Is All Disease Infectious?

(Cartoon from Biocomicals)

Twenty years ago or more, I remember seeing an article in a scientific magazine that asked, in essence: Is all disease infectious? I can’t find the article any more but it made a lasting impression. So… is it?

Of course not, right? It seemed like a silly question posed just to be provocative. Some diseases are hereditary. Some are due to dietary deficiencies. Some are due to wear and tear, or trauma, or environmental factors.

The authors were asking with tongue in cheek, just asking readers to consider whether more diseases might have an infectious cause than we realize. Today they sound less flippant than they seemed to intend.

Cancer

Around 1980, Robert Gallo published evidence that human T-cell lymphotrophic viruses (HTLV-1 and HTLV-2) cause adult T-cell leukemia. It was the first time anyone had proven that a specific virus is the cause of, not just something associated with, a specific cancer.

Ordinarily a discovery that big would be all over the news everywhere, but AIDS was emerging and took the limelight. HTLV is retroviral. After Luc Montagnier at the Pasteur Institute isolated and described the retrovirus we now call HIV, it seemed natural that Gallo and his team should be the first to do the same and confirm the discovery. Gallo failed and refused for years to admit it, thereby delaying global research into AIDS.

I’ve dropped that story in for a reason. Scientists are human. They can be just as confusing a mixture of good and not so good as anyone else. They make glorious discoveries and they make mistakes. As with Gallo, any individual scientist can do both. In a moment you’ll see why I want us to remember that when we look at current research.

But when we separate wheat from chaff, Gallo’s HTLV discovery shook modern medicine. From that moment onward, we have known that some viruses cause cancer. Scientists have been looking for more links between viruses and cancer ever since.

Once we know a virus is responsible for a particular cancer, we can look for ways to block infection by the virus and thereby prevent that type of cancer. As the saying goes, an ounce of prevention is worth a pound of cure.

Among the connections found so far, we learned human papillomavirus (HPV) causes cancer. It’s sexually transmitted and the cancers it causes are in body parts directly exposed to it. Nearly all cervical cancer is caused by HPV. This virus-to-cancer connection is among the most widely known because a vaccine has been developed that prevents infection by HPV. If you have kids, getting that vaccine into them when they reach the age for it is probably already on your radar.

Osteoarthritis

When we reach a certain age, people start needing artificial hips or knees due to osteoarthritis. Not everyone needs a hip or knee replacement, but many people do.

Conventional wisdom used to be that osteoarthritis is due to wear and tear.

It turns out that isn’t the whole truth. Scientists began to find evidence that elevated inflammation is also involved.

Inflammation can occur for a variety of reasons. One of its causes is infection. We don’t know yet whether there are some types of infections that raise the level of inflammation and thereby somehow lead to osteoarthritis, but finding out is among the next steps for research into the condition.

This started coming into focus around 10 years or so ago.

A Family of Troublemakers

More recently, viruses in the herpes family have made stunning news.

When anyone says herpes virus, people tend to think only of herpes simplex virus (HSV) 1 and 2. They think of cold sores and genital herpes.

Those are not the only ones. Nine herpes viruses are known to infect humans so far. They offer some unexpected lessons about what infectious agents can do.

Most people, 90% to 95%, acquire cytomegalovirus (CMV), usually as small children. In kids, it typically isn’t a big deal but can be similar to mononucleosis. If acquired by a hospital patient in a weakened condition or by someone with a compromised immune system, it can be more serious, even fatal. For example, in some AIDS patients it can cause blindness or dementia. This is why a person who has never caught CMV should only be transfused with blood that has been treated (often irradiated) to render it CMV-free.

Until vaccines became available against it, many children caught herpes varicella zoster virus (VZV) during their early years. Children still do in the UK because we don’t vaccinate against it here. Herpes varicella zoster causes chicken pox.

In both of my countries, about 9 people out of 10 have caught Epstein-Barr virus (EBV) by the age of 30. Some people don’t get sick when they catch it. Others develop infectious mononucleosis (glandular fever in the UK).

There are other herpes viruses. Most of them aren’t well known and go by such glamorous names as human herpes virus (HHV) 6, 7 or 8.

Some of the herpes viruses can make people miserably sick soon after they get infected and the acute illness can linger for quite a while. Mononucleosis is miserable and lasts weeks or months. But often people acquire a herpes virus without getting sick enough to realize anything happened.

Once you catch any of the herpes viruses, your body can’t get rid of it. You carry it for the rest of your life. After the human immune system wrestles the initial infection down, it is usually pretty good at forcing herpes viruses into latency. Although the virus is still in residence, it isn’t causing acute sickness any more.

However, the virus will make fresh mischief if it gets a chance.

Herpes simplex is notorious for flaring up whenever the immune system stumbles. You don’t even need to be weakened enough to feel like anything is amiss, but HSV will grab the opportunity and then there will be active sores again for a while.

Herpes varicella zoster is well known for causing shingles in people whose immune systems get knocked back (e.g. by chemotherapy) or simply lose some potency in old age.

Conventional wisdom was that unless you are in a very bad way, such as on chemotherapy or battling AIDS, reactivations are limited and relatively brief.

What are Those Viruses Showing Us? Starting with EBV…

For many many years, we didn’t realize how frequently conventional wisdom doesn’t fit.

In patients with myalgic encephalomyelitis (ME, called Chronic Fatigue Syndrome in the USA), it is common for EBV to reactivate and stay reactivated for years. It’s as though patients have an active case of mononucleosis that refuses to end.

Long term EBV reactivation is so common in ME that for a few years scientists thought EBV was the cause of that disease. The ME community got excited about knowing what needs to be treated until it became clear that reactivation of the virus is an effect of ME, not causal.

Long term EBV reactivation is common in Long COVID patients too.

Remember my cautionary note about occasional mistaken conclusions in science? We’re getting into recent material. We shouldn’t rely too heavily on a recent finding until more scientists have looked at the same question and, with their separate work, reached the same result. Please keep that in mind as you read on.

The article Epstein–Barr virus and multiple sclerosis in Nature last August made a splash in mainstream media.

A dear friend has severe MS, so this grabbed my attention. You probably saw headlines along the same lines I did, as though EBV has been found to be the cause of MS. Unfortunately, the journal article was misrepresented in mainstream media. If you read the actual article, in key places it sounds uncomfortably akin to articles that proclaimed EBV causes ME.

The text is chock full of terminology most of us (including me) don’t recognize, but the parallels are in plainer language. At one point the article asserts flatly “EBV is a trigger (that is, it must be acquired before the onset of disease).” Elsewhere the article admits EBV is not always found in MS patients, so the stated conclusion does not stand on a solid basis.

What is going on there? Let’s sift through it.

Over 90% of MS patients have EBV in their bodies. It’s easy to think that must mean it is the culprit… until we remember that over 90% of the general population have EBV in their bodies too.

From details in the article, it looks like where EBV is present, it gets involved in MS and may be responsible for causing major damage. However, I am skeptical about claiming it is the cause of MS when a noticeable proportion of MS patients don’t carry EBV at all.

We went through this with ME. By now we should know not to be too quick to jump to conclusions about what EBV causes. We should draw careful distinctions between strong association versus causation.

It’s still a valuable article. As a meta analysis, it pulls together information from multiple studies. Sprinkled through it are details about how EBV is associated with various cancers, not just details pertinent to MS. I went through this journal article until my brain hurt.

The way I see it, EBV turns out to be an opportunist.

We thought latency meant it was sitting quietly, doing nothing except in people unlucky enough to have something like ME or Long COVID that gives it a chance to wake up. Not so! It can be busy in stealth mode. We simply aren’t very clear yet about what it is doing and why it chooses whichever mischief it wreaks.

Isn’t it eerie, the way Long COVID, which is a disease definitely kicked off by a particular viral infection, has so much overlap with ME and MS? Maybe some other pathogen we haven’t pegged yet causes ME and MS.

From what we know so far, for people with MS, ME, or Long COVID, whether or not the patient carries EBV and whether or not EBV reactivates look like important factors in how severe the MS, ME or Long COVID becomes. We’re back to the question of whether more diseases trace to an infection than we realized.

On top of that, we have the complication of wondering whether the effects of different infections can combine to produce a bigger problem than either pathogen could produce alone.

Moving On to Alzheimer’s

EBV isn’t the only virus in the herpes category capable of very bad impact, but we are on the right track when we start asking whether combined infections can do something different from separate infections.

Some viruses double-team to do their worst.

Working with a bioengineered model of the human brain, a research team found that if they introduced HSV-1 (herpes simplex virus), waited until it became latent, then later introduced VZV (chicken pox virus), the HSV-1 reactivated and their brain model got the plaques that are characteristic in Alzheimer’s disease.

This didn’t happen if they only introduced VZV. It only happened with the one-two punches of HSV followed by VZV.

To their credit, this team did not announce their findings as the cause of Alzheimer’s. They announced what they learned as one possible pathway to the disease. They explicitly called attention to the idea that other sequences of infections (or events) could lead to the same outcome. The importance of their study is not the specific sequence they used. It’s the evidence that a combination of infections can create a disease more severe than what either infection can do alone.

So, Is All Disease Infectious?

No, we can’t say that all disease is infectious. There are still diseases with such causes as genetics, diet, environment, hard use or injury.

But we have learned that some diseases trace to infections where we used to not be aware it is possible. We have also learned that infections can have interacting consequences that produce entirely different diseases from the ones they can create separately.

Where a disease traces to infection, we have a chance to do what we did with cervical cancer and vaccination against HPV. We can look for ways to block the infection from ever happening at all, thereby preventing disease.

The question of whether all disease is infectious may have been flippant, but it has led us to realize more diseases can ultimately be preventable than we used to believe. That’s progress.

(In case you wonder, the relevance of today’s image is in the second link in the Gallo story.)