Key Point:

• Two strains of avian influenza type A have crossed over to humans. Rapid reporting of outbreaks and swift diagnosis, treatment, and containment are required to prevent further spread.

NEW YORK CITY—Recently, in both the Netherlands and Southeast Asia, influenza viruses typically found in birds have been transmitted to humans. The Netherlands experienced an outbreak of 89 human cases of H7N7 avian influenza A, which had a predominantly mild course (conjunctivitis).[1] In Southeast Asia, however, an outbreak of avian influenza A H5N1 led to severe respiratory illness and death. On March 10, the World Health Organization reported 11 cases of H5N1 influenza in Thailand and 22 in Vietnam. Twenty-two deaths occurred during this outbreak.[2,3]

FROM ANIMALS TO HUMANS

Viruses that contain RNA—as influenza A does—can undergo rapid mutation. All subtypes of influenza A circulate in birds, while only a few are normally found in mammals. Interestingly, both the H5N1 and H7N7 influenza subtypes cause severe illness and death in domestic poultry, whereas in humans only H5N1 tends to cause death. Thus, disease severity or course in humans cannot be determined by looking at how the virus affects animals.

Infected birds shed the avian influenza virus in saliva, nasal secretions, and feces. Other birds are infected when they come into contact with the infected secretions, and it is thought that most human cases of H5N1 and H7N7 infection occur as a result of direct contact with infected birds or contaminated surfaces.

PROBLEMS WITH DIAGNOSIS

“Influenza viruses, including the avian viruses, can be grown in cell cultures,” explained Marion Koopmans, DVM, PhD, Head of the Virology Section at the National Institute of Public Health and the Environment in Bilthoven, the Netherlands. “The next step is determination of a subtype. When a virus grows but cannot be subtyped, that is the first signal of a possibly unusual event.”

In both outbreaks of avian influenza, reverse transcriptase polymerase chain reaction (RT-PCR) was used to diagnose the virus. In the H7N7 outbreak, RT-PCR performed on cultures taken from eye swabs was able to isolate the virus in 82 of 89 primary cases. However, in the single fatal H7N7 case, RT-PCR was performed by two different laboratories one week after the patient was exposed to the virus, and both tests were negative. Subsequently, a bronchoalveolar lavage sample taken on day 11 and lung tissue sampled during autopsy tested positive for H7N7 via cell culture and RT-PCR.

In the H5N1 outbreak, RT-PCR, using samples from nasal or throat swabs and primers specific to H5 and N1 subtypes, confirmed the presence of the virus after a median illness duration of six days. However, performing these tests was not easy.

“There are very few facilities in the developing world for making any diagnosis—especially for new and emerging pathogens,” said Jeremy Farrar, MD, PhD, Director of the University of Oxford Research Unit at the Hospital for Tropical Diseases in Ho Chi Minh City, Vietnam. “Serological responses are difficult to measure and interpret, viral culture is only possible in a few centers, and PCR is very limited and expensive. Both culture and PCR are reasonably sensitive but not widely available,” he added.

Unfortunately, all efforts at rapid diagnosis of H5N1 were less sensitive than RT-PCR. Because of the speed with which patients’ health declined, the authors reporting on the Vietnamese outbreak suggested that clinical findings—such as cough, fever, diarrhea, shortness of breath, and abnormalities on chest films—may be better used for rapid identification of patients with H5N1 infection.

SAFEGUARDING AGAINST RESISTANCE

How do you treat patients without risking the evolution of a resistant strain? “Number one, people need to be instructed about the proper way of taking the medication,” said Dr. Koopmans. Second is drug selection, he noted. “We chose antivirals [that were] reportedly not likely to induce resistance.” Monitoring for the development of resistance would be ideal, he continued, “but in practice, this ended up low on the list of priorities due to the high burden that an outbreak of this size puts on a public health system.”

In the H7N7 outbreak, the virus was susceptible to oseltamivir, which was used for both treatment and prevention of the virus.

However, in the H5N1 outbreak, oseltamivir was used but did not seem to reduce the mortality rate. “It is unknown how effective treatment is in human cases of H5N1—it probably depends on early diagnosis and treatment,” said Dr. Farrar. “After a week of illness, it is possible that antiviral agents will not work.”

H5N1 has demonstrated resistance to amantadine and rimantadine, and ribavirin was ineffective as well. In the absence of a proven effective treatment, supportive care may be the best treatment option.

WORST-CASE SCENARIO

So far, nearly all cases of avian influenza A (both H7N7 and H5N1) have been in people who had direct contact with infected poultry. What happens when a virus that was previously spread from animals to humans gains the ability to spread via human-to-human contact?

Influenza A viruses, when they do cross over from birds to humans, can adapt quite rapidly and acquire the ability to travel from person to person. Adaptation can take place when an avian virus genome mutates or when it mixes with a virus already present in humans. In the H7N7 outbreak, there were three cases in which a close family contact became ill without having been exposed to infected birds. This suggests that the virus may have acquired the ability to spread between people.

Because these viruses do not often infect people, humans have little or no immunity against them. “The key issue in terms of human health is whether the virus gains the potential to be transmitted between humans,” Dr. Farrar pointed out. “The fewer viruses there are circulating in the animal reservoir, the less chance there is that one will develop the capacity to transmit between humans.” In addition, he stressed the importance of ensuring that avian viruses do not infect other animals, such as pigs, which could then act as reservoirs.

The reassortment of an avian virus with a human influenza virus, leading to potential transmission between humans, could produce a global health threat. “This happened on a number of occasions in the 20th century,” said Dr. Farrar, “leading to an enormous loss of life.”

Last year, the SARS coronavirus crossed the species barrier and person-to-person transmission became possible.

PROTECTIVE MEASURES TO BE TAKEN

In the Netherlands, infection control precautions were in place one week after the first confirmation of human H7N7 infection. These included having at-risk groups wear eye protection and mouth and nose masks when working around poultry. The influenza vaccine was offered to all poultry workers, and immediate treatment with oseltamivir was recommended for those with new cases of conjunctivitis. Prophylactic oseltamivir administration was started for all people handling infected poultry. The recommendations for vaccination were later expanded to include all poultry farmers and their families within a 3-kilometer radius of infected poultry farms.

The Dutch investigators acknowledged that they had been concerned about widespread prophylactic antiviral use. Among the reasons they cited:
• Ethical concerns about giving possibly healthy people a drug that could produce side effects.
• The potential for resistance to develop.
• Personal protective procedures might be more effective than prophylactic drug therapy.
• The nonadherence rate is high.

During the H7N7 outbreak, they noted, many people declined antiviral treatment until after the one death had occurred.

One measure that was taken in both the Dutch and Southeast Asian outbreaks was the killing of all infected and exposed poultry. In the H5N1 outbreak, patients were isolated and treated as quickly as possible to contain the infection. However, noted Dr. Farrar, “There needs to be some way of encouraging countries to act faster and acknowledge problems earlier when outbreaks happen. At the moment, countries are fearful of admitting to outbreaks because doing so will cause such devastation to industries. This holds true for Japan, Europe, and the United States—and, of course, for developing countries, which can least afford it.”

Dr. Koopmans emphasized “the extreme importance of joint preparedness planning between the veterinary health response systems and human health response systems. This is broadly applicable,” he said. “Many emerging diseases are zoonoses—for example, look at SARS, monkeypox, and West Nile virus. We need the veterinary and medical sides working closely together.”

However, as he and his colleagues observed, “[B]y the time full prophylactic measures were in place … more than 1,000 people from all over the Netherlands and from abroad had been exposed. Therefore, if a variant with more effective spreading capabilities had arisen, containment would have been very difficult.”

—Gale Jurasek

References
1. Koopmans M, Wilbrink B, Conyn M, et al. Transmission of H7N7 avian influenza A virus to human beings during a large outbreak in commercial poultry farms in the Netherlands. Lancet. 2004;363:587-593.
2. Hien TT, Liem NT, Dung NT, et al, for the World Health Organization International Avian Influenza Investigative Team. Avian influenza (H5N1) in 10 patients in Vietnam. N Engl J Med. 2004;350:1179-1188.
3. World Health Organization. Confirmed human cases of avian influenza A (H5N1). Available at: www.who.int/csr/disease/avian_influenza/country/cases_table_2004_03_10/en. Accessed March 16, 2004.

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