When swine flu gets serious

In 2009 the swine flu, caused by the H1N1 virus, was recognized as this century’s first pandemy. In Brazil at least 19,000 people suffered the fever and aches caused by the flu, and over 1,300 were killed.
As it is now the northern hemisphere’s turn to fight the flu, it may be useful to draw from what was learned by researchers from southern countries. Some of it is summarized by Ricardo Zorzetto in the article published in the December issue of Pesquisa Fapesp, a Brazilian science news magazine: in some cases, the immune response against the virus is so strong that it destroys the lungs.
A companion article in the same issue discusses the benefits of vaccination against swine flu in the northern hemisphere. Bellow is a translated version of both stories.
by Maria Guimaraes
Exaggerated reaction
Influenza A, H1N1 virus, the cause of swine flu, induces inflammation that destroys lung cells
by Ricardo Zorzetto
In mid-spring, the 2009 flu season came to an end in Brazil. This year, the chief villain was the influenza A, H1N1 virus, the cause of swine flu and of this century’s first pandemic. In the second week of October, the Health Ministry recorded only 78 severe cases of swine flu in Brazil, a dramatic drop (97%) in relation to the mid-August peak. In six months, the H1N1 virus caused at least 19 thousand Brazilians to get a high temperature, along with severe muscular pain and a painful shortness of breath, and killed 1,368 – almost one third of the 4,735 deaths by flu recorded worldwide during this period, when 399 thousand cases were confirmed. As Brazil and other countries started to prepare for the second wave of swine flu that is already spreading in the Northern Hemisphere, as winter approaches, researchers from the University of São Paulo (USP) concluded the first analyses of H1N1 damage to the body. The São Paulo group found that, in the most severe cases, the body produces such a strong immunological reaction that it kills the virus, while also damaging the lungs so heavily that they stop working.
The most obvious sign of such damage is labored breathing (dyspnea), very frequent among those who developed the most serious and sometimes lethal form of swine flu. “All doctors should be alerted to this symptom, which indicates that the infection may be severe,” states pathologist Thais Mauad, from USP, the main author of the study published online on October 29 in the American Journal of Respiratory and Critical Care Medicine, the first to describe systematically the fatal lesions induced by H1N1.
Thais and another 14 researchers from the USP Medical School, who worked under the coordination of pathologists Paulo Hilário Saldiva and Marisa Dolhnikoff, came to this conclusion upon examining samples of different organs of 21 swine flu victims who died in São Paulo. “These cases are representative of the Southeast and South, which accounted for the majority of cases in the country,” states epidemiologist Denise Schout, from the USP team.
Heavy damage – In almost all cases – 20 out of the 21, to be precise – the lungs suffered mass destruction of their alveoli, microscopic cavities within which gas exchanges occur. Though with lower incidence (29% of the people), there was also severe inflammation and cell death in the bronchioles, the ramifications of the tubes that carry the air from the trachea to the lungs. Additionally, in 24% of these cases, bleeding (hemorrhage) due to the bursting of the blood vessels that irrigate the alveoli was also identified.
“This kind of damage is similar to what was observed in other flu pandemics, such as those in 1918, 1957 and 1968, though in the previous ones and in the first one in particular the death rate was far higher,” comments Thais. Another finding that struck the researchers was that 38% of these patients also had infections by Streptococcus pneumoniae, bacteria that cause respiratory system problems. “In cases such as these, it is important to add antibiotics to the antiviral drug treatment,” says Thais. “This information helps us to understand how the infection sets in and advances and, in the future, it can provide guidance for treatment,” comments Denise.
Natural killers – The concentration of the damage in the lungs does not mean that H1N1 only affects these organs. In almost all cases, the virus invades the cells that internally line the upper respiratory tracts (nose and throat), just causing typical flu symptoms: coughing, pain and a runny nose. Only in a very small number of people does the H1N1 escape the layer of mucus that helps to protect the upper respiratory system and reaches the lungs, which are normally sterile, complicating matters – in 7% of such cases, according to data from the USP team, the lung infection becomes so severe that it leads to death.
Microscopic and biochemical analysis of the lungs, however, indicated that the damage to these organs is not caused by the virus directly. Once infected by H1N1, which takes over control of the genetic apparatus, the alveoli cells start to make a chemical signaler, interferon-gamma, which inhibits the multiplication of the virus and activates the defense cells known as natural killers (NK). The NK, in turn, pour toxic compounds into the infected cells inducing the cells’ programmed death, i.e., apoptosis. At a suitable level, this sequence of actions in the defense system eliminates the infectious agents and helps to reestablish the organ’s health. However, when the level is exaggerated, it damages the organ – irreversibly, in some cases.
In the lungs of the fatal victims of swine flu, Thais and Ludhmila Hajjar found interferon-gamma levels and NK cells in numbers far greater than exist in healthy individuals’ lungs. It is not yet known what triggered the exaggerated response. “Some factor that we haven’t identified yet must have created this imbalance,” says Thais. Out of the 21 people analyzed by the USP team, 16 had already suffered from other serious diseases, such as cardiovascular conditions or cancer, before they caught swine flu. In Thais’s opinion, it is likely that their immunity had already been jeopardized, to the point of allowing the infection’s severity to rise sharply. Until answers to these questions are found, experts worldwide believe that the best protection against the virus is to take the vaccine, which some countries have already started distributing.
The second wave and the vaccine
Countries in the Northern Hemisphere start pre-winter vaccination drive
Weeks ago, the United States and China started vaccination drives against the influenza A, H1N1 virus, of swine origin, that caused the flu pandemic in the first half of 2009 and created panic in many countries. Health authorities worldwide consider immunization the chief means of preventing swine flu deaths and of containing the spread of this virus, which started in the Northern Hemisphere even before the onset of winter and is likely to become the chief cause of flu in upcoming years.
Despite the confidence of health administrators in immunization, in countries such as the United States, part of the population is skeptical about having the vaccine. The same feeling that the virus awakened at the beginning of the year is what underlies this doubt: fear. If before people feared the virus’s aggressiveness, now they question the vaccine’s safety and fear its side effects. This is so because, even before trials for safety and effectiveness had been completed, the FDA (the United States Food and Health Administration) released the production and application of two types of H1N1 vaccines: one in injectable form, made from inactive viruses and suitable for any person aged 1 or above; and another in breathable form, made from attenuated viruses and recommended for healthy people aged 2 to 59. As these only protect against swine flu, they are being applied along with the seasonal flu vaccine.
Danielle Ofri, a professor at the New York University Medical School, published an article in November in the New England Journal of Medicine describing the contradictory behavior of people seen at the Bellevue hospital, the oldest one in the United States. At the onset of the epidemic, fear of this unknown virus drove them to demand a vaccine that did not exist. However, now that it is available, most people, being less anxious and more used to the virus, refuse to take it.
Experts have no doubt that the vaccine works, although some disagree as to the level of protection it provides. “Even if the vaccine doesn’t protect 100% of the people, it should protect at least some 75%,” states Edison Durigon, head of the Virology Laboratory at the Biomedical Sciences Institute of the University of São Paulo. According to him, those who have the vaccine may even catch the flu, but it will be less severe. “The vaccine will only lose its effectiveness if the epidemic’s predominant virus variety undergoes very drastic genetic changes, which is rare.” Should this occur, the loss of efficacy will become known in a while, after more people have been vaccinated and the level of protection provided by the vaccine is analyzed.
Up to mid-November, the World Health Organization (WHO) estimated that 65 million people in 16 countries had already taken the H1N1 vaccine. In one report, the WHO stated that in China 11 million people were vaccinated, with 15 cases of serious side effects being recorded and two deaths, although the latter did not necessarily result from the immunization. As the vaccine production will be insufficient for all (WHO expects world production to reach 3 billion doses a year), the priority is to immunize those who are at particular risk: children from the age of one, people with serious diseases and healthcare professionals. In Brazil, where the H1N1 death rate was 0.8 per group of 100 thousand people (the rate of seasonal flu is 0.5 per 100 thousand), the swine flu vaccine is expected to be available before the winter of 2010.

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