Читать книгу The Fevers of Reason - Gerald Weissmann - Страница 13

2.

Ebola and the Cabinet of Dr. Proust

The death of millions of people whom we do not know barely touches us, and almost less unpleasantly than a current of air.

—Marcel Proust, Remembrance of Things Past (ca. 1916)

Cordon sanitaire—we call it a cordon when someone who presents any symptoms of that disease is transferred, if their condition permits, to a hospital or to an equivalent place designated by the local authorities.

—Adrien Proust, “Essay on International Hygiene” (1873)

We believe these new measures [taking temperatures and administering questionnaires at JFK and other airports] will further protect the health of Americans, understanding that nothing we can do will get us to absolute zero risk until we end the Ebola epidemic in West Africa.

—Thomas R. Frieden, Centers for Disease Control and Prevention (October 8, 2014)

WE’VE LEARNED FROM THE EBOLA OUTBREAK of 2014 that to stop pandemics, we must regulate the transport of host and virus alike. Public transmission and cellular invasion depend on the unimpeded traffic of people across borders and of viruses across cell membranes. Barring the traffic of people across the Atlantic from Liberia would certainly have prevented the first four cases of Ebola in the United States. Blocking the traffic of the virus in human cells would have prevented thousands of cases worldwide. The Ebola epidemic in West Africa presented a major challenge not only to our public health system but also to our capacity to develop antiviral drugs. Thanks to cell and molecular biology, we already understand some of the critical pathways of virus entry and replication. We’ve also learned that these conduits can be blocked by novel drugs such as dynasore [sic] and Dyngo (no kidding) that are slowly coming to the clinic. To everyone’s surprise, papers by Harper et al. and Masaike et al. showed that bisphosphonates, drugs widely used to treat osteoporosis, also inhibit the traffic of Ebola virus in cells.

So now that we have the tools available—dynasore, vaccines, adenosine analogues, inhibitors of RNA dependent-RNA polymerase, and so on (as shown by Oestereich et al.)—isn’t it time to launch a major effort, like those against smallpox, polio, and AIDS, to bring the benchwork of pharmacology to the bedsides of West Africa?

IF DRUGS OR VACCINES HAVEN’T BEEN DEVELOPED for an infectious disease, there are only two time-tested ways to quell an epidemic: quarantine and sanitation. In the case of Ebola, the first step would have been to stop reliance on thermometers and telephones to keep infected victims from transmitting the disease. Temperatures vary, Tylenol can mask fever, and reliable information via telephones depends on who’s asking and who answers. Those protocols didn’t work in Dallas in the case of the first victim, the unfortunate Thomas Eric Duncan. Also fallible was the CDC’s policy of voluntary self-monitoring by people exposed to active Ebola victims: ask the many passengers between Dallas and Cleveland. The third American Ebola victim, Amber Joy Vinson, got permission for flights between Dallas and Ohio “because her elevated temperature of 99.5 degrees was below the no-fly threshold of 100.4 degrees,” the New York Post reported. Once it became known that Ms. Vinson had been involved in Mr. Duncan’s care, Dr. Frieden of the CDC confessed that “she should not have traveled on a commercial airline”—let alone take a taxi or visit a popular bridal shop. In contrast, quarantine of Mr. Duncan’s immediate family seemed to have worked.

The CDC and the White House presented cogent arguments against a strict ban on flights from Liberia, Guinea, and Sierra Leone, arguing that such a ban would wreck the fragile economies of the area. “Trying to seal off an entire region of the world—if that were even possible—could actually make the situation worse,” said President Barack Obama. A ban would also have curtailed free passage of sanitary supplies and aid workers. Many public health experts agreed and warned that the threat of Ebola to the United States and Europe would not end until its exponential spread was stopped on the ground. They’re right to have worried. The early speed and extent of the 2014 outbreak in West Africa certainly dwarfed all earlier ones, and according to the World Health Organization, that outbreak was the worst ever, with 28,639 confirmed cases and 11,369 deaths by March 13, 2016. That toll and that extent are the best reasons why—next time—a travel ban, with visa restrictions and monitored quarantine, should be in place until WHO criteria for an end to the outbreak are met. That would be the quarantine part of the equation.

What about sanitation? Well, I’m afraid that all the noble efforts of Médicins Sans Frontières (Doctors Without Borders) or U.S. Army engineers were unable to produce a timely change in the sanitary culture of West Africa. Among expected obstacles, they faced unfamiliar ritual bathing and burial practices such as those that had sparked earlier Ebola outbreaks. Ebola, which is endemic in African fruit bats, first appeared in 1976 in rural Sudan and the Democratic Republic of the Congo (formerly known as Zaire): 284 were infected and 117 died. By 2000 it was Uganda’s turn, with 425 cases and 224 deaths. The index case in Uganda was that of Esther Awete, a villager who died in her mud hut on September17, 2000, after several days of fever and pain. Seven of her relatives also died after they had ritually bathed Awete’s corpse and washed their hands in a communal basin as a sign of communion with the dead. Ritual bathing remains common in West Africa today: three months into the 2014 epidemic, The Economist cited a WHO study reporting that “60% of all cases in Guinea were linked to traditional burial practices that involve touching, washing or kissing the body.” Not only in Guinea: thanks to gravesite infection, Ebola remained endemic in the Democratic Republic of the Congo, with 66 cases and 49 deaths in 2014. In September 2014, WHO had called for a 70–70–60 target plan aimed at isolating 70 percent of suspected new cases of Ebola, a safe burial of 70 percent without the risk of infecting others, all within the next 60 days—and no new cases by January 1, 2015. The goal was not achieved until January 15, 2016! That’s an unanswered call for quarantine and sanitation.

There are other factors in play. Until the 1990s, Ebola afflicted sparsely populated areas of the continent, but in 2014, the disease ran wild in Monrovia (Liberia), Freetown (Sierra Leone), and Conakry (Guinea), capitals with populations of over one million each. These cities, which retain many neighborhoods lacking clean water and adequate sewage, have also suffered from civil war and bloody coups. In Liberia, where UN peacekeepers remained until 2013, 14 years of civil war killed 200,000 of its citizens. Helene Cooper reported in the New York Times, “The war produced mad generals who led ritual sacrifices of children before going into battle, naked except for shoes and a gun.” Sadly, there are also public health problems at the beginning of life. According to a CIA World Factbook, even before Ebola the infant mortality rate stood at 69/1000 in Liberia, 73/1000 in Sierra Leone, and 91/1000 in Guinea (versus 6/1000 in the United States).

That’s why it will be a long time before we can completely revamp the local conditions that permitted Ebola to spread. Dr. Barry R. Bloom, a specialist in infectious diseases, told the New York Times that, in the big picture, “the most important thing that can be done to protect Americans from Ebola is controlling Ebola in West Africa.” I agree, but in epidemic times we’re never in the big picture, and the virus remains a latent threat which, like Zika, can arrive on the next plane.

SUPPORTERS OF THE ORIGINAL CDC PROTOCOLS argued that thermometers, questionnaires, and telephones are more humane than the “medieval” solution of official quarantine. But a more rigorous model has been around for a while. Twenty-first-century Monrovia and Freetown could take lessons from nineteenth-century New York and Paris. It took the better part of that century, but the two capitals overcame five lethal epidemics of Asiatic cholera, as it was known, despite polluted water, civil war, and urban grunge. In good part this was because enlightened sanitarians came up with solutions like Croton Reservoir in New York and Baron Haussmann’s roadways and sewage systems in Paris, as I described in “Cholera at the Harvey.”

But sanitation alone was not the answer. The measures in New York followed the principles of the French cordon sanitaire: those showing signs of the disease were “taken to a hospital or to an equivalent place designated by the local authorities,” according to Adrien Proust in his “Essay on International Hygiene.” The places in New York designated by local authorities included quarantine ships in the East River near Bellevue Hospital and quarters at Castle Garden at the Battery, which from 1820 until 1892 was the entry point for immigrants. Inspectors washed its walks and walls with carbolic acid. Ellis Island, which opened on January 1, 1892, was equipped with larger processing, hospital, and quarantine facilities. The following September, in response to the last major cholera outbreak in Europe, President William Henry Harrison approved the last major quarantine order for New York: “no vessel from any foreign port carrying immigrants shall be admitted to enter at any port of the United States until said vessel shall have undergone a quarantine detention of twenty days . . . ” —that’s Ebola-level timing. A congressional act followed, but soon enough, when cholera no longer threatened from overseas, the quarantine order was lifted, never again to be used by an American president.

Opponents of quarantines against Ebola in 2014 believed that a visa-based travel ban on people from West Africa had racial overtones. We’ve heard that objection before. In 1892, when New York was faced with both cholera and an influx of Eastern European Jews, a prominent government official complained to the New York Times that “Europe is showing no anxiety to keep cholera away from us. Why should the United States accept her miserable paupers anyhow? In my opinion the President [should] ask Congress to absolutely prohibit immigration for the present.” Some advocates of travel bans today may indeed be objecting to West Africans coming into our country, whatever the circumstances. I’d simply view these bans as mistaken versions of the cordons sanitaires that effectively stopped epidemics of cholera in the nineteenth century. We’re not talking about thirty-foot walls!

THE CHAMPION OF THE cordon sanitaire was Dr. Adrien Proust (1834–1903), father of Marcel Proust. Six pandemics of Asiatic cholera ravaged Europe and spread to the United States in the nineteenth century. The disease, which originated in Bengal, reached the West by land and sea; its greatest damage was wrought at times of civil or imperial war. In France, cholera reached epidemic proportions during periods of political strife in 1830–1845 and during the German siege of Paris in 1870. In 1866, Adrien Proust, clinic chief at the Hôpital de la Charité represented France at an international sanitary conference at Constantinople. Proust, who held the official title of Inspecteur Général des Sanitaires Internationaux, persuaded both European and Ottoman officials to agree that the disease was carried by contaminated water: “Water would seem, according to the observations made principally in England by Dr Snow . . . to contribute, in certain circumstances, to the development of cholera in a locality.” To map the itineraries of earlier epidemics, Proust trekked to Persia, Mecca, Turkey, and Egypt. Since he was able to trace the origin of each Parisian epidemic to the Middle East, Proust pleaded repeatedly that vessels with disease on board be prevented from traversing the newly dug Suez Canal. Egypt was the key! In La defense de l’Europe contre le choléra he declared, “We must absolutely close the Suez Canal, to all vessels, of whatever nationality, with cholera on board or with recent exposure.” Not surprisingly, Ferdinand de Lesseps, president of the Suez Canal Company, objected strongly. (Does the airline industry today oppose a flight ban?) At the Academy of Sciences, de Lesseps opposed strict cordons as “futile and inconsistent with current enlightened opinion, which now held that emanations from local miasma” were responsible for contagious spread of disease (the story is told in LaVerne Kuhnke’s Lives at Risk).. De Lesseps and Company won out, and sure enough, the fifth cholera pandemic of 1884 arrived in France carried on ships that passed through the canal. Eventually, cordons sanitaires were set up as a second line of defense around Toulon and Marseilles to prevent spread of cholera to the rest of France. Cordons around Marseilles were so troublesome that the English gentry transferred their winter watering holes to the French Riviera: Cannes, Nice, and Villefranche became the holiday paradises of the next century.

The state-enforced cordons sanitaires saved Toulon and Marseilles from outbreaks of cholera. How about today? A cordon sanitaire had, by the fall of 2014, effectively prevented Ebola from crossing the borders of a score of African nations, while British Airways and Air France had curtailed flights. Senegal had closed its borders and suspended air flights, and Nigeria’s airline canceled flights after eleven cases of Ebola were tracked to an American passenger from Liberia. Sure enough: as of October 23, 2014, WHO had already declared these two countries free of Ebola. Meanwhile, in Dallas, Mr. Duncan’s family was free of Ebola after twenty-one days of enforced quarantine, and the two nurses he infected were convalescing after treatment in the most modern isolation units. That’s the sort of good news a cordon sanitaire can bring.

THERE’S ALSO GOOD NEWS FROM THE LAB. Basic science works: dynamin, a mechano-chemical enzyme responsible for shuttling cargo in cells (Ahearn et al.), was discovered in 1989 by Howard Shpetner and Richard Vallee, then at the Worcester Foundation (now part of the University of Massachusetts). It turned out that dynamin can choreograph the pathway of viruses in cells. Dynamin not only hobbles the sticking of the virus to the cell’s surface, but also promotes uptake of virus-filled vesicles from cell membranes. Dynamin opens the door to Ebola virus, as described in Aleksandrowicz et al., and helps unload the backpacks. Happily, we’ve moved closer from the lab to the clinic: in animal experiments, dynamin inhibitors such as dynasore already have been seen to stop the virus (Macia et al.). Better yet, the newest dynamin inhibitors (the bisphosphonates used to prevent osteoporosis) can already be found on many a woman’s medicine shelf.

Has the time come to use osteoporosis drugs for Ebola? To quote Mary McCarthy’s Pokey, “Who would have thunk it?”