Coronary artery disease;

Should patients previously immunized against Covid-19 receive selected monoclonal antibodies when diagnosed with a breakthrough infection?

FA Manian MD, MPH, , , , , , , , , , , , , , , , , , , , , , , , Leave a comment

Although published studies supporting monoclonal antibody therapy in mild to moderate Covid-19 preceded availability of Covid-19 vaccines and the emergence of new variants of concern,1,2 given the possibility of severe breakthrough Covid-19 in high risk vaccinated patients with suboptimal immunity and the retained activity of certain monoclonal antibody products (ie, casirivimab and imdevimab-Regeneron-Cov and sotrovimab) against common variants of SARS-CoV-2 , their use is recommended even in vaccinated individuals with mild to moderate Covid-19.3-5

In fact, the CDC states that “For people who have received one or more doses of Covid-19 vaccine and subsequently experience SARS-CoV-2 infection, prior receipt of a Covid-19 vaccine should not affect treatment decisions (including use of monoclonal antibodies, convalescent plasma, antiviral treatment, or corticosteroid administration) or timing of such treatment.”3

In its July 30, 2021 Emergency Authorization Use (EUA) letter regarding use of casirivimab and imdevimab – REGEN-COV), the FDA does not distinguish between vaccinated and unvaccinated individuals for its indications,4 similar to those of guidelines posted by the Department of Health and Human Services and the NIH.5-6

When indicated, high risk vaccinated individuals with Covid-19 should be offered  an FDA approved (under EUA currently) monoclonal antibody product (such as  casirivimab and imdevimab antibody cocktail or sotrovimab) soon after diagnosis and certainly no later than 10 days.

Vaccinated individuals with mild to moderate Covid-19 not requiring hospitalization and for whom monoclonal antibody treatment may be indicated include older patients and those with risk factors for severe disease, such as obesity, pregnancy, chronic kidney disease, chronic lung disease (including COPD), immunocompromised state, serious heart conditions (eg, heart failure, coronary artery disease, cardiomyopathies), sickle cell disease and type 2 diabetes.7

Of note, casirivimab and imdevimab is indicated for adults (weighing at least 40 kg) and children 12 years or older and is administered by IV infusion or subcutaneously, if IV infusion is not feasible and would lead to delay in treatment.4

Bonus Pearl: Did you know that in phase III trials, casirivimab and imdevimab  antibody cocktail reduced hospitalization or death by 70% in non-hospitalized patients with Covid-19?2

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References

  1. Interim clinical considerations for use of Covid-19 vaccines currently authorized in the United States. 2021. Available at https://www.cdc.gov/vaccines/covid-19/info-by-product/clinical-considerations.html. Accessed August 22, 2021.
  2. March 23, 2021 https://www.roche.com/media/releases/med-cor-2021-03-23.htm
  3. Dougan M, Nirula A, Azizad M, et al. Bamlanivimab plus Etesevimab in mild or moderate Covid-19. N Engl J Med, July 14, 2021. https://www.nejm.org/doi/10.1056/NEJMoa2102685
  4. Letter, EUA REGEN-COV, July 30, 2021. https://www.fda.gov/media/145610/download
  5. Department of Health and Human Services. High risk Covid-19 outpatients may avoid hospitalization with monoclonal antibody treatment. July 16, 2021. https://combatcovid.hhs.gov/sites/default/files/documents/High-Risk-COVID-19-Outpatients-072021.pdf
  6. Anti-SARS Cov-2 monoclonal antibodies. Accessed August 22, 2021. https://www.covid19treatmentguidelines.nih.gov/therapies/anti-sars-cov-2-antibody-products/anti-sars-cov-2-monoclonal-antibodies/
  7. Science brief: evidence used to update the list of underlying medical conditions that increase a person’s risk of severe illness from Covid-19. Accessed August 22, 2021. https://www.cdc.gov/coronavirus/2019-ncov/science/science-briefs/underlying-evidence-table.html

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Should patients previously immunized against Covid-19 receive selected monoclonal antibodies when diagnosed with a breakthrough infection?

My middle-aged patient with a history of mediastinal irradiation for Hodgkin’s lymphoma in his 20s now has moderate aortic regurgitation. Could his valvular disease be related to the radiation he received over 20 years ago?

FA Manian MD, MPH, , , , , , , , , , , , , , , , Leave a comment

Absolutely! Mediastinal irradiation is associated with several cardiac complications, including coronary artery disease, pericarditis, systolic or diastolic dysfunction and valvular disease. Valvular disease may occur in 2-37% of patients after mediastinal irradiation, is dose-dependent, and generally does not manifest until 10-20 years after the radiation exposure.1 Since mediastinal irradiation is common in young adults diagnosed with Hodgkin’s lymphoma, these complications may be seen in early middle-age or later.

Valvular retraction is usually the first radiation-induced valvular change, and most commonly leads to mitral and aortic valve regurgitation.2 This retraction tends to occur within 10 years of the radiation therapy, followed by fibrosis and calcification of the valves after 20 years.

Although the pathophysiology of radiation-induced valvular disease is not entirely understood, activation of fibrogenic growth factors (eg, tissue growth factor β1 and myofibroblasts) which promote the synthesis of collagen has been postulated.1 Additionally, irradiation of aortic interstitial cells has been shown to cause transformation to an osteogenic phenotype that produces bone morphogenic protein 2, osteopontin and alkaline phosphatase, all important factors in bone formation and possibly valvular calcification.3

Since radiation-induced heart disease is the most common cause of non-malignant morbidity and mortality in patients who have undergone mediastinal irradiation, some have recommended screening of asymptomatic patients for valvular disease every 5 years by echocardiography beginning 10 years after radiation therapy. 2  If an abnormality is found, the screening frequency should increase to every 2-3  years,  if the valvular abnormality is mild, or annually if the abnormality is moderate. For severe valvular abnormalities, the patients should be considered for valve replacement.

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References

    1. Gujral DM, Lloyd G, Bhattacharyya S. Radiation-induced valvular heart disease. Heart 2016;102:269–276. https://heart.bmj.com/content/heartjnl/102/4/269.full.pdf
    2. Cuomo JR, Sharma GK, Conger PD, Weintraub NL. Novel concepts in radiation-induced cardiovascular disease. World J Cardiol. 2016; 8 (9):504-519. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5039353/
    3. Nadlonek NA, Weyant MJ, Yu JA, et al. Radiation induces osteogenesis in human aortic valve interstitial cells. J Thorac Cardiovasc Surg 2012;144:1466–70. doi:10.1016/j.jtcvs.2012.08.041 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3665422/

Contributed by Rachel Wallwork, MD, Mass General Hospital, Boston, MA

 

My middle-aged patient with a history of mediastinal irradiation for Hodgkin’s lymphoma in his 20s now has moderate aortic regurgitation. Could his valvular disease be related to the radiation he received over 20 years ago?

What is the significance of the diagonal ear lobe crease or “Frank’s sign”?

FA Manian MD, MPH, , , , , Leave a comment

Frank’s sign, also known as diagonal earlobe crease (DELC), has often been considered a sign of coronary artery disease (CAD), originally described in patients 60 years of age or younger in 1973 (1). Since then, the majority of clinical, angiographic, and postmortem reports seem to support the association of this physical finding (see figure) with atherosclerotic coronary disease (2,3). In addition, it may be associated with peripheral vascular disease (4) as well as cerebrovascular disease (5).

In a study of hospitalized patients, there was a significant association between DELC and cardiovascular events with a sensitivity of 43% and specificity of 70% (3).

Although the mechanism for this association is unclear, microvascular disease involving the middle ear lobe end-artery territory has been implicated (6).  Free radical oxidative stress activation of the metalloproteinases that break down type 1 collagen has also been suggested (7).

It is fair to conclude, however, that the value of this sign as a screening tool for CAD has not been firmly established and its utility in clinical practice remains uncertain, particularly in those older than 60 years of age or those with diabetes (6).

franks2

 

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 References

1. Frank ST. Aural sign of coronary-artery disease. N Engl J Med 1973;289:327-8. https://www.ncbi.nlm.nih.gov/pubmed/4718047

2. Friedlander AH, Lopez-Lopez J, Velasco-Ortega E. Diagonal ear lobe crease and atherosclerosis: a review of the medical literature and dental implications. Med Oral Patol Oral Cir Bucal 2012;1:e153-9. http://www.medicinaoral.com/pubmed/medoralv17_i1_p153.pdf 

3. Rodriguez-Lopez C. Garlito-Diaz H, Madronero-Mariscal R, et al. Earlobe crease shapes and cardiovascular events. Am J Cardiol 2015;116:286-93. https://www.sciencedirect.com/science/article/abs/pii/S0002914915011200?via%3Dihub

4. Korkmaz L, Agac MT, Acar Z, et al. Earlobe crease may provide predictive information on asymptomatic peripheral arterial disease in patients clinically ree of atherosclertotic vascular disase. Angiology  2014;65:303-7. https://reference.medscape.com/medline/abstract/23449604

5. Celik S, Erdogan T, Gedikli O, et al. Earlobe crease is associated with carotid intima-media thickness in subjects free of clinical cardiovascular disease. Atherosclerosis 2007;192:428-31. https://www.sciencedirect.com/science/article/abs/pii/S0021915006005284

6. Shoenfeld Y, Mor R, Weinberger A, et al. Diagonal earl lobe crease and coronary risk factors. J Am Geriatr Soc 1980;28:184-7. https://www.ncbi.nlm.nih.gov/pubmed/7365179/

7.  Fabijanic D, Culic V. Diagonal ear lobe crease and coronary artery disease. Am J Cardiol 2012;110:1385-6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4697048/ 

Contributed in part by Kathryn Dinh, Medical Student, Harvard Medical School, Boston, MA.

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis or its affiliate healthcare centers. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you

 

What is the significance of the diagonal ear lobe crease or “Frank’s sign”?