Interesting article from Reuters
Last Updated: 2009-04-30 9:16:50 -0400 (Reuters Health)
By Laura MacInnis - Analysis
GENEVA (Reuters) - Swine flu will carry the name "pandemic" even if the new virus turns out to cause mainly mild symptoms as it sweeps the world, raising questions about how serious the global alert actually is.
Although it has been deadly in the disease epicenter, Mexico, and caused the death of one Mexican infant in the United States, in other countries people infected with swine flu have fared well, with diarrhea the biggest complaint.
The World Health Organization is expected to move quickly to designate a full pandemic -- at level 6 of its 6-point scale -- within days to reflect the continuing spread of swine flu among people who have not been to Mexico, including in Europe.
Margaret Chan, the WHO's director-general, on Wednesday night raised the world flu alert level from 4 to 5 and said: "It is really all of humanity that is under threat during a pandemic."
Echoing other infectious disease experts, and drawing on her experience fighting SARS and bird flu outbreaks as health director of Hong Kong, she said viruses such as the H1N1 swine strain needed to be closely watched in case they worsen.
"We learn from previous pandemics. Pandemic virus is precarious, unpredictable, and will take us by surprise," she told reporters at the WHO's headquarters.
PATIENTS RECOVERING WITHOUT DRUGS
But Chan acknowledged that the disease may well cause more discomfort than death, noting that many patients infected in the United States have recovered on their own and without medicine.
"It is possible that the full clinical spectrum of this disease goes from mild illness to severe disease. We need to continue to monitor the evolution of the situation to get the specific information and data we need to answer this," she said.
"There may be a possibility that the virus will die out and stop, and that would be the best for us. But it can turn the other way."
Several theories are circulating about why swine flu has killed as many as 176 people in Mexico while having mild and more manageable effects elsewhere.
Some experts speculate that the Mexican victims did not receive appropriate medical care or suffered other health complications that made them vulnerable to the flu.
For the time being, the WHO's own guidance to people who suspect they have been infected with swine flu is essentially the same as advice for seasonal flu care.
Its website's "frequently asked questions" about the virus tell people who have a high fever, cough or sore throat to rest and take plenty of fluids, wash hands frequently, and avoid work, school or crowds as much as possible. (www.who.int/csr/disease/swineflu/faq/en/index.html#q11)
MILD OR SEVERE PANDEMIC?
Keiji Fukuda, the WHO's acting assistant director-general, said that swine flu appeared very similar to normal seasonal flu, a disease that is rarely fatal for healthy adults but can kill the elderly and infirm.
Between 3 and 5 million people experience severe illness due to regular, seasonal flu around the world each year, and between 250,000 and 500,000 die as a result.
Fukuda said it was not yet clear whether swine flu would turn into a mild or severe pandemic, raising the possibility that the virus could have more serious effects as it continues to permeate new communities or as climate conditions change.
There were three pandemic flu outbreaks in the 20th century -- in 1918, 1957 and 1968 -- known respectively as Spanish, Asian, and Hong Kong influenza. An estimated 50 million people died in the first outbreak, about 2 million in the second and between 1 and 3 million in the third.
"In the 1918 pandemic, the first wave was mild, but by fall, the second wave killed many people. So whichever way this virus swings, we can't possibly know," said Guan Yi, a microbiologist at the University of Hong Kong.
"At this point, chances are it will be mild, but we can't rule out it will turn virulent. And even if it turns milder, it can still kill, depending on the kind of person it infects."
Health experts fear swine flu could be especially dangerous for the old and infirm, especially those with immune-system suppressing diseases such as HIV/AIDS.
Its spread to poor countries that lack medical staff, drug stockpiles, and diagnostic tests -- and where tropical and other diseases are also prevalent -- is another serious concern.
Guan Yi said that if it spread to Egypt or Indonesia, where H5N1 bird flu is endemic, it might combine with that virus.
"It could turn into a very powerful H5N1 that is very transmissible among people. Then we will be in trouble, it will be a tragedy."
A cytokine storm, or hypercytokinemia is a potentially fatal immune reaction consisting of a positive feedback loop between cytokines and immune cells, with highly elevated levels of various cytokines.[1]
The primary symptoms of a cytokine storm are high fever, swelling and redness, extreme fatigue, and nausea.[citation needed]
When the immune system is fighting pathogens, cytokines signal immune cells such as T-cells and macrophages to travel to the site of infection. In addition, cytokines activate those cells, stimulating them to produce more cytokines. Normally, this feedback loop is kept in check by the body. However, in some instances, the reaction becomes uncontrolled, and too many immune cells are activated in a single place. The precise reason for this is not entirely understood but may be caused by an exaggerated response when the immune system encounters a new and highly pathogenic invader. Cytokine storms have potential to do significant damage to body tissues and organs.[citation needed] If a cytokine storm occurs in the lungs, for example, fluids and immune cells such as macrophages may accumulate and eventually block off the airways, potentially resulting in death.[citation needed]
The cytokine storm (hypercytokinemia) is the systemic expression of a healthy and vigorous immune system resulting in the release of more than 150 inflammatory mediators (cytokines, oxygen free radicals, and coagulation factors).[citation needed] Both pro-inflammatory cytokines (such as Tumor necrosis factor-alpha, Interleukin-1, and Interleukin-6) and anti-inflammatory cytokines (such as interleukin 10 and interleukin 1 receptor antagonist) are elevated in the serum of patients experiencing a cytokine storm.[citation needed]
Cytokine storms can occur in a number of infectious and non-infectious diseases including graft versus host disease (GVHD), adult respiratory distress syndrome (ARDS), sepsis, avian influenza, smallpox, and systemic inflammatory response syndrome (SIRS).[2]
The first reference to the term cytokine storm in the published medical literature appears to be by Ferrara et al.[3] in GVHD in February 1993.
It is believed that cytokine storms were responsible for many of the deaths during the 1918 influenza pandemic, which killed a disproportionate number of young adults.[1] In this case, a healthy immune system may have been a liability rather than an asset. Preliminary research results from Hong Kong also indicated this as the probable reason for many deaths during the SARS epidemic in 2003.[4] Human deaths from the bird flu H5N1 usually involve cytokine storms as well.[5] Recent reports of high mortality among healthy young adults in the 2009 swine flu outbreak has led to speculation that cytokine storms could be responsible for these deaths.[6] However, the Centers for Disease Control and Prevention (CDC) has indicated that symptoms reported from this strain so far are similar to those of normal seasonal flu,[7] with the CDC stating that there is "insufficient information to date about clinical complications of this variant of swine-origin influenza A (H1N1) virus infection."[7]
In March 2006, despite previous success in animal trials, all six men who had received the experimental drug TGN1412 suffered extremely serious symptoms[8] from what were most likely the effects of a cytokine storm.[9] Based on results from animal trials, the company had claimed that TGN1412 could activate T-cells in a way that would not cause the cytokine storm one would expect based on results from other drugs with similar mechanisms of action. All six men had been participating in a Phase I trial.
A 2003 report in the Journal of Experimental Medicine published by researchers at Imperial College London demonstrates[10] the possibility of preventing a cytokine storm by inhibiting or disabling T-cell response. A few days after T cells are activated, they produce a biologic molecule called OX40, a "survival signal" that keeps activated T-cells working at the site of inflammation during infection with influenza or other pathogens. OX40 binds to receptors on T-cells, preventing them from dying and subsequently increasing cytokine production. A combined protein, OX40-immunoglobulin (OX40-Ig), a human-made fusion protein, prevents OX40 from reaching the T-cell receptors, thus reducing the T-cell response. Experiments in mice have demonstrated that OX40-Ig can reduce the symptoms associated with an immune overreaction while allowing the immune system to fight off the virus successfully. By blocking the OX40 receptor on T-cells, researchers were able to prevent the development of the most serious flu symptoms in these experimental mice[10] and reported the results in New Scientist.[11] The drug, to be made by a company called Xenova Research (Xenova Research was purchased by Celtic Pharma, a private equity firm, in September 2005), was supposed to be in phase I clinical trial in 2004, but its status is currently unknown.[12]
The Renin Angiotensin system (RAS) has been implicated in the mediation of the cytokine storm,[13] suggesting a potential benefit for Angiotensin Converting Enzyme (ACE) inhibitors and Angiotensin II Receptor Blockers (ARBs), and ACE has been implicated in inflammatory lung pathologies.[14] Shigehara et al. published research confirming that serum angiotensin-converting enzyme (ACE) is a useful marker for disease activity in cytokine-mediated inflammatory lung disease.[15] Marshall and co-workers also found that angiotensin II was associated with cytokine-mediated lung injury[16] and suggested a role for ACE inhibitors.
Wang and co-workers published data that cytokine-mediated pulmonary damage (apoptosis of lung epithelial cells) in response to the pro-inflammatory cytokine TNF-alpha (implicated in the cytokine storm) requires the presence of angiotensin II, suggesting that ARBs might have clinical utility in this setting.[17]
Das published a review of ACE inhibitor and angiotensin-II receptor blocker use in a number of cytokine-mediated inflammatory pathologies and suggested that ACE inhibitors and Angiotensin receptor blockers have theoretical benefit in downregulation of the cytokine storm.[18]
Although frequently employed to treat patients experiencing the cytokine storm associated with ARDS, corticosteroids and NSAIDs have been evaluated in clinical trials and have shown no effect on lung mechanics, gas exchange or beneficial outcome in early established ARDS.[2]
Preliminary data from clinical trials involving patients with sepsis-induced ARDS have shown a reduction in organ damage and a trend toward improvement in survival (survival in ARDS is approximately 60%) after administering or upregulating a variety of free radical scavengers (antioxidants).[2]
Some types of arthritis medications are designed to reduce inflammation by inhibiting the tumor necrosis factor-alpha pathway to immune cell activation; these drugs are known as TNF-alpha blockers. One study[19] found that three different TNF-alpha blockers afforded a slight reduction in antibody presentation after vaccination against influenza in a group of immunocompromised patients, however it did not significantly affect patients' protective factor gained from inoculation. More research is necessary before any conclusions may be made regarding the efficacy of TNF-alpha blockers at reducing the effects of a cytokine storm in hospitalized flu patients.
MEXICO CITY – Now that the swine flu virus has passed from a farmworker to pigs, could it jump back to people? The question is important, because crossing species again could make it more deadly.
The never-before-seen virus was created when genes from pig, bird and human viruses mixed together inside a pig. Experts fear the virus that has gone from humans back into pigs in at least one case could mutate further before crossing back into humans again. But no one can predict what will happen.
"Could it gain virulence? Yes," Juan Lubroth, an animal health expert at the U.N. Food and Agriculture Organization in Rome, said Sunday. "It could also become milder. It could go in both directions."
Canadian officials announced Saturday that the virus had infected about 200 pigs on a farm — the first evidence that it had jumped to another species. It was linked to a farmworker who recently returned from Mexico, where 19 people have died from the virus. The farmworker has recovered, and the mildly infected pigs have been quarantined.
Agriculture officials believe the worker may have sneezed or coughed near the pigs, possibly in a barn. About 10 percent of the herd experienced loss of appetite and fever, but all are recovering.
Experts say pork — even from infected pigs — is safe to eat.
Lubroth stressed that sick people should avoid contact with swine, but said healthy farmworkers don't need to take any extra precautions because the chance of catching flu from a pig is small.
Unlike the H5N1 bird flu virus, which infects the blood, organs and tissue of poultry, most swine flus are confined to the respiratory tract, meaning the risk of a human getting infected by a pig is "probably 10 or a 1,000 times less," Lubroth said.
But pigs are of special concern because they share some basic biological similarities with humans, and they have served as "mixing vessels" in which various flu strains have swapped genetic material. That's what happened to create the current swine flu strain.
Scientists are unsure when the virus leaped from pigs to humans — possibly months or even a year ago — but it was identified as a new strain about a week and a half ago. Since then, nearly 800 cases have been confirmed worldwide. The only death outside Mexico occurred when a Mexican toddler died in a Texas hospital.
There have been sporadic cases of pigs infecting humans with influenza in the past. Most cases resulted in mild symptoms, typically among people who were in close contact with sick pigs. A few deaths have been recorded, and limited human-to-human transmission also has been documented, but nothing sustained.
Dr. Tim Uyeki, an epidemiologist with the U.S. Centers for Disease Control and Prevention who has worked on SARS and bird flu outbreaks, said there may be more pig-to-human cases that have gone unnoticed because surveillance among swine populations tends to be weaker than among poultry stocks.
Given that the past three flu pandemics — the 1918 Spanish flu, the 1957-58 Asian flu and the Hong Kong flu of 1968-69 — were all linked to birds, much of the global pandemic preparedness has focused on avian flus.
"The world has been watching and preparing and trying to prevent a pandemic from an avian influenza reservoir," he said. "The focus has been on birds, and here is a virus that's coming from a swine reservoir. Now it's a human virus."