The sergeant and physician of the American army Ogden Bruton became intrigued when, in 1952, he came across an 8-year old boy with constant serious respiratory infections. Medicines would produce temporary results and the pneumonias would not take long to reappear, even more intense. When investigating the case, Bruton was surprised: the boy’s immune system did not produce the antibodies called gamma globulins, which help to protect the organism from invaders like viruses, funguses and bacteria. This report by the American doctor inaugurated the studies about primary immunodeficiencies, today a group of over a hundred diseases that mainly affect children, leaving them more vulnerable to infections.
More common than is imagined, these immunodeficiencies affect about 3 million people in the world and almost 90 thousand in Brazil alone. Even so, they are little known, even to doctors, because their most obvious signs, which in general arise in the third year of life, are mistaken for those of children’s humdrum problems.
The specialists are recommending pediatricians to forward the children they assist for more detailed examinations, should they show two or more episodes of pneumonia or eight or more episodes of ear infections (otitis) in the period of one year; use antibiotics for two months or more without there being the desired effect; show frequent abscesses on the skin or in other organs; have persistent thrushes or lesions on the skin after the first year of life; show difficulty in gaining weight or in growing normally; need an intravenous antibiotic to cure infections; show two or more serious infections like meningitis, osteomyelitis and septicemia or a family history of immunodeficiency.
The difference between what in normal in childhood and immunodeficiencies is that these infections are more frequent and difficult to combat. As a consequence, those who have the problem and do not know may not get proper treatment or may take medicines without any need. In the more serious cases, they may even die.
Causes
In spite of the name in common with the most well-known of the immunodeficiencies – the acquired immunodeficiency syndrome, or Aids -, the primary immunodeficiencies show a very different origin. “People with primary immunodeficiency are already born with defects in the workings of the defense system, caused by genetic faults, while in Aids the immune system is destroyed by the HIV, an external agent”, explains pediatrician Magda Carneiro Sampaio, from the Children’s Institute of the São Paulo Hospital and Clinics.
Magda coordinates a group of researchers from the University of São Paulo (USP) and from the Federal University of Federal de São Paulo (Unifesp) that is investigating the characteristics of primary immunodeficiency in the Brazilian population and has started a campaign to warn pediatricians about this problem. This team recently identified new defects in genes associated with a specific kind of primary immunodeficiency: chronic granulomatous disease.
Discovered in the 1950s by American physicians Robert Good and Charles Janeway, this ailment jeopardizes the functioning of some types of defense cells of the organism and leaves children more inclined to develop serious infections. In partnership with researchers from Chile, Colombia, Mexico, the United States, and, in Brazil, from Campinas, Rio de Janeiro and Ribeirão Preto, Magda’s team carried out tests on blood samples from 14 children and adults with chronic granulomatous disease – there were 10 Brazilians, 2 Mexicans and 2 Chileans.
Half of the participants in the study showed small defects in the NCF1 gene, according to the analyses done in USP’s Human Allergy and Immunodeficiencies Laboratory and in the Molecular Biology and Cell Culture Laboratory at the State University of Campinas (Unicamp), headed up by Antonio Condino Neto. Located in chromosome 7, the NCF1 genes lead to the production of an enzyme that assists the defense cells to eliminate bacteria, throwing onto them highly toxic molecules, known as free radicals. In the other half of the victims of chronic granulomatous disease, the faults or mutations, including two hitherto unknown, were in the CYBB gene. Located in the X sex chromosome, this gene contains the recipe for another protein essential for the production of the free radicals used against foreign microorganisms.
Described about in a scientific article published in this month’s issue of the Pediatric Blood and Cancer magazine, these defects impair the functioning of the most abundant defense cells in the organisms, the neutrophils. Produced in the inside of the long bones of the body in a quantity of 100 billion per day, the neutrophils generally circulate in the blood for only eight hours, like watchmen standing guard over a castle.
When bacteria invade the organism of a healthy person, the neutrophils quickly penetrate the tissues, envelop them and destroy them efficiently. Mutations in one of these genes, though, eliminate the power to fight of these defense cells and leave vulnerable to the invaders the main entry doors of the body: the skin and the mucous membranes of the digestive and respiratory apparatuses.
As the disease is of a genetic origin, the only way of curing the person is to be submitted to a bone marrow transplant, an expensive procedure that does not always produce the desired effects in the case of chronic granulomatous disease. The treatment in general is done with sulfamethoxazole-trimethoprim and antifungals, used continuously to fight the infections already installed and also to prevent the occurrence of others. “The expectation is that in a few years this problems can be treated with gene therapy currently being tested in Germany, but still distant from the patients’ reality”, comments pediatrician Beatriz Costa Carvalho, from Unifesp, a member of the group.
Until gene therapy arrives, the identification of mutations like those discovered by the team from São Paulo contributes towards the perfecting of the diagnosis of chronic granulomatous disease. Examinations carried out at USP and at Unicamp confirmed 41 cases of this disease in the last five years. “As there are various mutations associated with this problem, we intend to investigate how genetic alterations influence the clinical picture, which would facilitate diagnosis and treatment”, says Condino Neto.
The precise identification of the genetic defect behind immunodeficiency makes it possible for the doctor to find out the most suitable moment for starting the use of medicines. It is also useful for counseling couples. An example facilitates understanding. Chronic granulomatous disease can be caused by about 400 different mutations in five genes, each one with a different probability of occurring.
The most frequent ones are the alterations in the CYBB gene, corresponding to 60% of the cases of this immunodeficiency. As this gene is found in the X chromosome, women carry in their cells two copies of the CYBB, while men have only one. In a couple, if the husband does not have the immunodeficiency – hence his copy of the gene has not suffered mutations –, but his wife shows one unaltered copy and the other defective, the probability of having a sick male child is 25%. “It is an extremely high risk for a disease for which the mortality rate is high”, says Condino Neto, who began to investigate the genetic defects of chronic granulomatous disease almost ten years ago.
There is no lack of reasons to justify the quest for more precise techniques for identifying primary immunodeficiencies. Children with chronic granulomatous disease and other genetic ailments that debilitate the defenses of the organism – like severe combined immunodeficiency, in which the body produces neither defense cells nor antibodies, or makes them in an insufficient quantity – usually should not be given some of the vaccines applied in the early months of life.
Vaccines like BCG, produced from a bacterium to prevent tuberculosis, or Sabin vaccine, made with the virus of infantile paralysis itself, can put the bearers of immunodeficiencies at risk of dying. The possibility is great of the components of these vaccines, even when attenuated, setting off severe infections in these people, since their defense systems are naturally debilitated. According to Beatriz, one in every three children with severe combined immunodeficiency that take BCG can develop severe fatal reactions.
Underdiagnosis
“It would be easy to avoid this risk if soon after the childbirth, during the Guthrie test to detect phenylketonuria and hypothyroidism, one drop more of blood were taken to assess the child’s immune system”, says Condino Neto. Simple measures like this would reduce the risks for the immunodeficients and would help to identify with more precision who ought to be given treatment already in the early years of life.
Although it is estimated that one in every 2 thousand persons may show one of the forms of primary immunodeficiency – which would correspond to 90 thousand victims in a population of 180 million -, there are only 700 cases registered by the Brazilian Group of Immunodeficiencies (BRAGID in the Portuguese acronym), an organization that brings together 1,800 doctors dedicated to the study of the immune system.
Another fact reaffirms the suspicion of underestimated diagnosis: it is calculated that 1,200 children are suffering from severe combined immunodeficiency, resolved only with a bone marrow transplant, a procedure with a high cost usually carried out before the second year of life. However, from 1992 until now, the Bone Marrow Transplant Center of the Federal University of Paraná, one of the few that carry out this procedure in Brazil through the Centralized Health System, has done only 32 transplants to treat primary immunodeficiencies. “Many children may be dying for the lack of a correct diagnosis”, Beatriz laments.
Even the most frequent forms of immunodeficiency – the production of defective antibodies, which is treated with monthly injections to replace these components of the immune system and corresponds to 60% of the cases of primary immunodeficiency – seem to pass unnoticed in the doctors’ offices and first aid posts. Last year, the Brazilian Group of Immunodeficiencies carried out a survey with 34 thousand pediatricians from all over the country. The objective was to assess what they knew about primary immunodeficiencies.
Ten signs – To sum up, there is a lot to be done in terms of medical education. Of the 3,047 pediatricians who answered the questionnaire, 30% had learnt nothing about primary immunodeficiencies as undergraduates or as medical residents in pediatrics. Even after specialization, two out of every ten pediatricians had never heard of primary immunodeficiency, although 97% of them had attended to children with repeated infections, one of the signs of the problem, and 20% did not know that children with primary immunodeficiency should not be given vaccines produced from live microorganisms.
To change this scenario, the Brazilian Group of Immunodeficiencies started an educational campaign and fed its page on the Internet (www.imunopediatria.org.br) with information for physicians. It also sent 34 thousand pediatricians a card with ten signs associated with primary immunodeficiencies, suggesting they forward for detailed examinations their patients with at least one of the symptoms: two or more pneumonias or eight or more ear infections in one year; the use of antibiotics for two months or more without the desired effect or of an intravenous antibiotic to fight infections; frequent abscesses; aphthae or persistent lesions on the skin after the first year of life; difficulty in gaining weight or growing normally; two or more severe infections like meningitis, osteomyelitis and septicemia or a family history of immunodeficiency. “Disseminating information to physicians”, says Magda, “is the main way for transforming primary immunodeficiencies into a public health issue, as happened with Aids”.
The drawings that illustrate this article were done by children attended to by researchers at the Children’s Institute of the São Paulo Hospital and Clinics.
The Projects
1. Primary immunodeficiencies in pediatric patients at risk (nº 02/05880-4); Modality Thematic Project; Coordinator Magda Maria Carneiro Sampaio – USP; Investment R$ 625,319.95
2. Standardization of the method for evaluating in vitro cell immunity (nº 04/04472-5); Modality Regular Line of Grants for Research Projects; Coordinator Beatriz Tavarez Costa Carvalho – Unifesp; Investment R$ 31,900.70
3. Molecular genetic defects of chronic granulomatous disease (nº 01/14365-3); Modality Regular Line of Grants for Research Projects; Coordinator Antonio Condino Neto – Unicamp; Investment R$ 217,613.74
