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Medicine

Exaggerated reaction

Influenza A, H1N1 virus, the cause of swine flu, induces inflammation that destroys lung cells

Before the vaccine: biologist assesses the quality of eggs used to generate copies of the virus

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.

H1N1Natural 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.

Scientific article
Mauad, T. et al. Lung pathology in fatal novel human influenza A (H1N1) infection. American Journal of Respiratory and Critical Care Medicine. In press.

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