From our anonymous insider…
Virus week. Long days of lectures followed by three hours of studying old material on infectious bacteria in the evenings.
“The more I study, the less I know,” reflects Gigolo Giorgio, the class alcoholic frequently found on the dance floors of downtown clubs. One classmate asked Giorgio, “Is Campylobacter jejuni gram-positive or negative?” We were all impressed when Giorgio responded, “Gram-negative.” We were stunned: “How did you know that!” He answered, “Well I haven’t heard of it, and I’ve only studied gram-positives.”
This block is particularly challenging because the material doesn’t build on previous lessons. I feel more behind each day. “I’m still on gram-positive bacteria! I have not even started gram-negatives!” wails a classmate as we begin virology.
If you model a physician as an information processor, the result of this block is a database that is indexed in only one direction. For example, we study by investigating the properties of each pathogen one at a time. We can reliably regurgitate information from yesterday about a single bacterial species. However, when we attempt to develop a differential based upon symptoms, we have difficulty identifying potential culprits. For example, both S. pyogenes and an acute HIV infection can lead to sore throat. There were many blank faces when we were asked, “What are the common causes of sore throat?” Fortunately electronically implemented databases can be indexed in multiple ways. This is what gives clinical-assistance programs, e.g., UpToDate.com, their power to boost physician efficiency, especially in regions where ID doctors are scarce.
A 60-year-old internist who specializes in herpes and whose two children are also practicing physicians at the hospital introduces virology to us with four hour-long lectures. The Internist introduced infectious disease: “ID is not rocket science. It’s an approachable field if you have the interest and dedication to learn a lot of diseases.” Jane actually shadows the son and mistakenly thought he would be teaching us.
There are three types of viruses: RNA, DNA, and retrovirus. RNA and DNA viruses hijack host cell machinery to produce proteins of their own design. Retroviruses actually insert their own DNA into host cells.
A basic virus is a small particle containing genetic information (DNA or RNA) that encodes for its infective vector (the proteins that enable the virus to get into cells and reproduce). These proteins include the structural capsid protein(s), the polymerase(s) used to replicate the genome, and critical docking proteins to allow access into the host cell. The mode of transmission is restricted if the virus is enveloped in a lipid bilayer. “Enveloped viruses have an easier way to get into cells, but are much more susceptible to drying out on a surface. Non-enveloped viruses can last for days on a surface.”
The internist asked the class, “What is the difference between herpes and love…? Herpes is forever.” Herpesviridae is a large class of enveloped DNA viruses that include herpes simplex (genital warts and labial cold sores), varicella zoster (chickenpox and shingles), and the college-drag epstein-barr (“mono”). “Sixty to seventy percent of the population is infected with HSV1 [herpes simplex 1, mouth cold sores],” said our lecturer. “Most people do not have reactions, but some people have outbreaks, particularly under stressful conditions. Does anyone want to tell their story about cold sores?” Two students volunteered that they have outbreaks, particularly around exam week. They both have a prescription for the antiviral drug acyclovir, which can reduce symptoms if administered during the beginning of the outbreak (typically a tingling or burning sensation). Herpes viruses remain latent in sensory nerves until the immune system is weakened. Reactivated virus will travel to the skin to cause an outbreak.
Shingles, caused by the latent varicella, will typically infect only a single dermatome (region of skin innervated by a single spinal nerve). We also learned about flaviviridae, which causes several nasty tropical diseases, including Dengue, Zika, and Chikungunya. “Each of these is transmitted through the same Aedes mosquito, so it is possible to get multiple outbreaks simultaneously. I’ve had patients with two at once.”
A number of students thought the viral lectures would have been more effective after a dermatology block (scheduled in two weeks). The early symptoms of viruses are typically nonspecific, with the exception of some characteristic rashes. For example, we looked at pictures for the common rash-causing diseases of childhood (measles, scarlet fever, rubella, slapped cheek and roseola) without having an understanding of what pathophysiological mechanism is causing these lesions.
The ID physician spent about 30 minutes on the hepatitis viruses. “There is now a ninety-five percent cure rate for all genotypes of Hep C. It’s truly unbelievable the surge in drug innovation. Five years ago we had almost nothing. Now there are over 12 drugs.” He commented how the first Hep C drug recently dropped in price to remain competitive as it only covers a few genotypes compared to the newer drugs.
Why are there are so many genotypes and viruses? Some viruses purposefully use an error-prone polymerase (enzyme used to replicate DNA/RNA) to accelerate their mutation rate. For example, influenza pandemics occur when a “genetic shift” arises that is sufficiently different from previous strains so that past exposure provides no immunity. This also means the influenza viruses make up to 10 percent null copies, incapable of infecting, but that is okay for an organism that is expending someone else’s energy.
We also learned that many cancers are thought to be a result of past viral infections. For example, cervical and anorectal cancer are almost entirely attributed to sexually-transmitted human papillomavirus (HPV) infection. This is a DNA virus and the cancer-causing strains are primarily HPV 16,18,31, and 33, which are covered by the Gardasil 9 vaccine (ideally administered to both males and females at age 11-12). Viruses typically induce a cell growth state to increase DNA and RNA replication. Some viruses even encode proteins that suppress growth inhibitors such as tumor-suppressor gene p53.
Wednesday and Thursday featured lectures on HIV led by a quirky, cynical ID physician specializing in HIV patients and speaking in a voice that was a bit like Brian Boitano’s. “Do you think he is gay?” a student asked after lecture. Type-A Anita quickly responded, “Of course he is gay. He treats HIV patients.”
HIV is a retrovirus with machinery to integrate its viral genome into the host genome. HIV’s genome encodes for (can produce) only nine proteins. Gp120 is a glycoprotein inserted into the cell membrane envelope that allows the virus to bind to CD4, a protein found on specific white blood cells. When bound, the hidden Gp41 aggregate to bring the viral envelope closer to the host membrane and eventually fuse allowing access to the host T cell. Other host proteins are necessary for viral fusion, including CCR5. One student sent a case report to the class GroupMe about an HIV-positive individual inadvertently cured of HIV when he received a transplant of bone marrow that lacked this protein. (http://www.nejm.org/doi/full/10.1056/NEJMoa0802905).
Two lectures were dedicated to managing HIV. The ID physician began: “My patient was diagnosed with HIV around age 40. She was confused until her husband admitted that for decades he would go on business trips and have unprotected sex with men. She got a divorce.” A student whispered, “I wonder if health insurance survives after divorce?” (Answer: depends on the state; see Real World Divorce)
The ID physician continued, “You are now supposed to prescribe antiviral drugs to anyone with HIV as opposed to those below a CD4 count threshold. Europeans still wait for a low CD4 count to develop, probably because of the cost of these drugs.” HIV antivirals, if taken regularly, are able to wipe out detectable virus particles in the blood and return CD4 count to normal. “There was a study conducted in West Africa where married individuals with one HIV-positive partner was treated. They evaluated how many HIV-negative partners contracted HIV over several years. Almost no one who adhered to the medication regiment passed the HIV to their partner. Some partners tested positive for HIV, but it turned out to be a different genetic strain. The partner had to have caught it from someone other than the spouse.”
We also learned about HIV prophylaxis treatment. At-risk individuals, such as healthcare workers in a high-risk region, or high-risk sexually-active individual, are prescribed HIV antivirals to prevent transmission. “If you are stuck with a needle from an HIV-infected patient, TELL SOMEONE. If you get started on prophylaxis drugs within 48 hours, we can basically guarantee a zero percent transmission rate. You have to hit the virus before its genome is integrated into CD4 T-cells.” One classmate asked, “Are there certain regions of the country where all gay people should be on prophylaxis?” The lecturer was slightly confused, but responded, “No. Assess the risk. If someone is having unprotected sex with two-three different partners a week, yes. If they are in a monogamous relationship, no. Also it depends on what insurance they have.”
A few classmates discussed afterwards if medical education weights HIV too much compared to more common viral infections. Less than 1 percent of the world is infected with HIV. In the US, 1.1 million individuals are HIV-positive, about 0.3 percent of our 325 million population.
Our patient case: Taylor, a 41-year-old black female, presents to the ED in respiratory distress. She reports worsening shortness of breath and persistent cough over the past 4 weeks. Chest x-ray shows glassy white highlights on the normally black air-filled lungs. This suggests diffuse intralobular infiltrates (infection in numerous spots within the lungs; a typical pneumonia is just one big spot). She is admitted and placed on antibiotics. However, her pulmonary function continued to deteriorate and she is transferred to the ICU. Her CBC revealed elevated lymphocytes with a CD4 T cell count less than 100. She is immediately started on antifungal medication to address a suspected Pneumocystis jiroveci infection. HIV test is positive.
Her two-week hospital course is challenging. Because of her low immune function from the HIV, she arrived at the hospital coinfected with several viruses. Then once in the hospital she acquired a conventional pneumonia from intubation and urinary tract infection (UTI) from the foley catheter. She makes a full recovery and is discharged for outpatient follow-up.
Taylor, now 55, is energetic and recently became a grandmother. “At the time of the diagnosis, my three children were 14, 16, and 21. I was in complete denial. I went to four doctors in town to get another HIV test. I finally accepted it while talking on the phone with my internist. I dropped the phone and wept. My children came into the kitchen and asked what was wrong. It felt impossible bringing this up with them.” Once Taylor acknowledged her HIV, she quickly began antiviral treatment without serious side effects. Her CD4 count has improved to normal, and she has not been hospitalized since the above episode.
How did your friends and family react? “I was severely depressed for several years. I’ve been on every single antidepressive that you can think of. You never know who will be there when you are most vulnerable. My best friends were the first to flee. Three of my siblings still do not speak with me. My sister will occasionally visit me, but she refuses to hug me, or let me see her children. People, especially in my community, remember the 1980s epidemic. They think if they touch, or even come near someone with HIV they will get infected.”
“I told my oldest son a few months after my diagnosis. He asked, ‘Do you know who did this to you?’ I told him the truth. ‘Yes. The man knew he had HIV, but still slept with me. When I found out and confronted him, he moved far away.’ I was scared my son would search him out and attack him. I fortunately calmed him down.”
How about coworkers? “I do not tell my coworkers about my health. I get my work done and get home for my kids. No socializing for me.”
The last question asked by a student was, “If you could go back, would you not sleep with that man?” The whole class put their heads down in shame. Taylor seemed a little taken aback, but responded, “Yes, I regret getting HIV.” Several students went up afterwards and gave her a group hug.
Back in lecture we were treated to three 2.5-hour sessions led by an experimental psychologist who studies human engineering in medicine: cognitive-biases, leadership and systems engineering in healthcare. She explained that she had worked at another institution on applying human engineering principles to the cardiac OR and had been recently hired into a newly created position at our hospital and school. “I am by no means an engineer. In fact, my former boss who was an engineer would always get frustrated when we had a meeting. We just think different.” She now conducts studies evaluating the use of checklists, standardized communication protocols, team meetings before and after surgery, and sleep schedules.
“Healthcare systems are not engaging in improvement by pinpointing individuals anymore. Instead, they are trying to improve the system in which actors engage,” she noted. “There were three occasions at the hospital where different nurses administered a full vial of insulin [about 300 cc; triple the correct dose]. The problem was that the nurses were used to getting insulin shots in a pre-formulated syringe with the dosage measured out instead of a whole vial. We implemented a standard insulin dispensary protocol.”
Lanky Luke, a conservative-leaning 25-year-old, vented his spleen after the third session: “What a complete waste of our tuition dollars. We have already had that lecture about respecting other professions [working in the hospital, such as nurses and technicians]. I am all for sitting down and figuring out ways to minimize errors but you have to maintain individual responsibility or the whole system shuts down. I don’t need an overpaid psychologist who knows nothing about medicine to teach me that. Why don’t you just bring in an experienced PA or nurse who can tell what it is like getting talked down to by a PGY1 [intern year].” Another student added, “Why are we discussing how to improve team communication when we don’t even know how to diagnose strep throat?”
Statistics for the week… Study: 10 hours. Sleep: 8 hours/night; Fun: 1 days. Example fun: Jane and I joined Luke and his wife Samantha for beers downtown followed by a space-themed Escape Room. Luke and Samantha had successfully completed one before. Three medical students and one PA student were not able to escape in the one-hour time slot. Let’s hope that we do better when solving medical mysteries.