LASSA AND EBOLA
On average, the world experiences one or more new emerging communicable disease problems each year. Often they are known conditions whose cause is suddenly revealed. Legionellosis, to be discussed later, falls into this category. Other times, an organism is enhanced by some change in how we do things. Toxic shock syndrome is an old problem, for example, but a new type of tampon, introduced in the late 1970s, enhanced its incidence, causing a widespread, frightening outbreak among menstruating women. Sometimes a slight variation in an old organism provides new threats. The introduction of new influenza strains is a constant concern for the public health community, for example. And sometimes we actually identify new organisms not previously recognized. Lassa and Ebola virus infections, which suddenly arose in Africa in 1969 and 1976, were newly discovered pathogens but, undoubtedly, had been causing disease in Africa for many years. Sometimes the problem is indeed new, as with AIDS.
Lassa Fever
Nurse Lily Lyman Pinneo led a life of adventure and service—and had a very close call. Pinneo grew up in a family of medical people and missionaries. After obtaining a nursing degree from the Johns Hopkins Hospital School for Nurses, she arrived in Nigeria a year after the end of World War II. She started a health care center in Jos, Nigeria, which soon acquired a doctor and additional nurses and became known as the Bingham Hospital.
January 1969 would be known by some as the date of release of the first Led Zeppelin album. Others would recall it as the date that Richard Nixon was inaugurated the thirty-seventh president of the United States. Pinneo would recall it as the beginning of a nightmare. That month, an American nurse, working in Lassa, a village east of Jos, became sick with fever that progressed to hemorrhagic symptoms. She was flown to Bingham Hospital, where she died within a day. One week later, a nurse at Bingham Hospital became sick with the same symptoms and died.
Nurse Pinneo had cared for both of these nurses, and now she developed symptoms. Her temperature was said to have reached 107 degrees. She was flown to Lagos and was hospitalized and cared for by Stan Foster, a CDC physician working on smallpox eradication.
It was decided that Pinneo needed to be cared for in the United States, and she was flown to New York on a commercial flight. Her area on the plane was curtained off from the rest of the cabin. Lyle Conrad, another CDC physician, cared for her on the flight.
On arrival in New York, John Frame, a physician at the Columbia-Presbyterian Hospital, drew blood samples and sent them, along with specimens from the two nurses who had died, to the Yale Arborvirus Research Unit. Pinneo was admitted to Columbia-Presbyterian Hospital, where doctors ruled out every known tropical disease.
Meanwhile, at the Yale lab, three physicians (Jordi Casals, Sonja Buckley, and Wilbur Downs) studied the samples. No one else was involved in the studies or handled the blood specimens. When Dr. Casals became ill, he assumed he had the flu. But he was persuaded to be admitted to Columbia-Presbyterian Hospital, where the staff suspected he had the same, as yet unnamed, illness as Pinneo. The staff suspicions turned out to be correct.
The hospital staff tried something radical. With no treatment available for Dr. Casals, they drew two units of blood from Pinneo and separated her plasma, which they reasoned would, with her recovery, contain the antibodies that had defeated the virus in her body. They were correct; Dr. Casals received Pinneo’s antibodies and recovered.
But there was one more shock. Back at Yale, Juan Roman, a laboratory worker with no known contact with the specimens, developed hemorrhagic fever and died. Yale ceased work on the virus and sent its specimens to the CDC in Atlanta. There, the virus was ultimately isolated and characterized as a single-stranded ribonucleic acid (RNA) virus. How common was the illness? How could it be diagnosed? Was there a way to treat patients with the virus? All were unanswered questions.
Pinneo returned to her work at Bingham Hospital in 1970. She arrived with vials of her own convalescent-phase plasma antibodies to treat other patients with the disease. Her arrival came too late for staff physician Jeanette Troup, from Colorado, who had performed an autopsy on a patient who had Lassa fever. Dr. Troup had incurred a cut during the autopsy and subsequently developed Lassa fever. She died ten days before Pinneo returned with her lifesaving plasma.
Pinneo continued her work as nurse-midwife but also continued to work on Lassa fever both in Nigeria and in other West African countries. After forty years of work in Africa, she retired in the United States. She died on August 17, 2012, at age 95. The Pinneo strain of Lassa fever was named in recognition of her being the first person to have laboratory-confirmed Lassa fever.
Meanwhile, Joseph McCormick and other scientists at the CDC studied the virus, the disease it caused, and the means of transmission. They found that the disease is common in West Africa, resulting in about 5,000 deaths a year and perhaps 500,000 cases of illness. That means the fatality rate is only about 1 percent because, in most cases, it is a mild and unrecognized illness. If the illness is sufficiently severe to bring a person to the hospital, up to 20 percent will die.
Why the string of four American deaths in a single chain of transmission? It could be that the strain was unusually deadly, that the outsiders had no immunity from an earlier exposure to less lethal strains (a significant percentage of Nigerians were later shown to have antibodies to the virus), or a combination of several factors.
Dr. McCormick discovered that the Mastomys rat of West Africa is a reservoir for Lassa virus. This rat is widely found in the savannas and forests of West Africa, but it appears to enjoy living in human homes. In an interview (1), McCormick described his understanding of the spread of the virus:
One way is from the urine of the rodent Mastomys natalensis, which is the common rodent called the “multi-man” rat that you find throughout much of Africa, as a matter of fact, but especially in West Africa. This rodent tends to live in houses with humans. It will live there for long periods of time. What usually happens in West Africa is that the people wake up in the morning, they get a bit of breakfast, and then they close their houses up, leaving them dark inside, and go off to their day’s activities. Of course, when they come back in the evening, it becomes dark at 6:30 p.m. or 7 p.m., and what this means for the rodent is that it sometimes has almost 24 hours of nighttime activity. During that time, the rodent will circulate through the house and deposit urine on surfaces such as the floors, the tables, and even in food if the rodent is able to get into the food and other places … even on beds. And we believe that people get infected most frequently when they come into contact with the deposited rodent urine on one of these surfaces, usually transmitting the virus through cuts and scratches on their hands and feet.
Another method of spread is person to person, as with the nurses at Jos.
While a vaccine is not available, work continues on vaccine development, and a treatment is now available. Ribavirin, an antiviral drug, appears effective if it is administered early and intravenously.
Ebola Hemorrhagic Disease
Other new, deadly, and frankly scary viruses continue to be discovered and understood. One is Ebola.
It was August 1976. Gerald Ford had just won the Republican presidential nomination but would lose the election to Jimmy Carter. Thousands had died in an earthquake and tidal wave in the Philippines, and thousands more had died in an earthquake in China. But none of that mattered to 44-year-old Mabalo Lokela, a teacher in Yambuku, Zaire. He was feeling lousy, and because of a high fever, he went to the local hospital.
The hospital was always overburdened, forced to treat many people on an outpatient basis for conditions that would have automatically led to hospitalization in Europe or in the United States. One of the nurses assumed Lokela had malaria and gave him a shot of quinine. She had no way of knowing that, in truth, he was the first known case in an epidemic of a previously unrecognized disease, Ebola hemorrhagic fever.
Over the years, this disease would spread fear in villages in Africa (especially in Uganda, The Congo, and Sudan), in workers exposed to outbreaks, and in countries around the world that feared an importation of the virus. How Lokela got the Ebola virus is unclear. A third of a century later, the natural history of this virus is still under investigation. Thousands of tests on animals, insects, and birds now cast suspicion on three types of fruit bats. It is believed that they can carry and spread the disease without becoming ill, thereby providing a reservoir for the virus between human outbreaks. Fruit bats may spread the virus to people directly or through animals.
What is clear is that other people in the hospital got the virus from the inadequately cleaned syringe and needle used to administer the quinine to Lokela, as well as from close personal contact with him.
Lokela was sent home, where he died. The women of his family prepared his body for the traditional funeral, a ritual that included removing blood from his body. Most of them soon also developed Ebola infections and died.
At the hospital, if there had been only one break in hygiene, it might have led to an additional case. But the actual break in hygiene was far more substantial. The hospital had only a handful of needles, and these were used over and over. The staff lacked the time and inclination for suitable sterilization between patients. Many patients, admitted for a wide spectrum of health concerns, were about to share a common problem due to contaminated needles. Previous outbreaks of the disease had probably occurred, but Lokela’s was the world’s first recognized outbreak of Ebola hemorrhagic fever.
When the government of Zaire realized that they were faced with a terrifying hemorrhagic disease problem, they requested help, and an international response was launched by the World Health Organization (WHO) with the help of the CDC. The team included physicians Karl Johnson from the CDC, a well-known expert in hemorrhagic fevers; Joel Breman, a veteran of the smallpox program; Joe McCormick, mentioned earlier, who had grown up in Africa and worked with highly dangerous viruses; and Peter Piot, who would later head up the United Nations AIDS (acquired immunodeficiency syndrome) program. Later, Mike White, an epidemiologist from CDC, would join the team.
These were experienced scientists, but the risks involved in such an outbreak are sobering. Investigators do not know what the agent is, and they don’t know whether it is a newly recognized virus. (In this case, it turned out to be a newly recognized virus and one of the most lethal known.) If the agent is new, scientists don’t know anything about its method of spread, lethality, infectiousness, incubation period, or susceptibility to usual containment measures. They don’t know whether it is airborne and, if so, how far it can be transmitted through the air. Will it go meters or hundreds of meters? They don’t know whether apparently healthy people can spread the agent to others. Everything is cause for worry. In addition, scientists in such situations need to work in special quarantine suits that make the tropical heat even more unbearable. One can stay only an hour or less in such a suit before seeking relief, which raised another concern: how do you avoid contamination from the outside of the suit as you remove it?
On the flight from Geneva, Switzerland, to Kinshasa, Democratic Republic of the Congo, Breman and Piot met one of the most important people of the entire response operation. William Close, an American physician and father of actress Glenn Close, was on his way to the United States on home leave when he heard of the outbreak and immediately returned to Zaire. Raised in France and educated in England and the United States, Dr. Close was a pilot during World War II and attended medical school at Columbia University. In Kinshasa, he ran the large Mama Yemo Hospital and was the personal physician for President Mobutu Sese Seko. Dr. Close became a crucial link in the outbreak investigation, procuring refrigerators, supplies, permits, and even the president’s personal aircraft to provide transportation for the investigation team members and the supplies they required.
The WHO/CDC team found chaos and fear. And they had an overwhelming to-do list. They had to find the people with the disease and provide them with quarantine, food, and shelter to make sure they were no threat to others. They had to locate the dead to find whether next of kin were sick. They had to do a house-to-house survey of the town and the surrounding areas. They had to characterize the outbreak. Who was the index case-patient? What chains of infection extended from that case? Who were now at risk? The scientists had to get specimens for lab analysis, attempt to isolate an organism, and then look for antibodies to that organism in sick and in well people. They had to identify survivors and determine why they had survived. They also had to figure out the natural history of this organism. Was it usually confined to an animal species with occasional infections of humans? Would it become a permanent and ongoing human disease? Were insects or animals involved as vectors?
And always, the scientists were dealing with unrelenting heat and rain, suffocating humidity, difficulty sleeping, and the unsettling presence of insects and rodents. Amid all of this, they had to find a place to stay and an area for washing themselves and their potentially contaminated clothes without endangering others. They had to arrange for food, transportation, and communications in Yambuku and surrounding villages, where they were strangers and did not speak the local Ngbandi language. There is nothing easy about this kind of investigation. It sounds exciting and glamorous only to those who have never been in this situation.
The team, with the help of Dr. Close, managed to import protective equipment for investigators and clinicians who cared for patients. They also imported medical supplies, sterilization equipment, and necessities for quarantining patients. To quarantine a patient so he or she cannot transmit the virus requires providing everything the patient needs. This includes food, water, medicines, clothing, blankets, and pillows. Otherwise, the patient will find a way out or loved ones will find a way in. A complication is the possibility of feverish patients’, unaware of what they are doing, trying to break out of a strange and terrifying environment.
The team determined that this was a devastating outbreak with unbelievably high mortality rates. They would eventually identify 318 cases, 280 fatal. The area was seized by understandable panic. When 11 of the medical staff at the hospital died, even the hospital was forced to close down. Ironically, the inability to continue staffing the hospital was important to halting the outbreak because contaminated needles and syringes were an important vehicle of transmission. Yambuku and surrounding villages were considered quarantined and visits from other areas were discouraged. President Mobutu flew to France to escape the outbreak.
The best guess initially was that the virus might be Marburg or a variation of that virus. Marburg virus was first recognized in the 1960s, in Germany, after humans were exposed to tissues of infected African green monkeys from Uganda. Of the 31 persons infected, 7 died of hemorrhagic fever.
When it was determined this was a virus never previously isolated, the investigators had the privilege of naming it. To name the virus after the village, as had been done with Lassa fever, could lead to long-term bias against the people of the village. It was decided to name it after the Ebola River, not the closest river but close enough to identify an area.
The isolation of cases and close surveillance of contacts finally brought the outbreak to an end. But the team left, after trapping many animals and insects, without understanding the natural hosts of the virus or what caused its crossover to humans.
And then it was found that an earlier outbreak had been in process but not initially recognized as a new disease. Two months before the first case in Yambuku, a storekeeper in Nzara township in Sudan had become ill with fever, headache, and chest pain. He was admitted to the hospital on June 20 and died on July 6, 1976. A brother also developed symptoms but recovered.
Again, the WHO organized an international response. The team had members from France, Germany, the United Kingdom, and the United States, including Dr. Don Francis, who had distinguished himself in the Smallpox Eradication Program; CDC performed many of the laboratory tests. Again, the team had to contend with all of the problems inherent in the Zaire investigation with little knowledge of the things being learned in Zaire. These scientists eventually discovered 284 cases of Ebola hemorrhagic fever, about half fatal. It was later determined that the Ebola strain in Sudan was slightly different from the strain in Zaire.
Similar to the Zaire outbreak in many ways, the Sudan outbreak was magnified by both direct contact with patients and the amplifying potential of a hospital. The initial outbreak was concentrated in Nzara but then spread to Maridi, 75 miles away, where 213 of the 284 cases appeared.
This was the beginning of the ongoing odyssey with the Ebola virus. There have been dozens of outbreaks and hundreds of deaths recognized since that time. Each one brings fear and uncertainty, heroism from clinicians and families, and mystery for responders.
On at least five occasions the outbreaks have involved more than 100 persons. In 2014, an outbreak occurred in Guinea, a first for that area, but then spread to Liberia, Sierra Leone, Nigeria, and Senegal. By far the largest outbreak of Ebola recorded, it led to global concern. On August 2, 2014, the first person with Ebola infection was moved to the United States and admitted to Emory University in Atlanta for intensive care. Others were to follow.
Each outbreak has been tragic. But until the 2014 outbreak, not one outbreak has bothered me as much as the outbreak in Gulu, Uganda, in 2000. On October 7, 2000, the medical director of St. Mary’s Hospital, Dr. Matthew Lukwiya was on leave to attend a course in public health. He received an urgent request to return to the hospital because of a mysterious illness that had killed two student nurses. He arrived back at the hospital that night, just as a third nurse died. He evaluated the evidence presented and spent the night reading reports from the CDC and the WHO. By morning, he concluded the hospital was dealing with Ebola virus, and he set up a model response to the outbreak.
Dr. Lukwiya was an uncommonly gifted man. His father had drowned when Matthew was 12. His mother was a petty trader, and that was his expected future. He was already learning how to smuggle goods from Sudan to be sold in markets in Uganda. But he was a gifted student, and he led his class in grade school and secondary school. There are many gifted children in Africa, but few have the opportunity to develop those gifts because of scarce resources or the lack of a system for recognizing their gifts. Matthew was different and fortunate. Teachers recognized his abilities and urged him to continue school. He received scholarships that allowed him to go beyond secondary school to the university and, then, with more help from others, he was able to attend medical school. He became an intern at St. Mary’s Hospital. Within three months, the founders of the hospital were so impressed with him that they decided they had found its next medical director. He was sponsored for a pediatric degree at Liverpool with the expectation that he would return to St. Mary’s Hospital to take up the medical director position.
Dr. Matthew Lukwiya, Gulu, Northern Nigeria, October 2000. Photo by Seamus Murphy, courtesy of Panos Pictures
Dr. Lukwiya turned down offers to remain in Liverpool and returned, as planned, to lead St. Mary’s to new heights. His ambition to understand all aspects of medicine had led to the training sabbatical for a public health degree. In the midst of that training in 2000, he was called back to determine the cause of the deaths and to lead the effort to stop the outbreak.
He set up an isolation ward and developed such an efficient response that when the WHO team arrived, they found they had little to suggest. But this is not a forgiving virus. Any break in protocol can place one at risk.
After six weeks of exhausting work, Dr. Lukwiya made his one mistake. He was awakened from a sound sleep on November 20 because one patient, close to death and probably no longer aware of what he was doing, got up, pulled out his tubes, and walked out of the ward. Dr. Lukwiya, on awakening, put on all of his protective clothing, including two pairs of gloves. But in his haste to respond to a man who was exposing others to this deadly virus, he forgot his goggles and face shield. He quickly worked to guide the man back to his isolation ward. It was a short exposure and the path of the virus is unknown, but somehow the virus managed to make it from the patient to Dr. Lukwiya.
The patient died within the hour. Six days later Dr. Lukwiya developed “the flu,” and he and the nurse diagnosed malaria. But they feared worse. Dr. Pierre Rollin, from the CDC, took blood for testing. He diagnosed Ebola, and Dr. Lukwiya entered the isolation ward that he had designed. I can only imagine what a depressing moment that must have been, when the person who knew most about the virus and its means of spread, suddenly realized that something had gone wrong in all of the precautions that had been taken. He appeared to be improving and then hemorrhaged into his lungs and died on December 5, 2000. It was a tragedy for everyone—his family, the hospital, his future patients, the country, and the world. Superior intelligence was no match for this diabolical virus.
As I write this, the world is in the throes of an outbreak of Ebola, unlike any seen before. The outbreak was the first in West Africa. For months, as Dr. Thomas Frieden, then director of CDC, told Time magazine (2), the WHO did not want the help of the CDC. Within months, it was clear the outbreak exceeded the capacity of the WHO and help materialized from the CDC and many other sources. Ebola spread rapidly and soon included urban areas. Three countries—Liberia, Sierra Leone, and Guinea—bore the brunt of the outbreak. Nigeria, Senegal, and Mali also had cases but controlled the outbreak quite rapidly.
By December 2014, there were still hundreds of new cases a day in West Africa, and even the United States had cases and two deaths.
Thirty-six years after the first outbreak, we do not want to learn so many new lessons. If we thought this was chaotic in rural areas, it was absolute bedlam in urban areas. The virus spread in treatment facilities, at home, and especially during the traditional burial practices, in which bodies are washed, there is close contact, and often times many loved ones touch the body.
Care of the sick was needed. Finally, with the assistance of military units from the United States and other countries, facilities began to meet the need. But the epicenter continued to shift, and therefore facilities were not always available.
The lessons of the first outbreaks, to isolate cases and follow contacts closely, looking especially for fever, paid off in the recent West African outbreak, when Ebola was imported to Lagos, Nigeria. This could have been an urban disaster but was quickly contained by Nigerian epidemiologists trained by the CDC. These epidemiologists swung into action and made hundreds of home visits, following contacts, looking for fever and signs of illness. The outbreak in Lagos was quickly contained.
We now know the following steps are also critical in Ebola outbreaks: global coordination of facilities for care and isolation; clinical care of the sick; point-of-service diagnostic abilities to avoid moving blood specimens out of the patient area and to get rapid results; assistance in burying those who die; logistic support for everything from obtaining supplies to providing transportation of patients, food, and other assistance; and superb surveillance, analysis, and communication with all who need information.
There were lessons beyond the scientific findings. Public health infectious disease outbreaks can destroy local economies and have worldwide implications. The constant drumbeat of nations trying to reduce the WHO budget was successful in keeping down that organization’s growth—and it was absolutely devastating not to have an organization able to respond to the challenge.
We also learned how politicians can make things worse. States quarantining health workers when they returned from West Africa reduced the desire of experts to volunteer for service. When the US Department of Health and Human Services asked me for recommendations, I was able to include one facetious recommendation. Because the Republican governor of New Jersey and the Democratic governor of New York had both imposed unscientific rules on the quarantine of returnees who were not sick and only needed to have their temperatures checked each day, I suggested the federal government halt all flights out of those two states in an attempt to reduce the spread of political stupidity.
But there are also hopes. Perhaps we will now get the strong WHO the world needs—one without a board of 194 ministers of health and regional offices constantly trying to undercut headquarters in Geneva, a WHO that has an adequate budget, a way to reduce the political barriers to employment of the best people possible, and a mandate to follow the science rather than the politics.
Perhaps we will get a global United Nations synthesis that reduces the tension and antagonism between UN agencies intent on protecting their turf. This global health problem may have been required to force us all to look at the lessons of the past seventy years and ask if we can’t do better.