Study: Plasma from former H1N1 patients saved lives

Jan 20, 2011 (CIDRAP News) – A report from Hong Kong says that the use of blood plasma donated by recovered H1N1 influenza patients reduced the death rate in severely ill H1N1 patients.

The report, published online this week by Clinical Infectious Diseases (CID), says the authors recruited 93 critically ill H1N1 patients, of whom 20 agreed to receive the plasma treatment while the rest served as controls. The death rate in those who received the plasma was 20%, versus about 55% in those who didn't receive it.

The study "demonstrated that convalescent plasma treatment may have a place in the treatment of patients with severe H1N1 2009 infection," the researchers write. They say the treatment also reduced the patients' viral load and inflammatory cytokine response.

Plasma from recovered patients has been used to treat a number of infectious diseases, as it contains antibodies that latch onto pathogens, enabling the plasma recipient's immune system to identify and fight them. The use of this approach to treat severe flu cases has been discussed for years but not widely attempted.

A meta-analysis of reports from the 1918 flu pandemic, published in 2006, suggested that plasma treatment used at that time saved some lives, the CID report notes. The approach has also been used with apparent success in a few H5N1 avian flu patients.

Two US experts on blood transfusion who commented on the Hong Kong report said the idea of using plasma treatment in flu patients is promising, but it faces a number of practical and regulatory barriers, and much more research is needed.

Seven hospitals participated
Seven hospital clusters participated in the Hong Kong study, which ran from September 2009 through June 2010. Adult patients with severe H1N1 illness were recruited to receive the plasma treatment or to serve as controls, with informed consent.

In September and October of 2009, the Hong Kong Red Cross Blood Transfusion Service invited patients who had recovered from H1N1 to voluntarily donate plasma to treat patients with severe disease. Donors were eligible if they had had a lab-confirmed case of H1N1, had been healthy for at least 2 weeks, and met other standard criteria for donating plasma. The researchers used the plasma only if the titer of H1N1 neutralizing antibodies was 1:160 or greater.

Patients in the treatment group received 500 milliliters of plasma over 4 hours, in most cases on their second day in an intensive care unit (ICU), the report says. No adverse effects of the treatment were observed.

The treatment and control groups in the study were matched by age, sex, and disease severity, though obesity was more common in the treatment group, the report says. The death rate in the treatment group was 20.0% (4 of 20 patients), versus 54.8% (40 of 73) in the control group, a significant difference (P=.01). Statistical analyses also showed that acute renal failure was independently associated with death.

The researchers assessed viral load and cytokine levels in a subgroup of 44 patients. The levels were the same in treatment and control patients on the first day of ICU but later diverged. Viral loads were significantly lower n the treatment group on days 3, 5, and 7 after ICU admission. The levels of several cytokines were significantly lower in the treatment group by day 5.

The authors say their findings suggest that the single infusion of plasma was effective in reducing mortality, viral load in the respiratory tract, and serum levels of cytokines. However, they note that they couldn't exclude the possibility that the patients had undetected community-acquired infections that responded to the plasma therapy.

The researchers comment that neutralizing antibodies don't suffer from the problem of drug resistance, which can arise with antiviral drugs such as oseltamivir. They say their approach should next be tested with a double-blind, randomized controlled trial in patients with severe flu.

Promising findings, practical obstacles
Two blood transfusion experts described the findings as promising but said a number of practical concerns stand in the way of broad use of the approach any time soon.

"I think it's promising, but it's not ready for prime time," said Louis Katz, MD, chair of the Transfusion-Transmitted Diseases Committee of the American Association of Blood Banks and executive vice president for medical affairs at the Mississippi Valley Regional Blood Center in Davenport, Iowa.

"I don't want anyone to think that if they get a bad flu, their doctor is going to get this stuff," he said. "The operational and regulatory hurdles are very substantial."

Katz said that during the H1N1 pandemic he discussed with a number of people the possibility of passive immunotherapy. "The difficulty primarily is identifying those potential donors who have what you're looking for, having a good test that's specific and proves that the donor has antibodies against the pandemic strain," he said. "It's a little hard to mobilize outside a research setting to do that."

He also commented that the Hong Kong study is not randomized and that more rigorous studies are needed.

Jed Gorlin, MD, medical director of Memorial Blood Centers in Minneapolis, said that in a flu pandemic, it's far from clear whether blood banks would be able to harvest large amounts of suitable plasma quickly enough to be useful.

He said it takes 4 to 6 weeks after an infection for antibody titers to reach robust levels, which would delay the availability of suitable plasma. Also, blood centers would probably be unable to gather suitable plasma from more than a few hundred donors in a month, he said. If a pandemic unfolded fairly quickly, "by the time we could start collections, much of the mayhem might be over."

Gorlin also observed that a major pandemic would affect his agency's staff the same as everyone else, probably limiting the ability to collect blood.

Katz said the US military and the National Institute of Allergy and Infectious Diseases are conducting small pilot studies of plasma therapy. "There's a decent amount of clinical and animal research that suggests some efficacy," he added.

Hung IFN, To KKW, Lee CK, et al. Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection. Clin Infect Dis 2011 Feb 15;52 (early online publication) [Full text]

See also:

Jan 19 press release from the Infectious Diseases Society of America

Jun 8, 2007, CIDRAP News story "Human antibodies protect mice from H5N1 avian flu"

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