intend to evaluate 250,000 newborns participating in the Minas Gerais’ neonatal triage program over a 12-month period. Judging from the prevalence found in the U.S. studies – 1 case in 35,000 – we estimate that we will find 5 to 10 newborns with SCID and other serious lymphopenias in this project,” said Jorge Andrade Pinto, a professor in UFMG’s Department of Pediatrics.

In the United States, neonatal triage is being conducted routinely in the majority of states, having begun in Wisconsin in 2008. The result of this work was presented by John Routes of Children's Hospital of Wisconsin during the 2nd ESPCA-PID.

“Throughout the United States, 20 babies have been diagnosed with SCID thanks to tracking. If you look at the numbers of states where this test is conducted, the incidence is 1 in every 50,000 live births. However, the estimate according to national records of known cases was one in 100,000. There are certainly many babies that died without being diagnosed,” commented Routes to Agência FAPESP.

According to the researcher, babies who are SCID carriers have a normal appearance, which makes detection of the problem with a simple clinical exam difficult. “If the disease is discovered before the baby gets sick, the chance of a cure is 90% to 95%. In addition to saving lives, tracking allows for identification of new causes of the disease. We have discovered unexpected genes related to the development SCID,” he noted.

The test for diagnosis of the disease is conducted with the same blood collected from newborns for the traditional neonatal heel prick test, which aims to detect congenital diseases such as phenylketonuria. Everything is analyzed in the same laboratory.

“There are diverse genetic mutations that could cause SCID, but all have a common result: a very low number of T cells, which are extremely important for cellular immunity. The test that we apply can detect whether the number of T cells is normal or not. When it is altered, the family is called and subjected to a blood test to confirm the diagnosis,” commented Routes.

In the United States, according to Routes, the test costs an average of US$ 5. According to Condino Neto, in Brazil, the test costs approximately R$ 15 and can also be used as a method of diagnosis in the postnatal period. “If there is a suspicion of immunodeficiency in the first months of life, it is a low cost method that can rapidly identify the disease,” he said.