Ed Engleman, MD, Stanford Blood Center’s director, strode briskly into the large lecture hall at UC-San Francisco, eager to describe the screening test he and his colleagues had just developed — a test they thought could help save the nation’s blood supply from a looming threat.

It was October 1983, Engleman was 29, and a bizarre, deadly agent was percolating in the population. It had first surfaced among gay men, leading to uncommon cancers, pneumonias and other infections, some of which had rarely been seen before in humans. But the mysterious microbe would soon invade the broader population and present a massive public health threat, becoming an epidemic for all time. The source later came to be known as the human immunodeficiency virus, or HIV — the cause of AIDS. 

Faced with the unknown, blood bank officials nationwide resisted Engleman’s plea to test blood donors, with the result that at least 20,000 transfusion recipients — surgery patients, hemophiliacs, new mothers and their babies — would become infected with HIV. Few, if any, would be patients who received blood at Stanford, where the screening test likely saved at least 33 people from an AIDS death.

The experience would make him a pariah in the blood banking community and reset the course of his career, which would shift to AIDS. It would also lead to a transformation of the blood banking industry. The blood supply, then vulnerable to potentially dangerous agents, would ultimately become much safer, though much more costly to maintain, as a result of the crisis, Engleman says.

The first signs of the new threat emerged in June 1981 in the form of an obscure report from the federal Centers for Disease Control and Prevention. Five gay men in Los Angeles had developed a rare form of pneumonia then known as Pneumocystis carinii.

Jeff Lifson, MD, then a medical student at Northwestern University, thought the report was fascinating, but “way too strange” — that it described a rare disease he would never have to deal with in his lifetime. He read it only because it seemed obscure enough that he figured he’d be quizzed on it by his attending the following week.

But this strange disease did not go away, and the number of reports grew, along with public alarm and much acrimonious debate about how to respond. In the spring of 1983, Engleman and Lifson — by then a pathology resident at Stanford and postdoctoral scholar in Engleman’s lab — heard from colleagues that two patients had come to Stanford Hospital suffering from early signs of the illness, characterized by unusual infections that generally afflict people with severely reduced immunity.

Neither patient fell into one of the known risk groups of the time, which included gay men with multiple sex partners, Haitian immigrants and intravenous drug users. But when doctors queried the patients about their histories, they discovered they shared one common trait: Both had received blood transfusions.

“We were very anxious to know if our blood bank had been the source,” recalls Engleman, who, still at Stanford, continues directing the combined blood bank/blood research center he founded in 1978. “It turned out both had received transfusions from blood that originated in San Francisco.”

It was among the early hints that the still-unidentified agent could be transmitted through blood. The previous year the CDC had published a report of a 20-month-old infant in San Francisco with symptoms similar to those seen in ailing adults. The parents had become frantic when the baby boy became sick with a series of strange infections that wouldn’t go away; doctors were baffled by the case. The baby had received multiple transfusions shortly after birth, including platelets from a man who seemed healthy when he donated blood but who showed symptoms of the disease eight months later.

“We said, ‘what can we do?’ The one thing we came up with was that affected individuals had a characteristic anomaly in their T cells.”

“We felt then it was the tip of the iceberg. It was like Armageddon. It was scary,” recalls Engleman, a professor of pathology, who was convinced this was a new infectious agent transmissible through blood. The problem kept him up at night; he felt an urgent need to respond to protect patients. But how do you screen for something in the blood when you don’t even know what it is?

“We said, ‘What can we do? We don’t have an agent. We don’t have a specific test,’” recalls Lifson, now director of the AIDS and Cancer Virus Program at the National Institutes of Health’s Frederick National Laboratory. “The one thing we came up with was that affected individuals had a characteristic anomaly in their T cells,” critical immune system cells that fight disease.

A new research project

Engleman, an immunologist, had started the blood center specifically because he wanted to study human immune cells — which include white blood cells such as lymphocytes that course through blood, fighting infection. Blood banks routinely toss out these cells because they can harm transfusion recipients, but for Engleman they were material for his research.

Photo by Erin KunkelEd Engleman, MD
He thought his blood test for AIDS would be welcomed with open arms.

Preoccupied with the disturbing, new, apparently blood-borne disease, Engleman, who tracked the immunology literature, noted that people with signs of the disease had a peculiar immune profile. Normally people have twice the number of a type of lymphocyte called T-helper cells (also known as CD-4 cells) as they do of T-suppressor cells (also known as CD-8 cells). But in people with this new ailment, the ratio was significantly reduced.

What if they just tested donors to see if they had this anomaly? This idea of using a surrogate marker to ferret out an unwanted microbe rather than doing a direct test was a relatively new concept in blood banking then. Engleman and Lifson did a pilot study in which they screened 100 people — all symptomatic gay men and their partners — to see whether the test would be cost-effective and practical on a larger scale. One of the advantages to being a blood bank embedded in a medical school (an unusual arrangement) is that the reagents and equipment, including a new cell-sorting machine, to do the screening were readily available.

The results of the 10-minute test on the participants were all abnormal. “That suggested they were either carriers or were sick with the disease,” Engleman says. He says they concluded it would be cost-effective to do the test, at least in a relatively small center like Stanford’s.

Engleman and Lifson decided to present the results to the larger scientific community and prepared for that auspicious gathering, a laboratory medicine grand rounds at UCSF, just over 30 miles to the north. Engleman walked into the large lecture hall expecting to be embraced for his foresight by the several hundred scientists and blood bank officials gathered there.

“I gave this talk thinking that it would be cheered,” he recalls. “They would be enthusiastic because it provided the blood bank community with a way to improve the blood supply. But the opposite happened. They were horrified and felt this was the worst thing ever. It was the beginning of a long, painful haul.”

Engleman bucked the trend and began using the surrogate T-cell test to screen all blood supplies, beginning in July 1983. Stanford thus became the first U.S. blood bank to screen for HIV.

Lifson says he doesn’t remember the specifics of the meeting, other than the feeling that he’d walked into a lion’s den.

“I played quarterback in high school, and I would rather face blitzing linebackers than that audience,” he recalls.

Engleman says he was confronted with a series of hostile questions. He was stunned.

“They were extremely critical, publicly so,” he says. “They felt that in doing this test we were saying that the blood supply was contaminated…. Ninety-eight percent of people involved in the blood-banking world circled the wagons and argued that there was no proof the disease was spread by transfusions and that screening would create a blood shortage. It had to do with money — the cost of testing. And they didn’t like the idea of blood banks being associated with this horrible, scary, deadly illness.”

The T-cell test also was impractical for most blood centers because the cell-sorting machines, now a staple in research labs around the world, were at that time expensive and rare.

Clash of the blood banks

The talk followed another highly contentious gathering in January 1983 of the blood bank working group at the CDC in Atlanta — a microcosm of the debate that was raging throughout the nation. Dozens of scientists and leaders from the National Institutes of Health, the CDC, New York and San Francisco health departments, the blood banks and the gay community arrayed themselves around a large square table to wrangle over whether the new agent could be transmitted through blood. By this time, there had been isolated reports of patients thought to be infected through transfusion, including seven hemophiliacs and the baby in San Francisco.

Few realized then they were dealing with a different kind of biological threat — one in which a person could be an infectious carrier but show no symptoms, resisting active disease for years. By the time of the working group’s meeting, the CDC had received reports of nearly 900 documented cases of AIDS, though there were many thousands more people who were infected and didn’t know it.

The scientists and blood bankers argued over the value of surrogate tests and whether they were needed. And though gay men were among those at high risk, blood banks had never asked donors about their sexual preferences and didn’t want to tread into that delicate territory. Moreover, they believed that asking donors if they were gay would be useless and possibly even counterproductive.

Donald Francis, MD, PhD, a leading CDC virologist and expert on epidemics, had been convinced early on that the mystery disease was caused by a new virus. He banged on the table, saying, “How many people have to die before you blood bankers have to do something?” recalls Herbert Perkins, then medical director of the Irwin Memorial Blood Bank in San Francisco, now part of the Blood Centers of the Pacific.

Perkins says the atmosphere at the CDC meeting was chaotic. “There was no agreement about anything,” he says. “It was a mess in all directions. Everybody was worried about what to do, but we knew so little and didn’t have the right tools.”

Because the disease then was prevalent among gay men, Perkins, now 94 and a senior research scientist at the blood center, says he initially dealt with the problem by meeting with leaders of the gay community, asking them to get out the message that gay men should refrain from donating. The San Francisco center also devised a new donor questionnaire listing gay men with multiple partners and injection drug users as risk groups; potential donors could check a box and discreetly exclude themselves.

The American Association of Blood Banks, or AABB, a 2,400-member group of nonprofit blood centers, likewise recommended that blood banks hand out information identifying the risk groups and discouraging at-risk people from donating. It did not recommend use of any kind of laboratory screening tests, with the result that most blood banks did not screen blood supplies at all during that critical period of time. Still unconvinced of the threat and concerned about the economic and public relations impact, the AABB, the American Red Cross and the Council of Community Blood Centers also issued a joint statement, based on the U.S. Public Health Service estimates, which assured the public that the odds of getting infected from a transfusion was “one in a million” — a statement that would later prove tragically wrong.

Good enough

Meanwhile, Engleman, impatient and angry at the blood banks’ head-in-the-sand approach, bucked the trend and began using the surrogate T-cell test to screen all blood supplies, beginning in July 1983. Stanford thus became the first U.S. blood bank to screen for HIV. The blood center then had some 20,000 donors a year; those samples that did not pass muster were frozen for future testing.

“I felt the blood banks went against science and rational behavior because they refused to use our test or other tests, like the hepatitis B test.”

Engleman also submitted an abstract on the T-cell test for presentation at the AABB meeting later that year. Though abstracts are routinely accepted for the meeting, this one was not; Engleman received a form letter of rejection, which he kept for posterity. In his mind it was yet another indicator of the industry’s unwillingness to come to grips with the problem.

At that time, Stanford Hospital & Clinics received much of its blood from Peninsula Memorial Blood Bank in Burlingame, not the Stanford Blood Center, says Susan Galel, MD, then a postdoctoral scholar in pediatric hematology/oncology in Engleman’s lab. Because of the hospital’s safety concerns, she says the Stanford center ramped up its production to become the hospital’s primary supplier. At the same time, the hospital notified Peninsula Memorial that its supplies would no longer be accepted unless the center screened blood with the T-cell or other surrogate test, says Galel, now the Stanford Blood Center’s director of operations. Peninsula Memorial complied by adopting a test that detects antibodies to hepatitis B, which at the time was seen as another way to screen indirectly for AIDS.

The hepatitis B test then was also the focus of hot national debate. The test indicates exposure to hepatitis B, though not necessarily infection. Early CDC studies had shown that more than 80 percent of patients with AIDS also had hepatitis B antibodies. In early 1983, the U.S. Public Health Service recommended blood banks evaluate the test as a way to screen out donors with AIDS.

San Francisco’s Irwin Memorial began evaluating the hepatitis test for this purpose in 1983, but its initial study indicated it wouldn’t be useful in San Francisco, in part because of its large Asian population. Hepatitis B exposure is common among Asians.

Irwin officials also were worried about the test’s high rate of false positives, which could create donor hysteria, as well as the likelihood that screening would attract people who wanted the test to find out whether they had AIDS — which as a result could pump more infected blood into the supply, says Michael Busch, MD, PhD, now director of the Blood Systems Research Institute at the Blood Centers of the Pacific.

Perkins at Irwin initially had this same concern but by the spring of 1984 most gays in San Francisco had stopped donating, and the blood bank felt it was safe to introduce the hepatitis B test, he says.

Some Bay Area blood banks followed suit in implementing the hepatitis B test, but others around the country did not. One of the few blood banks to use a screening test was Tulane University, which adopted the Stanford T-cell technique.

Meanwhile, Stanford was starting to get some validation for its approach. Eight months after it began using the T-cell test, Lifson says he got a call from a doctor in Southern California who was treating a man dying from Kaposi’s sarcoma, a rare skin cancer often seen in particularly aggressive form in AIDS patients. The patient said he had donated blood at Stanford and elsewhere. Lifson was able to trace back the Stanford donation to a unit donated within the first few weeks of the screening program and found to have a dramatically abnormal T-cell profile; the unit had been withheld from transfusion because of the abnormal result.

“My response was, ‘Boy, I’m glad we pulled that unit,’” Lifson recalls. “We were using a test that we knew was not completely specific, and many of the units we were withholding were not going to be from people with AIDS, but by losing 1.5 percent of our donated units, we felt we had a good chance of reducing the risk. We thought that was worthwhile, and having that case was validation for that.”

Ultimately, the blood bank ended up discarding 586 donations that did not pass muster, Galel says. When a federally approved screening test became available in 1985, Stanford was able to confirm that 11 of those donations — or 1.9 percent — were positive for HIV. Because each unit of donated blood is typically divided into three components — red cells, plasma and platelets — for transfusion into different patients, the removal of those 11 HIV-infected units potentially saved 33 people from an AIDS death, Galel says. It’s quite likely additional lives were spared as most donors give blood repeatedly, and some with abnormal tests were deferred from future donation, Engleman says.

Although the T-cell test was not that specific, as some critics would note, and some “good” blood was wasted, he says he believes it eliminated the majority of the contaminated donations.

“It certainly was satisfying to know that the test was successful. The patients at Stanford were protected. The hospital was one of the few in the country that wasn’t sued,” says Engleman, who was called as an expert witness in several lawsuits.

The cost of the screening test amounted to $10 to $14 per unit, and though others had warned that laboratory testing would scare away some donors and lead to blood shortages, that was never the case at Stanford, Galel says.

The story was different in San Francisco. Though self-exclusion eliminated some 86 percent of the risk, later analysis showed that at least 1 percent of those transfused — or at least 2,000 recipients — became infected with HIV, Busch says. That was “vastly different” from the earlier one-in-a-million estimates, he notes in a paper published in October 2010 in the journal Transfusion. The San Francisco blood bank would face some 50 lawsuits, which it successfully defended.

In retrospect, he says his blood center was wrong about the hepatitis B antibody test, which would have picked up significantly more infected donors than originally believed — between one-third and one-half of the HIV-positive donors.

Paul Volberding, MD, director of the AIDS Research Institute at UCSF and one of the pioneers in the epidemic, says Irwin and other blood banks can’t be faulted for their actions, which were based on what very little was known at the time.

“My own position was that the blood banks were doing what they could, not knowing what was going on, given that blood is a precious thing,” Volberding says. “You could have shut down the whole blood system and eliminated AIDS, but then people would have died of not having blood. Or you could have instituted broad tests that may or may not have reduced HIV but rejected units that were perfectly safe.”

But Engleman is still defiant, believing that blood banks acted irresponsibly. “I felt the blood-banking system had let the public down,” he says. “I felt the blood banks went against science and rational behavior because they refused to use our test or other tests, like the hepatitis B test.”

It was not until May 1984 that the existence of HIV, first isolated in 1983, was officially confirmed in a series of reports in Science magazine. Margaret Heckler, former secretary of the Department of Health and Human Services, then famously declared that a blood test would become available within six months and a vaccine ready for testing within two years. But it would be almost a year — March 1985 — before the FDA approved the first assay to detect HIV, and most U.S. blood banks waited until then to adopt the first official HIV test. An effective vaccine has yet to be developed.

In the interim, between the critical period of 1983 and 1985, it’s estimated that at least 20,000 people nationwide, and possibly as many as 29,000, became infected with HIV through blood transfusion.

Since then, HIV tests have been significantly refined. With the early assays, there was an estimated 56-day lag between the time of infection and the detection of antibodies. Later tests reduced the window to three weeks. Today, with use of nucleic acid tests, which detect sequences of specific HIV genes, the window has been reduced to nine days, Galel says.

The risk now of receiving HIV-tainted blood is estimated to be about one in 1.5 million. And in this age of highly effective screening, the FDA continues to prohibit gay men from donating blood — an exclusion that remains controversial.

The AIDS experience ushered in a new era of tight controls over the blood-banking industry. The Institute of Medicine issued a detailed analysis of the crisis in 1995, criticizing blood banks and federal agencies for a “failure of leadership and inadequate institutional decision-making.” It recommended sweeping changes, including new federal oversight and surveillance. Engleman also testified twice before Congress, which directed the FDA to overhaul its regulatory process for the industry.

“I think the whole AIDS experience completely transformed how the FDA looks at blood safety,” Galel says. “This showed that an infectious agent could be in the population and be transmitted for years without anybody being aware of it.”

But she says the FDA may have gone too far in its regulatory zeal. For one thing, Stanford could not do today what it did back in 1983 — introduce a test without regulatory approval, she notes. And that has proved frustrating and problematic at times. For instance, a parasite known as Babesia, which causes a malaria-type disease, has infiltrated blood supplies on the East Coast, with more than 100 reported cases of infection through transfusion.

Though some blood banks would like to screen for Babesia, they cannot do so until a test has undergone clinical trials, which are now under way, and has been approved by the FDA.

“Times have changed to make it very hard to respond in real time to a newly recognized threat,” Galel says.

Despite today’s rigorous and costly screening programs for a wide range of agents, it is theoretically still possible for something dangerous to slip through, Engleman says. “But if you look at the bigger picture, blood is much safer today than it has ever been before.”

 

Contact Ruthann Richter