Could blood from H5N1 flu survivors help others?

Sep 8, 2006 (CIDRAP News) – A recent report about the use of blood products to treat patients in the Spanish influenza pandemic of 1918 has sparked interest among those concerned about the threat of the next pandemic, but experts say it's far from clear whether the approach would be practicable in a pandemic today.

In a report published last week, US military researchers said blood products obtained from recovering influenza patients apparently helped save the lives of some patients in the 1918 pandemic, and the same approach should be considered today in the face of another pandemic threat.

Combing the medical literature from the Spanish flu era, the researchers found six controlled studies in which the use of blood plasma, serum, or whole blood from recovering flu patients reduced mortality in seriously ill patients. The authors hypothesize that antibodies in the blood products blunted the effects of the flu virus.

"Patients with Spanish influenza pneumonia who received transfusion with influenza-convalescent human blood products may have experienced a clinically important reduction in the risk for death," say Thomas C. Luke, of the Navy Bureau of Medicine and Surgery, and colleagues. Their report was published online by Annals of Internal Medicine.

Luke and colleagues write that borrowed antibodies in blood products have been used to prevent and treat a number of infectious diseases, including rabies, measles, hepatitis B, cytomegalovirus, and respiratory syncytial virus.

Six studies showed benefit
The authors searched eight major medical journals for controlled trials of the use of blood products from recovering flu patients to treat a minimum of 10 severely ill patients. They found eight studies that met their criteria, ranging in size from 43 to 551 patients, with a total of 1,703. None of the trials was blinded or randomized, and the methods were rated as poor by today's standards. Most of the patients were men between the ages of 17 and 45.

Six of the eight studies showed that the treatment improved survival. The overall case-fatality rate for treated patients was 16% (54 of 336), versus 37% among the controls (452 of 1,219). In addition, all eight reports said that patients showed clinical improvement after treatment. Moderate to serious transfusion-related adverse events occurred in 4% (9 of 235) of patients in studies that included such data.

The timing of treatment made a difference. On the basis of data from four studies, patients treated within 4 days of the onset of pneumonia had an overall case-fatality rate of 19% (28 of 148), whereas those treated later had a fatality rate of 59% (49 of 83).

Acknowledged limitations of the analysis include the small size of the studies, the lack of blinding, and the lack of placebo treatment. The authors also say they can't exclude the possibility that other studies yielded negative findings but went unpublished. Therefore they couldn't reach a firm conclusion about the effectiveness of the treatment.

Nonetheless, they recommend that a committee of experts be set up to consider using plasma treatment for H5N1 patients and to recommend a research strategy.

In an editorial accompanying the report, John J. Treanor, MD, an infectious disease expert at the University of Rochester, says the strategy deserves consideration, but he also raises some caveats.

Passive immunotherapy for flu viruses, including H5N1, has worked in lab mice, Treanor writes. Such treatment prevents many viral diseases in humans, but little recent evidence supports using this approach to treat sick patients, he says. Also, obtaining and using blood products for treatment in the midst of an outbreak would involve "formidable logistical hurdles."

Proving the concept of "serotherapy" for H5N1 would require running controlled trials in regions where human H5N1 cases are occurring, Treanor asserts. He believes the effort would be worthwhile: "We can, should, and must explore these issues about serotherapy now, in advance of the pandemic."

Serotherapy called impractical
Other experts who were asked about using this approach in the next pandemic expressed views ranging from guarded interest to dismissive skepticism.

Michael T. Osterholm, PhD, MPH, didn't question the scientific plausibility of the idea, but argued that it wouldn't be practical in a pandemic. Osterholm is director of the University of Minnesota Center for Infectious Disease Research and Policy, publisher of the CIDRAP Web site.

"We won't have the capacity to do much plasmapheresis [harvesting of plasma] of recovered patients because the system—healthcare workers and equipment—will collapse," Osterholm told CIDRAP News. "And with today's safety regulation, you couldn't do it like you did in 1918."

He said supplies and equipment needed for blood transfusions and processing are likely to run out. "The entire healthcare system is a just-in-time delivery system for virtually everything. . . . You couldn't do it if you wanted to, because you just won't have the equipment. Blood banks don't have months and months of inventory on hand. The bags, tubing, needles, and reagents are made offshore."

"Transfusion medicine is going to be severely challenged during a pandemic," Osterholm said. "Just transfusing the blood we need [will be difficult], let alone doing this kind of thing."

Blood-bank official sees logistical problems
Louis Katz, MD, chair of an American Association of Blood Banks task force on pandemic flu and the blood supply, acknowledged that supplies are likely to be a problem but said that using plasma from recovered patients could be helpful in a pandemic.

The idea "is something we're trying to think about, but it hasn't made it into the first edition of our pandemic flu planning guidelines," said Katz, who is executive vice president of the Mississippi Valley Regional Blood Center in Davenport, Iowa.

He said blood banks are likely to run short of both personnel and supplies in a pandemic, but supplies are the bigger worry.

"We take delivery twice a month on critical lab reagents and once or twice a month on pheresis kits, so the maximum [inventory on hand] is a month," Katz said.

His center doesn't have space to store 8 to 12 weeks' worth of supplies, and even if it did, suppliers might not be able to ramp up deliveries to permit stockpiling, he said. "The just-in-time economy has its advantages in terms of efficiency, but in a crunch there are serious problems," he added.

Further, few recovered flu patients would be available to donate plasma in the early stage of a pandemic, Katz said.  "I think there are substantial barriers to providing a lot of it during the first wave." He predicted the task would be "substantially easier" in the second wave of a pandemic.

Katz thinks blood banks could get recovered patients to donate plasma, but not until weeks into the pandemic. "I think they'd come in, but whether we could process enough [blood products] to treat meaningful number of patients, I don't know," he said.

If the pandemic resembled those in 1957 and 1968, in which "business operations weren't horribly disrupted, we probably could ramp up and make immune plasma fairly quickly," Katz said. "It totally depends on what happens."

Another question is whether the Food and Drug Administration (FDA) would approve the use of blood plasma to treat flu patients. "It's complicated, but it becomes an issue of labeling," Katz said. "As long as I didn't label it 'hyperimmune influenza plasma,' I think they'd be fairly permissive." Before allowing such a label, the FDA would require clinical trials and other steps to certify the safety, purity, and potency of the product, he said.

Summing up his thoughts on the topic, Katz said, "While theoretically it's a great idea, the logistics are going to be difficult."

Dr. Jed Gorlin, medical director of Memorial Blood Centers in St. Paul, said the concept of using plasma to treat flu patients has been under discussion in blood-bank circles for a while.

Gorlin said blood banks are worried about shortages of blood donors and of staff to collect blood in a pandemic. But he was more optimistic than Katz on the question of supplies and equipment.

The 1918 flu pandemic lasted about 2 months in most places, he said, adding, "For things like bags and so on we easily have a month and often 2 months, so that part we're not particularly concerned about." On the other hand, other supplies, such as N95 breathing masks, may well run out, he said.

"Blood centers are ahead of most hospitals in that we already have lists of critical reagents and equipment," Gorlin said. "We're already sensitive to our supply chain and in some cases we have alternative suppliers."

Transfusion specialist interested
Robert J. Bowman, MD, a transfusion medicine specialist at the University of Minnesota Medical School in Minneapolis, called the proposal "very interesting," at least theoretically.

"I am unsure of the relative success of immunoglobulin preparations in treating viral illness but given the paucity of treatment options the strategy ought to be tried," he commented by e-mail.

Criteria for acceptance of plasma donors would have to be developed, he said. Plasma could be tested for antibodies and used directly, or many units could be pooled and used to make a standardized intravenous immunoglobulin preparation (IVIG), he suggested.

"Not only do I think this is possible, I think the idea should be tried with standardized IVIG preparations," Bowman wrote. If the treatment worked, its applicability would depend on collection agencies having enough staff and enough money to pay for the IVIG, he added.

Bowman predicted that safety and other regulatory issues would be "manageable," but he acknowledged that supply interruptions could be a problem.

He also said he was uncertain how much IVIG would cost or how long it would take to prepare. "We're not talking about days, we're talking weeks or months," he said. "It takes some time to pool it, then you have to fractionate it, and then there's testing. So it's a big deal. But all the technology is there."

Luke TC, Kilbane EM, Jackson JL, et al. Meta-analysis: convalescent blood products for Spanish influenza: a future H5N1 treatment? Ann Intern Med 2006 Oct 17;145(8) (early online publication) [Full text]

Treanor JJ. Avian influenza: exploring all the avenues. (Editorial) Ann Intern Med 2006 Oct 17; 145(8) (early online publication) [Full text]

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