A Previously Healthy 18-Year-Old Male With Fever, Arrhythmia, and Shock

The patient is a previously healthy male individual aged 18 years with no significant past medical history who presented to the emergency department in April of 2020 with 5 days of fever, dry cough, myalgia, and headache. On the day before presentation, he developed dizziness, shortness of breath, and chest pain, which progressed to near loss of consciousness, prompting him to visit the emergency department. He complained of nausea, vomiting, abdomen discomfort, and decreased appetite over the past 2 days. He also reported having a respiratory illness 4 weeks before, characterized by fever, cough, and anosmia, which lasted for over a week. He did not seek medical care, and his parents were sick with similar symptoms at the time. The patient denied recent exposure to sick individuals, but his parents reported contact with a person with an influenza-like illness before the onset of symptoms. He denied consumption of unpasteurized, raw, or undercooked products or exposures to domestic or wild animals. There was no history of recent travel or visitors from outside of the household. He reported not being sexually active.

On arrival, his vitals included a temperature of 39.6°C, heart rate of 151 beats per minute, respiratory rate of 45 breaths per minute, oxygen saturation of 97% on room air, and blood pressure of 80/52 mm Hg. His weight was 54.4 kg (14th percentile) and height was 175 cm (44th percentile). On physical examination, he was thin, pale, and ill appearing. Head, neck, and oropharynx examination were within normal limits, except for dry oral mucosa and mild scleral injection. There was no lymphadenopathy. Lung auscultation revealed no adventitious sounds. Cardiac examination revealed normal S1 and S2 with physiologic split, bounding peripheral pulses, and brisk capillary refill. His abdomen was soft, nontender, and nondistended, with no abdominal masses palpable and no hepatosplenomegaly. There were no rashes. His musculoskeletal examination was normal, and his neurologic examination revealed no focal deficits.

Dr Wilkerson, as an intensivist, what would be the best next steps in the management of this patient?

This patient presented with clinical signs and symptoms (tachypnea, tachycardia, altered perfusion, and hypotension) that are consistent with the diagnosis of shock. Shock is defined as inadequate delivery of oxygen to the tissues; therefore, the next best step in management is to focus on improving tissue perfusion and oxygen delivery. The patient should receive supplemental oxygen and intravenous (IV) fluid resuscitation. Fluid administration should be titrated to effect, and the patients should be monitored for signs of fluid overload. Inotropes should be added if there is minimal improvement with fluid resuscitation alone. Antimicrobial therapy should be started. A preliminary workup including a complete blood count (CBC), a complete metabolic panel, inflammatory markers, blood gas, chest radiograph (CXR), cultures (blood and urine), and viral testing should be obtained. Once the patient is stabilized, more testing to localize the source and identify the etiology should be pursued.

IV access was obtained, and after collecting a blood culture, empirical antibiotics (ceftriaxone and vancomycin) were administered. Blood lactate level was 2.2 (normal range: 0.4–1.3). He received 3 boluses of normal saline, and norepinephrine infusion was initiated for management of fluid-refractory shock. An arterial line and a central line were placed for closer monitoring of hemodynamics. A CBC revealed neutrophilia, lymphopenia, and thrombocytopenia (Table 1). Inflammatory markers were elevated, and a coagulation panel was abnormal (elevated d-dimer and fibrinogen), needing initiation of subcutaneous heparin. His troponin was 0.11 ng/mL (0–0.09 ng/mL). A complete metabolic panel revealed normal renal function, normal electrolyte levels, and less than 2× elevation in liver transaminases. Urinalysis and cerebrospinal fluid parameters were not suggestive of infection. CXR revealed streaky opacities in the bilateral lungs (Fig 1). A computed tomography (CT) scan of the brain was done to rule out any intracranial process before proceeding with lumbar puncture and did not reveal any acute changes. His severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) nasopharyngeal test was negative twice. The telemetry revealed intermittent junctional escape rhythm (heart rate: −85 beats per minute) with low-voltage complexes and ST segment depression in the anterolateral leads noted in the electrocardiogram (ECG). An echocardiogram revealed mildly depressed left ventricle (LV) function with an ejection fraction of 52%, and epinephrine was initiated. Coronary artery origin and dimensions were normal.

Dr Logan, what would be your differential diagnosis in a patient with the above clinical presentation?

A previously healthy 18-year-old-male individual presenting with shock has a broad differential. We consider typical causes of sepsis, such as Staphylococcus aureus, streptococcal species, Neisseria meningitidis, Gram-negative organisms, and the possibility of toxic shock syndrome (TSS), based on multiple systems involved. Additionally, an adolescent could have acquired immunodeficiency, such as acute retroviral syndrome due to HIV, an ingestion (ie, cocaine) or toxin-mediated illness, endocrinopathies, thromboembolic event, or the onset of a new autoinflammatory disorder, such as systemic lupus erythematosus or Churg-Strauss Syndrome. However, along with this differential, this young man also has cardiac enzyme elevations with abnormal conduction on ECG and mildly depressed LV function, suggesting the possibility of acute myocarditis. In a normal host, acute myocarditis is most often viral in etiology.

Dr Sosnowski, there is a high suspicion for myocarditis due to the elevation of cardiac enzymes and ECG changes. What is the most common presentation of myocarditis in children?

In children outside of the infancy period, acute myocarditis can present in multiple ways, depending on the age of the patient. There is usually a preceding history of a respiratory or gastrointestinal viral illness. In infants, it most commonly presents with a clinical phenotype similar to congestive heart failure (CHF), including poor feeding and lethargy, tachypnea, tachycardia, hepatomegaly with cardiomegaly noted on CXR, and ECG changes (low-voltage QRS complexes and ST-T flattening). In older children like our patient, the phenotype is similar to acute coronary syndrome, and they usually present with fever, chest pain with elevated cardiac enzymes, and ECG changes (ST segment elevation). CXR often does not reveal any cardiomegaly in the absence of CHF. The presence of rhythm abnormalities is common in patients with myocarditis, ranging from complete heart block, bradyarrhythmias and tachyarrhythmias, and, rarely, sudden cardiac arrest. The presence of a junctional escape rhythm, although uncommon in myocarditis, is not unusual and falls within the spectrum of myocarditis-associated rhythm abnormalities. Because our patient developed this rhythm after the onset of his illness, it indicates the inflammation of the conduction system, which usually improves with defervescence or resolution of the inflammatory state.

Dr Logan, what further testing would you suggest, and what are the recommended treatment options?

While we search for an etiology, his antiinfective regimen should include coverage for bacterial sepsis (vancomycin for Gram-positive coverage, including methicillin-resistant S aureus and broad-spectrum β-lactams for Gram-negative coverage, as well as clindamycin for toxin-mediated effects associated with TSS).

In the interim, further testing for infectious causes of myocarditis (enteroviruses, adenoviruses, influenza, Epstein-Barr virus, cytomegalovirus, hepatitis C, HIV, parvovirus, human herpesvirus 6, Mycoplasma pneumoniae, and Chlamydia pneumoniae), including repeat testing for SARS-CoV-2 because coronavirus disease 2019 (COVID-19) infection has been associated with myocardial dysfunction, preferably obtaining a sample from the lower airway. Considerations for imaging and examination include an abdominal ultrasound or CT scan with contrast (to localize any focus of infection with notable gastrointestinal symptoms) and contrast CT scan of the chest (to look for microthromboembolism), along with an ophthalmologic examination (to assess for immune-related pathology, such as retinitis or uveitis, as well as for thrombi).

Dr Wilkerson, what is the expectant medical management in a patient with myocarditis with possibility of deterioration of ventricular function and CHF?

In any child with a suspicion for myocarditis, close monitoring for symptoms and signs of CHF is essential. Signs and symptoms, including increase in work of breathing, edema, hepatomegaly, crackles on lung auscultation, jugular venous distention, progressive tachycardia, and gallop rhythm on cardiac auscultation. In children with CHF, aggressive fluid resuscitation might lead to decreased cardiac output and cardiovascular collapse. Therefore, IV fluids should be given judiciously with continuous clinical and hemodynamic monitoring. One may consider administering a diuretic during or after transfusions to prevent the adverse effects of fluid overload. During the acute phase of myocarditis, sinus rhythm should be maintained, and when accompanied with decreased ventricular function, epinephrine is a good choice for inotropic support because it supports cardiac function by increasing contractility. Patients with CHF and increased systemic vascular resistance may benefit from having epinephrine paired with milrinone, an afterload-reducing agent with inotropic properties. However, use of inotropic support must be balanced with the cost of increase in myocardial oxygen consumption; therefore, judicious use is recommended.

On hospital day (HD) 2, he appeared to have mild clinical improvement with weaning of inotropic support and cardiac enzymes down trended. He had a normal eye examination.

However, on HD 3 and HD 4, he had clinical worsening with persistence of fever, hypotensive episodes, chest pain, and first-degree heart block with intermittent episodes of junctional escape, with a heart rate of 70 beats per minute. His cultures and retesting for SARS-CoV-2 by PCR were negative. His coagulation parameters (D-dimer and fibrinogen) remained abnormal. A CXR was repeated and suggestive of fluid overload, needing treatment with diuretics; however, the echocardiogram revealed normal function. Because of the presence of chest pain and abnormal coagulation, a chest CT scan was done and was negative for thrombus. Vancomycin, acyclovir, and clindamycin were discontinued. His inflammatory markers continued to rise despite antimicrobial therapy.

Dr Logan, is there a role for empirically treating COVID-19 infection despite testing negative? What other testing would you recommend?

At present, there is no role for empirical therapy for the treatment of COVID-19 infection in children who do not fit the criteria as defined by Pediatric Infectious Disease Society guidelines.¹  This presentation, however, is similar to the recent reports suggesting a multisystem inflammatory syndrome in children (MIS-C) secondary to exposure to SARS-CoV-2, and children can test negative for acute COVID-19 infection (ie, by antigen or real-time PCR). The thought is that it is more consistent with a delayed hyperinflammatory response syndrome. If available, antibody testing against SARS-CoV-2 should be performed because many children thus far with MIS-C have also been positive for SARS-CoV-2 antibodies. The history of his parental contact with an individual with an influenza-like illness and the patient’s symptomatology of fever, cough, and anosmia before the onset of this illness ∼4 weeks before presentation again suggests this possibility.

Other testing, especially antibody tests should be done before the initiation of intravenous immunoglobulin (IVIG), a treatment used for many severe systemic inflammatory conditions, including MIS-C. Such tests, depending on exposure history, include antistreptolysin O and anti-DNAse B (for acute rheumatic fever); Mycoplasma, Lyme, Rickettsia, Bartonella, or Toxoplasma antibodies; and blood smear for parasites, with any relevant travel history. In view of starting immunosuppressive or immunomodulating agents, testing for Mycobacterium tuberculosis should be performed (ie, interferon-γ release assays). Further testing for noninfectious etiologies include an autoimmune panel; T-cell, B-cell, and natural killer cell subsets; laboratory tests for hemophagocytic lymphohistiocytosis and thyrotoxicosis; and toxicology screening.

Additional workup was sent to search for any other etiologies. Dr Sosnowski, what are the diagnostic modalities that can help to confirm the diagnosis of myocarditis?

Cardiac enzymes, CXR, ECG, and echocardiogram can act as supportive diagnostic measures for detecting myocarditis. Elevated cardiac enzymes are suggestive of myocardial injury possibly secondary to viral invasion or can be due to trauma, toxins, ischemia, or infarction. CXR is usually normal but can reveal cardiomegaly in the setting of CHF or myocardial edema. ECG changes can be seen if the conducting myocardium is affected. Echocardiogram can reveal patchy or global dysfunction (systolic more than diastolic) of the ventricles (LV more than the right ventricle). However, none of these measures confirms the presence of myocarditis because the diagnosis is largely clinical or often one of “presumed myocarditis.”

Cardiac MRI has evolved as the preferred diagnostic modality for confirming myocardial inflammation. Although an endomyocardial biopsy remains the gold standard confirmatory test, MRI has become increasingly used because it is a noninvasive diagnostic test with comparable sensitivity and specificity. In cardiac MRI, signs of active inflammation (myocardial hyperemia and edema) and signs of irreversible damage (infarction and necrosis) can be detected and localized. Because he has persistent rhythm abnormalities, a Holter monitor would help in better characterizing the origin, pattern, and burden of arrhythmias.

What are the treatment modalities available for the treatment of myocarditis in children?

The only proven treatment of myocarditis in children is supportive care. However, immunomodulatory therapies, such as steroids and IVIG are often used in many centers, especially in the setting of rhythm disturbances, although the data are limited as to their overall benefit in the setting of myocarditis.

The patient was started on IVIG (2 g/kg) on HD 3 and HD 4 for myocarditis.

He showed clinical improvement during the rest of his hospitalization and remained afebrile and normotensive without inotropic support, and his cardiac enzymes normalized. He was noted to have developed neutropenia on HD 7. He continued to have ECG changes with intermittent ventricular escape rhythm (Fig 2). A cardiac MRI confirmed the diagnosis of myocarditis (Fig 3).

Dr Logan, although the patient recovered well from the illness, he developed neutropenia. What are the causes of neutropenia in an adolescent with a history of fever who has received multiple antibiotics and IVIG?

A viral infection leading to myelosuppression is a common cause of leukopenia. He also received multiple mediations, including acyclovir and antibiotics, some of which can cause neutropenia. IVIG recipients can also develop leukopenia. Headaches and anaphylactic reactions may additionally occur from IVIG. A detailed history for recurrent and/or familial neutropenia should be undertaken. Close follow-up with repeat testing after resolution of illness is useful.

The patient was discharged on HD 8 after demonstrating significant clinical improvement. He was advised to closely follow-up with infectious diseases and cardiology. He was counseled to refrain from any competitive sports and/or exercise for 6 months because of myocarditis and ongoing arrhythmia. A day after his discharge from the hospital, serology for Mycoplasma antibodies returned positive, with significantly elevated immunoglobulin (Ig) M titers (1756 U/mL, reference <770) and low-positive IgG titers (1.1 Index, reference <0.91).

Dr Logan, can you comment on the Mycoplasma serology results and the relation to his illness?

M pneumoniae is a well-known cause of atypical pneumonia in older children (aged >5 years) and adults. However, although not common, it can cause extrapulmonary manifestations, which are more common in children than in adults. M pneumoniae is a rare but described cause of myocarditis in children and may be associated with pneumonia and pleural effusion. The treatment of acute M pneumoniae infection is with azithromycin and, secondarily, fluoroquinolones or doxycycline; however, in the case of extrapulmonary disease, the illness may be due to an immune response to M pneumoniae, and therefore antibiotics may not be efficacious. Additionally, there is concern for the reliability of the Mycoplasma antibody testing, and to this day, it proves difficult to know if such results are causal. However, the level of positivity of IgM testing, in conjunction with timing and presentation, was concerning for this possibility, and there was an inability to complete reliable follow-up testing because of IVIG initiation for myocarditis. There have also been reports of coinfections in SARS-CoV-2, including M pneumoniae in children.

He was treated with doxycycline for Mycoplasma infection. Macrolides and fluoroquinolones were avoided because of ongoing arrhythmia. He continues to be free of any symptoms, and his neutropenia had improved with mild decrease at the 2-week follow-up. His ECG changes, although hemodynamically insignificant, continue to be present, and he is being followed-up long-term by a cardiac electrophysiologist. His cardiac MRI ∼2.5 months after his presentation revealed complete resolution of myocarditis.

M pneumoniae classically causes community-acquired pneumonia in school-aged children, adolescents, and adults. M pneumoniae lacks a cell wall and is notoriously difficult to culture. Diagnosis is typically obtained by PCR or by detection of antibodies in the serum. Treatment considerations include macrolides or tetracyclines because antibiotics that target the cell wall are ineffective.²  However, increasing resistance patterns to macrolides have been described.^3,4 

Extrapulmonary manifestations in M pneumoniae include cardiac, gastrointestinal, hepatic, pancreatic, skin (ie, erythema multiforme and Stevens-Johnson syndrome), musculoskeletal (ie, arthritis and arthralgia), neurologic, and hematologic syndromes.^5–7  Extrapulmonary manifestations can occur in up to 25% of infected patients, and the time to presentation is variable.⁸  Differences include that pulmonary manifestations are believed most often a result of active infection, whereas extrapulmonary manifestations might be secondary to an immune response. However, acute severe increases in proinflammatory cytokines and hyperimmune response syndromes (eg, hemophagocytic lymphohistocystosis and macrophage activation syndrome) have been described in association with both pneumonia and extrapulmonary manifestations of M pneumoniae.^7,9–11  Extrapulmonary manifestations of M pneumoniae have been associated with increases in serum IgE⁶  or may be the result of molecular mimicry and/or increases in inflammatory mediators and/or cascades, including interleukin (IL)-1, IL-2, IL-6, interferon-α, and tumor necrosis factor-α.^6,8 

The cardiac manifestations of illness are rare (1%–8.5%)⁸  but include pericarditis, myocarditis, and conduction abnormalities. Cardiac symptoms may be the primary presenting symptom and may present with or without concomitant respiratory symptoms. Related cardiac complications after M pneumoniae myocarditis include complete atrioventricular block.¹² 

The pathophysiology of cardiac manifestations remains unclear; however, age-specific differences in immune response to infection, including increased levels of circulating immune complex and better-developed humoral and cell-mediated immune systems that can influence end-organ damage, may contribute to increased disease in older children.⁸  T-cell immunoglobulin and mucin domain 1 titers were found to be elevated in studies of children with M pneumoniae and correlated with elevated cardiac enzymes, suggesting their importance in the pathogenesis of cardiac complications in M pneumoniae.¹³  Vascular manifestations involving the cardiac structures have also been reported, mainly occurring in the form of thrombi formation noted in aorta as well as cardiac chambers. This is in association with a hypercoagulable state mediated by antiphospholipid antibodies and has been found to most often fully resolve after the illness subsides.¹⁴  A timely, full recovery is the most common outcome; however, long-term sequelae have been described.^2,3 

Although M pneumoniae was identified as the cause of this patient’s illness, it is important to discuss MIS-C. Because the patient presented during the height of the COVID-19 pandemic, the M pneumoniae result was not available until after discharge, and management of MIS-C would be a consideration in the absence of alternative diagnoses.

In late April 2020, cases from the United Kingdom found evidence of a new MIS-C thought to be potentially related to SARS-CoV-2 infection. Noted in a report from England, there were 8 cases in previously healthy children in a short span of 10 days in the United Kingdom.¹⁵  Most common cardiovascular involvement was myocarditis with elevated cardiac enzymes and varying degrees of LV dysfunction. All patients presented with fluid-refractory shock requiring inotropes, with 1 reported death.

Since then, multiple cases have been reported in the United States with similar presentation that led to the Centers for Disease Control and Prevention releasing a health advisory and creating a case definition, which in summary is an individual aged ≤21 years presenting with fever for ≥24 hours, laboratory evidence of inflammation, and evidence of clinically severe illness requiring hospitalization, with multisystem (≥2) organ involvement and no alternate plausible diagnosis and positive for current or recent SARS-CoV-2 infection or exposure to a suspected or confirmed COVID-19 case ≤4 weeks before symptom onset.^16,17 

Feldstein et al¹⁸  reported 186 children with MIS-C from 26 states in the United States between March 15 and May 20, 2020, with gastrointestinal, cardiovascular, and respiratory involvement noted in 92%, 80%, and 70% of the cases, respectively. Although 80% were admitted in the ICU, the total mortality in the cohort was low (2%). This was followed by another report including 570 MIS-C patients from >40 states from March 2 to July 18, 2020. Cardiac complications noted were cardiac dysfunction (40%), shock (35%), myocarditis (23%), and coronary abnormalities (18%).¹⁹ 

Currently, although still relatively rare overall, compared with the number of COVID-19 infections in US children (476, 439 cases), ∼800 cases of MIS-C have been reported in the United States as of November 2020, with a mortality rate of 2.02%.^20,21  The available data suggest that a history of COVID-19 infection, whether symptomatic or asymptomatic, is associated with delayed onset of this hyperinflammatory syndrome. MIS-C overlaps with features similar to Kawasaki Shock Syndrome (KSS), TSS, hemophagocytic lymphohistiocytosis, and macrophage activation syndrome, and some children have required mechanical ventilation and/or extracorporeal membrane oxygenation.²² 

In an editorial commentary, Shulman²³  proposed that MIS-C syndrome is distinctive from Kawasaki disease (KD) for the following reasons: the affected age group is older (mean age 8–10 years), whereas KSS is relatively uncommon and KD and/or KSS is more common in younger patients aged <5 years. Moreover, this syndrome has not been a significant illness in children in China, Japan, or other Asian nations in which KD is more prevalent, again suggesting a different origin. Acute kidney injury and significant abdominal symptoms are common in MIS-C but not typically seen in KD. Laboratory evidence of myocardial involvement and injury (increased pro–brain-type natriuretic peptide [BNP], BNP, and troponin) are present in MIS-C, whereas KD more commonly presents with coronary artery involvement mostly without elevations in cardiac enzymes.²⁴ 

The clinical picture of MIS-C reported in children is similar in many respects to our patient. Although M pneumoniae is the infectious reason for the illness in our patient, it is important to note that there have been cases described of COVID-19 coinfection with M pneumoniae.²⁵  MIS-C, however, is a diagnosis of exclusion.¹⁵  Because the M pneumoniae titers were not available during hospitalization, MIS-C would remain in the differential, and treatment of MIS-C would be considered. At the time of our patient’s presentation, MIS-C was only initially being described, and antibody (serology) testing for COVID-19 was not routinely available.

In the reported cases of MIS-C, IVIG with or without steroids is revealed to be of benefit, suggesting modulation of cytokine activation plays a key role in treatment. There has been evidence that use of other immunomodulators, such as anakinra (IL-1 blockade), tociluzumab (IL-6 blockade), and infliximab (tumor necrosis factor blockade), as well as anticoagulation, improves outcomes in MIS-C.^20,26  More research is needed to better understand the most beneficial therapy and long-term outcomes in MIS-C.

Our case was a diagnostic challenge describing a previously healthy adolescent who presented with a severe acute illness with a broad differential, including MIS-C, and required close monitoring in the ICU and treatment of shock and acute myocarditis. At the time of his presentation, COVID-19 antibody testing was not reliably available. However, an extensive diagnostic workup revealed a recent M pneumoniae infection, a known but uncommon cause of acute myocarditis. The M pneumoniae antibody results were not available until after the patient was discharged, leaving the diagnosis unknown during the time of hospitalization. The etiology of shock and acute myocarditis includes a broad differential, and a high index of suspicion is necessary to diagnosis rare but important infectious and noninfectious causes of illness.

We thank Dr Keyur Parekh for his expert advice and contribution in acquiring the cardiac MRI study images.

BNP

brain-type natriuretic peptide

CBC

complete blood count

CHF

congestive heart failure

COVID-19

coronavirus disease 2019

CT

computed tomography

CXR

chest radiograph

ECG

electrocardiogram

HD

hospital day

KD

Kawasaki disease

KSS

Kawasaki Shock Syndrome

LV

left ventricle

Ig

immunoglobulin

IL

interleukin

IV

intravenous

IVIG

intravenous immunoglobulin

MIS-C

multisystem inflammatory syndrome in children

PCR

polymerase chain reaction

SARS-CoV-2

severe acute respiratory syndrome coronavirus 2

TSS

toxic shock syndrome