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Vulnerable Defenses

Doctors are mobilizing for early detection of diseases caused by failures in the barriers against microorganisms

Primary immunodeficiencies mainly affect infants

CLAUDIA GUIMARÃES / FOLHAPRESSPrimary immunodeficiencies mainly affect infantsCLAUDIA GUIMARÃES / FOLHAPRESS

Pediatricians, government representatives and researchers from Brazil and other countries gathered on the first Saturday of March to open a São Paulo School of Advanced Science on Primary Immunodeficiencies, at which they formalized the establishment of a consortium of medical reference centers for the diagnosis and treatment of the so-called primary immunodeficiencies (PIDs). These immunodeficiences consist of a cluster of approximately 180 rare diseases with a high rate of mortality that are characterized by a malfunctioning immune system. Because of the inability to produce immune cells or antibodies against viruses and bacteria, children and adults with PIDs are very susceptible to infections, even to those caused by microorganisms that are usually harmless in normal people; they may also develop autoimmune diseases, such as diabetes and cancer, more frequently than the general healthy population.

Formed to expand access to diagnosis and improve the treatment of these diseases, which are generally detected at a late stage, the consortium will initially consist of physicians and researchers from four population centers in the Northeast (Fortaleza, Natal, Recife and Salvador), two in the Central-West (Brasilia and Cuiabá), seven in the Southeast (Belo Horizonte, Rio de Janeiro, Campinas, Ribeirão Preto, Botucatu and two in São Paulo) and three in the South (Curitiba, Florianópolis and Porto Alegre). It is estimated that 160,000 Brazilians have PIDs, but only 2,000 are in treatment and more than 18,000 are waiting for a diagnosis.

As a first step, the group began publishing leaflets in Portuguese, English and Spanish with a list of 12 warning signs that can help pediatricians recognize primary immunodeficiencies at an early stage in the first year of life. These early signs include persistent infections or diarrhea, lack of a thymus, a gland of the immune system clearly visible on chest X-rays, skin lesions and intense reactions to vaccines with attenuated microorganisms, especially BCG, used against tuberculosis and administered a few days after birth (see table on next page).

“Since primary immunodeficiencies mainly affect infants, we can not wait for infections to repeat,” says Dr. Magda Carneiro Sampaio, a pediatrician and the PID group coordinator of the University of São Paulo (USP) Children’s Institute of the Hospital das Clínicas and the new consortium institutions. “We have to think about the first signs.”

The recommendations to pediatricians, now available on the Ministry of Health’s Web site, rely on a review of similar proposals and on 35 years of medical experience at USP and were published in 2011 in the journal Pediatric Allergy and Immunology. This is the latest proposal regarding warning signs and it focuses on the first symptoms of immunodeficiency, but it is not the only one. In 2009 the USP Ribeirão Preto physician and professor, Dr. Pérsio Roxo Júnior, published a list of 10 warning signs for the Brazilian Immunodeficiency Group in the Brazilian Journal of Pulmonology. Adapted from the proposal presented in 1999 by the US based Jeffrey Modell Foundation and the American Red Cross, the set of measures included “two or more pneumonias within the last year,” “four or more new ear infections within the last year” and “a family history of immunodeficiency.”

BCG risks
The inability to produce immune cells or antibodies can be detected through a simple blood test, says Dr. Sampaio. Similarly, some simple precautions could help reduce the number of deaths that usually accompany these diseases. According to her, before administering mandatory vaccines such as BCG, nurses should always ask those responsible for the baby’s care if they are aware of any children in the family who died from infections or know of cases of intermarriage among close relatives, which can facilitate the emergence of these diseases, which are almost always genetic in origin.

“In the event of uncertainty, it is best not to vaccinate and forward the case to a reference center for diagnosis and treatment,” says Dr. Sampaio. “Children with primary immunodeficiencies should not be vaccinated.” Vaccines can be fatal to infants whose bodies are unable to produce immune cells or antibodies against bacteria or viruses. “We are in the process of educating doctors to pay more attention to these problems, because most children with primary immunodeficiencies die from infection or septicemia before they are correctly diagnosed,” she says.

Based on the frequency of PID in the population of the United States (one case per 1,200 people), it is estimated that there are 160,000 people with PIDs living in Brazil, of which 34,000 are in the state of São Paulo, but only 3,000 have been diagnosed. A study published in the January issue of the Journal of Clinical Immunology examined 1,008 cases of children and adults from across the country diagnosed and treated between 1978 and 2011 at the USP Hospital das Clínicas. It was the largest national survey — and one of the largest in the world — done at a single medical center.

In this study, doctors identified 62 different types of primary immunodeficiencies. A deficiency in the production of antibodies — especially immunoglobulin A (IgA) — represented the largest category (61% of the total). The percentage of deficiency in the production of antibodies showed an increase with age ranges, from 15% in the group of children up to age 2 to 84% in the group of people age 30 and over.

As expected, since most severe PIDs are caused by a malfunction of the X chromosome genes, male infants and men predominated (566 cases or 56% of the total), although the gender distribution varied greatly among age groups. Boys constituted 75% of the patients under age 2 and 64% in the group ages 2-5, while women predominated (58%) in the group age 30 and over.

Once diagnosed, several primary immunodeficiencies can be treated by administering monthly doses of antibodies, in the form of gamma globulin, available from the public health network. The most serious cases involve the transplantation of hematopoietic stem cells, offered in three medical centers connected to the Unified Health System (SUS). “Usually we use cord blood cells stored in public banks, but in some cases it is possible to use stem cells extracted from the bone marrow of siblings. It is a therapy with a high success rate, which enables a child to lead a normal life in the future,” says Dr. Sampaio. Antibiotics fight infections, at doses similar to those used in persons with normal immune systems, but generally for a longer period of time.

Neonatal screening
At the São Paulo School of Advanced Science on Primary Immunodeficiencies, the international meeting supported by FAPESP that followed establishment of the consortium, Dr. Jorge Andrade Pinto, a professor at the Federal University of Minas Gerais (UFMG), announced a pilot project to track a group of diseases known as severe combined immunodeficiency diseases (SCID), which reduce B and T lymphocyte production and leave infants highly susceptible to infections. Examinations are expected to begin ​​in the second half of this year at the Hospital das Clínicas, with funding from the Ministry of Health. A similar neonatal screening project for PIDs has been in progress since 2010 in São Paulo.

If infected, the scar left by the BCG injection may indicate a deficiency of the immune system

SCIENCEPHOTOLIBRARY / GLOW IMAGESIf infected, the scar left by the BCG injection may indicate a deficiency of the immune systemSCIENCEPHOTOLIBRARY / GLOW IMAGES

“We intend to evaluate 250,000 newborns in 12 months,” he told Agência FAPESP. Based on the prevalence reported in US studies, one case per 35,000 screened, Dr. Pinto expects to find 5 to 10 newborns with SCID and other serious diseases characterized by a reduced lymphocyte population in the blood. In the United States, 20 infants with SCID were identified through neonatal screening, which is routinely performed in most states. “Certainly, many babies died undiagnosed,” said John Routes of the Children’s Hospital of Wisconsin. “If the disease is discovered before the baby gets sick, the chances of being cured are 90% to 95%.”

The causes and types of treatment for some forms of primary immunodeficiencies are still poorly understood. Such is the case of hemophagocytic lymphohistiocytosis or HLH, in which macrophages eliminate other defense cells. In one of the presentations, Geneviève Saint-Basile and Fernando Sepulveda, both of the Necker Hospital in Paris, demonstrated advances in the study of mice in which they were able to induce the disease in a manner similar to the disease in humans. According to them, the overactivation of macrophages can be caused by an infection of the Epstein-Barr virus (EBV), a virus that infects B lymphocytes, generally without major consequences, and can cause some types of cancer, especially in adults.

“Adults may also have primary immunodeficiencies, which are generally less severe than those of children,” says Cristina Kokron, one of the coordinators of a clinic of the Hospital das Clínicas (HC), which in the last 15 years has treated 840 adults with suspected PIDs, most having already been diagnosed (449 cases) with antibody production deficiencies (398 cases). Often infections persist for decades before being linked to the inability to produce cells or antibodies capable of stopping the infectious microorganisms. One of the 155 patients receiving intravenous immunoglobulin every month was 81 years old and had suffered from constant diarrhea since childhood. “In adults,” says Kokron, “infections caused by a deficiency in antibody production are not always fatal.”

The use of medications that weaken the body’s defenses, such as corticosteroids, were the cause of 58 cases of immunodeficiency (secondary) treated at the USP hospital. “All doctors should pay close attention to the side effects of the medications they prescribe, because the consequences can be dramatic,” warns Kokron.

Of the 14 adults with agammaglobulinemia, a type of PID, nine came from the HC Children’s Institute, indicating that children who once died are now surviving. In one study, Kokron, Ana Karolina Oliveira and Maira Pedreschi found that the flu vaccine administered to 22 adults with antibody production deficiency helped to reduce the frequency of colds, sinusitis and pneumonia, as well as the use of antibiotics, even though it did not stimulate antibody production against the influenza virus.

1.  Autoimmunity in children: investigation of the molecular and cellular bases of early onset autoimmunity (20008/58238-4); Coordinator Magda Maria Sales Carneiro Sampaio – FM-USP; Grant Mechanism Thematic Project; Investment R$1,827,061.70 (FAPESP).
2. São Paulo Advanced School on Primary Immunodeficiencies (2012/50308-9); Coordinator Magda Maria Sales Carneiro Sampaio – FM-USP; Grant Mechanism São Paulo School of Advanced Science; Investment R$354,969.80 (FAPESP).
3. Evaluation of Th17 profile in Common Variable Immunodeficiency (CVID) patients with and without autoimmunity (2011/22076); Coordinator Cristina Maria Kokron – FM-USP; Grant Mechanism Regular Line Project Assistance Research; Investment R$108,770, 83 (FAPESP).

Scientific articles
CARNEIRO SAMPAIO, M. et al. Primary immunodeficiency diseases in different age groups: a report on 1,008 cases from a single Brazilian reference center. Journal of Clinical Immunology. 2013 (online).
CARNEIRO SAMPAIO, M. et al. CARNEIRO SAMPAIO, M. et al. A proposal of warning signs for primary immunodefciencies in the first year of life. Pediatric Allergy and Immunology. v.22, p. 345-6. 2011.
ROXO, P. Primary immunodeficiency diseases: relevant aspects for pulmonologists. Brazilian Journal of Pulmonology. V. 35, p. 1008-1117. 2009.