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Charles Naspitz

Charles Naspitz: Epidemic in the air

Child allergy expert talks about the challenge of understanding and treating asthma

miguel boyayanIn March 2007, the São Paulo doctor Charles Naspitz received a surprising letter from the AAAAI, the American Academy of Allergy, Asthma and Immunology, the world’s most prestigious organization in this field. The letter informed him that a study of his published in 1968 had been considered one of the six most important articles – and the only one by a Latin American – in the field of allergy and immunology in the last 40 years.

In this study, which he conducted while doing his master’s degree at McGill University in Canada, Naspitz showed, for the first time, that  grains of pollen cause morphological changes in lymphocytes, the defense cells that identify and help to eliminate infectious microorganisms or alien substances from the body. This discovery led to the identification of other cell mechanisms in the in vitro response to ragweed, a pollen to which the patients were sensitive.

Having returned to Brazil after two highly productive years, during which he published a total of 17 scientific works, Naspitz provisionally took over the immunology area at the Paulista Medical School, currently part of the Federal University of São Paulo (Unifesp), from where he had graduated in 1959. After proving to himself that he could do relevant work provided he had the necessary conditions, he showed that it is also possible to do a lot even in the absence of such conditions. At Unifesp, he organized the allergy, clinical immunology and rheumatology discipline and helped to train a generation of specialists in these fields. He published a total of 162 scientific articles and 4 books that are benchmark references in these fields. Three of them were only published in English.

A father of three children and grandfather of five, Naspitz is celebrating his 73rd birthday this month. He is currently regarded as one of the most important experts in children’s immunology and allergies in Brazil. Officially retired since 2005, he continues to appear at the university, though less often than during the previous 54 years. In the interview below, he talked about the epidemic of respiratory allergies that affects the entire world, its possible causes and the harm people and society suffer when they are improperly treated.

In the last few decades, allergies, especially the respiratory ones, such as asthma and rhinitis, have been on the rise, worldwide. Why?
In the last 30 or 40 years, in some countries, there has been an epidemic that has reached a plateau. We don’t know why, but there are some attempts to explain this. One of them is called the hygiene hypothesis, put forth by English researcher David Strachan in 1989. He said that the western way of living has caused water to be chlorinated and food to be sterilized, antibiotics to be used for prophylactic reasons and sewage systems to be built. In sum, we began living in an environment with an unprecedented level of hygiene. Probably, part of the immunological gear, designed to protect us from  environmental aggression, now eliminated by hygiene, found itself at loose ends, ready to fight allergens [substances that induce allergy], such as pollen and certain foods. The hypothesis states that by eliminating a certain number of microorganisms, one is freeing the immune system to focus on other activities.

Do you believe this?
It may be valued in certain western countries. In South America and in Brazil, however, hygiene is not that great: there is a shortage of sewage systems, but still the prevalence of asthma is very high – it’s the second or third highest in the world. Perhaps the hypothesis is regionally applicable and unable to cover all the variations of everything going on. It is an ingenious theory that has opened a vast field of research. Some parasites have probably accompanied man since the earliest days of evolution and co-exist with man very well to this day. It is said that parasites are the disgrace of the immune system, because they cannot be eliminated by it.

These are organisms that are more complex that a bacterium.
Yes, and they’re strange. The immune system works within a rationale of self and non-self. In other words, of what belongs and what does not. It has an obligation to recognize what doesn’t belong and eliminate it. That is why transplants are a problem. When you transplant a kidney from one person to another, the kidney is recognized as a foreign element and rejection occurs. The parasites, however, have found a way to live within humans. The body makes a protein called lgE. It’s a type of immunoglobulin against parasites and allergens. Parasites have virtually disappeared in Europe, the United States and Australia, in the world of Anglo-Saxon culture, basically. Eastern Europe was not well known for hygiene, but now things are changing. The prevalence of allergies in Africa is low, probably because of the widespread parasitosis in its population.

How does IgE work?
It appeared millions of years ago to protect man from parasites. In fact, it tries to do this because it is unable to destroy them. As soon as any parasite is present, lgE production rises. The normal lgE level in advanced countries goes up to 100 kU/L (thousand units per liter). Our normal level, however, is higher: in Brazil, some 300 to 400 kU/l are the norm, because of the large number of adults with parasites. When we determine total lgE, we don?t know what it is targeting: parasites or other allergens.

There is a proposal to use parasites as a form of therapy. Might this be useful here?
Certain centers have been putting forth this treatment proposal. Our bodies make lgE antibodies against the schistosome, the worm that causes schistosomiasis, which is a public health problem in Brazil. This parasite, which is large, is in the intestine. The lgE sticks to the parasite’s wall and phenomena similar to those involving the elimination of bacteria take place. However, the schistosome is smarter. When the lgE hits it, it changes the structure of its wall, so that the original antibody stops working. A new antibody becomes necessary and the process starts all over again. What happens – and this is what we forget – is something called evolutionary pressure. This also applies to parasites and bacteria, which have learnt that the more similar they become to our organism, the less likely they are to be rejected. There are theories that can explain diseases such as ulcerative colitis, caused by the bacterium Escherichia coli, which is not eliminated because it creates a shield with a lot of human antigens, so that the body doesn’t recognize it as foreign, allowing it to proliferate. This is the result of the so-called evolutionary pressure on single-cell beings.

Can genetics explain the rising incidence of allergies?
No. Genetic factors, for instance, can’t explain changes that have taken place over 30 or 40 years. As far as genetics are concerned, this is minutes. Some countries, like the Scandinavian ones, have virtually pure populations. But Brazil is a genetic melting pot; there is none like it in the world; there’s a mixture of everything, so that the genetics of Brazilians are different from that of other people – different in terms, because we’re all 99% the same as mice – and there were no great advantages. We don’t know why there is this epidemic; we haven’t found a clear, transparent reason.

How prevalent are allergy problems in Brazil?
The latest SUS [Single Health System] data show that 350 thousand people are hospitalized for asthma in the country a year. It’s the fourth highest reason for hospitalization, accounting for two or three percent of the total. It is also the third main reason among children and youngsters. In 1996, asthma hospitalization costs amounted to R$ 76 million, or 3 percent of the total spent on hospitalization. Childbirth comes first. Actually, the prevalence of allergic diseases wasn’t really known until a study appeared called ISAAC [International Study of Asthma and Allergies in Childhood]. Created in New Zealand, it was based on a standardized questionnaire that was validated worldwide. The study determined the prevalence of allergic diseases among children and adolescents. It is carried out in two age groups: 7 to 8 years old and 13 to 14. The prevalence of asthma ranged from 3% in Albania to 30% in England.

Was this questionnaire used in Brazil?
The first ISAAC was carried out here seven years ago. Then there was a second one. It’s a worldwide survey, conducted by researchers from each country. In Brazil, for instance, prevalence varies widely according to the region. There isn’t much of an explanation for this. Certain cities are on the coast, others are not, but the prevalence of asthma in Brazil is around 20 to 25%, taking children and adolescents into account. We have no data on adults.

Isn’t it a very high figure?
Yes. Australia, New Zealand and England top the list; in second place, we have the United States, and in third, Brazil and Peru. This concerns the prevalence of asthma. The prevalence of allergic rhinitis has been increasing a lot. In certain cities, like Salvador, it is as high as 40%.

Might the cause be related to factors such as pollution?
It’s hard to tell. In the rural areas prevalence is lower than in urban areas. But asthma has existed for over two thousand years, when there was no pollution. Some years ago, when the two Germanies came together, there was a unique opportunity for epidemiologists to study the issue. For the first time there were genetically homogenous populations that had lived in different environments for more than 50 years. West Germany had a high standard of living and was clean. East Germany was thoroughly dirty, very polluted. The epidemiologists conducted a study on prevalence and found that in East Germany asthma was less frequent than in West Germany. Pollution as an isolated factor would not explain this prevalence.

In Brazil, prevalence is a little higher in the urban areas than in the rural ones and asthma affects the poorer people. Can we see a pattern in this?
Outside Brazil, higher social classes are more affected, epidemiologically speaking. However, there is a study by Antonio Carlos Pastorino, from the Clínicas Hospital in São Paulo, carried out in the city of São Paulo, in which he shows that social class does not influence asthma prevalence. There is also a study by Dirceu Solé, from Unifesp, who is in charge of ISAAC in Brazil. In an article published in 2006, he compares phases 1 and 3 of the ISAAC study – there is a seven-year gap. The prevalence of asthma was 27.7% seven years ago, and now it is 20%, a statistically significant difference. But severe asthma remains unchanged, at 5.2%, as is also the case of night coughing, 32%. The study’s conclusion was that Brazil had a small, but significant, reduction in the prevalence of two asthma symptoms: wheezing and night coughing. However, the trend was not consistent across all cities studied: it went up in one, down in another, etc.

Why, after all, is asthma a challenge for medicine?
Because it is a syndrome with dozens of causes. Some are known, others are not. Besides, one asthmatic person is quite different from the next, and not all people with asthma are allergic.

What changes from one person to the next?
Some maintain normal hygiene and we are unable to identify any allergen. These are the so-called non-atopic asthmatic persons. We don’t know what causes their asthma. There is non-atopic rhinitis. There is a study in Rio Grande do Sul involving a very poor population, with a high level of parasites, in which most of the asthmatic people were non-atopic. Their conclusion was that the parasitosis protected people from allergic diseases. But this doesn’t mean that allergic diseases are indeed allergic. They are called allergic in general terms, but often one cannot find their causes. For instance, in the case of chronic hives, which mainly affect women, only 30% have their cause diagnosed. In 70% of the cases one has no idea what is happening.

How should this be treated?
You treat the symptoms. We use several drugs and we can control the diseases, but we can’t cure them.

Is there anything in common among the “non-allergic” allergic diseases?
There is a lot of divergence among the doctors. The inflammatory process within the lungs is the same, but the cause has not been identified. One classifies an individual as atopic, or as allergic, when this person has a positive result for an allergen. One tests for acari, dog and cat fur; in sum, one conducts a battery of tests and if one of them is positive the person is considered atopic. When we put the allergen on the skin, the IgE causes a local reaction. That local reaction is similar to what we would see in the breathing system or in the intestine. But we can carry out 500 tests with an individual and the allergen to which this person is allergic may be a substance not included in the battery of tests. This patient would be classified as non-atopic. Recently, in Finland, they identified a number of children that tested positive for acari. However, they have no symptoms and are called by researchers “exposed children with a positive response.” It doesn’t mean they are allergic, because they only have that marker, with no symptoms. It might be that in the future they may develop allergies, but at that time they had none. They say that calling these people allergic is an exaggeration. Do you know what the definition of a normal individual is? It’s the person who hasn’t been sufficiently investigated. Because we don’t know whether or not this person is normal.

Recently, has there been any change in how asthma and rhinitis are treated?
In Brazil, 90% of the population is treated by SUS [the state-run single healthcare system], in hospitals that are broke and poorly equipped. Asthma, like all chronic diseases – ulcer, hypertension – demands what we call a doctor-patient relationship. We establish a connection that should cover emotional needs. My patients haven’t been hospitalized for asthma in years. We agreed that as soon as the first symptoms appear, we’ll use early-stage medication, so that we don’t get to a hospitalization situation. But in most cases this is not what happens. Every time a child or an adolescent goes to a SUS clinic, after waiting in line, he or she sees a different doctor. If this doctor is in a good mood, he or she will give the patient five minutes  attention. Afterwards this patient will return, in a crisis, and find a different doctor, who will provide different guidance. For as long as these children are not treated within a consistent doctor-patient relationship, there is no way to solve the problem in Brazil.

miguel boyayanIs there no model, an alternative within the healthcare system?
At the clinics that provide care for private patients, yes. At SUS, no. Most consulting physicians see patients that have private healthcare plans that pay them, at best, some R$20 to R$30 per consultation; the doctor therefore needs to see to a large number of patients, which does not allow for suitable treatment.

So this situation affects the quality of life of people and healthcare expenses.
Worldwide, there are 300 million people with asthma. In the United States, more than 16 million adults and 7 million children have it, generating 1.8 million visits to emergency rooms and half a million hospitalizations per year. More than 10 million work days and 3 million school days are lost because of asthma. The direct costs involve doctors, medication, etc. The indirect costs are the lost days of work or school. If one adds the two, some US$ 20 billion a year are spent on asthma in the United States. The prevalence varies depending on the population segment. For example, among the Puerto Ricans, it is 20%; for North-American children, it is 8%; for Afro-Americans, 13%. An Afro-American or Hispanic child’s risk of developing asthma is six times greater than that of a white child.

You are known for having published a lot.
Our discipline has three areas: allergy, immunology and rheumatology. We started with allergy and added connected fields, such as clinical immunology and rheumatology. The three areas, at present, have produced 450 published works. I was involved in 162.

Recently one of these was especially cited in the United States.
That one I did when I was training at McGill University, in Montreal, Canada, from 1965 to 1967. I worked a lot, I worked like a horse, with a grant of US$ 5 thousand a year that was not enough for anything. I went with my wife and two children, at the age of 30. I published 17 articles during these two years. Forty years later, in March 2007, I got a letter from the AAAAI, the American Academy of Allergy, Asthma and Immunology, saying that they had selected one of my papers as one of the most important of its time. Then they invited me to write a comment explaining where my findings fit today, for this to be shown on a large panel at the annual congress. The article in question was published in the Journal of Allergy in 1968. This later became the Journal of Allergy and Clinical Immunology, the most highly regarded one in its field, with an impact factor greater than 8.

What is the importance of this work for immunology?
When I got to Montreal, the head of the division, Professor Bram Rose, told me to hang around for about three months in order to choose someone to work with and a line of study. I chose a researcher, Maxwell Richter, who worked with a substance called phytohemaglutinin, which, when it is put together, in vitro, with lymphocytes from peripheral blood, transforms it into blastic cells. In other words, the lymphocytes are un-differentiated, becoming a much more primitive cell. Theoretically, this primitive cell would be comparable to a stem cell, which in turn would give rise to several other cells. Studying children with cellular immunodeficiencies, we found that their lymphocytes did not respond to phytohemaglutinin. To this day, this test is used to diagnose immunodeficiencies. It is called blastic transformation with phytohemaglutinin.

And it is used to identify what immunological disease?
None, because phytohemaglutinin transforms the lymphocytes of any person, other than of those who suffer from some immunodeficiency. But this was just a consequence of the basic work with phytohemaglutinin. At the time, we didn’t know that there were lymphocytes T or B. They were just lymphocytes. We felt that, as the lymphocytes had differentiated themselves, they might differentiate themselves again. We did hundreds of cultures and learned the technique well. We had a radioactive marker and the lab had a radiation counter. We left the little tubes in the machine at night and, the following morning, the results were printed out. The Cold War was at its height at the time. So we sent the project to the American government, to the Ministry of Aeronautics, proposing to take cells from soldiers’ blood, conduct the culture, transform them into blast cells and store them in a freezer. If an atom bomb went off and the bone marrow of these soldiers was destroyed, the primitive cells culture would be re-injected into the person and these cells would differentiate themselves and become blood cells again. At that time, all we wanted was for them to differentiate themselves into peripheral blood cells, for the person to survive. The project went through to the Pentagon and they sent a colonel to interview us in Montreal. We talked to him and he said he liked the project. However, each one of us had to be checked. He asked my name, where I was born, where I lived. He wanted to know who would be involved in the project. One day he came back and said that the project was virtually approved, but that in third grade I had had a communist teacher. My boss said: “If we don’t get the money because of this I’ll kill you.”

Was the project approved?
When everything was ready to be signed, major changes started happening in the US government and all aid to other countries was cancelled.

And what did you do?
We continued working. The idea arose that if we put together the allergen (antigen) and the blood of individuals sensitive to this allergen, and not only to the phytohemaglutinin itself, we might get blastic transformation, in other words, make the lymphocytes return to the primitive state of a blast cell, that is a primordial cell. We studied hay fever, which occurs when a given plant proliferates and produces the anemophilous fungus, which is spread through the air, carried by the wind; people then breathe it in and it causes allergic respiratory problems. We added the antigen to the blood of these individuals who suffered from hay fever and blastic transformation took place.

Did the allergy also recede?
No. It was just an in vitro process. We thought that allergic diseases were only of an immediate nature; in other words, that an allergen would enter the organism and trigger the production of IgE, releasing from mast cells several substances inducing an allergic reaction. It was shown that this was not the case, that the cell had a behavior similar to that of phytohemaglutinin. There was an immunity that was also mediated by cells.

Did an opening occur in immunology as a result of this research?
In 1966, when we wrote the article, very little was known about lymphocytes T and B. IgE wasn’t known as an antibody to allergens. Our work led to detailing what the immune response is. It helped to show that an allergic response didn’t just have an immediate component, but also a belated component, that was cellular. At that time, this was a lot. Perhaps the work’s merit was that it was pioneering.

Has there been any change in how these allergies are treated, in the last few years? For example, asthma and rhinitis are currently regarded as related conditions.
They are probably a condition of the combined breathing system, in other words, of the nose and lungs. At present, we treat the symptoms. For example, the most common cause of respiratory problems in Brazil is the acari of home dust. To treat them, we basically use pulmonary and nasal anti-inflammatory drugs and bronchodilators, besides specific immunotherapy. Many children suffer from exercise-induced asthma. In the 2004 Olympics, 20% of the American athletes suffered from asthma. Most started doing sports in order to outdo themselves and overcome this illness. The most famous of them was Marks Spitz, who had asthma. Even so, he won seven gold medals at Munich in 1972, now outdone in Beijing by Michael Phelps.

Doesn’t asthma also have a psychological component?
Not as a primary cause, but as something that can aggravate it, yes.

What was it like, when you returned to Brazil?
I got a little room where I remained alone for four or five years doing my own thing. I saw to patients, tested my vaccines, swept the floor; I did everything. During those years, I collected approximately 400 samples of serum from allergic children, in preparation for the arrival of the necessary equipment. Until on a Monday morning I got to the university and discovered that the janitor had unplugged the refrigerator to use the floor polisher during the weekend and had forgotten to switch it back on. Everything that was stored was lost. I was lucky that the window was closed, because I almost threw myself out of the ninth floor. It was one of the greatest shocks in my life.

And even so, you remained there?
I stayed for another few months. There was an immunology chair at the Paulista medical school (currently part of the Federal University of São Paulo), held by Otto Bier, one of the school’s founders. He retired in 1967 and, upon my return to Brazil, I oversaw immunology until an exam was held. It was meant to be temporary, but I was there provisionally for almost ten years. I had no interest in permanently holding this chair because this would require full time work and the salary was very low. The solution was to see to patients in the consulting room. My last salary at the Paulista medical school, as a full professor, with all the five-year wage additions, totaled R$ 3 thousand, after 40 years. Now I’m retired and I earn this amount a month.

When did you create the allergy sector at Unifesp?
I organized the Allergy, Clinical Immunology and Rheumatology Sector in 1978. Afterwards, in 1985, the school’s board of governors transformed this into the discipline of Allergy, Clinical Immunology and Rheumatology, which became part of the students’ curriculum. It took them almost 20 years to recognize the discipline’s value. Whenever I went to them to ask for something, they said it was like a witch’s brew, of people who do little tests, little vaccines. That was the case because the understanding of allergy in Brazil was very poor.

What was it like to get into research again back in Brazil?
It was like being clobbered over the head. In Montreal, in two years, I published 17 articles. Here, we took more than 10 years to publish something. However, little by little, with FAPESP’s help, we managed to structure research in the sector and got more people to work on it. Our projects were approved, we got the funding, we bought equipment. It was difficult, but we managed to advance.

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