Category: History

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Uncertainty to Despair to Hope and Redemption: My Professional Life Battling an RNA Virus

I feel  like I am reliving a bad dream. The race to find a treatment and/or cure to SARS-CoV-2 is reminiscent of decades of practicing gastroenterology while hepatitis C roamed the hospital wards as a death sentence for many. I found myself recently recalling a patient whose story ends with science finding a cure.  The story begins in a community hospital’s ICU.

 As I peered around the ICU curtain, I could see the outline of a motionless ill man. I was visually greeted by a panoply of colors not usually seen in human health. Yellow skin and eyes, violaceous bumps on his extremities and blue hued fingertips. As I entered the room, I recognized him as the car salesman I had spoken to several months ago discussing the pros and cons of  an SUV versus a minivan. His labs and physical exam delivered the bad news that his liver and kidneys were not working and he had vasculitis, an inflammation of the blood vessels. While he had a case that medical students study intently, private doctors rarely see in decades of practice: essential mixed cryoglobulinemia secondary to Hepatitis C. In an attempt to curtail the virus, antibodies bind to viral proteins. Excess antibody-protein complexes, instead of being  cleared from the blood circulation, get deposited in the blood vessel walls causing inflammation and sometimes closure of the vessel. He was in danger of losing his kidneys, his liver and his life. A National Institute of Health study had shown a few years earlier that the immune stimulating natural agent interferon could have a beneficial effect on Hepatitis C. Interferon was started and miraculously the bumps disappeared, the kidneys started to make urine, dialysis was stopped and the jaundice receded. He left the hospital and completed 12 months of interferon, combating fatigue, low white blood counts and depression due to drug side effects. He had been cured of Hepatitis C and had dodged a fatal complication of the virus using a toxic biologic agent.  

This early success had been a rare gold nugget amidst multiple disappointing and tragic events in my experience with the RNA virus, hepatitis C. The lessons learned from this virus are worth retelling as this is a story that parallels our current ordeal with another RNA virus, SARS-CoV-2. 

The biologic veil of Hepatitis C was heavy and was only lifted in fits and starts. In the alphabet soup of hepatitis viruses, A and B were discovered early but “C” was undetectable and given the placeholder non-A-non-B for years until special techniques were devised to recognize its presence. Infection was through blood transmission, usually through blood transfusion, sharing of needles or instruments that were contaminated with the virus and inadvertently inoculated through the skin. In contrast to SARS-CoV-2, which has a presymptomatic stage of a few days, Hepatitis C’s silent period was years or decades before disaster would take hold. Cirrhosis, or significant scar tissue in the liver could impair the sieve like blood circulation within the liver shunting blood to places it normally wouldn’t go resulting in gastrointestinal bleeding, ascites and encephalopathy. Years of infection can lead to liver cancer with a dismal prognosis. 

My early encounters with hepatitis C felt like bailing water from the Titanic while it was taking on water. I could band bleeding blood vessels, start water pills and limit salt in those with fluid overload and give antibiotics to reduce the toxin burden and reduce hepatic coma risks. But without specific treatment for the virus, we were on a slowly sinking ship. Then the drug interferon came along. It was a mixed blessing. It was toxic, causing fatigue in most and depression in a significant minority. It could lower white blood counts and damage the nervous system. It worked in only 10% of patients with the most common genotype of the virus. Most diabolically, those who needed it most were cirrhotics, and for patients with this condition, it was the most toxic and had the lowest response rate. I saw harsh drug side effects that included suicidal thoughts, absenteeism from work on the drug and plummeting white blood counts in countless patients. I questioned whether it was worth the one in ten chance that the drug would work. Slow progress (too slow for patients on the liver transplant waiting list) was the rule of the day. Ribavirin, an oral drug, used with interferon, raised the response rate to over 40% at the expense of the new side effects of anemia and potential birth defects. Most of my discussions with afflicted patients were often discouraging treatment, waiting for “some breakthrough in the future.”

The initial breakthrough came: direct acting antiviral drugs were available in 2011. They were protease inhibitors, drugs that blocked the assembly of viral proteins within the cell. The first generation protease inhibitors had novel side effects including disabling rash, headaches and mouth sores.

I came to dread the newly diagnosed hepatitis C consult. It felt like a “pick your poison” option.  I could offer an imperfect and potentially toxic mix of therapy, not unlike the oncologist administering chemotherapy to a cancer victim. 

This all changed with the synthesis of the drug sofosbuvir, an RNA polymerase inhibitor not unlike Remdesivir, an encouraging agent for SARS-CoV-2. Sofosbuvir, coupled with new protease inhibitors was the miracle I had not witnessed in my four decades rendering care to my patients. It’s side effect profile was no different than placebo and amazingly the cure rate would climb to over 98%. It worked equally well in patients with cirrhosis and the course of therapy was “weeks” rather than “years.” And, it was a cure! Patients who would have been candidates for liver transplantation saw improvement and were removed from the transplant lists. Liver cancer risks were reduced. Other non-liver conditions like heart disease, immune function and cognitive function improved with eradication of the virus. I felt my office was the equivalent of a Lourdes destination for the hepatitis C patient.

Science rendered a disease that afflicted 3.5 million Americans and killed up to 20,000 people a year to an affliction that most likely will be eradicated from the planet in our lifetime. The success of the treatment for hepatitis C can be looked upon as a template for our next RNA viral battle: SARS-CoV-2.  Hopefully, we can build from the success of the hepatitis C RNA polymerase inhibitor and extrapolate to a drug combination that can treat the disease as we wait for a definitive cure and vaccine.  Covid-19’s fate must be one that someday, when I reminisce about this time, I write another science driven medical success story.

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The Art and Science of Barriers

“Good Fences make good neighbors” is a memorable and salient line from Robert Frost’s poem, “Mending Walls.”  While the context of its meaning is a plea for the importance of privacy, it is a useful phrase for the COVID-19 pandemic as we all try social distancing as our physical defense and protective barrier from the Coronavirus. Six feet away from one another and swathed with a nose and face covering mask seems to be the barrier du jour. It has been that throughout life we must deal with barriers that represent either obstacles, as in the poetic verse of Robert Frost, or provide succor to our existence. In our current COVID-19 world, our imposed barrier, a protective mask, will be critical to manage our “new normal” prior to a transformative drug or vaccine. In essence, we need a science driven mask that is effective, comfortable and re-wearable.

Biologic barriers are present from conception. Surrounded by the amniotic membrane, we are protected from most pathogens. Upon its rupture and our ride down the birth canal we start the self versus society struggle.  Hepatitis B, polio, rotavirus, diphtheria, tetanus and pneumococcal vaccinations are our initial immune barrier. Child proofing mechanical barriers (plug locks, stair locks, edge protectors) are present during our formative years. Car seats and later seat belts protect us from motor vehicle morbidity. Science has driven these medical protections and public health measures have orchestrated their distribution to the public and their acceptances as standards of care.

Societal barriers have protected humans for eons from human aggression, accidents and microbes. The Caves of Lascaux  protected Paleolithic man, The Great Wall of China retarded invasion by the Mongols. The Roman emperor Hadrian built his namesake “wall” in Northern England to keep out the “barbarians.” Ramparts and moats around European castles in the Middle Ages slowed the devastation wrought by the Vikings. In our lifetime we put up with anti-terrorist barriers at TSA checkpoints at all U.S. airports. Physical barriers and screening techniques have been shown over time to decrease disease and death from outside threats to our well-being.

Our protection from COVID-19 now demands a barrier to our nasopharynx. We are now safely surrounded by our homes’ four walls and limited “world” contact through our UPS and Amazon delivery services. In order to integrate into society we need extra protection from the virus. A mask or “facial condom” could provide us with the protection and turn human interaction into an acceptable risk. We are now familiar with the N95, surgical, and home-made masks. We have YouTube videos of media celebrities constructing masks. Now,  “mask science” is the next logical step to assure that our efforts are working to prevent Covid-19 transmission. What we really need is some evidence based guidelines developed from a controlled study.

 The geometry is well known: N95 keeps out 95% of particles that are as small as 0.3 microns; droplets containing COVID-19 are 50 microns or less. Droplet spread is 6 feet, more if sneezing or aerosol transmission is involved from the contact. What we don’t know is what materials and layering are most effective against virus spread when used in a real world scenario.

Compliance and comfort are inextricably linked. When I donned a mask in the OR, my face felt like I was in the microclimate of Miami during the summer and my eyeglasses fogged up like winter in London. We have designers and aerosol engineers that can overcome “wearability” issues that could lead to improved compliance. We have industry and universities that have the capability of testing combinations of fabric under simulated and actual environmental conditions.  Distribution capabilities are available to send masks to every household in the United States utilizing the Postal Service.

Americans have internalized the use of seatbelts and TSA screenings in my lifetime. Introducing and complying with  a “new fence” is easier when the alternative may be a painful respiratory death. Wearing a fashionable, comfortable and effective face mask should become the “new normal.”  The design, efficacy and distribution is simply just one more barrier for science to overcome.

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COVID-19: Musings of a Baby Boomer: The Human Challenge

I was quite young but I could sense the unease in my mother when she first sent me off to elementary school amidst an uncertain risk of paralytic polio in the 1950’s era. She maintained her frightened countenance until 1960 when the Sabin vaccine miraculously appeared.  Many years later, my wife, a pediatrician, had intubated a young patient with measles who needed ventilatory support. A few days later, she staggered into my office, ashen and lightheaded. Her blood pressure was 70 and her sclerae were icteric. She had contracted rubeola and measles hepatitis. Looking up from her hospital bed she uttered, “if I don’t make it, you’ll need to find someone to help raise our (1 year old) son.  My nurse is wonderful and I give you permission to date her if I die.” My wife recovered and is my social distance partner 35 years later. These are but a few of my anecdotal “high anxiety” moments of contagious disease in my “baby boomer” memory. And that’s the point. These events are distant memories, rarely surface and are almost never mentioned. We move on and forget the lessons they taught until the next infectious insult makes us scramble for direction and hopefully solutions. In fact, throughout history this repetition is startling.

Humans have constructed great civilizations in only 10,000 years, surmounting  challenges and establishing the supply chains that provide food, clothing and shelter for the billions that inhabit this planet.  Yet we are impeded by one major human foible: selective long term memory loss in order to cope with the next medical task at hand. What do I mean?  Take human memory and the history of contagious disease in society. We learn, at an early age, that American and international history were shaped by infectious disease. Early settlements in Virginia in the 16th century failed due to malaria outbreaks. In 18th century Philadelphia, an outbreak of yellow fever forced our founding fathers to flee the city.  Bubonic plague outbreaks in Europe in the 6th and 14th centuries killed 50% of the inhabitants and changed Roman and Medieval society. The medieval citizens fled the crowded cities for pastoral domiciles sensing that social distancing would prevent the deadly illness. Great armies were felled by typhus and cholera during the Napoleonic Wars and World War II.  We don’t have to go back very far to see a world where our parents and grandparents had a stark recollection of epidemic infectious disease. Diphtheria, polio and measles, to name a few childhood illnesses were part of their daily reality. Parents banned their children from community swimming pools, recognizing that distancing them from the source was paramount.  I, born in 1953, recall fellow students in my class with leg braces from polio following summers spent hospitalized. As I entered medicine in the 1970’s, there were reminders of past epidemics on the wards. I rounded in iron lung wards in Rancho Los Amigos Hospital in Downey, California. I ambulated the pediatric wards at L.A. County-USC Medical Center, puzzled by the prominent parapets outside the patient rooms. “They were there so that physicians could round and quarantine themselves during polio outbreaks,” my attending noted.  Again, in the early 1980s a mystery illness with a severely immunocompromised picture in the patient appeared in daunting numbers. The AIDS epidemic was upon us as we scrambled for its cause and cure. As time passed, the memories of these debilitating epidemics receded whereupon complacency and the rise of the anti-vaccination movement became the cause celebré of the 1980’s and beyond. The resurgence of the measles due to lack of sufficient vaccination in the 1980’s did little to discourage the anti-science crowd. Perhaps a lack of firsthand experience with the measles contributed in part to their anti-vaccine stance.  As I gazed into the mouth of a patient during the measles outbreak and saw a Koplik spot, a physical finding that indicates measles, I realized that the outdated knowledge of this physical finding I learned 10 years prior was not so archaic. Actually, I had simply forgotten about this pathognomonic signal of impending rubeola. “Out of sight,out of mind,” I said to myself.

Now, the COVID-19 pandemic has arrived and upended our lives as did the many infectious diseases of bygone years.  Initial roll-out efforts for mass testing, tracking and isolating has been less than adequate. We have finally resorted to social distancing, an ancient form of infection avoidance.  Clearly, the same weapons seen in the great mortality known as the Bubonic Plague during the 14th century. Ultimately, a vaccine will rescue us along with medical mitigation via drugs and antibody rich plasma from those who have recovered. Let us take the lessons of this catastrophic time and the stories from our heroes: the first responders, the healthcare team and informed public servants with us for centuries to come.  Otherwise, we sentence ourselves to repeat the same mistakes.