The New York Times - October 2, 1984
Lawrence K. Altman, M.D.

The concept that one virus may link with or help another to cause infection is an old one and virologists have found some examples in animals. But delta hepatitis is widely believed to be the first documented example of that phenomenon producing disease in humans.

As a result, the discovery of the apparently novel mechanism that produces delta hepatitis has led some scientists to broaden their thinking about the nature of infectious diseases and to realize that the cause of many ailments may be much more complicated than generally believed.

Delta hepatitis results from the piggybacking of the delta virus with the hepatitis B virus. Although the hepatitis B virus is one of the most common causes of disease in the world, the delta virus is defective and seems incapable of producing disease by itself. Yet interaction of the delta and hepatitis B viruses can produce a lethal infection.

Dr. Jonas E. Salk, who developed the injectable polio vaccine, said the discovery of delta hepatitis was "not a quirk." Moreover, it was "not too farfetched to theorize" that similar mechanisms might be at the root of other now mysterious diseases, he said in an interview.

Most searches for new causes of infectious diseases have focused on identifying individual microorganisms as a reflection of a general scientific principle that holds a one- on-one relationship between a single microorganism and a disease. That principle underlies the practice of immunizations, which are developed against the causative agent (or in some cases closely related agents).

Moreover, for scientific proof that a microorganism causes a condition, scientists usually rely on fulfilling what are known as Koch's postulates. They are named after Robert Koch, a German bacteriologist, and are often summarized in four steps. First, the microorganism is observed in all cases. Second, the microorganism is grown in pure culture. Third, inoculations of the pure culture in susceptible animals reproduce the condition. Fourth, the microorganism is recovered from the experimentally infected animal.

However, scientists have sometimes used other experimental evidence to support contentions that a microorganism causes a condition. And if combinations of viruses cause some human diseases, then Koch's postulates might have to be revised.

Not long ago many scientists thought they had found all the disease-causing bacteria there were to discover. But in recent years a previously unknown bacteria has been found to cause legionnaires' disease. Scientists also discovered that members of the so-called retrovirus family can cause rare types of leukemia and probably the disease known as acquired immune deficiency syndrome, or AIDS. Also, Australian doctors have reported finding a spiral-shaped bacterium that they believe causes peptic ulcers and a common stomach ailment called gastritis.

Many doctors have long suspected that infectious agents cause lupus and other so-called autoimmune disorders. Other doctors have reported the "discovery" of putative infectious agents as the cause of the inflammatory bowel conditions known as ulcerative colitis and regional enteritis. But their findings have not been confirmed. Still other researchers have reported similar "discoveries" of infectious agents as the cause of rheumatoid arthritis. Again, confirmation is lacking.

Perhaps some day it will turn out that the reason researchers have failed to reproduce a disease experimentally in the laboratory is that more than one agent is needed.

Viruses are known to combine in other ways to cause human disease. The bacterium that causes diphtheria, for example, is harmless for humans until it is infected with a virus known as a phage. When that happens, the bacterium is capable of producing the toxin that causes diphtheria.

The influenza virus and others can temporarily paralyze the immune system of an individual, thereby lowering resistance and enhancing the opportunity for a secondary invasion by staphylococci and other microorganisms.

Also, researchers have found that dental abscesses can result from combinations of certain bacteria but not from individual members of that combination.

In addition, surgeons treat many infections that are caused by mixtures of bacteria, as Dr. Richard L. Simmons and Dr. Richard J. Howard point out in their textbook, "Surgical Infectious Diseases."

Some such infections result from synergistic effects in which combinations of bacteria act more powerfully than members of the combination can when they act individually.

Discovery of the delta agent has led Dr. John Gerin of Georgetown University and other researchers to look for such as yet unknown defective viruses that might link with hepatitis B to produce other forms of hepatitis.

Dr. Gerin said his team planned to study specimens from China and other areas of the world where little delta infection has been detected but where hepatitis B virus infection is common. "We wonder whether there is another agent filling that ecological niche," Dr. Gerin said.

Dr. Gerin speculated that not only might other delta-like agents be found in hepatitis but that he could "see no reason why it shouldn't be true for other chronic viral infections."

However, another hepatitis researcher, Dr. Saul Krugman of New York University, expressed skepticism about extrapolating the concept that combinations of viruses caused other diseases because of unusual features of hepatitis B infection.

Dr. Krugman said that he did not know of any other infectious agent that could be seen so easily when a sample of blood is examined through an electron microscope. The copious amounts of hepatitis B virus made it easier for the delta virus to form its essential linkups.

Nevertheless, Dr. Krugman urged scientists to keep an open mind about the possibility of combinations of viruses causing other disorders.

How, then, might scientists seek combinations of viruses as the cause of human disease?

Dr. Salk suggested that in such searches scientists might have to proceed more like a naturalist, finding clues empirically from observation rather than by experimentation.

Scientists also would have to look harder for biological events that produce little if any symptoms or damage as they occur over a lifetime but that in sequence or combination can produce disease. Scientists, then, may have to do more prospective, or forward-looking, studies to find the evidence that might have disappeared if scientists work backward in looking at the problem.

For instance, the causative polio virus may have disappeared from the blood by the time someone is paralyzed by the infection.

Dr. Salk said that while such studies would be extraordinarily complex, "that is what makes it intriguing and worthwhile."

Not the least important aspect of detecting ailments caused by combinations of microorganisms is that some might be cured or prevented with drugs and vaccines that attack only a segment of the total microbial population.

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