Picking up pericarditis or missing myocarditis

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I must confess that myocarditis was not really on my diagnostic radar until I heard a talk about it at BADEMFest by Andrew Redfern. The context he was talking about is very different from the one I face – there is very little HIV or TB to consider in my part of the world – but the challenge of making the diagnosis is still there.

Before the advent of endomyocardial biopsy, the only time that clinicians could make the definitive diagnosis was at autopsy. Although a number of criteria exist that make the diagnosis of myocarditis more likely there is no way to differentiate actual from possible myocarditis when looking at clinical features alone.

Why are we talking about this now?

SARS-CoV-2 makes its way into cells via ACE₂ receptors and may also directly attack cardiac myocytes in a similar fashion to the Coxsackie virus. It is also possible that mRNA vaccines may cause a focal antibody response in a subset of the population in the same way that the virus causes MIS-C/PIMS-TS. Certainly, post-vaccination myocarditis is not an unheard of entity. Back in 1957, when smallpox was the scourge, myocarditis complicated the provision of preventative vaccination. Is this a case of the prevention of an illness being worse than the disease it was created to treat?

In mid-June 2021, Israeli health regulators reported a series of 275 cases of myocarditis (from December 2020 to May 2021). This cohort was drawn from over 5 million people that had received mRNA vaccines against COVID-19 (Pfizer–BioNTech and Moderna). This means nothing if you do not know the baseline incidence of the disease – reported as between 1.95 per 100,000 (in Finnish children under 15) and 2.16 per 100,000 in fit, young US military service folk.

It is certainly more prevalent in the male population. The risk of developing some form of cardiac inflammatory process, after the second dose, is 1 in 100,000 girls and 1 in 16,000 boys (aged 12-17).

PREDICT have come out with a flow chart to assist the emergency provider in picking up pericarditis and not missing myocarditis. As a member of the ACEM team that helps come up with some of these guidelines, I wanted to look into the evidence a little more.

History

So how does a child with pericarditis (or myocarditis) present?

The symptoms may be non-descript. A small case series by Das et al. (2021) described the following, all occurring within five days of the second dose:

  • Chest pain (24-42%)
  • Fever (31-58%)
  • Palpitations (16%)
  • Shortness of breath (35-69%)
  • Fatigue (25-70%)
  • Nausea/vomiting/abdominal pain (28-48%)
  • Diarrhoea (8%)

Numbers are based on Law et al’s Scientific Statement for the American Heart Association in 2021.

So, whilst cardiac-sounding complaints like chest pain and palpitations should set your Spidey-sense tingling, we need to be aware that teens, who have been recently vaccinated, may well present with the very vague complaint of fatigue. If you can find me a teenager who does not complain of fatigue then we could probably publish a case report. Every piece of information needs to be taken in context.

Physical examination findings

We’ve taken our history and now want to move on to the next step – examination. Are there any examination findings that increase the likelihood of pericarditis being the diagnosis? Once again, the majority of signs are incredibly non-specific.

  • Tachypnoea (52-60%)
  • Tachycardia (32-57%)
  • Murmur (26%)
  • Gallop (20%)
  • Diminished pulses (16-21%)*
  • Hepatomegaly (21-50%)*
  • Oedema (7%)*
  • Hypotension*
  • Signs of low cardiac output*

*Clearly these are signs of imminent cardiovascular collapse.

Pericardial friction rub

Have you ever heard it? First described by Victor Collin, an assistant of René Laënnec, in 1824, it has made its way into exam questions and textbooks alike. I remember being told to imagine sandpaper on stone. I would close my eyes and listen, oh so intently, until one day, I actually heard it. And, like a lot of historical signs, there have been little data around either specificity or sensitivity, with a reported prevalence between 35% and 85%.


It is mainly heard over the left sternal border and is louder on leaning forward and on inspiration (as the pericardium is brought nearer to the diaphragm of the stethoscope). It’s worth considering that you may not be able to hear a friction rub if a large pericardial effusion is present.

The pericardial friction rub is typically triphasic – heard in atrial systole, ventricular systole and ventricular systole. It shouldn’t be mistaken for the biphasic pleural rub. That sounds more like an old leather-bound family bible being creaking open and disappears if you ask the patient to hold their breath.

(MP3 taken from University of Washington Department of Medicine)

Pulsus paradoxus

If you measured my blood pressure as I sit here, calmly writing this post, you might spot that my systolic blood pressure drops a little as I breathe in, then goes back up when I breathe out. This is completely normal.

Swings of more than 10mmHg produce pulsus paradoxus. Increased intrathoracic pressure (in acute severe asthma, for example) reduces left ventricular stroke volume and thus systolic BP. Biventricular interdependence also plays a role so, in cardiac tamponade, one can also see big swings in systolic blood pressure and pulsus paradoxus. It’s an early sign, that develops before the ensuing hypotension of tamponade. So, not specific to either pericarditis or pericardial effusion or tamponade, but another clue.



Although, officially, you should be using a sphygmomanometer to measure the systolic BP most of us tend to rely on a surrogate marker, the pulse oximetry trace.

Distant heart sounds

Distant, or muffled heart sounds suggest that there is some acoustic barrier between your stethoscope and the heart. In this case, we are worried about a pericardial effusion.

ECG changes

We know that paediatricians could be better at interpreting ECGs, though I would challenge most adult cardiologists to successfully interpret paediatric ECGs (there’s a study in that). What should you be looking for?

Non-specific changes

The most common findings are sinus tachycardia, or non-specific ST changes, followed by more specific changes related to the underlying pathology.

Pericarditis

Pericardial inflammation causes ECG changes through four classical stages. These are present in about 50-60% of cases.

  • Widespread ST elevation and PR depression with reciprocal changes in aVR (first couple of weeks)
  • Pseudonormalization – ST changes resolve and T waves flatten (1 to 3 weeks)
  • Flattened T waves invert (3 to several weeks)
  • ECG normalizes (several weeks onwards)
Spodick’s sign is a downsloping TP segment
Global concave ST elevation and PR depression in early pericarditis

The global ST changes make pathophysiological sense as the underlying disease process is not associated with any particular arterial territory.

Myocarditis

As a pericardial effusion develops the QRS voltages shrink in size, pulsus paradoxus develops and the patient may develop AV conduction delays. There are no ECG changes that can really differentiate myocarditis from pericarditis. The sensitivity of ECG in diagnosing myocarditis has been estimated to be around 47%.

Small complexes and electrical alternans in pericardial effusion, taken from Plant and Tie (2020)

As the pericardial effusion grows in size the heart swings around from beat to beat subtly altering the axis. This is known as electrical alternans.

Blood tests

It’s clear that if the history and exam are not suggestive of myo/pericarditis and the ECG is normal then we can stop. Do not pass go. Do not collect $200. And reassure the patient and parents and send them on their merry way with good safety netting advice and reassurance that they made the right decision to get vaccinated. But what value do blood tests hold?

It would be nice if viral serology helped but it has a low negative predictive value when compared to the gold standard biopsy. Many reported cases of mRNA vaccine-associated pericarditis have had a normal WBC, a normal CRP and a normal ESR.

ESR/CRP

I am not a fan of the Completely Random Protein as a test in the emergency department though I do understand how some of my impatient colleagues love to draw pretty graphs charting its rise and fall. Fortunately (or unfortunately, depending on your point of view) a normal CRP does not rule out acute inflammation of the myocardium.

It may be more useful to monitor disease progression or the impact of treatment.

Troponin

A rise in troponin suggests concomitant myocardial injury.

BNP

Although not a commonly requested test in paediatric medicine BNP (Brain Natriuretic Peptide) and NT-proBNP (N-terminal pro-BNP) are often raised in the setting of fulminant myocarditis with deteriorating myocardial function. Hopefully, you should be able to detect the signs of heart failure long before you think of ordering this blood test.

Imaging

If any Paediatric Emergency Medicine provider has access to same-day cardiac MRI then let me know. The rest of us mere mortals might want to do something else – a chest x-ray or bedside echocardiogram perhaps?

CXR

The latest NSW safety notice recommends a chest x-ray as one of the initial investigations for a young person presenting with symptoms of pericarditis or myocarditis. However, chest x-rays are usually normal. It takes a moderate to large-sized pericardial effusion to manifest as an increased cardiothoracic ratio.

It is probably more useful to help rule out alternative causes of chest pain.

Large pericardial effusion – taken from pediatricimaging.org

POCUS/Echo

If chest radiographs are not overly sensitive for potential peri/myocarditis then perhaps it is time to wield the trusty ultrasound probe. The following changes have been reported but it is important to note that normal ventricular function does not rule out myocarditis:

  • Altered global ventricular function
  • Isolated left or right ventricular dysfunction (including regional wall motion abnormalities)
  • LV enlargement
  • Thickened myocardium from wall oedema
  • Pericardial effusion
  • Intracardiac thrombus
  • Functional valvular regurgitation

It takes little training to be able to visualize an effusion so take five minutes to watch this great video from Jacob Avila.

Cardiac MRI

I doubt any of us have easy access to cardiac MRI but it can certainly help clinch the diagnosis if it is in doubt. 69% of cases of myocarditis in the Das et al. series had late phase gadolinium enhancement.

The Bottom Line

Young people with a normal ECG and a normal troponin do not need any further workup.

Those with an abnormal ECG AND/OR troponin AND are haemodynamically stable should be followed up and ideally get an echocardiogram within 48 hours.

Those who are not haemodynamically stable clearly require more emergent imaging, not so much to define cause but define myocardial function.

The incidence of myocarditis, in the setting of COVID-19 infection, is estimated to be around 11 cases per 100,000 people. The incidence of myocarditis after vaccination is estimated to be around 2.7 cases per 100,000 people vaccinated.

mRNA vaccines really have made a difference and have reduced both the number and severity of cases of COVID worldwide. But it can also reduce the complications of long COVID too – something that many forget to consider. There are also indirect benefits to the individual. Higher community levels of vaccination will mean less disruption to education as transmission in schools becomes less of an issue.

The majority of reported cases of myocarditis are mild and resolve with rest and symptomatic treatment and with no serious sequelae.

Current advice is that if someone has developed probable or confirmed myocarditis as a result of an mRNA vaccine they should not receive a second dose or a booster. The advice is less clear if the patient has developed mild pericarditis and so liaison between the local cardiology team and primary is vital.

Selected references

Aretz, H.T., 1987. Myocarditis: the Dallas criteria. Human pathology, 18(6), pp.619-624.

Bertoncelli, D., Guidarini, M., Della Greca, A., Ratti, C., Falcinella, F., Iovane, B., Dutto, M.L., Caffarelli, C. and Tchana, B., 2020. COVID19: potential cardiovascular issues in pediatric patients. Acta Bio Medica: Atenei Parmensis91(2),

Body, R. and Ferguson, C., 2008. Should we be measuring troponins in patients with acute pericarditis? Emerg Med J25, pp.253-524.

Buttà, Carmelo, Luca Zappia, Giulia Laterra, and Marco Roberto. “Diagnostic and prognostic role of electrocardiogram in acute myocarditis: A comprehensive review.” Annals of Noninvasive Electrocardiology 25, no. 3 (2020): e12726.

Calcaterra, G., Mehta, J.L., De Gregorio, C., Butera, G., Neroni, P., Fanos, V. and Bassareo, P.P., 2021. COVID 19 Vaccine for Adolescents. Concern about Myocarditis and Pericarditis. Pediatric Reports13(3), pp.530-533.p.177.

Cantarutti, N., Battista, V., Adorisio, R., Cicenia, M., Campanello, C., Listo, E., Campana, A., Trocchio, G. and Drago, F., 2021. Cardiac Manifestations in Children with SARS-COV-2 Infection: 1-Year Pediatric Multicenter Experience. Children8(8), p.717.

Das, B.B., Moskowitz, W.B., Taylor, M.B. and Palmer, A., 2021. Myocarditis and Pericarditis Following mRNA COVID-19 Vaccination: What Do We Know So Far?. Children8(7), p.607.

Dimopoulou, D., Spyridis, N., Dasoula, F., Krepis, P., Eleftheriou, E., Liaska, M., Servos, G., Maritsi, D. and Tsolia, M., 2021. Pericarditis as the Main Clinical Manifestation of COVID-19 in Adolescents. The Pediatric Infectious Disease Journal40(5), pp.e197-e199.

Gargano JW. Use of mRNA COVID-19 Vaccine After Reports of Myocarditis Among
Vaccine Recipients: Update from the Advisory Committee on Immunization Practices — United States, June 2021. MMWR Morb Mortal Wkly Rep. 2021;70. doi:10.15585/mmwr.mm7027e2

Goitein, O., Sabag, A., Koperstein, R., Hamdan, A., Di Segni, E., Konen, E. and Matetzky, S., 2015. Role of C reactive protein in evaluating the extent of myocardial inflammation in acute myocarditis. Journal of Cardiovascular Magnetic Resonance, 17(1), pp.1-2.

Hamzaoui, O., Monnet, X. and Teboul, J.L., 2013. Pulsus paradoxus. European Respiratory Journal42(6), pp.1696-1705.

Imazio, M., Klingel, K., Kindermann, I., Brucato, A., De Rosa, F.G., Adler, Y. and De Ferrari, G.M., 2020. COVID-19 pandemic and troponin: indirect myocardial injury, myocardial inflammation or myocarditis?. Heart, 106(15), pp.1127-1131.

Law, Y.M., Lal, A.K., Chen, S., Čiháková, D., Cooper Jr, L.T., Deshpande, S., Godown, J., Grosse-Wortmann, L., Robinson, J.D., Towbin, J.A. and American Heart Association Pediatric Heart Failure and Transplantation Committee of the Council on Lifelong Congenital Heart Disease and Heart Health in the Young and Stroke Council, 2021. Diagnosis and management of myocarditis in children: a Scientific Statement from the American Heart Association. Circulation144(6), pp.e123-e135.

Liao, Y., Jin, H., Huang, X., Gong, F. and Lijun, F., 2021. Hot Issues on Myocarditis, Pericarditis and Cardiomyopathy in Children. Frontiers in Pediatrics9, p.734.

Luk, A., Clarke, B., Dahdah, N., Ducharme, A., Krahn, A., McCrindle, B., Mizzi, T., Naus, M., Udell, J.A., Virani, S. and Zieroth, S., 2021. Myocarditis and Pericarditis following COVID-19 mRNA Vaccination: Practical Considerations for Care Providers. Canadian Journal of Cardiology.

Marinella, M.A., 1998. Electrocardiographic manifestations and differential diagnosis of acute pericarditis. American Family Physician, 57(4), p.699.

Mohammed, N.A.M., Tammam, F.A.A.A.A. and Ibrahiem, A.G.M., 2021. Clinical audit of the management of pericarditis in children in a Tertiary Referral University Hospital in Egypt. Journal of Current Medical Research and Practice6(2), p.15

Park, H., Yun, K.W., Kim, K.R., Song, S.H., Ahn, B., Kim, D.R., Kim, G.B., Huh, J., Choi, E.H. and Kim, Y.J., 2021. Epidemiology and Clinical Features of Myocarditis/Pericarditis before the Introduction of mRNA COVID-19 Vaccine in Korean Children: a Multicenter Study. Journal of Korean Medical Science36(32).

Pepe, S., Gregory, A.T. and Denniss, A.R., 2021. Myocarditis, Pericarditis and Cardiomyopathy After COVID-19 Vaccination. Heart, Lung and Circulation30(10), pp.1425-1429.

Plant, A. and Tie, S., 2020. A swinging heart in cardiac tamponade. The New Zealand Medical Journal (Online), 133(1518), pp.79-80.

Raymond, T.T., Das, A., Manzuri, S., Ehrett, S., Guleserian, K. and Brenes, J., 2020. Pediatric COVID-19 and pericarditis presenting with acute pericardial tamponade. World Journal for Pediatric and Congenital Heart Surgery11(6), pp.802-804.

Saxena, S., Skirrow, H. and Wighton, K., 2021. Should the UK vaccinate children and adolescents against covid-19?.

Sharif, N. and Dehghani, P., 2013. Acute pericarditis, myocarditis, and worse!. Canadian Family Physician, 59(1), pp.39-41.

Shay, D.K., Shimabukuro, T.T. and DeStefano, F., 2021. Myocarditis occurring after immunization with mRNA-based COVID-19 vaccines. JAMA cardiology.

Spodick DH. Pericardial rub. Prospective, Multiple observer investigation of pericardial friction in 100 patients. Am J Cardiol. 1975 Mar;35(3):357-62.

Spodick DH. Acute pericarditis: current concepts and practice. JAMA. 2003;289:1150

Vogel, G. and Couzin-Frankel, J., 2021. Israel reports link between rare cases of heart inflammation and COVID-19 vaccination in young men. Science10.

Xanthopoulos, A. and Skoularigis, J., 2017. Diagnosis of acute pericarditis. EJ Cardiol Pract15.

Yale, S.H., Tekiner, H., Mazza, J.J., Yale, E.S. and Yale, R.C., 2021. Physical Signs and Medical Eponyms of Pericarditis: Auscultation. In Cardiovascular Eponymic Signs (pp. 247-260). Springer, Cham

Yoldas, T. and ÖRÜN, U.A., The Diagnostic and Clinical Approach to Acute Myopericardial Syndromes in Children and Adolescent. Türkiye Çocuk Hastalıkları Dergisi14(5), pp.402-407.

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