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March 11, 2014

How virus sleuths and public health officials track the cause of a mysterious illness

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When a mysterious disease fells people - as happened in California recently, with as many as 20 children experiencing unexplained paralysis - teams of physicians and epidemiologists quickly mobilize. Perhaps you saw the movie "Contagion"? The idea is to find the culprit before it spreads but also to prevent public panic.

The investigation typically begins with a doctor reporting a sudden increase in patients with a particular disease or symptom to a state health department. It then falls to the government to determine whether the report is a false perception, a statistical quirk or a genuine surge.

The paralysis cases are a classic example: The symptoms are well known but their incidence appears to have spiked. Acute flaccid paralysis, the technical term for the symptoms observed in California, is something that many pediatricians have seen, and it has myriad causes. "I probably see one case like this every five years," says Keith Van Haren, the Stanford neurologist who is leading the hunt for an explanation for the paralysis reports. "Five cases in one year seems like an abnormality."

It's much harder to prove an abnormality than to perceive one, though. Surveys by the World Health Organization suggest that approximately one of every 100,000 children each year develops acute flaccid paralysis. It's not clear whether the rate is the same within the United States, but, since approximately 7.7 million kids younger than 15 live in California, 20 cases in a year might be within a normal range. A final determination on that question, however, will depend on whether the cases are related and whether they are clustered within a small geographic range. There is also a risk that clusters of cases can generate more such reports, especially once the media get involved.

"What you start looking for, you see," says Daniel Firkin, epidemiology branch chief in the division of viral diseases at the Centers for Disease Control and Prevention. Physicians usually don't report childhood paralysis, he explains, because the CDC doesn't require it.Now that they're on notice, however, more cases are going to be reported. It can be difficult to distinguish a surge in cases from a mere surge in reports.

Another challenge is determining which cases to include in the count. Establishing a case definition - a concise statement of what the patients have in common - prevents unrelated cases from leading investigators astray. According to Stanford's Van Haren, the working definition for the California cases is "paralysis with evidence of injury to the motor neurons in the anterior horn of the spinal cord."

That definition explains why the disease is being described as "polio-like." It's not simply that the children have become paralyzed. Several medical conditions can lead to paralysis. The autoimmune disease Guillain-Barre syndrome and the inflammatory disease transverse myelitis, for example, can paralyze children. Poliovirus, however, has a specific profile, ending in paralysis, that sets it apart from most other illnesses.

Polio is a classic fecal-oral disease. The virus usually spreads from one person's stool to another person's mouth, often through contaminated water or unclean hands. Since 95 percent of people who are infected with the pathogen never experience symptoms, polio victims rarely have reason to suspect they have come into contact with the disease; this is one reason that the eventual paralysis seems sudden.

In some patients, polio progresses to a brief bout of flulike symptoms, which has been observed in a few of the California patients. In a small minority of cases, the virus reaches the central nervous system. Poliovirus has proteins on its surface that match proteins on certain human nerve cells, as a key fits into a lock. Because the fit must be precise, poliovirus typically unlocks only the cells responsible for controlling muscles in the arms and legs - the motor neurons - in the front part of the spinal cord. Sensation usually remains intact in the paralyzed limbs, because polio can't enter the sensory nerves.

This clinical observation - paralysis of the limbs with little or no loss of sensation - probably rules out a large number of possible causes for the California cases, according to John Modlin, a physician working to eradicate polio at the Bill and Melinda Gates Foundation. Herpes simplex and varicella zoster, the pathogen responsible for chickenpox, are known to paralyze children in rare cases, but they usually affect sensation as well. The same is true for Guillain-Barre.

Since polio has been eradicated in the United States and the patients in California were vaccinated against it, the suspicion has fallen on other members of the enterovirus family, to which poliovirus belongs. Based on symptoms, doctors can probably rule out many of those viruses as well. Many enteroviruses have protein "keys" to other parts of the central nervous system. Some enteroviruses, such as the worrisome Enterovirus 71, which has caused outbreaks in Asia and other parts of the world, can inhibit breathing or heart rhythm by attacking respiratory or cardiac nerves. Those symptoms have not occurred in the California cases.

Despite all of these clinical clues, doctors can't know for certain what caused the paralyses until they catch the virus in the central nervous system. That's difficult, because enteroviruses typically remain in the spinal fluid for only a few days, or sometimes just hours. If the patient doesn't appear at the hospital immediately after the first signs of weakness, physicians have to sample other areas of the body to find the disease. Enteroviruses remain in nasal and oral secretions for up to 10 days and can be found in the stool for several weeks. Two of the victims in California had Enterovirus 68, another relative of poliovirus, in their nasal secretions.

That doesn't prove anything, because enterovirus can be present without causing paralysis. The probability is significant, though. Modlin, a globally recognized expert on enteroviruses, sets the odds that Enterovirus 68 caused the paralyses in the children where it was found at "well in excess of 80 percent." Of course, it's entirely possible that one virus caused some of the paralyses while other pathogens were responsible for other cases.

There's one important question remaining to be answered: If an infectious agent is responsible for the paralyses in California, is this an outbreak that puts other children in danger? The question has even reached Washington, where Sen. Barbara Boxer, D-Calif., is urging the CDC to open an investigation.

At this point, there appears to be little likelihood of an epidemic, according to doctors investigating the cases in California. The children had no apparent contact with each other, and physicians are still attempting to determine whether they have anything else in common, such as travel or contact with certain animals. If an enterovirus is the cause, the disease is unlikely to spread.

Aside from polio and Enterovirus 71, few of the pathogens in that family have shown any ability to cause epidemics. The California cluster may just be a tragic and infrequent consequence of a fairly rare infection.

 

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