Just published in the New England Journal of Medicine (Persistence of Ebola Virus in Ocular Fluid during Convalescence, Varkey, JB et al online May 7, 2015) is the story of finding Ebola in the left eye of a physician patient thought to have been cured of the disease. I marvel at the men and women who placing other people’s lives above their own, stood up to the epidemic and saved lives.  Equally brilliant were clinicians treating persons in American hospitals so critically ill, some requiring weeks of dialysis and ICU care, who looked like they would surely die. When an ICU patient seems hopelessly ill, we tend to give up on them. We withdraw care, sometimes prematurely.  One valuable lesson from Ebola is that the best clinicians don’t abandon patients. We should never forget how sometimes its possible to rescue someone from the jaws of death. Medicine at its best.

Ebola persists also in some populations in Africa as well. An article in the NY Times of May 10, 2015 mentions cases in Sierra Leone. There are no new cases in Liberia yet the virus has devastated evangelical churches where the scourge was spread unwittingly by burial practices and laying on the hands. Apparently early sufferers expected to be cured in their church.

What caught my attention is that this physician who’d been infected with Ebola and survived and who was now in his convalescent phase, had acquired uveitis in the eye. That is something which imperils vision and most experts view uveitis, literally an inflammation of the uveal lining of the eye including the retina and other structures as an inflammatory, usually an “autoimmune” condition of the eye. Here, some 14 weeks post infection, his brilliant and skillful clinicians, taking all extreme safety measures required for this dread disease, withdrew fluid from the aqueous humor of the eye and were able to prove that there was in fact, persistence of viral infection that caused this inflammatory response. Their excellent work done at great pains, had proven the uveitis was caused not by autoimmunity, but persistent infection in an isolated immunologically privileged part of the body.  The eye is relatively isolated from abundant blood circulation where the virus had been eradicated.  Ebola can persist in other body fluids, especially the testes and thus in sperm.

I have written in these pages, about persistence of infection. The common idea of acute infection causing inflammation high fever and eventual cure, is overly simplistic. Infections do not usually conform to a common abscess model where an organism extirpated and bathed in antibiotic is cured. Yet this is the picture patients and clinicians carry in their mind. Even neurologists are beset with people who know not what is good for them pleading for antibiotics.  Invading organisms, be they bacteria, viruses, fungi, protozoa, tend to persist in the body even if in a relatively harmless state over long periods. Persistent infection can be widespread.  In other instances it hides in relatively unguarded or even friendly corners of the body,  like Al Qaeda in Waziristan. Not only micro-organisms but tumor cell invaders behave in this way. It is hard to expunge them. Many organisms such as those of the herpes virus family have co-evolved with humans for thousands of years and once gaining a foothold, persist. These actors can only be thought of as part of our identity. I have written about this phenomenon in other essays.

I’ll tell you why this interests me so much. It’s because I suspect (I am by no means alone)  that many diseases until now thought of as “auto-immune” errors in self-recognition or defects on our immune system are actually chronic infections which induce a chronic smoldering, sometimes vigorous, immune response. One disease close to my heart since I have treated so many patients with this over the years, is multiple sclerosis. Neurologists treat MS with immune suppression, drugs that impair the immune systems of patients. For those with more aggressive disease, more powerful immunosuppressants are used. I have used these powerful measures extensively including treatments with considerable side effects and have had clinical failures and successes. Some immune suppressants include plasmapheresis where antibodies are removed, and a large number of potent immune poisons, as cyclophosphamide, rituximab, mitoxantrone and lesser agents including steroids and others we use to prevent worsening act by inhibiting immunity.  Although there is a demonstrated inflammatory response in MS and we have extensive empirical patient trials to show they do work, it may well be that MS and other “autoimmune” diseases, that the underlying process is really a chronic infection. If so we’d do better fighting the invader and not to impeding  the patient’s defenses. In earlier offerings on this site I described a chronic tug of war between microorganism invaders and immunity. I am worried about weakening defenses in a manner again resembling foreign policy where the real enemies are most vexing and difficult to defeat.

One Herpes family virus of interest is Epstein-Barr virus (EBV) responsible for a group of diseases, mononucleosis that Americans are familiar with, but also nasopharyngeal carcinoma and Burkitt’s lymphoma in other countries. Why EBV causes different disease in other places is unclear, perhaps from different strains of virus or EB infection might be more recent and less common in other populations increasing its virulence. Mononucleosis is actually a self-limited lymphoma or lymph cancer of sorts. The EB virus has been with humans for thousands of years and a milder form of disease has persisted and is now part of us. At least 90% of Americans evidence exposure to EBV even though few of us recall a mononucleosis infection. Repeated studies have shown that those who do recall mononucleosis, fever, tiredness, sore throat lymph node swelling and especially among those who had been hospitalized with mononucleosis, there is a many fold increase in the risk of having multiple sclerosis. It is rare for an MS patient to test negative for exposure to EBV. MS patients show higher titers of specific EBV antibodies especially those directed against the nuclear antigen than persons without a diagnosis of MS. Many MSers harbor specific clones of antibodies in their spinal fluid directed against components of EBV.  For decades epidemiologists have wondered why MS is more common in temperate northern latitudes and had for this reason suspected infectious involvement, especially a virus passed indoors.  EBV “kissing disease” conforms to this pattern. However,  where 90% of a population has had exposure to an agent, it is exceedingly hard to prove that it causes a disease like MS in a tiny fraction of people.  You have to ask what is unique about folks who have the disase? Recollection of infection may provide some of the answer in that it may be a sign of late exposure.  In privileged protected high income Western countries the obsessive cleanliness of neurotic mothers seems to lead to delayed exposure to a healthy variety of dirt and organisms.  This is the now famous hygiene hypothesis that helps explain medical phenomena ranging from the increased prevalence of peanut allergy to asthma.  Now comes a study that is most suggestive where EB virus has been found in 100% of brain tissue samples of persons with MS. (Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain Barbara Serafini, et al J Exp Med. 2007 Nov 26; 204(12): 2899–2912)  That is a striking finding. It all means that there is tons of circumstantial evidence but no Koch’s postulates, no smoking gun so far as causation between MS and EBV. (Also  see Epsteine-Barr Virus and Multiple Sclerosis, Lucas RM et al J Neurol Neurosurg Psychiatry. 2011;82(10):1142-1148.) All of this relates to just one organism, EBV yet it is possible that MS might be induced by other organisms  or even a combination, be they viral bacterial or otherwise.

Another supposed auto-immune inflammatory condition that has plagued medical practice for years is temporal arteritis. A new study demonstrates that when you look carefully enough at affected tissue, by doing meticulous careful sections and testing for viral DNA, fully 74% of samples test positive for the Herpes zoster virus. (Gilden D, White T, Khmeleva N, et al. Prevalence and distribution of VZV in temporal arteries of patients with giant cell arteritis. Neurology 2015;84:xxx–xxx. pubilsihed early on-line Feb 15, 2015).  Yes, temporal arteritis seems to be caused by Herpes zoster! Another auto-immune disease is related to infection.  For some years clinicians have been aware of the propensity of H. zoster to cause widespread arteritis, due to, the persistence of viral infection. This comes on the heels of another paper in the NEJM (Efficacy of an Adjuvanted Herpes Zoster Subunit Vaccine in Older Adults Himal Lal, M.D.for the ZOE-50 Study Group
April 28, 2015 published early on line) that found nearly 100% immunogenicity over the short term with this adjuvanted vaccine something more likely to incite the immune system. Shingles caused by Herpes zoster is not a minor but can be a terrible and disabling disease as I have witnessed in so many cases over the years, so much so that as an advocate of vaccines in general I raced to get my own dose as soon I was allowed. But now I will be sure to test for antibody protection and likely get the new more immunogenic vaccine when it becomes available.

Infection is rarely once and done. Bugs hide out in privileged domains and where you least expect them. One other fascinating example is Whipple’s disease that was described in 1900 but took 100 years before infection with a bacterium Tropheryma Whipplei was proven by modern techniques. Whipple’s is now a model of what was thought to be an autoimmune disease proven to be a chronic infection treatable  but not necessarily curable, with long courses of killing antibacterials. From the neurologist’s perspective the bug hides out in the nervous system as well as the gut and causing eye movement abnormalities seen in no other condition. It can also affect the hypothalamus affecting sleep and appetite  (Please see Whipple’s Disease Florence Fenollar, M.D., Ph.D., Xavier Puéchal, M.D., Ph.D., and Didier Raoult, M.D., Ph.D., N Engl J Med 2007; 356:55-66January 4, 2007DOI: 10.1056/NEJMra062477). One other much more famous example of such a disease that can affect the nervous system is Lyme disease. But Lyme disease is so popular that doctors and patients are hyper vigilant and testing for it constantly. A short course of antibiotics seems to cure the condition but certain persons are treated for years with antibiotic. Still another entity that has become an Internet phenomenon and has gone viral on its own is gluten sensitivity. I cannot say how much sickness may reasonably be attributed to it, but a host of sensitive and not necessarily specific tests are increasingly positive. Is gluten another example of an antigen sensitivity caused by overly zealous hygiene? I cannot say.

This begs the question regarding many other chronic medical conditions. It is possible some assumed degenerative diseases such as Alzheimer’s or Parkinson disease could turn out to be chronic infections. In those conditions there is only limited evidence of inflammation. But other even commoner conditions do seem to involve inflammation as in the rupturing plaque of atherosclerosis where the CRP, a  protein and  non specific blood marker of inflammation seems to correlate with atherosclerotic disease. For many years it had been noted that stroke and heart attacks occur more frequently in the setting of infection for example active dental caries and with rotted teeth, pneumonia and sepsis. For a time it was felt infection inside an artery wall such as caused by Chlamydia were related to carotid plaque formation. It may well be the case, that infection plays a role, now that we have better means of examining arteries more carefully especially the tool of PCR which helps find nucleic acid determinants of chronic infection.  Yet no antibiotic regimen has proven effective for carotid disease even if some have been tried, neither has any been found to lower CRP or stroke rate. Perhaps the carotid arteries need to be examined more carefully as has been done in the temporal arteries.

I’m embarrassed to report as an opinionated and vociferous supporter of medical care throughout my professional life, who loves to practice medicine, that the one thing I hoped we’d mastered was infectious disease. We were all especially proud antibiotics even if we were cowed by viruses and other invaders. Our chests were out and we were into bragging.  Doctors had only begun to appreciate the role of these little fellows maybe 150 years ago since the days of Pasteur and Lister.  But now we come to find out these little devils are smarter than we are and may yet get the better of us. Swallow your pride.