A case report of long COVID-19 and chronic active myocarditis

Abstract

Background

Post-acute sequelae of SARS-CoV-2 infection (PASC), commonly known as ‘Long COVID-19’, are progressively emerging in the population. While it was clear from the pandemic outbreak that pre-existing cardiac conditions were exacerbated by the infection even after its resolution, little is known about the rare cases of de novo heart failure onset, whose mechanisms are still not fully understood.

Case summary

A 74-year-old man was admitted to the emergency department with SARS-CoV-2 bilateral interstitial pneumonia at the computed tomography scan. A few months after, he developed acute myocarditis that slowly led to progressive myocardial fibrosis, systolic dysfunction, and a pro-arrhythmic state. Furthermore, these manifestations were associated with growing ‘mental dullness’ and chronic psychophysical asthenia. The patient underwent two cardiac MRI over 3 years witnessing the worsening of cardiac involvement and started full pharmacological therapy for heart failure. We report here the initial presentation, medical care, and clinical course of this patient.

Discussion

In SARS-CoV-2 patients, long COVID-19-related myocarditis is one of the more severe complications. A thorough multimodal evaluation of these patients should be conducted, as presentation symptoms can appear subtle or misleading. Early identification of a chronic process of myocardial damage is crucial to implement early therapeutic strategies and prevent the potential worsening of heart failure.

Learning points.

• Clinical symptoms (e.g. dyspnoea) of late heart involvement during long COVID-19 are often misleading and overlap with other conditions, increasing the risk of misdiagnosis.

• There is a shortage of broad functional specific tools for the diagnosis long COVID-19 chronic myocarditis.

• A thorough multimodal evaluation of these patients should be conducted in order to achieve early diagnosis and improve therapeutic strategies.

Introduction

The emergence of post-acute sequelae of SARS-CoV-2 infection (PASC, commonly known as ‘long COVID-19’) poses a major issue, affecting even those who seem to have completely recovered from the initial infection. The World Health Organization (WHO) defines this condition as the persistence of symptoms beyond 3 months of the primary infection, lasting for at least 2 months and not explained by any other illness.¹ Patients often report a persistent physical and mental weariness, as part of a ‘chronic fatigue syndrome’,² although the involvement extends beyond neurological manifestations. Long COVID-19 is characterized by a wide spectrum of symptoms and signs involving numerous organ systems including respiratory, gastrointestinal, endocrine, dermatological, and notably cardiovascular systems.³ Several models of cardiac damage have been proposed, varying with the disease stage and for which the precise pathophysiological mechanisms still require further understanding.

We report here the case of a 74-year-old man, with an isolated myocarditis due to SARS-CoV-2 infection, followed by chronic myocardial fibrosis leading to progressive heart failure (HF) and arrhythmogenic state.

Summary figure

Time	Events
23 March 2021	A 74-year-old man presented to the emergency department with exertional dyspnoea (NYHA Class III) and mild fever (38°C) Real-time polymerase chain reaction (RT-PCR) swab resulted positive for SARS-CoV-2. Blood tests revealed a slight increase in C-reactive protein of 10.49 mg/dL (normal < 0.5 mg/dL) and mild Type 1 respiratory insufficiency Chest computed tomography (CT) scan revealed interstitial pneumonia with multiple ground-glass areas The patient was discharged with oxygen therapy, oral dexamethasone, and oral amoxicillin/clavulanate
23 August 2021	Worsening of dyspnoea and mental fog onset Transthoracic echocardiogram (TTE) revealed a severe reduction in left ventricular ejection fraction (LVEF) (38%) and diffuse hypokinesia
6 October 2021	Coronary angiography showed widespread atheromatosis without significant stenoses Bisoprolol 1.25 mg and canrenone 100 mg were started
January–March 2022	A 12-lead Holter electrocardiogram (ECG) revealed numerous isolated polymorphic premature ventricular contractions (PVCs), pairs, triplets, and brief phases of ventricular bigeminy
3 May 2022	Cardiac MRI (CMR) showed a mildly reduced LVEF (50%) and normal segmental kinetics. There was infero-lateral mesocardial late gadolinium enhancement (LGE), consistent with myocarditis sequelae. There was also a widespread increase in T1 relaxation time on T1 mapping
4 April 2023	Palpitations and a syncopal episode Repeated Holter ECG showed an increased burden of complex PVCs and supraventricular premature contractions (SVPCs), as well as non-sustained ventricular tachycardias (NSVTs) lasting up to 26 s. Bisoprolol was discontinued, in favour of metoprolol 100 mg b.i.d. The TTE showed a LVEF of 50% and a reduction in global longitudinal strain (GLS) of −13.9% with reduced basal velocities in the anterior basal septum, anterior wall, and infero-lateral basal wall
February 2024	Repeated CMR showed further deterioration of LVEF (43%), widespread hypokinesia, and the expansion of LGE also in the mid-basal portion of the infero-lateral mesocardial side. Furthermore, there was an increase in T1 values at the T1 mapping sequences in these regions The patient was discharged for further ambulatory follow-up, with the addition of empagliflozin 10 mg
October 2024	The patient was asymptomatic with a substantially stable LVEF at 45%, and Holter ECG showed a reduced burden of PVCs and no complex arrhythmias

Case presentation

A 74-year-old man with a medical history of chronic obstructive pulmonary disease, obstructive sleep apnoea, carotid vasculopathy, and well-controlled arterial hypertension with ACE-inhibitors (ACE-i), previous smoker, with a familial history of ischaemic heart disease, presented to the emergency department with exertional dyspnoea (New York Heart Association functional class III - NYHA III), worsening fatigue, and mild fever (38°C). A RT-PCR swab was performed and returned positive for SARS-CoV-2 infection, while a multiplex RT-PCR panel for other viruses resulted negative. The patients previously underwent a cardiological check-up including a TTE, which did not show any alterations. At that time, any vaccination for SARS-CoV-2 was performed and later dosage confirmed seroconversion (IgM and IgG antibodies). On admission, haemodynamic parameters were within the normal range, while the arterial blood gas analysis revealed Type 1 respiratory insufficiency (clinical and laboratory data are summarized in Table 1). The ECG showed signs of overload and hypertrophy of the left ventricle, as well as frequent PVCs (Figure 1A). Chest CT scan revealed bilateral interstitial pneumonia with multiple ground-glass areas (Figure 1B). Considering the clinical stability, the patient was discharged with oxygen therapy, oral dexamethasone, and an antibiotic regimen including amoxicillin/clavulanate. No antiviral therapy was prescribed. Five months later, after a period of symptom regression, the patient underwent a cardiological evaluation due to worsening exertional dyspnoea despite pulmonary improvement as witnessed by the follow-up chest CT. The patient was evaluated also by his primary care physician considering his progressive ‘mental dullness’ and psychophysical asthenia, able to impair his daily activities. The TTE showed diffuse hypokinesia with a LVEF at 38%, left ventricular end-diastolic volume index (LVEDVI) of 72 mL/m², normal right ventricular function, no significant valvular disease, and normal pulmonary pressure without inferior vena cava dilatation. No pericardial involvement was detected.

Table 1.

Overview of the clinical and laboratory data of the patient on admission at the emergency department

BP (mmHg)	130/80
HR (b.p.m.)	87
Temperature (°C)	38
Arterial blood gas analysis (FiO2 21%):
pO2 (mmHg)	62.2 (P/F 296)
pCO2 (mmHg)	36.8
HCO3− (mEq/L)	26
SaO2 (%)	93.2
Lactate (mmol/L)	0.6
hsTnT (ng/L; normal < 14.00 ng/L)	8.52
CRP (mg/dL; normal < 0.5 mg/dL)	10.49
PCT (ng/mL; normal < 0.5 ng/mL)	0.1
White blood count (×103/µL)	4.03
Neutrophils (%)	63.9
Lymphocytes (%)	24.8
Monocytes (%)	11.1
Creatinine (mg/dL; normal 0.67–1.17)	0.73
eGFR (mL/min/1.73m2; normal > 60)	92
LDH (mg/dL)	270
D-dimer (ng/mL; normal < 500)	1440
NT-pro-BNP (pg/mL; normal <125 pg/mL)	1675
Fibrinogen (mg/mL; 180 mg/mL-400 mg/mL)	341
Ferritin (ng/mL; range 22 ng/mL-322 ng/mL)	312

BP, blood pressure; HR, heart rate; SaO2, arterial oxygen saturation; hsTnT, high-sensitivity troponin T; CRP, C-reactive protein; PCT, procalcitonin; WBC, white blood cells; eGFR, estimated glomerular filtration rate; LDH, lactate dehydrogenase; NT-pro-BNP, brain natriuretic peptide.

Figure 1.

(A) Electrocardiogram recorded at the admission showed signs of overload and hypertrophy of the left ventricle, as well as frequent premature ventricular contractions. (B) Chest computed tomography scan showed interstitial pneumonia with multiple bilateral ground glass areas, mostly in the right upper lobe.

To rule out ischaemic aetiology given the high pre-test probability of coronary artery disease, the patient underwent coronary angiography 2 months later, which showed widespread atheromatosis but no significant stenoses. Consequently, the patient was discharged with an addition of bisoprolol 1.25 mg and canrenone 100 mg. It has been tried to replace ACE-i with sacubitril/valsartan, but it was poorly tolerated by the patient due to significant episodes of arterial hypotension.

A 12-lead Holter ECG revealed numerous isolated PVCs, also arranged in pairs, triplets, and brief phases of ventricular bigeminy. After 2 months of beta-blocker titration and reduction of the extrasystolic burden, it was possible to perform a reliable CMR. It showed a mildly reduced LVEF at 50% and normal segmental kinetics, associated with linear mid-wall LGE in the infero-lateral wall, consistent with a fibro-scar myocarditis pattern (Figure 2). T1 mapping revealed a widespread mild increase in T1 values and in T1 native sequences (1378 ± 58.5 ms, with reference to local data). However, STIR and T2 mapping sequences did not show the presence of oedematous areas. The patient had a follow-up visit after 1 year, reporting palpitations and a syncopal episode, alongside an increase in the burden of complex PVCs and SVPCs, as well as NSVTs up to 26 s at 12-lead Holter ECG monitoring. Consequently, bisoprolol was discontinued, in favour of metoprolol 100 mg twice daily. The TTE showed a LVEF of 50% and a reduction in GLS of −13.9% with reduced basal velocities mostly in the anterior basal wall, septum, and infero-lateral basal wall (Figure 3C). A second CMR was originally scheduled 1 year after the onset of HF, but had to be slightly rescheduled due to an episode of perforated diverticulitis, which needed surgical intervention. It showed an increase in LVEDVI (86 mL/m²), further deterioration of LVEF (43%), and widespread hypokinesia; it also revealed an expansion of LGE in the mid-basal portion of the infero-lateral mesocardial side, in addition to the same regions previously involved (Figure 4). There also was an increase in T1 values at the T1 mapping sequences in these regions, whereas STIR and T2 mapping still did not show any pathological features. The patient was then discharged for further ambulatory follow-up, with the addition of empagliflozin 10 mg to the treatment regimen. At the last outpatient follow-up 8 months after the second CMR, the patient was asymptomatic with a substantially stable LVEF at 45% and the latest Holter ECG showed a reduced burden of PVCs and no complex arrhythmias.

Figure 2.

(A–C) First cardiac MRI (short-axis view) showed linear mid-wall late gadolinium enhancement in the infero-lateral wall consistent with fibro-scar tissue, possibly related to healed acute myocarditis (arrows). (D–F) T1 mapping based on modified Look–Locker imaging sequences revealed a widespread mild increase in T1 values. Extracellular volume measurements were not performed.

Figure 3.

(A–C) ‘Bull’s-eye’ representation of the regional strains through time. In the last one, a global impairment is presented, with a global longitudinal strain of −13.9%, mostly in the anterior basal wall/septum and infero-lateral basal wall. (C) Global longitudinal strain of left ventricular measured by 2D speckle tracking echocardiography.

Figure 4.

(A–C) Second CMR (short-axis view): expansion of late gadolinium enhancement in the mid-basal portion of the infero-lateral mesocardial side (arrows), in addition to the same regions previously involved. (D–F) In these areas, a corresponding increase in T1 values on T1 mapping can be seen.

Discussion

There are few studies that have documented the onset of de novo HF in patients recovered from SARS-CoV-2 infection. Current state of the art reviews demonstrated how pre-existing obesity, ischaemic heart disease, and HF significantly increase the risk of developing long COVID-19 and therefore to develop further cardiac complications.^3–5 Sokolski et al.⁶ reported de novo HF onset in 76/1282 (5.9%) patients hospitalized for COVID-19-19. It has been theorized that persistent viral reservoirs in the heart along with molecular mimicry mechanism could trigger chronic inflammatory response that lead to tissue fibrosis and ultimately to impaired ventricular contractility/compliance, perfusion, and scarring-related re-entrant tachycardias.⁷ Furthermore, the long-lasting pro-inflammatory cytokine (PIC) tone contributes to the progression of cardiovascular disease by increasing metabolic demand and favouring coronary plaque rupture and thrombotic events.⁸ Long COVID-19 myocarditis has been classified in two different histopathological entities: chronic active myocarditis vs. chronic persistent myocarditis.^7,9 The first category, to which our patient presumably belongs, is identified by clinical relapses with the development of left ventricular dysfunction and myocardial fibrosis; on the other hand, the second form has no ventricular dysfunction but shows active persistent inflammatory infiltrate at the endomyocardial biopsy (EMB).

The EMB and CMR criteria are considered the gold standard of diagnosis for myocarditis. The CMR study in our patient only partially fulfilled Lake Louise criteria for acute myocarditis, since T2 and STIR sequences showed no sign of tissue oedema, according to the remission stage of myocarditis in which it has been executed. Nonetheless, the patient presented an increase in the timing of the native T1 sequences, which, according to the updated Lake Louise criteria of 2018, represents the parameter with greater diagnostic sensitivity, especially when compared with the ‘old’ LLC (85% vs. 74%, P = 0.02).¹⁰ Furthermore, there is evidence that even a single positive criterion can support the diagnosis of myocardial inflammation, when clinical suspicion justifies it.¹¹

The EMB was not performed because of periprocedural risk and relatively low sensitivity. Even if it had reported some evidence of viral infection, no clear therapeutic or prognostic benefit is demonstrated in the setting of chronic myocarditis.¹ Furthermore, if that was the case, the most commonly used antiviral drug in acute SARS-CoV-2 complications during early 2021 was remdesivir, against which already in 2020 the WHO highlighted the negligible effect on mortality.¹²

While during the acute phases of the infection can be observed an increase in PICs (CPR, TNFα, IL6, IL1, D-dimer, high mobility group box 1, IL33, ferritin, and many others), serving as non-specific markers of inflammation, some studies have aimed to identify a subset of clinically relevant markers specific to the long COVID-19 stage. However, no such markers are currently available, and thus, the diagnosis remains primarily clinical.^13,14 The same implications applies for anti-cardiac antibodies such as anti-histone antibody, which can be present after months from the primary infection.¹⁵

Conclusion

Long-term complications and cardiovascular involvement are relevant aspects of the management of patients with previous COVID-19 infection. Dedicated therapeutic paths must include multidisciplinary management to promptly recognize the signs of new cardiac involvement, preventing major adverse events such as worsening of HF and the occurrence of malignant ventricular arrhythmias.

Lead author biography

Dr Stefano Elia is a 26-year-old resident in the Division of Cardiology, University of Eastern Piedmont, Novara.

Consent: In accordance with the COPE guidelines, the authors confirm that the patient has provided written consent for the submission and publication of this case report.

Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Data availability

The data underlying this article will be shared on reasonable request to the corresponding author.