V-A ECMO for neonatal coxsackievirus B fulminant myocarditis: a case report and literature review

Background Neonatal (enteroviral) myocarditis (NM/NEM) is rare but unpredictable and devastating, with high mortality and morbidity. We report a case of neonatal coxsackievirus B (CVB) fulminant myocarditis successfully treated with veno-arterial extracorporeal membrane oxygenation (V-A ECMO). Case presentation A previously healthy 7-day-old boy presented with fever for 4 days. Progressive cardiac dysfunction (weak heart sounds, hepatomegaly, pulmonary edema, ascites, and oliguria), decreased left ventricular ejection fraction (LVEF) and fractional shortening (FS), transient ventricular fibrillation, dramatically elevated creatine kinase-MB (405.8 U/L), cardiac troponin I (25.85 ng/ml), and N-terminal pro-brain natriuretic peptide (NT-proBNP > 35,000 ng/L), and positive blood CVB ribonucleic acid indicated neonatal CVB fulminating myocarditis. It was refractory to mechanical ventilation, fluid resuscitation, inotropes, corticosteroids, intravenous immunoglobulin, and diuretics during the first 4 days of hospitalization (DOH 1–4). The deterioration was suppressed by V-A ECMO in the next 5 days (DOH 5–9), despite the occurrence of bilateral grade III intraventricular hemorrhage on DOH 7. Within the first 4 days after ECMO decannulation (DOH 10–13), he continued to improve with withdrawal of mechanical ventilation, LVEF > 60%, and FS > 30%. In the subsequent 4 days (DOH 14–17), his LVEF and FS decreased to 52% and 25%, and further dropped to 37%–38% and 17% over the next 2 days (DOH 18–19), respectively. There was no other deterioration except for cardiomegaly and paroxysmal tachypnea. Through strengthening fluid restriction and diuresis, and improving cardiopulmonary function, he restabilized. Finally, notwithstanding NT-proBNP elevation (>35,000 ng/L), cardiomegaly, and low LVEF (40%–44%) and FS (18%–21%) levels, he was discharged on DOH 26 with oral medications discontinued within 3 weeks postdischarge. In nearly three years of follow-up, he was uneventful, with interventricular septum hyperechogenic foci and mild mitral/tricuspid regurgitation. Conclusions Dynamic cardiac function monitoring via real-time echocardiography is useful for the diagnosis and treatment of NM/NEM. As a lifesaving therapy, ECMO may improve the survival rate of patients with NM/NEM. However, the “honeymoon period” after ECMO may cause the illusion of recovery. Regardless of whether the survivors of NM/NEM have undergone ECMO, close long-term follow-up is paramount to the prompt identification and intervention of abnormalities.


Case presentation
A previously healthy 7-day-old boy born at 38 weeks and 2 days' gestation with a birth weight of 3.35 kg required admission due to intermittent fever for 4 days with a maximum body temperature of 38.3°C, nasal congestion, runny nose, and increasing lethargy, despite treatment with piperacillin sulbactam at the local hospital.On admission, his vital signs and body weight were axillary temperature 37.9°C, pulse rate 168 beats/min, respiratory rate 60 breaths/min, blood pressure 57/32 mmHg, and 3.65 kg, respectively.Although the heart sounds were normal, he was slightly lethargic, with a tight anterior fontanelle, stiff neck, hypertonia, dyspnea, cyanosis (SpO 2 75%) corrected by continuous positive airway pressure (CPAP, FiO 2 30%), obvious abdominal distension, weak bowel sounds, and hypoperfusion.

Continuous low-dose intravenous epinephrine (gradually
Post-ECMO (middle stage) (DOH 14-17/PND 20-23): After discontinuing epinephrine and diuretics, LVEF and FS decreased to 52% and 25%, respectively (Table 1), and his heart except for the right ventricle began to enlarge on DOH 17, but other than that the overall clinical improvement was manifested by fine tolerance after formula feeding (DOH 15), stable breathing under noninvasive ventilation support (NIPPV→CPAP→HFNC, high flow nasal cannula), normal cTnI (Table 1) and electrocardiogram, and absorption of bilateral IVH (DOH 17).

"Refractory" ascites
Systemic edema in this case was caused by heart failure and capillary leak secondary to CVB infection, and reached its peak along with fluid overload at ECMO initiation (14).Subsequently, owing to the efficacy of ECMO, soft tissue edema and pulmonary edema were gradually alleviated.However, despite timely abdominal drainage, ascites persisted (Figure 1D).This may be associated with the relative insufficiency of gastrointestinal blood flow because of the unrestored gastrointestinal peristalsis caused by infectious toxic enteroplegia.Moreover, the usage of sedatives, analgesics, and muscle relaxants during ECMO further inhibited gastrointestinal motility and blood supply, which jointly limited the absorption of ascites by the peritoneal capillary network, and postural restriction during ECMO additionally hindered the discharge of ascites through the abdominal drainage tube.With the cessation of ECMO, the lifting of postural restriction, the reduction of sedatives, analgesic, and muscle relaxants, and the recovery of gastrointestinal function, yellow ascites was soon discharged through the abdominal drainage tube by changing posture and no longer recurred.Therefore, during the treatment of NM/NEM with ECMO, if the gastrointestinal tract is not inflated and/or ascites is persistent, it should not be pessimistically assumed that the child has necrotizing enterocolitis induced by enterovirus infection unless there are clear evidences.

Static IVH
Neonatal IVH often occurs in preterm infants rather than term infants, and its most important pathogenesis is ascribed to the fragility of germinal matrix vasculature, and the anomalies in cerebral blood flow, platelet, and coagulation (27).Severe intracranial hemorrhage, the most serious complication of neonatal ECMO, may not only lead to premature ECMO decannulation but also be life-threatening (14).In our case, bilateral grade III IVH occurred on the third ECMO day, closely related to anticoagulation and fluctuations in blood volume and pressure.Meanwhile, fluid overload at ECMO initiation may have inestimable impacts on cerebral blood perfusion.Inevitable iatrogenic blockage of the right internal jugular vein and common carotid artery blood flow due to ECMO cannulation may also be involved.When this case of IVH occurred, the newborn had not yet met the decannulation criteria, while blind decannulation may cause all in vain.Unless absolutely necessary, the newborn should not be weaned from ECMO.At this moment, it is necessary to further optimize the cardiovascular and coagulation status and to closely monitor the changes in IVH via POCUS (14).If intracranial hemorrhage develops rapidly, ECMO must be terminated (14).Fortunately, the IVH in our case remained static and was finally absorbed.

Relapse after the "honeymoon period"
His heart had got rest on V-A ECMO, so that in the first 4 days post-ECMO his condition continued to improve, and LVEF and FS were maintained above 60% and 30%, respectively.He perfectly passed the "honeymoon period", causing a "false recovery".Thereafter, because of incomplete recovery, his heart was overwhelmed again, inducing decline of LVEF and FS, tachypnea, and cardiomegaly.After strengthening fluid restriction and diuresis and improving cardiopulmonary function, he was discharged smoothly.However, it should be noted that in the second stage of myocarditis pathophysiology (within several weeks after presentation), the body may suffer acquired T-cell and B-cell immune responses, leading to persistent myocardial damage or even cardiac dysfunction (28).In our case, the relapse of heart failure post-ECMO tends to be caused by incomplete cardiac recovery rather than acquired immune responses mediated myocardial damage.

Unpredictability
In neonates, persistently increased CK-MB, cTnI, and NT-proBNP, together with significantly reduced LVEF and FS commonly indicate NM after excluding asphyxia, etc., particularly when there is an enterovirus infection prodrome.Through our case, we believe that combined monitoring of the dynamic changes in heart sounds, rhythm, cardiac function, CK-MB, cTnI, NT-proBNP, LVEF, and FS is useful for the diagnosis of NM/ NEM, and that the levels of NT-proBNP, LVEF, and FS can also reflect whether the child is recovered to some extent.However, how to early diagnose NM/NEM and how to accurately predict its development trend are more important for prompt precision therapy and improvement of the outcome.The development of more perfect biomarkers and monitoring methods for myocardial injury is expected to enable early diagnosis and intervention of NM/NEM, thereby ameliorating its prognosis.
Compared to myoglobin, heart type fatty-acid-binding protein, with earlier release and higher cardiac specificity, is an ideal biomarker for the early detection of myocardial injury (29).It can increase within 1.5 h after myocardial injury, peak at approximately 6 h, and return to baseline concentration in 24 h (29).However, myoglobin rises within 1-3 h after myocardial injury, peaks at 6-9 h, and returns to normal range in 24 h (30), and the variation patterns of cTnI and CK-MB are 3-4 h/16-18 h/2 w (31) and 4-6 h/16-18 h/48-72 h (32), respectively.
Cardiac magnetic resonance (CMR) imaging, compared with echocardiography, may have advantage in the early diagnosis and late follow-up of both pediatric and adult myocarditis (22,33).The 2018 Lake Louise Criteria improves CMR accuracy in diagnosing (acute) myocardial inflammation (34).CMR is beneficial for the detection of LVEF-preserved myocarditis and suspected myocarditis (33), but it requires sophisticated techniques (22).Moreover, upon suspicion of NM/NEM, the critically ill neonates may require intensive cardiopulmonary support and may deteriorate any minute, so pursuing CMR scan at this moment is risky, not to mention its time-consuming nature.Howbeit, whenever this happens, the real-time and portability of POCUS will be highlighted (22).
Notably, increased wall thickness suggesting myocardial inflammatory edema may precede cardiomegaly in myocarditis (35), which can be detected by initial echocardiography.Compared to conventional echocardiography, speckle tracking echocardiography can detect myocardial dysfunction early (36) even in patients with LVEF-preserved myocarditis (37), is highly consistent with CMR in the diagnostic and prognostic evaluation of myocarditis (38), and is helpful in identifying pediatric myocarditis at risk for arrhythmias (39).Furthermore, in NEM, compared to newborns who died or needed cardiac transplant, transplant-free survivors have better global longitudinal and circumferential strain at the initial echocardiography without differences in demographic or laboratory variables (age at onset, sex, gestational age, birth weight, cTnI, creatine kinase, BNP, or NT-proBNP) and in other echocardiographic measures (LVEF and LV diastolic/systolic diameter/volume), though the latter may ultimately live with common sequelae such as chronic LVA and left ventricular dysfunction (13).
Although ECMO may improve the hospital survival of NM/ NEM patients, there is no large multicenter research to decipher the long-term prognosis of NM/NEM patients supported with ECMO (3).NM/NEM may develop sequelae such as interventricular septum hyperechogenic foci (2, 24), LVA (4, 13), and DCM (4,24,33).The pathogenesis of LVA secondary to viral myocarditis is unclear (13), which may be in connection with the long-term fiber scar repair of the necrotic myocardium (4), while Th17 cells/IL-17A-mediated autoimmunity and myocardial fibrosis may involve DCM formation postmyocarditis (40).Nevertheless, the mechanism determining the chronic transformation of cardiac dysfunction post-myocarditis and the reason why some patients cannot recover have not yet been fully elucidated (33), which may be linked to the persistence of viral infection, inflammatory damage, and immune reaction (22,28).Additionally, genetic factors such as deleterious variants involving myocardial structure and function genes might play an important role in the phenotypic outcome of myocarditis (33,35).Currently, there are interventricular septum hyperechogenic foci without significant expansion left in our case (Figure 2), which have proven to be dystrophic calcifications after myocardial necrosis according to previous studies (2, 24).LVA and DCM usually occur within weeks to months (4) and months to years (4,33) post-myocarditis, respectively, so the probability of LVA and DCM may gradually decrease over time in our case.
Taken together, in this case of NM/NEM, we closely monitored the changes in neonatal condition through POCUS, etc., ensured the normal operation of ECMO and efficacy, maximized the prevention and treatment of the concomitant complications of ECMO, and the newborn eventually recovered smoothly.However, limited to sample size, the following conclusions should be cautiously extrapolated.

Conclusions and prospects
Although NM/NEM is rare, it is unpredictable with occult onset, fulminant processes, high mortality, and poor prognosis.Dynamic cardiac function monitoring via POCUS is of great value in the diagnosis and treatment of NM/NEM.As a lifesaving option, ECMO may improve the survival rate of patients with NM/NEM.However, the management of the peri-ECMO period is extremely important, especially during the "honeymoon period" after ECMO, which may easily cause the illusion of recovery.Regardless of whether the survivors of NM/ NEM have undergone ECMO, close long-term follow-up is crucial to the early identification and timely intervention of abnormalities to improve their quality of life.The most difficult to predict may be that which newborns infected with enteroviruses will experience NM/NEM.More researches are imperative to further detailed, reliable, and feasible prevention and control consensus for NM/NEM.