Internal Medicine
Board Review

Educational Objective: 

Identify the immune response to mRNA COVID-19 vaccines and compare it to the immune response of the other 4 most common vaccine models.

Key Point: 

Similar to live, attenuated and vector vaccine models, the recently developed mRNA COVID-19 vaccines are the only other vaccine model to trigger both robust humoral (antibody) and robust cellular (T-cell) immune reactions. This is important because humoral PLUS cellular immunity is required in order to overcome pathogens that invade the host’s cell (such as SARS-CoV-2).

Explanation: 

To date, there are 5 main categories of vaccines: 

• Inactive virus vaccines 

• Protein subunit vaccines 

• Live, attenuated virus vaccines 

• Virus vector vaccines 

• [NEW] The novel mRNA vaccines.

Research has recently confirmed that the novel mRNA vaccines produce an excellent humoral (antibody) as well as cellular (T-cells) response. The same is true for the more traditional live, attenuated vaccines and also the newer vector vaccines (e.g. another novel COVID-19 vaccine and the well-established smallpox vaccine). In the latter case, a harmless virus vector (e.g. adenovirus) transports a piece of the offending virus’s protein into host cells. These 3 vaccine models have in common that the host’s cells are invaded, after which they display foreign virus antigen on their cell surface. This display of foreign antigens on the body’s own cells is the key event that triggers the cellular immune response. These vaccine models are all effective at triggering a robust humoral plus cellular immune response; however, they are often less well tolerated, especially by immunocompromised people.

Inactive virus vaccines (e.g. polio virus vaccine) and protein subunit vaccines (e.g. hepatitis B vaccine), on the other hand, circulate within the host with less (or zero) invading of the host’s cells. As a result, they mostly trigger a humoral immune response. with the cellular response being relatively weak and variable. Since elimination of a viral infection requires the cellula immune system for elimination of infected host cells (because viruses invade host cells and hijack them for the reproduction of the virus), these latter two vaccine categories typically require multiple booster doses. Their benefit is the fact that they are well tolerated by all categories of people, including those who are immunocompromised.

Review of humoral and cellular immunity:

-> KEY POINT: Notice in the following review that free-floating viruses mostly activate the humoral system whereas infected host cells activate BOTH the humoral and cellular immune systems. Thus, a vaccine that creates a mimic of infected cells activates both systems, whereas a vaccine that mimics free-floating virus mostly triggers the humoral system.

1. Neutralization (Humoral System = B-Cell Antibodies): When circulating B-cells detect foreign antigens on the surface of a freely circulating virus, they produce antibodies that detach from the B-cell to swarm and “coat” the antigens of the virus. This hampers the virus’ ability to enter the host's cells to initiate infection. 

   Recent research also shows that even if an antibody-coated virus manages to enter a host cell (because antibodies may not cover the entire virus), the antibodies stay attached and interfere with the virus’s ability to reproduce inside the host cell. 

   Antibodies also attach to the viral antigens presented on the cell surface of infected cells (as the virus emerges from the host cell), which will be discussed under point 3.

   This entire process is referred to as neutralization. It at least slows, and often even prevents, infection.

   
2. Opsonization and Phagocytosis: The antibodies attached to free-floating viruses send signals that attract phagocytes (and other immune cells not pertinent to this point). The phagocytes engulf the entire “blob” of virus (or multiple viruses linked together) plus the attached antibodies, which is referred to as opsonization. This process kills viruses that are outside of the host’s cells; however, the phagocytes are too small to engulf infected cells, which therefore continue to produce more viruses.

3. Cytotoxic Response - Cellular System (T-Cells): In order to terminate the ongoing, intracellular production of new viruses, the immune system must also kill its own, infected host cells. This process is executed as follows:

Infected host cells first produce individual viral particles that individually migrate to the host’s cell membrane, where they are assembled into new viruses. In order to assemble the virus, the host cell holds – and thereby inadvertently displays - the pathogen’s antigens on its own cell surface. To the host’s immune system, the infected host cell now looks like a giant virus with viral antigens all over its surface. Antibodies bind to these presenting antigens on the infected host cell just like they bind to them on individual viruses (see point 1). These antibodies attract killer cells (and other immune cells not pertinent to this point) that bind to these antibodies. 

Once attached, the killer cells release cytotoxic chemicals that kill the infected host cell, thus terminating this cell’s production of viral particles. This killer cell system is referred to as antibody-dependent cell-mediated cytotoxicity (ADCC). 

ADCC is a necessary component of an immune response to any pathogen that invades the host’s cells because only ADCC can remove infected host cells.

References:

Ng WH, Liu X and Mahalingam S. Development of vaccines for SARS-CoV-2 [version 1; peer review: 2 approved]. F1000Research 2020, 9 (Faculty Rev):991

Highly readable version of Ng WH publication: Suresh Mahalingam, Adam Taylor. From adenoviruses to RNA: the pros and cons of different COVID vaccine technologies. The Conversation: Academic Rigor, Journalistic Flair. (Uploaded September 17, 2020) (Accessed December 20, 2020) 

Abbasi J. COVID-19 and mRNA Vaccines—First Large Test for a New Approach. JAMA. 2020;324(12):1125–1127. doi:10.1001/jama.2020.16866

Frank Lectures - Illustrative Video. Action of Antibodies: Neutralization, Opsonisation, Complement Activation, and ADCC.  

Educational Objective:

Examine the signs and symptoms of carcinoid syndrome.

Key Point:

Carcinoid syndrome is characterized by flushing, diarrhea, valvular disease, wheezing, and pellagra. The disease is caused by metabolites produced by carcinoid tumors of the midgut. The diagnosis is confirmed by detection of 5 hydroxyindole acetic acid in 24-hour urine collection samples.

Explanation:

The most appropriate next step is a 24-hour urine 5-hydroxyindoleacetic acid test. This patient's clinical presentation is typical of carcinoid syndrome, which occurs when metastatic carcinoid tumors secrete chemicals such as tryptophan, serotonin, and histamine. The release of these compounds generates the symptoms classic of carcinoid syndrome. Approximately 8% of patients with carcinoids develop carcinoid syndrome. Symptoms include flushing, diarrhea, cardiovascular disease, wheezing, and pellagra.

Carcinoid syndrome is usually produced from midgut carcinoid tumors that can originate in places such as the Meckel diverticulum. A diagnosis of carcinoid syndrome involves measuring serotonin or one of its breakdown products.

The 24-hour urine 5-hydroxyindoleacetic acid test is more sensitive for detecting carcinoid syndrome than urinary 5-hydroxytryptamine excretion or a serum 5-hydroxytryptamine assay. Imaging with CT or ultrasonography would not detect small carcinoid tumors. Serum gastrin is useful in diagnosing Zollinger-Ellison syndrome or gastrinoma.

Reference:

Jensen RT, et al. Neuroendocrine tumors. In: Feldman M, et al, eds. Sleisenger and Fordtran's Gastrointestinal and Liver Disease. 2016:501-541.e15.

Educational Objective:

Identify the endoscopic findings associated with high rates of mortality.

Key Point:

Various endoscopic findings during active bleeding are associated with different rates of mortality. Active bleeding carries an 11% mortality risk.

Explanation:

Of the options given, active bleeding portends the greatest risk for recurrent upper GI bleeding and mortality from peptic ulcer disease. Active bleeding on endoscopy is associated with an 11% mortality rate and a 55% risk of recurrent bleeding from the same site. A nonbleeding, visible vessel is the next worst prognostic factor, with a 43% risk of recurrent bleeding and an 11% mortality rate. A clean-based ulcer and a flat, pigmented spot have less than a 10% likelihood of recurrent bleeding.

Reference:

Kovacs TO, Jensen DM. Gastrointestinal hemorrhage. In: Goldman L, Schafer AI. Goldman-Cecil Medicine. 2016:879-884.e2.

Educational Objective:

Discuss the appropriate treatment for venous ulcers.

Key Point:

The most important therapy of venous ulcers is control of edema with compression therapy.

Explanation:

The patient has a large venous ulcer. The erythema seen above and below the ulcer represents stasis dermatitis and not cellulitis. Compression therapy is a key component of the therapy required to treat venous insufficiency and venous ulcers. This can be achieved with the use of compression stockings or multilayer compression wraps. Edema control is the most important element to allow for healing of the ulcerations.

Debridement of the ulceration is indicated in the presence of sloughing or devitalized tissue. Collagenase is an option for some patients; however, this patient has predominantly granular tissue on the surface of the wound, a sufficient base for healing without the need for collagenase.

Superabsorbent dressing will help the patient control her symptoms and will provide her comfort. Dressings are an important element for the treatment of venous ulcers; however, the drainage will continue unabated unless compression therapy is applied at the same time.

All wounds are colonized with bacteria. A diagnosis of infection is based on clinical findings. This wound does not appear to be infected and does not require antibiotic treatment.

References:

O’Donnell TF, Passman MA, et al. SVS/AVF Joint Clinical Practice Guidelines Committee-Venous Leg Ulcer. Journal of Vascular Surgery.2014; 60: 3S-59S

Bonilla-Martinez ZL, Kirsner RS. Venous Ulcers. Diseases of the Skin. Conn’s Current Therapy. 2014; 14: 889-990

Educational Objective:

Recognize the appropriate settings for prescribing blood transfusion.

Key Point:

Transfusions should be prescribed in patients with hemoglobin levels of 7 g/dL or less.

Explanation:

Most patients in the intensive care unit are anemic. Most have anemia of chronic inflammation combined with anemia from serial phlebotomy. A large clinical trial showed that using a transfusion trigger of a hemoglobin level of 7 g/dL was not inferior to a trigger of 10 g/dL. Transfusions have been associated with complications of death, infection, respiratory distress, and organ dysfunction in the intensive care unit. The only group that seemed to show benefit of earlier transfusion were patients with active ischemic cardiac disease. Studies to date have not shown a benefit of erythropoiesis-stimulating agents in critically ill patients.

References:

Hebert PC, Wells G, Blajchman MA, et al; Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med. 1999;340(6):409-417.

Kress J, Hall J. Approach to the patient with critical illness. In: Longo D, et al, eds. Harrison’s Principles of Internal Medicine. 18th ed., 2011:2196-2204.

Watson S, Kendrick K. Management of anaemia and blood transfusion in critical care-implementing national guidelines in ICU. BMJ Qual Improv Rep. 2014;3(1):pii:u202106.w1109.