COVID-19 infection-induced worsening of recurrent CK-MB isozyme elevation due to macro-CK type 1 in a child: case report

Abstract

Background

Macro-creatine kinase (macro-CK) type 1, a macroenzyme composed of creatine kinase (CK) and immunoglobulin, is associated with hypothyroidism, tumour, autoimmune diseases, myositis, and cardiovascular diseases, and may even be found in the absence of associated pathology. However, its relationship with coronavirus disease (COVID-19) infection remains unreported.

Case summary

An 11-year-old male patient presented with recurrent myocardial enzyme abnormalities, mainly manifested as elevated activities of CK and CK isoenzyme [particularly CK-myocardial band (MB)] with activity inverse (CK-MB higher than CK). Dynamic examinations revealed a continuous increase in CK-MB activity closely related to infection, peaking immediately after COVID-19 infection (CK 1838 U/L and CK-MB 1644 U/L). Nonetheless, the patient remained asymptomatic, with the normal results of cardiac magnetic resonance imaging and muscle biopsy and persistently normal results of echocardiogram and electrocardiogram. He had normal values of CK-MB mass and high-sensitivity troponin T (hs-cTnT) suggesting possible false elevation of CK-MB activity assayed via immunoinhibition-based CK-MB measurement. Macro-CK type 1 was confirmed by CK isoenzyme electrophoresis with a macro-CK type 1 band detected in the patient’s serum. The patient remained asymptomatic over a year’s follow-up.

Discussion

The sustained pseudoelevation of CK-MB activity caused by macro-CK type 1 is often misdiagnosed as myocardial damage. This diagnosis can be established via agarose gel electrophoresis of CK and CK mass assay. This case illustrates that COVID-19 infection closely correlates with macro-CK type 1 occurrence. It highlights the clinical value of understanding the relationship and emphasizes the importance of education for differential diagnosis to avoid misdiagnosing myocardial damage.

Learning points.

• Consider macro-CK type 1 when encountering unexplained false elevated CK-MB levels even activity inverse over CK, whereas CK-MB mass is normal; as this can prevent unnecessary cardiac investigations.

• Infections, especially COVID-19 in this case, may trigger macro-CK type 1 formation through immune responses, warranting careful interpretation of abnormal elevated CK-MB in post-infection patients.

• Macro-CKaemia type 1 can be diagnosed by CK isoenzyme electrophoresis with a macro-CK type 1 band detected in the patient’s serum.

Introduction

Creatine kinase (CK), crucial for intracellular energy balance, exists for four forms—CK-muscle band isoenzyme (CK-MM), CK-brain band isoenzyme (CK-BB), CK-myocardial band isoenzyme (CK-MB), and CK-mitochondrial isoenzyme (CK-MiMi). As a marker of muscular integrity,¹ CK measurement is widely used in diagnosing and monitoring conditions like myocardial infarction and muscular disorders. Additionally, two macro-CK forms exist: macro-CK type 1 (CK-immunoglobulin complex) and macro-CK type 2 (mitochondrial CK oligomer).² Macro-CK can cause false CK elevations in standard laboratory tests due to immunoinhibition method limitations in excluding abnormal CK-BB content. While macro-CK type 1 has been associated with various health conditions, its association with COVID-19 infection remains unreported. This is particularly relevant as COVID-19’s cardiovascular effects and immune response activation could influence macro-CK formation, making accurate biomarker interpretation challenging.

This case report describes an unusual presentation of macro-CK type 1 in a paediatric patient, with particular attention to its temporal relationship with COVID-19 infection, offering new insights into potential triggers of macro-CK formation and its clinical implications.

Summary figure

Time	Events
Jun 2021, at admission (other hospital)	The patient presented with recurrent fever and cough for over a week and was diagnosed with bronchopneumonia with elevated enzyme activity of CK and CK-MB. This elevation was in contrast with normal values of the other tests, including creatine kinase isoenzyme mass spectrometry, high-sensitivity troponin, myoglobin, electrocardiogram, and echocardiogram.
Aug 2021, outpatient examination	The patient became asymptomatic; however, CK and CK-MB activities remained elevated and demonstrated an upward trend.
Oct 2021, outpatient visit	The patient presented with fever and cough and was diagnosed with pertussis. CK and CK-MB activities were further increased, while other test indicators remained normal.
Nov 2021, Dec 2021, Jan 2022, Feb 2022, outpatient examination	The patient had no symptoms, and activity of CK and CK-MB demonstrated a downward trend, though remained significantly higher than the normal ranges.
May 2022, at admission	The patient was diagnosed with bronchopneumonia with markedly elevated enzyme activity of CK and CK-MB.
Dec 2022, outpatient visit	The patient was diagnosed with COVID-19 with the highest levels of enzyme activity of CK and CK-MB. The patient remained almost asymptomatic except for a low-grade fever lasting 3 days.
3 Jan 2023, 30 Jan 2023, 15 Apr 2023, outpatient examination	The patient was asymptomatic, and the activity of CK and CK-MB displayed a trend of gradual decrease, though remained significantly higher than the normal range.
27 Nov 2023, outpatient examination	The CMRI results demonstrated that the patient had normal cardiac structure and function, and the pathological biopsy with HE and NADH-TR staining revealed no abnormal changes in the muscle. The patient remained asymptomatic, though enzyme activity of CK and CK-MB remained significantly elevated.

Case presentation

In June 2021, an 11-year-old male patient presented to a regional hospital with complaint of cough and fever for 3 days, and the test of cardiac enzyme profile revealed unnormal values with CK activity [272 U/L (normal range, 24–229 U/L)] and CK-MB activity [264 U/L (normal range: 0–25 U/L)]. After discharge, CK and CK-MB activities were tested at one week, two months, and four months, showing fluctuations ranging from 296 to 566 U/L and 289 to 432 U/L, respectively. In October 2021, he was diagnosed with pertussis and had CK and CK-MB activities of 608 and 632 U/L, respectively, with activity inversion. From November 2021 to April 2022, the patient had intermittent low-grade fever two–three times, lasting 1–2 days each time, and four checks of myocardial enzymes showed persistently elevated CK and CK-MB activities. In May 2022, he was diagnosed with acute bronchitis, and CK-MB activity increased to 800 U/L.

In December 2022, after contacting a COVID-19 patient for 1 day, he developed fever lasting 3 days (highest temperature: 38.5°C) and paroxysmal cough. His COVID-19 DNA test was positive. One week later, the cough resolved. Two weeks later, myocardial enzymes were checked, revealing peak CK and CK-MB activities of 1838 and 1644 U/L, respectively, without symptoms of muscle soreness, fatigue, palpitation, or chest tightness. In January 2023, he presented to our hospital’s cardiovascular department with a chief complaint of ‘abnormal myocardial enzymes for more than a year and a half.’ The patient had a generally favourable physical condition but was prone to fever since childhood. Physical examination reveals no obvious abnormalities. His parents were non-consanguineous and denied a family history of hereditary diseases. Table 1 summarizes the patient’s myocardial enzyme spectrum tests since disease onset; Figure 1A illustrates the dynamic curve of CK and CK-BB activity values. Table 2 lists results of the patient’s serum CK-MB mass and hs-cTnT test.

Table 1.

Analysis of the patient’s myocardial enzyme spectrum

Date	CK	CK-MB	LDH	α-HBDH
(Normal range)	(24–229 U/L)	(0–25 U/L)	(120–250 U/L)	(72–182 U/L)
12 Jun 2021	272↑	264↑	209	145
19 Jun 2021	296↑	289↑	209	161
16 Aug 2021	434↑	344↑	266	202↑
7 Oct 2021	566↑	432↑	175	137
10 Oct 2021	608↑	632↑	230	156
17 Nov 2021	508↑	401↑	214	158
8 Dec 2021	466↑	402↑	189	166
25 Jan 2022	442↑	440↑	194	158
23 Feb 2022	581↑	509↑	175	166
21 May 2022	815↑	800↑	202	167
13 Oct 2022	1184↑	894↑	226	174
29 Dec 2022	1838↑	1644↑	200	161
3 Jan 2023	879↑	1344↑	187	155
30 Jan 2023	941↑	1788↑	189	151
15 Apr 2023	866↑	1510↑	204	–
20 Nov 2023	1284↑	1991↑	210	153

CK, creatine kinase; CK-MB, creatine kinase-MB; LDH, lactate dehydrogenase; α-HBDH, α-hydroxybutyrate dehydrogenase.

Figure 1.

(A) This panel shows the dynamic monitoring of serum creatine kinase (CK) and CK-MB activities in a paediatric patient from 2021 to 2023, with arrows marking the times when various infections occurred. (B) A representative agarose gel electrophoresis image displays the patient’s serum CK isoenzymes. Notably, macro-CK type 1 and the CK-muscle isoenzyme (CK-MM) are identified. (C) Cardiac magnetic resonance imaging (CMRI) scans reveal no significant structural or functional abnormalities. (D and E) Muscle biopsy samples stained by haematoxylin–eosin (HE) (D) and nicotinamide adenine dinucleotide dehydrogenase–tetrazolium reductase (NADH-TR) (E) show no evident muscle damage.

Table 2.

Test of the patient’s CK-MB mass and hs-cTnT in serum

Date	CK-MB mass	hs-cTnT
(Normal range)	(<6.22 ng/mL)	(0–14pg/mL)
20 Jun 2021	1.08	3.99
19 Aug 2021	1.3	0.0087
12 Oct 2021	1.1	0.0005
14 Oct 2021	0.9	0.0009
3 Jan 2023	0.98	–

CK-MB mass, creatine kinase-MB mass; hs-cTnT, high-sensitivity cardiac troponin.

The patient’s auxiliary examination results (normal values in parentheses) included: CK, 879 U/L (24–229 U/L); CK-MB isoenzyme, 1344 U/L (0–25 U/L); CK-MB mass, 0.98 ng/mL (<6.22 ng/mL); and normal findings for CK isoenzyme mass, hs-cTnT, myoglobin, thyroid function, and other indicators. Serum IgG, IgA, IgM, anti-nuclear antibody spectrum, electrocardiogram (ECG) (see Supplementary material online, Figure S1), echocardiogram (see Supplementary material online, Figure S2), and thyroid ultrasound were also normal. However, electromyography revealed possible but uncertain myogenic damage to the proximal muscles of the upper limbs. CK isoenzyme agarose gel electrophoresis (ISO CK reagent kit and HYDRASYS2 fully automatic electrophoresis instrument; Sebia, France) showed a visible macro-CK type 1 band (Figure 1B), leading to the diagnosis of ‘macro-CKaemia type 1’. To further rule out the possibility that the increased CK-MB subtype is caused by its release from an injured muscle, we biopsied the patient’s skeletal muscle. Both haematoxylin–eosin (HE) staining (Figure 1D) and nicotinamide adenine dinucleotide dehydrogenase–tetrazolium reductase (NADH-TR) staining (Figure 1E) showed no clear morphological abnormality in the muscle despite the possible impaired function shown in the electromyogram. Furthermore, cardiac magnetic resonance imaging (CMRI) showed no abnormalities in cardiac structure and function (Figure 1C, Supplementary material online, Figure S3). This finding was further supported by the persistent normal results of ECG (see Supplementary material online, Figure S1) and echocardiogram (see Supplementary material online, Figure S2).

Regarding management and follow-up, the patient was prescribed oral fructose-2,6-biphosphate and coenzyme Q10 since June 2021 when CK isoenzyme elevation was detected. Despite treatment, CK-MB activity increased, reaching the highest peak following COVID-19 infection in December 2022. After diagnosing macro-CKaemia, the medications were discontinued, leading to a stable condition without adverse symptoms for nearly a year, except for persistently high CK and CK-MB activities.

Discussion

This case presents the first documented instance of COVID-19 infection triggering elevated macro-CK type 1 levels in an 11-year-old male patient. Key features include persistent CK and CK-MB elevations over 18 months and activity inversion phenomenon vs. normal values of CK-MB mass, marked elevation following respiratory infections (especially COVID-19), and absence of clinical symptoms despite high enzyme levels. This case highlights how macro-CK interference complicates clinical assessment, potentially leading to unnecessary cardiac workups. Recognition of this phenomenon is crucial for accurate diagnosis and management.

CK-MB activity measurement relies on immunosuppression of the M subunit, assuming CK-BB absence. However, elevated CK-BB or incomplete M subunit inhibition can lead to false CK-MB elevations.³ Activity inversion, where CK-MB exceeds total CK, indicates analytical interference, typically from factors like macro-CK, which persists longer in the body due to its large molecular weight. In our case, the patient showed prolonged abnormal myocardial enzyme elevations with CK/CK-MB activity inversion for over a year following respiratory infections, despite being clinically asymptomatic. Normal results from CMRI, ECG, echocardiogram, and CK-MB mass tests, along with unremarkable muscle biopsy findings, supported this. Serum CK isoenzyme electrophoresis confirmed macro-CK type 1 presence, leading to the discontinuation of myocardial therapy and regular follow-ups.

Macro-CK type 1’s pathological significance remains unclear despite its association with various conditions.⁴ Our case revealed two distinct mechanisms of CK-MB elevation. First, our patient demonstrated recurring CK-MB increases following infections, most notably after COVID-19, likely occurring through infection-induced immunoglobulin production binding to CK isoenzymes to form macro-CK complexes. Second, independently, both pneumonia and COVID-19 can elevate CK-MB through tissue injury or inflammation.^5,6 However, distinguishing between true myocardial injury and macro-CK interference remains challenging, as current literature lacks clarity on this specific relationship. Understanding these distinct mechanisms, particularly in COVID-19 patients, is crucial for accurate interpretation of CK-MB results.

Asymptomatic macro-CKaemia type 1 is frequently misinterpreted as myocardial injury, necessitating improved diagnostic approaches. Key strategies include systematic laboratory screening with CK-MB/total CK ratio evaluation, CK-MB mass assay, and electrophoresis testing when activity inversion occurs. Diagnosis can be confirmed through positive electrophoresis and normal CK-MB mass results. While the exact prevalence remains unclear, healthcare professionals should consider macro-CK in cases of persistent CK-MB elevation without clinical symptoms, particularly following infections. Patient education about potential CK-MB fluctuations during infections and regular monitoring can help prevent unnecessary cardiac investigations.

In conclusion, our case demonstrates how COVID-19 infection triggered macro-CK type 1 formation, causing worsening of recurrent CK-MB activity elevations. This highlights the importance of distinguishing between true and false CK-MB elevations, and emphasizes the need for increased awareness among clinicians to prevent misdiagnosis.

Lead author biography

My name is Yanmin Zhang, MD and PhD. I have been working in the field of paediatric cardiovascular disease for 35 years. Meanwhile, I am also a scientist focusing on the paediatric arrhythmia and channelopathy. I hope that combination of clinical practice and basic scientific research could protect the life and health of children.

Supplementary material

Supplementary material is available at European Heart Journal – Case Reports online.

Data availability

The data underlying this article are available in the article and in its online Supplementary material.