The Fatal Strain

by Alan Sipress

  Hong Kong health officers had already visited Hoi-ka’s family. It had been a hard interview. The family was distraught, and it took a long time to explain to them how an entirely new virus could have claimed their son. Investigators had gathered what information they could from the parents and their housekeeper about the boy’s recent history. None of it seemed exceptional. When Fukuda arrived in Hong Kong, he asked to see the family again, but they refused to talk anymore. He didn’t press it.

  Fukuda had other angles to explore. His first priority was to determine whether this was simply much ado about nothing. The positive test result for H5N1 was so startling that he suspected it could be the result of a contaminated sample. Perhaps the boy had never been infected at all. So Fukuda and his team traced the precise route of the specimen. They went to Queen Elizabeth Hospital, the primary referral hospital on Hong Kong’s Kowloon peninsula, to see the intensive care unit where the boy had been treated. They checked to make sure that hospital staff had followed proper sampling procedures, and they examined the equipment. They asked whether any other patients had a similar respiratory disease and could have been the source of the virus. They asked about the health and habits of the staff. Perhaps some nurse had tracked the virus in. The team also visited the health department’s lab at Queen Mary Hospital on Hong Kong island, reviewing how the tests were conducted. They explored whether the virus might have been inadvertently introduced by technicians working at a veterinary lab in the adjacent building. After nearly a week of investigating, there was still no evidence of contamination anywhere.

  But the conclusive proof came in the lab. The team conducted an analysis using antibodies that would find the virus and cling to it. The antibodies were tagged with fluorescent stain so they could be identified under a microscope. When these were added to a sample from the dead boy’s windpipe, they attached to the inside of the human cells in the specimen. The antibodies did not simply float on top. This meant the virus had truly infected the boy’s cells and was not an accidental visitor.

  The cruel progression of the boy’s disease also seemed to confirm he’d been struck by a form of viral pneumonia arising from influenza. As Fukuda pored over the medical records, he learned that Hoi-ka was initially taken to a doctor after coming down with a high fever, sore throat, and dry cough. The doctor prescribed aspirin and antibiotics and sent him home. But the condition worsened. The boy didn’t seem to be thinking right or acting right. He was oddly irritable. He wasn’t his usual alert self. The doctor couldn’t put his finger on what was wrong. So he admitted Hoi-ka to a small private hospital. A day later, he was moved to the intensive care unit at Queen Elizabeth Hospital and put on a respirator, but to no avail. The boy was losing consciousness. His lungs were failing. Five days later, he was dead.

  Fukuda read the records and thought, “Wow. This is really bad. No matter what they could have done, they weren’t going to prevent him from dying.” Fukuda was struck by the relentless advance of the disease. “It was clear from the time the child got in. He started getting sicker and sicker and sicker and then he died. You don’t expect to see that in young healthy children.” It reminded Fukuda of the healthy young men he had seen in San Francisco in the 1980s struck down almost overnight by AIDS.

  It also made him think of his daughters. He couldn’t keep his mind off them. He wasn’t frightened, not yet. There was just one case. But he felt so sad. How awful for parents to lose a child out of the blue to such a mysterious intruder. “This,” he thought, “is just like a visitation from outer space.”

  Hoi-ka’s young lungs had been ravaged. The final diagnosis gave the cause of death as pneumonia and acute respiratory distress syndrome, in other words a severe inflammation of the lungs that culminated in their wholesale destruction. But the virus didn’t stop there. The boy suffered kidney failure, and his blood was poisoned, unable to clot normally. His liver and kidneys also showed evidence of Reye’s syndrome, a separate, potentially fatal disease that can occur when aspirin is taken to treat viral disease.

  This was indeed flu. But it wasn’t the flu most people know. Sure, ordinary seasonal flu can put you on your back with a fever, a cough that keeps you up at night, and aches that rack your bones. But in the vast majority of cases, these symptoms pass in just a few days. This new strain meant far more than a runny nose and chills.

  Often, viruses will adapt themselves to their human hosts over a period of time. They will soften their edges and temper their nastiest qualities. After all, the objective of any virus is to reproduce itself inside its host and then jump to another so it can continue to replicate. A death that comes too quickly does little to serve these ends.

  But H5N1 is an interloper, an unrefined newcomer, all fury without the seasoning of age. In human cells it has discovered a fresh target and it pursues its prey deep into the body, penetrating much farther than ordinary flu. Seasonal flu usually strikes the upper respiratory tract, the nose, and nearby throat. The result is sniffles. This novel virus, by contrast, advances on the lungs themselves, attacking the branches of the bronchial tree and the myriad little buds on their tips called alveoli, where the life-sustaining task of exchanging carbon dioxide for oxygen occurs. The pathogen infects the coating of mucus that protects the membranes of the lungs. But unlike regular flu, which cannot reach much beyond surface cells, this newcomer penetrates into the tissue itself. It thrusts deeper. It spreads farther, often infecting both lungs at nearly the same time. As the pathogen relentlessly erodes the cells of the deep lung, you find yourself increasingly short of breath. Your cough is often bloody and you may bleed from your nose and even gums.

  Once inside the cells, the virus begins reproducing madly. Even in the throat, which is at best a secondary target, the amount of virus can exceed that of normal flu. Down in the lungs, there are at least ten times more than in the throat, in some instances even a hundred times more. This is a virus in a hurry. And the human body, which has never encountered anything like it, has no ready arsenal of antibodies to choke off the process.

  The body can still marshal its innate, all-purpose defenses. But in doing so, it mounts a counterattack so furious that some scientists believe it’s more lethal than the virus itself. The besieged cells raise the alarm by dispatching messenger proteins called cytokines. These in turn prompt a counterattack by the body’s defensive forces. Immune cells of different stripes, including killer T cells, macrophages, and other white blood cells, flood into the infected lungs, ferociously attacking the virus and the cells that have fallen into enemy hands.

  This is the fateful battle on which life could turn. There is no restraint, nothing held back. The body throws everything it has at the intruder without regard to the tremendous collateral damage this causes the lungs themselves. The cytokines keep firing and firing in what scientists call a cytokine storm. (Researchers debate whether the massive response is due to the tremendous amount of virus in the system or the nature of the pathogen itself. Unlike regular flu viruses, which have a way of calibrating the immune response, this strain may not.) Ever more immune cells are summoned to the front and continue to blast away. The carnage mounts. The lung cavities fill with dead and damaged tissue, mutilated mucus cells, and other cellular wreckage. The lungs become rigid as the cells that make liquid to keep the lungs flexible are annihilated. The seal between the bloodstream and the air passages ruptures. Red blood cells and plasma leak into the lungs. The alveoli sacs are swamped with fluid and debris and are no longer able to exchange carbon dioxide for oxygen. If you listen closely, you can hear the liquid crackling. Your breathing accelerates. You desperately press all your chest muscles into helping you suck down precious oxygen. You’re gasping for air. This is the acute respiratory distress syndrome, known as ARDS, that struck Hoi-ka. On a series of X-rays, it appears like a white ghost consuming your lungs. You’re drowning.

  But the virus is not content to remain a solely respiratory disease like regular flu. From the lungs, the pathogen sets upon o
ther vital organs. It invades the digestive tract, perhaps when you swallow contaminated sputum, but more likely via the blood. The virus gets into the gut, often causing diarrhea and sometimes vomiting. It can assault the liver and kidneys, as it did with Hoi-ka. It can provoke heart failure. It can attack the eyes. It can even breach the brain and spine, on rare occasions causing encephalitis and related seizures. This virus has shown a singular facility to smuggle itself through the bloodstream and proliferate throughout the body.

  Yet in the end, the lungs are where this microbe concentrates its energies and takes its heaviest toll, whether by killing directly or inviting a suicidal counterattack. The lungs are also the means by which it casts its net for further prey. In this one regard, it is much like its seasonal cousin. They both spread their sickness through contaminated droplets coughed or sneezed into the air, one of the most efficient forms of transmission known.

  Influenza viruses, like all viruses, defy definition. Are they alive? On one hand, they lack the cell structure shared by all other living things from humans down to the amoebas that students study in science class. But at the heart of a virus is genetic material, the basic blueprint of all life, and viruses share the imperative of all living things to reproduce and pass on their genes before they perish.

  The flu virus contains eight pieces of RNA, accounting for all of its genes. These determine everything about the virus: how it’s structured, how it reproduces, how it spreads, who or what it infects, and how sick it makes them. In particular, the genes program the proteins that do all this heavy lifting.

  The virus itself is a microscopic sphere studded with two types of these proteins. One is the hemagglutinin, a spiky protrusion that the virus uses to break into the cells of its host. The other is the mushroomlike neuraminidase, which the virus uses to break out again. The two are called H and N for short. Each can take slightly different forms—scientists have so far discovered sixteen H subtypes and nine N subtypes—and the subtle variations that define them can mean life or death to the host. Human antibodies can recognize certain of these surface proteins and disarm them, but they are powerless against those that are totally new.

  The flu virus most often enters the human body by hitchhiking a ride on an inhaled droplet. As the virus is whisked through the nose and down the windpipe, it brushes along the cells lining the airway. These cells have special receptors. Some are a poor fit for the specific hemagglutinin subtype that has been inhaled, so the virus keeps going. But some are just right. When the hemagglutinin finds the right receptor, the spiky protein plugs in, allowing the virus to fasten to the outside of the cell like a pirate ship preparing to board another vessel. The human cell seeks to stem the attack by engulfing the virus, then walling it off while trying to digest it with acid. But all the cell has done is speed its own demise. The acid triggers a remarkable transformation of the flu virus. The hemagglutinin turns itself inside out, baring a hidden weapon often likened to a molecular grappling hook. The virus uses this to pull itself even tighter against the cell. The membrane of the virus dissolves, and the viral genes stream into the core of the cell like marauding buccaneers.

  A virus cannot reproduce on its own. But once inside the human cell, it finds everything it needs to do so. The viral genes hijack the cell’s own genetic machinery and deliver fresh commands. The innocent cell is soon churning out viral proteins, which are assembled into a brood of new viruses. Within hours, up to a million progeny are ready to explode forth and continue the mission.

  But escaping the cell is not so easy. The same receptors on the cell’s surface that first attracted the virus now try to ensnare its offspring. So the neuraminidase steps in to cut them loose, leaving behind the lifeless wreckage of a human cell.

  Most flu viruses fall into one of two types, either influenza A or influenza B. While the former can infect a wide array of species besides humans and cause severe illness, the latter tends to be found only in people and is less virulent. Influenza A viruses are further categorized by the proteins on their surface. The strain that struck Hong Kong in 1997 and continues to menace the world today is identified, for instance, by its H5-type hemagglutinin and its N1-type neuraminidase, hence influenza A (H5N1). Like all flu viruses, H5N1 originated in waterfowl, and that’s where most flu strains stay, circulating benignly among wild birds. But over the centuries, a few strains have succeeded in crossing the species barrier, either directly or via intermediate hosts like pigs, to infect people. Over time, these have evolved into the ordinary seasonal viruses that we usually associate with flu, losing much of their bite as humans develop immunity. The prosaic H1N1 strain that in recent years has kept millions of people in bed each winter, for example, is descended from a virus that first infected humans in the early twentieth century, sparking the catastrophic Spanish flu pandemic of 1918. The swine flu strain that erupted in early 2009 is also an H1N1 strain and it too can trace its lineage back to the Spanish flu. But swine flu, which scientists believe emerged only recently from pigs, has diverged so far from other H1 viruses over the years that vaccines against the seasonal H1N1 variant afford little protection against this new arrival.

  So what distinguishes avian and human flu strains? Research suggests there may be several factors explaining why some viruses circulate primarily or exclusively in birds while others spread easily among people. Much of the suspicion centers on the receptors in the human respiratory tract. The hemagglutinin of human flu viruses fit better into one type of receptor common in the nose, sinuses, and upper reaches of the airway. Avian viruses, including H5N1, prefer a different type of receptor that is characteristic of birds but relatively rare in the upper airway of humans. Instead, this avian-type receptor is found deep in our lower respiratory system. Scientists surmise this is why H5N1 primarily strikes the lungs, as opposed to the throat and nasal cavity. This could also explain why the virus remains hard to catch, since these avian-type receptors are buried and relatively inaccessible. And when the deep lung does get infected, the virus has a long trip back up the windpipe before being coughed or sneezed into the air, making it hard to spread.

  Yet all that separates the world today from an unprecedented calamity could be a slight retooling of the virus, some evolutionary tinkering with the hemagglutinin to make it a better fit for the receptors in the nose and throat, a change in another protein allowing the virus to better replicate in the temperatures of the upper airway, a few other genetic tweaks. Some researchers estimate it would take at most a dozen minor adjustments.

  Scientists were aware of H5N1 even before it killed Hoi-ka in 1997. A version of the strain had initially been detected four decades earlier in chickens in Scotland. But no one thought it could jump the species barrier to people. It was strictly avian. That’s why its sudden appearance in the lab sample from Hong Kong was so startling. By making the leap, the virus had satisfied two of three conditions for a pandemic. It was novel—no one had been exposed, so no one had immunity—and it had proven it could infect people. Now it just had to show it could get around.

  One day before Hoi-ka died in May 1997, Hong Kong’s public-health laboratory at Queen Mary Hospital had received a specimen of fluid from his windpipe. The sample was one of more than eighty collected every day from patients at the city’s hospitals and clinics. They were all sent to the lab, a small but hectic facility on the seventh floor of the clinical pathology building, erected on a hillside overlooking the western approaches to Victoria Harbor. The waters below were crowded with freighters emerging out of the mists of the South China Sea. Inside, the staff busily tested the samples, sorting them for flu, hepatitis, HIV, and other viruses, categorizing them by subtype when appropriate.

  The technicians suspected that Hoi-ka was suffering from influenza and placed his specimen in a cell culture designed to grow the virus. When they looked at it a little later under a microscope, sure enough, it was flu. But what sort? Using an antibody test, they determined it was a kind of influenza A. They assumed it was one o
f two run-of-the-mill subtypes, either H3N2 or H1N1. The lab had chemical reagents to identify each of these seasonal strains. Yet every time they ran the test, they came up empty. They were stumped.

  Dr. Wilina Lim was the adept yet unassuming chief of the virology lab. She spoke in quick, clipped sentences and had a no-nonsense manner that won her the respect of colleagues. Lim was sure the boy’s sample had to be seasonal flu. Since she never expected it to be something utterly new, she wasn’t particularly worried. Lim concluded that one of the ordinary strains must have evolved ever so slightly, which would explain why her lab’s reagents no longer picked it up. Still unaware that the boy had died, Lim decided to divvy up the specimen and ship these samples out for further analysis in specialized flu labs overseas, including the CDC in Atlanta and Mill Hill in London. She also sent a sample to a veteran Dutch virologist named Jan de Jong, who worked at an institute outside Utrecht in the Netherlands. Though they had never met, Lim and de Jong shared a fascination with odd and offbeat viruses and over the years had compared notes from time to time.

  More than two months passed. Lim never heard back. Then, on a Friday in early August, she got a call from de Jong. He was coming to Hong Kong, arriving in two days, and would like to see her. He didn’t say why. Lim assumed he was just passing through. She said she’d be pleased to finally meet him. She reserved him a room at the Ramada Hotel in Tsim Sha Tsui, a teeming quarter of narrow streets jammed with shops hawking clothes, shoes, and electronics, where the air was pungent with the smells of tropical cooking and the night skies blazed with neon.