Management of Idiopathic Viral Pericarditis in the Pediatric Population

Abstract

Idiopathic (viral) pericarditis (IP) is one of the most common etiologies of acute and recurrent pericarditis in children. IP is associated with significant morbidity, and recurrence rates of IP are high and require treatment to decrease risk of recurrence and pericarditis-related chest pain. Despite significant morbidity, sparse guidance exists to comprehensively address management of IP in children. The purpose of this review is to provide an overview of the pharmacotherapy of IP in children, including clinical pearls for managing pediatric patients. Clinicians should consider using the combination of colchicine and nonsteroidal anti-inflammatory drugs (NSAIDs) as first-line therapy, in order to reduce the risk of recurrence and foster symptom improvement in IP. Colchicine dosing may vary depending on patient age, weight, concomitant pharmacotherapies, and disease states. Choice of NSAID should be based on cost, tolerability, and adverse drug events (ADEs). Children should receive higher NSAID attack dosing for >1 week to ensure a reduction in high sensitivity C-reactive protein concentrations and symptom relief. Corticosteroids should be considered last-line for treatment of IP in children, because they increase the risk of recurrence. Immunotherapies may be considered for children with multiple recurrences related to IP despite the use of NSAIDs, colchicine, and/or corticosteroids. Similar to adults, diligent monitoring should be implemented, to prevent drug-drug interactions, drug-disease interactions, and/or ADEs in children.

Introduction

Pericarditis is an inflammatory disease that affects the pericardium, a double-layered sac that envelops the heart.¹ The pericardium functions to lubricate the heart during systole and diastole, provides defense against infection, and secures the heart to the mediastinum.¹ Within the spectrum of pericardial diseases, acute and recurrent pericarditis are most commonly encountered in clinical practice.¹ The inflammation causing pericarditis is associated with morbidity specifically in the form of incessant pericarditis, recurrent pericarditis, constrictive pericarditis, and cardiac tamponade (Table 1).^1–3 Recurrent pericarditis is defined as recurrence of pericarditis after a documented first episode of acute pericarditis, and a symptom-free interval of ≥4 to 6 weeks. Recurrence of pericarditis occurs commonly in children, noted in upwards of 40% of patients.^4,5 Compared with adults diagnosed with pericarditis, children have more inflammatory-related disease involvement, such as a higher incidence of fever or pleuropulmonary issues, and are more likely to have elevated C-reactive protein (CRP) concentrations, erythrocyte sedimentation rate, and leukocyte count. Pericarditis is usually diagnosed by documenting 2 of the 4 following criteria: pericarditis chest pain; electrocardiogram (ECG) changes consisting of PR-segment depression and/or ST-segment elevation; new or worsening pericardial effusion; and pericardial friction rub upon auscultation.¹ Cardiac magnetic resonance and computed tomography can also be used to detect pericardial inflammation.¹ Pharmacotherapy plays a vital role in preventing recurrence of pericarditis, especially within the context of idiopathic or viral etiologies of acute and recurrent pericarditis—the most common etiologies.^6–11 However, the landmark studies of patients with idiopathic or viral etiologies of acute and recurrent pericarditis include mostly adults. Much less has been elucidated regarding the treatment of pericarditis in children. While the European Society of Cardiology (ESC) published guideline recommendations for the management of pericarditis, including recommendations for children, it is apparent that there is a paucity of evidence regarding pericarditis treatment in children.¹ Table 2 provides a summary of the key recommendations for pediatric patients from the 2015 ESC guidelines for the diagnosis and management of pericardial diseases.¹ Additionally, there are limited comprehensive pharmacotherapy reviews regarding pediatric-specific considerations.¹² This article will review the pharmacotherapy of idiopathic (viral) pericarditis (IP), including clinical pearls specific to the care of children.

Table 1.

Overview of Different Clinical Manifestations of Pericarditis^3,11

Manifestation	Definition
Acute pericarditis	First episode of pericarditis
	Diagnostic criteria include: Chest pain (i.e., sharp pleuritic pain on inspiration that may radiate to shoulders) ECG changes (e.g., ST-segment elevation or PR-segment depression) New or worsening pericardial effusion (i.e., documented by transthoracic echocardiogram) to explore presence and severity of pericardial effusion and chest radiography Pericardial friction rub on auscultation
Incessant pericarditis	Defined as persistent symptoms of pericarditis without a precise remission after acute episode
Recurrent pericarditis	Defined as additional episode of pericarditis that occurs >6 wk after remission of symptoms
Constrictive pericarditis	Defined as pericarditis with chronic inflammation leading to inelasticity and scaring of the pericardium, leading to impaired ventricular diastolic filing
	Most likely associated with identifiable causes of pericarditis (e.g., infectious and non-infectious causes) and rarely associated with idiopathic pericarditis
Cardiac tamponade	Life-threatening condition associated with compression of pericardial accumulation of fluid, pus, blood clots, or gas
	Most likely associated with identifiable causes of pericarditis (e.g., infectious and non-infectious causes) and rarely associated with idiopathic pericarditis
	Associated with increased mortality and poor prognosis in patients with pericarditis

ECG, electrocardiogram

Table 2.

Summary of Key Recommendations for Pediatric Patients for Acute and Recurrent Pericarditis From the 2015 European Society of Cardiology¹

Line in Therapy	Agents	Recommendations	Class of Recommendation*	Level of Evidence†
First line	NSAIDs	Large-dose NSAIDs are recommended as first-line therapy for acute pericarditis until symptom resolution	I	C
		Aspirin is not recommended in children <12 yr of age owing to risk of Reye syndrome and hepatotoxicity	III	C
	Colchicine	Colchicine is recommended as an adjunct to NSAIDs for acute or recurrent pericarditis in children	IIa	C
Alternative agents	Corticosteroids	Corticosteroids are not recommended for first-line therapy for pericarditis in light of adverse events	III	C
		Small-dose corticosteroids could be considered for treatment of refractory pericarditis in patients receiving NSAIDs and colchicine or in a patient who does not tolerate or with a contraindication to NSAIDs and colchicine	IIa	C
	Anti–IL-1 agents	These agents may be considered in children with recurrent pericarditis who are considered corticosteroid dependent	IIb	C

IL-1; interleukin 1; NSAIDs, non-steroidal anti-inflammatory drugs

^* Class of recommendations used in the 2015 European Society of Cardiology include class I defined as evidence and/or general agreement that a given treatment or procedure is beneficial, useful, effective; class II defined as conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of the given treatment or procedure; class IIa defined as weight of evidence/opinion is in favor of usefulness/efficacy; class IIb defined as usefulness/efficacy is less well established by evidence/opinion; and class III defined as evidence or general agreement that the given treatment or procedure is not useful/effective, and in some cases may be harmful.

^† Level of evidence defined by the 2015 European Society of Cardiology includes level of evidence A defined as data derived from multiple randomized clinical trials or meta-analyses; level of evidence B defined as data derived from a single randomized clinical trial or large non-randomized studies; and level of evidence C defined as consensus of opinion of the experts and/or small studies, retrospective studies, registries.

Pharmacotherapy for Idiopathic Pericarditis in Children

Pharmacotherapy is a mainstay in the management of IP and is aimed at ameliorating the inflammatory sequelae that cause the signs and symptoms of pericarditis. Several inflammatory mechanisms of disease are involved, including the NLRP3 (NACHT, leucinerich repeat, and pyrin domain-containing protein 3) inflammasome, which is an intracellular complex that detects stress or injury and triggers a local and systemic inflammatory response, as well as the cyclooxygenase system, acute phase proteins (i.e., CRP), and cytokines (e.g., interleukins).¹³ Therefore, drug therapy is aimed at using relatively large doses or “attack doses,” in order to achieve swifter symptom control either in response to the drugs' pharmacokinetics and/or pharmacodynamics, including aspirin (ASA), non-steroidal anti-inflammatory drugs (NSAIDs), colchicine, corticosteroids, and some of the immunotherapies. Pharmacotherapy appears to have the most significant effect on incidence of recurrence in patients with IP, as the incidence of recurrent pericarditis can be upwards of 50% of patients who are treated inappropriately.^1,2,4–8 Five landmark studies in adults with acute or recurrent IP have shown that combination therapy with anti-inflammatory therapy (NSAID or ASA) plus colchicine decreases the risk of recurrence when compared with an NSAID or ASA alone.^2,4–7 Recurrence of pericarditis can potentially lead to serious complications such as constrictive pericarditis and/or cardiac tamponade, albeit rarely.¹ Relative to adults, there are limited publications reviewing the safety and efficacy of pharmacotherapy in children with IP. Much of the treatment recommendations are extrapolated from adult data, making it prudent for clinicians to consider potential differences in treating IP in children. Furthermore, treatment regimens within the pediatric population are based on patient age, drug-drug and disease interactions, access to care, and tolerability. The following sections will review safety and efficacy of the pharmacotherapy used to treat children with IP.

Non-steroidal Anti-inflammatory Drugs. NSAIDs remain one of the most commonly used agents in children with pericarditis.¹⁰ NSAIDs are hypothesized to decrease pericarditic pain associated with inflammation by inhibiting prostaglandin production. The 2015 ESC guidelines provide a class I level C recommendation for large-dose NSAIDs for pericarditis in children (Table 2).¹ Ibuprofen and indomethacin are the most studied agents within the adult landmark studies, with limited case reports and cohort studies using naproxen and ketorolac.¹⁴ In the landmark adult studies, compared with NSAID monotherapy, the combination of colchicine in addition to NSAIDs significantly increases the symptom-free interval and provides symptomatic improvement within 72 hours of treatment initiation.^2,4–7 The combination also decreases incessancy, prolongs time to subsequent recurrence, reduces pericarditis-related hospitalization rates, and improves remission rates at 1 week, especially in patients with multiple recurrences.^2,4–7 Even though ASA has been recommended for the management of IP in adults, it is not recommended in children <12 years owing to the relative contraindication risk of Reye syndrome, and therefore is a class III level C recommendation for children in the 2015 ESC guidelines (Table 2).^1,15,16 Owing to the paucity of data in children, and given there are no randomized controlled trials comparing the efficacy among NSAIDs, clinicians should choose an NSAID by basing their decision on their degree of familiarity, accessibility, and available dosage forms.¹⁴ Table 3 provides an overview of dosing, dosage forms, and clinical pearls. For children with pericarditis who may not be tolerating enteral medications, intravenous (IV) ketorolac could be considered for the acute and short-term management of pain associated with pericarditis in patients who are hospitalized. While there have been no published randomized controlled trials showing that ASA or NSAIDs mitigate the disease process of pericarditis, failure to respond to an NSAID therapy within 7 days is associated with a relatively poorer prognosis in patients with pericarditis.¹⁷ Additionally, NSAIDs are beneficial in pericarditis because they blunt the inflammatory pathway related to CRP.¹⁸ In a study involving 2 institutions in Italy, 200 patients with acute IP were stratified by elevated high-sensitivity (hs)–CRP concentrations. All patients were treated with ASA, indomethacin, or ibuprofen with gradual taper; colchicine was added at the discretion of their physician. An hs-CRP concentration in blood was obtained at presentation and then every week for 4 weeks until normalization. At presentation, approximately 22% of patients had a normal hs-CRP finding. After 1 week of treatment, only 60% of patients had a negative hs-CRP finding . By week 2, approximately 85% of patients had a negative hs-CRP finding, with complete resolution by week 4 for all patients. This study revealed that incomplete response to NSAID therapy after week 1 was an independent risk factor for recurrence. Ultimately, this study underscored the importance of potentially extending the attack dose of NSAIDs until normalization of hs-CRP concentration following the additional treatment course, especially in patients with a history of recurrence.¹⁸ Moreover, after multinomial logistic regression, a CRP concentration ≥125 mg/L was determined to be an independent risk factor for recurrence in children with pericarditis.¹⁹

Table 3.

Dosing, Monitoring, and Clinical Pearls for NSAIDs for Idiopathic Pericarditis in Children^{1,10,12–14,19}

Medication	Dosing	Recommendations for Tapering	ADEs	Monitoring*	Clinical Pearls
Ibuprofen	2015 ESC guideline recommendations: 10–16 mg/kg/dose every 8 hr PO (maximum 600 mg/dose or 1.8 g/day)	Decrease dose every 1–2 wk by 2 mg/kg/dose every 8 hr; discontinue once at 4 mg/kg/dose every 8 hr	GI irritation Bleeding AKI Thrombocytopenia CNS-related symptoms	SCr assessment CBC with differential Assess for neurologic symptoms (headache, dizziness, confusion)	Agent most likely to be used owing to familiarity in pediatrics and availability OTC Available as 20- and 40-mg/mL oral suspension
Indomethacin	2015 ESC guideline recommendations: Children >2 yr—0.25–1 mg/kg/dose every 6–12 hr PO (maximum 50 mg/dose or 150 mg/day)	Decrease dose every 1–2 wk by 0.25 mg/kg/dose every 6–12 hr; discontinue once at 0.25 mg/kg/dose every 12 hr	Same as ibuprofen above	Same as ibuprofen above	Only available with a prescription Available as 5-mg/mL oral suspension Associated with increased risk of neurologic ADEs
Naproxen	2015 ESC guideline recommendations: Children >2 yr—5–7.5 mg/kg/dose every 12 hr PO (or (maximum 500 mg/dose or 1 g/day)	Decrease dose every 1–2 wk by 2.5 mg/kg/dose every 12 hr; discontinue once at 2.5 mg/kg/dose every 12 hr	Same as ibuprofen above	Same as ibuprofen above	Available as 25-mg/mL oral suspension Oral tablet available OTC; oral suspension only available by prescription
Ketorolac	Dosing for children 2–16 yr of age or <50 kg: 0.5 mg/kg/dose IV q6h (maximum 15 mg/dose or 60 mg/day) for <5 days IV >17 yr of age or >50 kg: 30 mg IV q6h (maximum 120 mg/day) for <5 days IV	Not applicable	Same as ibuprofen above	Same as ibuprofen above	Associated with black-box warning for >5 days of scheduled use
ASA	Not routinely recommended owing to risk of Reye syndrome	Not applicable	Not applicable	Not applicable	Recommend to generally avoid or use with caution in children <12 yr of age owing to the association with Reye syndrome

ADE , adverse drug event; AKI, acute kidney injury; ASA, aspirin; CBC, complete blood count; CNS, central nervous system; ESC, European Society of Cardiology; GI, gastrointestinal; IV, intravenous; OTC, over the counter; SCr, serum creatinine

* Frequency of monitoring is dependent on the patient's clinical status.

Pharmacovigilance should be implemented in preventing NSAID-related adverse drug events (ADEs). All NSAIDs are associated with inhibition of platelet aggregation.¹⁴ This may result in risk for significant bleeding or bruising associated with the larger doses of NSAIDs required to treat pericarditis. Therefore, clinicians should follow complete blood cell counts on a routine basis and monitor for clinical signs of bleeding and/or bruising. In addition, children may be at increased risk of gastrointestinal (GI) bleeding due to diminished protective prostaglandin formation in the stomach. As a result, NSAIDs may result in an increased incidence of GI bleeding, ulceration, and/or perforation.¹⁵ Ketorolac is associated with increased risk of GI-related ADEs and has an US FDA (Food and Drug Administration (FDA) black-box warning for use >5 days.¹⁵ Subsequently, the 2015 ESC guidelines recommend that patients treated with NSAIDs should also receive a gastroprotective agent to prevent GI injury.¹ Previous landmark trials in adults, evaluating the use of colchicine with NSAIDs, used omeprazole.¹⁴ However, the choice of a gastroprotective agent may not be as straightforward in children. Reveiz and colleagues²⁰ conducted a systematic review of the use of proton pump inhibitors, histamine-2 receptor antagonists (H₂RAs), and sucralfate in critically ill children and found no difference in GI bleeding rates between agents. Therefore, it may be reasonable to consider the use of an H₂RA such as famotidine or a proton pump inhibitor for children receiving large-dose NSAIDs for IP.

Use of NSAIDs for IP could also increase the risk for a prerenal injury, potentiating the possibility of an acute kidney injury (AKI), acute interstitial nephritis, and/or acute renal papillary necrosis.^14,15 Consequently, children with pericarditis and a history of chronic kidney disease should receive NSAIDs with extreme caution. Owing to diminished glomerular filtration activity, NSAIDs should altogether be avoided in children with pericarditis who are younger than 6 months.¹⁵ With the relatively large doses of NSAIDs needed for pericarditis, clinicians should use strategies for preventing drug-induced AKI, including screening medications for concomitant nephrotoxicity on a daily basis, and ensuring adequate hydration with NSAID use.¹⁵ In addition, children with pericarditis, receiving large-dose NSAIDs during the initial treatment phase, require regular monitoring of renal function in the hospital, including assessing serum creatinine concentrations 2 to 3 times per week along with daily monitoring of urine output. NSAIDs may also be associated with cardiovascular, pulmonary, and neurologic complications. From a cardiac perspective, they have been associated with fluid retention and edema, especially in adults with congestive heart failure and cardiac decompensation. However, this finding may not be as problematic in children. Moffett and colleagues²¹ evaluated the use of IV ketorolac in 53 children after cardiac surgery and noted no significant complications secondary to increased fluid retention. NSAIDs are also associated with the development of neurologic manifestations including headaches, nystagmus, seizures, and coma. Among the NSAIDs used for pericarditis, indomethacin may be associated with the highest risk of neurologic manifestations, potentially exacerbating underlying psychiatric disturbances.¹⁴ Clinicians should discontinue NSAIDs in patients with significant neurologic manifestations, though it should be noted that these symptoms may be hard to assess in young children who may not be able to articulate some of these neurologic complications. Children with a history of asthma may develop an increased risk of asthma exacerbation due to an increase in leukotriene production.¹⁵ With the low prevalence of NSAID intolerance, this should not be considered a contraindication in children with asthma and IP, but clinicians should use close monitoring for worsening asthma symptoms.

Colchicine. Colchicine is postulated to ameliorate the inflammatory sequelae of pericarditis by inhibiting the activation of the NLRP3 inflammasome, which is involved in releasing the proinflammatory cytokine interleukin 1 (IL-1). Interleukin 1 is then responsible for recruiting neutrophils and macrophages to the site of injury.¹³ Colchicine is also thought to inhibit the inflammatory cascade by inhibiting the assembly of the mitotic spindle, essentially stopping mitosis at metaphase. Currently, the 2015 ESC guidelines provide a class IIa, level C recommendation for using colchicine as an adjunct to NSAID therapy in children with acute or recurrent pericarditis (Table 2).¹ At the time of writing, this lower class and level of recommendation was most likely due to the conflicting and relatively weak data that are available surrounding the use of colchicine for the management of pericarditis in children. However, since then, more data have been published that may support the use of colchicine in managing pericarditis in children. In a cohort of 110 Italian children diagnosed with acute and recurrent IP (median age, 13 years), colchicine was administered as an adjuvant agent in 61.8% of patients. The median number of recurrences decreased from 3.74 per year prior to initiation of colchicine to 1.37 per year after colchicine administration (p < 0.05) in patients receiving colchicine as part of adjuvant therapy.²² Another recent cohort study showed that colchicine was associated with a lower recurrence rate than when treated without colchicine.²³ Despite a potential decrease in risk of recurrence, a retrospective analysis of a multicenter database of pediatric hospitals in the United States revealed that colchicine use in children with pericarditis may not be as prevalent.¹⁰ Only 2.9% of the participating hospitals noted that children presumed to have idiopathic or viral etiologies of pericarditis received the combination of NSAID plus colchicine upon index admission.

Currently, colchicine does not have a FDA–labeled indication for pericarditis in adults or children and is used as an off-label therapy. Attack dosing of colchicine is usually 1.0 to 2.0 mg/day, and maintenance dosing ranges from 0.5 to 1.0 mg/day in children 6.5 to 16.8 years with IP.^22,24 The 2015 ESC guidelines specifically recommend colchicine at a dose of 0.5 mg/day in patients <5 years, and 1.0 to 1.5 mg/day in 2 to 3 divided doses in patients >5 years.¹ However, compared with landmark studies involving the adult population, the 2015 ESC guideline recommendations for colchicine in children are based on relatively weak data. The recommendations are also not representative of US demographics, or colchicine formulations available in the United States. In the United States, the scored 0.6-mg tablet formulation has an FDA-labeled indication for children ≥4 years for the treatment of familial Mediterranean fever (FMF).²⁵

Colchicine dose recommendations are provided in Table 4. For children >40 kg, adult dosing may be considered.^2–7 The pharmacokinetics of colchicine in children differ depending on the child's age. Berkun et al²⁶ conducted a pharmacokinetic study of children and adults with FMF who were receiving colchicine. In this study, they compared the pharmacokinetic parameters of 5 different age groups with different initial doses of colchicines, including >2 to <4 years (0.6 mg/day), >4 to <6 years (0.9 mg/day), >6 to <12 years (0.9 mg/day), >12 to <16 years (1.2 mg/day), and >16 to <65 years (1.2 mg/day). The investigators noted similar pharmacokinetic parameters for these different groups, with the exception of higher concentration maximum and area under the curve (AUC_0–24 hr) for children 4 to <6 years of age versus children <4 years of age and the older age groups. From these findings, they recommended children <6 years should receive 0.6 mg/day of colchicine (Table 4).²⁶ Treatment with colchicine for children with IP should be for 3 months in acute IP and 6 months for recurrent IP.^3,7 Overall, clinicians should be cautious when applying US formulations for dosing owing to colchicine's narrow therapeutic index, increasing the risk for ADEs, which are reviewed below.¹¹ In the United States, the capsule or liquid formulations of colchicine do not have an FDA-labeled indication in children.^25,27 For children who have difficulty swallowing tablets, the tablet formulation may be split; the manufacturer does not have any information available regarding whether or not crushing the tablet formulation is appropriate. The commercially available oral solution is available as a 0.6 mg/5 mL solution and can be used in place of the tablet formulation.²⁷ However, the maximum daily dose for the oral solution is 1.2 mg/day, and the current formulation is not available generically, making cost an important consideration.

Table 4.

Dosing, Monitoring, and Clinical Pearls for Colchicine for Idiopathic Pericarditis in Children^{1,10,16,25,26}

Dosing	Recommendations for Tapering	ADEs	Monitoring*	Clinical Pearls
2015 ESC guideline dosing recommendations: 0.5 mg/day PO in patients <5 yr† 1.0–1.5 mg/day PO in 2 to 3 divided doses, in patients >5 yr† Manufacturer (tablet) package insert recommendations20: 4 to 6 yr: 0.3–1.8 mg daily in 1–2 divided doses 6 to 12 yr: 0.9–1.8 mg daily in 1–2 divided doses >12 yr: Refer to adult dosing Alternative colchicine dosing recommendations for US formulation, based on available pharmacokinetic/pharmacodynamic studies21‡: 2–6 yr old: 0.6 mg/day† may use 0.3 mg/day in children 4–5 yr of age, as AUC was 25% higher than those observed in adults ≥6 to <12 yr of age: 0.9 mg/day ≥12 yr of age: 1.2 mg/day	Tapering of colchicine is not often used in clinical practice	GI-related Blood dyscrasias Neuropathy Rhabdomyolysis	SCr LFTs CBC with differential CPK	Twice daily dosing may be preferred Dose adjust in renal/hepatic impairment Drug interactions: metabolized by CYP 3A4; eliminated through p-gp Chronic use may result in cyanocobalamin deficiency Avoid grapefruit juice Maximum dose of oral solution is 1.2 mg/day

ADE, adverse drug event; AUC, area under the curve; CBC, complete blood count; CPK, creatine phosphokinase; CYP, cytochrome; ESC, European Society of Cardiology; GI, gastrointestinal; LFTs, liver function tests; p-gp, p-glycoprotein; SCr, serum creatinine

* Frequency of monitoring is dependent on the patient's clinical status.

^† Colchicine is available as a 0.6-mg scored tablet, oral solution, and a capsule in the United States; the capsule or oral solution has not been studied in the pediatric population and the manufacturer has no information available regarding opening the capsule and sprinkling the contents in food. Usual dosing is based on 2015 ESC guideline recommendations; patient population is primarily European.

^‡ Alternative dosing recommendations are extrapolated from available tablet formulation in the United States; clinicians should weigh the risk versus benefit of colchicine when considering therapy (i.e., drug-drug and drug-disease interactions); twice daily dosing is recommended.

Alongside efficacy, clinicians should also consider the safety concerns that are associated with the use of colchicine. To date, no pediatric studies have identified the type and/or frequency of ADEs associated with colchicine when used to treat IP in adults. Because patients are usually treated with colchicine for 3 to 6 months, caregiver vigilance for ADEs described in Table 4 is pivotal for the success of therapy and ensuring safety in children. Relatively mild and common ADEs of colchicine include GI symptoms, such as abdominal pain, nausea, vomiting, and diarrhea, with diarrhea being the most common.²⁸ Gastrointestinal symptoms are most frequently experienced within 24 hours of therapy and can be diminished by lowering the dose of colchicine.²⁸ If diarrhea does not subside and/or worsens, persistent diarrhea can lead to more serious complications such as dehydration, which could potentially worsen renal function, increasing the risk for colchicine-related toxicities.²⁸ Rare but serious ADEs include blood dyscrasias such as myelosuppression, leukopenia, granulocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia, which may develop within 24 to 72 hours, especially in patients with renal or hepatic impairment and patients concomitantly receiving drugs that may impair the metabolism of colchicine (i.e., inhibitors of cytochrome [CYP] P450 3A4).²⁸ In such cases the dose of colchicine should be decreased in half or treatment should temporarily be discontinued. Failure in doing so may potentiate further toxicities that range from organ failure (renal, respiratory, and cardiac), to coma, or even mortality.²⁸ Neuromuscular toxicity may manifest as sensory neuropathy and/or rhabdomyolysis, and occurs with chronic therapy.²⁸ Patients may present with muscle weakness and/or elevated creatine phosphokinase concentrations, neuropathy, and/or myopathy.²⁸ Chronic use of colchicine is associated with cyanocobalamin (vitamin B₁₂) deficiency, which is postulated to be a result of colchicine's ability to alter the intestinal mucosa's absorptive abilities.²⁸

Moreover, the safety of colchicine extends to considerations such as drug-drug and drug-disease interactions. Colchicine is metabolized in the liver by CYP 3A4 and eliminated via p-glycoprotein (p-gp). It is contraindicated in patients receiving a “strong” CPY 3A4 inhibitor who also have renal or hepatic impairment. Common “strong” CYP 3A4 inhibitors include select protease inhibitors and itraconazole; concomitant use of moderate CYP 3A4 inhibitors (e.g., erythromycin and fluconazole) or use within the last 14 days requires dose adjustment of colchicine.¹⁴ Likewise, inhibitors of p-gp are contraindicated in patients receiving colchicine who also have either renal or hepatic impairment. Common inhibitors of p-gp include cyclosporine and erythromycin. Because colchicine is metabolized and eliminated via the liver and kidneys, respectively, diligent monitoring of both hepatic and renal function is required in order to safeguard patients while maintaining the efficacy of colchicine therapy. Because there are no renal dose adjustment recommendations for patients using colchicine to treat IP, clinicians should extrapolate manufacturer-recommended renal dose adjustments, based on treatment of gout and FMF, and should do so carefully using the Schwartz equation.^25,29 Similarly, children with hepatic impairment of any degree should be carefully monitored if colchicine is initiated. The manufacturer of colchicine does not recommend dose adjustment in adults treated for FMF or gout who have mild to moderate hepatic impairment only. Treatment should be initiated at the lowest recommended dose and follow-up of liver function tests (LFTs) should be diligent.

Corticosteroids. Corticosteroids have historically been used in the treatment of IP because they achieve rapid symptom control and cause remission of pericarditis symptoms. Corticosteroids decrease inflammatory cytokine production and subsequently blunt the inflammatory processes. However, several landmark studies suggest that corticosteroids are especially associated with recurrence of pericarditis in adults with acute or recurrent IP.^2,4 It is hypothesized that corticosteroids possibly reactivate viral infections and therefore potentiate inflammation, and subsequent incessancy or recurrence.^2,4 The potential mechanism is that corticosteroids may potentiate DNA or RNA replication in pericardial tissue, leading to increased viral antigen, thus impairing the clearance of viral infections.¹¹ Subsequently, the 2015 ESC guidelines do not recommend corticosteroids as first-line therapy for pericarditis in children (class III, level C recommendation) (Table 2).¹ The guidelines recommend small-dose corticosteroids as a class IIa, level C recommendation for the treatment of recurrent pericarditis that is refractory to treatment with NSAID plus colchicine, or in cases where NSAIDs and colchicine are contraindicated or not tolerated.¹ Even though the 2015 ESC guidelines do not provide any suggested dosage regimens for corticosteroids in children, general dosing of oral prednisone for a variety of disease states in the pediatric population ranges from 0.125 to 0.5 mg/kg/dose every 12 to 24 hours with a maximum daily dose of 60 mg/day.^1,30 It is reasonable to use the 0.25- to 0.5-mg/kg/day dosing utilized in adults for pediatric patients with IP. It is important to note that the intensity of corticosteroid dosing used is associated with an increased risk of recurrence. Imazio and colleagues³¹ retrospectively studied corticosteroid dosing regimens in adults with IP. The study compared small-dose (0.2–0.5 mg/kg/day) with large-dose (1.0 mg/kg/day) prednisone in patients with recurrent IP. Results of the study showed that, compared with the small-dose group, patients in the large-dose group experienced higher rates of severe ADEs (life-threatening or fatal, resulting in hospitalization, significantly or permanently disabling, or requiring a significant medical or surgical intervention); smaller doses of corticosteroids were also found to be associated with significantly less recurrences and hospitalizations than observed in the large-dose group.³¹ In addition to corticosteroids increasing the risk for recurrence of pericarditis, corticosteroids may also attenuate the response of colchicine in pericarditis and can increase the risk of recurrence when added to colchicine therapy.³² Because the pharmacokinetic and pharmacodynamic profile of prednisolone solution is similar to that of prednisone and is more palatable for younger children than prednisone solution, prednisolone solution should be the preferred agent in younger children.

An even more limited amount of data exists surrounding the use of corticosteroids in children. Imazio and colleagues²² conducted a retrospective study evaluating therapies used for recurrent pericarditis in 110 children with idiopathic etiology and a median age of 10 years. Over 60% of patients in the study received prednisone at a starting dose of 0.5 to 2 mg/kg/day. The mean amount of recurrences for patients who received corticosteroids was 5.84 ± 4.86, versus 2.76 ± 1.36 in those patients who did not receive corticosteroids (p < 0.001). Additionally, the use of corticosteroids was significantly associated with multiple ADEs, compared with other treatment therapies, including NSAIDs and colchicine (p = 0.036). At baseline, patients treated with corticosteroids had a significantly higher frequency of ADEs, such as fever, pericardial effusion, as well as readmission. Risk for recurrence per 100 person-years was 93.2 for patients treated with corticosteroids and 45.2 for those without corticosteroid treatment. Corticosteroids were associated with an increase in recurrences, while colchicine was associated with a decrease in the risk of recurrence from 3.74 per year before initiation of colchicine to 1.37 per year.²² In a retrospective study involving 72 children with pericarditis, corticosteroids were deemed independent risk factors for recurrence, after multinomial regression analysis.²³ Another retrospective study also showed that corticosteroids were independently associated with an increase in recurrent pericarditis.³³ Conversely, other investigators conducted a retrospective multicenter study to evaluate the management of IP and pericardial effusions in 38 pediatric hospitals in the United States.¹⁰ In this study, they evaluated the epidemiology and management of inpatient hospitalizations for pericarditis and pericardial effusion in US children, as well as the risk factors associated with readmission. There were 543 patients included in the cohort, with a median age of 14.5 years. Upon admission, medications included NSAIDs (71.3%), corticosteroids (22.7%), ASA (7.0%), and colchicine (3.9%). The study found that none of these agents, including corticosteroids, were independently associated with readmission due to recurrent pericarditis. However, clinicians should consider several limitations of this study, including the fact that no dosage regimens were provided and that a small sample size of readmissions may have been underestimated and resulted in limited statistical power.

The ADEs associated with corticosteroids that are observed in children are similar to those that are commonly encountered in adults. Common acute ADEs for corticosteroids include peripheral edema, hypertension, hyperglycemia, and behavioral or mood changes.^30,34,35 In addition, corticosteroids can be associated with GI-related ADEs including increased appetite, which is associated with weight gain, nausea, and gastric irritation that may lead to peptic ulcer disease. It is the authors' opinion that when using corticosteroids for IP, clinicians should consider using a gastroprotective agent to decrease the risk of gastric irritation, especially for those patients who also receive concomitant NSAIDs and/or colchicine with corticosteroids.

Chronic use of corticosteroids can also cause endocrine-related disorders, such as hypothalamic-pituitary-adrenal (HPA) axis suppression, leading to decreased growth velocity in children. HPA axis suppression occurs even when small doses are used, as well as through any route of corticosteroid administration.^30,34 Therefore, prolonged corticosteroid courses (>14–21 days) should be tapered and gradually withdrawn to prevent occurrence of HPA axis suppression—especially because HPA axis suppression may persist for months after therapy is withdrawn, which is another reason why corticosteroid use should be restricted in children. Moreover, ADEs such as striae rubrae and growth impairment are particularly harmful in growing children and they should subsequently have their height and weight monitored frequently.^30,34 By decreasing bone formation and increasing bone resorption, corticosteroids may also inhibit bone growth in children, which may lead to osteoporosis, one of the most common and debilitating side effects associated with prolonged large-dose corticosteroid therapy.^30,35 Patients should receive supplementation for calcium and vitamin D to restore the normal calcium balance if receiving corticosteroids chronically.¹

Although corticosteroids are effective at initially managing symptoms related to pericarditis, if they are tapered too quickly, as often happens because of concerns for systemic ADEs, this could also contribute to the development of incessancy and/or recurrence of pericarditis symptoms.¹¹ Corticosteroid use has been associated with increased recurrence rates in children with IP and should not be recommended first-line for the treatment of acute IP in children.¹ Corticosteroids should be reserved for the treatment of acute IP in patients with contraindications and/or intolerances to NSAIDs or colchicine, with preexisting autoimmune disorders, or when response is incomplete to the first-line therapy. In such cases, small-dose corticosteroids should be used and tapered slowly. Corticosteroids should be tapered accordingly and should be discontinued after laboratory and clinical symptoms have ameliorated (Table 5).

Table 5.

Dosing, Monitoring, and Clinical Pearls for Corticosteroids and Immunotherapies for Idiopathic Pericarditis in Children^{1,7,10,28,29,32–46}

Drug	Dosing	Recommendations for Tapering	ADEs	Monitoring*	Clinical Pearls
Corticosteroids
Prednisoneor prednisolone	0.25–0.5 mg/kg/day (maximum dose of 60 mg/day) PO	Decrease dose every 1–2 wk by 0.25 mg/kg/dose every 12 hr every 1–2 wk; discontinue once at 0.25 mg/kg/dose daily	GI-related Edema Hyperglycemia Insomnia Mood disturbances Electrolyte/acid base disturbances HPA suppression Osteoporosis Infection	CBC with differential Basic metabolic panel Weight and height measurements	Switch to prednisolone in patients with hepatic impairment Prednisolone oral disintegrating tablet or oral solution may be preferred in younger children owing to improved palatability over prednisone
Immunotherapies
Anakinra	1–2 mg/kg/day subcutaneously	Not applicable	Injection site reactions GI-related Headache Arthralgia	LFTs Infections	Avoid administering live vaccines during therapy
Rilonacept	12–17 yr old: Loading dose: 4.4 mg/kg/dose subcutaneously Maintenance dose: 2.2 mg/kg/dose once weekly subcutaneously	Not applicable	Injection site reactions Sinusitis	Infections Lipid profile	Avoid administering live vaccines during therapy
Canakinumab	5 mg/kg/dose once monthly subcutaneously†	Not applicable	Injection site reactions	Infections	Avoid administering live vaccines during therapy
Parenteral IVIG	0.4–2 g/kg/day subcutaneously, IV, IM	Not applicable	Thrombosis Renal impairment Injection site reactions	SCr Ultrasonography	Can be administered as a single bolus dose or intermittent infusion

ADE , adverse drug event; CBC, complete blood count; GI, gastrointestinal; HPA, hypothalamic-pituitary-adrenal; IM, intramuscular; IV, intravenous; IVIG, intravenous immunoglobulin; LFTs, liver function tests; SCr, serum creatinine

^* Frequency of monitoring is dependent on the patient's clinical status.

^† Dosing extrapolated from 1 pediatric case report.⁴³

Immunotherapies. Use of immunotherapy is a relatively novel approach to the treatment of IP. For the purposes of this review, immunotherapy can be defined as the use of either immunosuppressive or immune-activating pharmacotherapy. A subset of patients with pericarditis is thought to possess an autoimmune-related pathophysiologic response, in which the immunotherapies inhibit pericarditis-related inflammation by a variety of mechanisms. A comprehensive review of the immunotherapies has previously been published, albeit in adults.³⁶ However, most of the experiences regarding the use of immunotherapy for the treatment of IP relate to children with recurrent pericarditis, specifically, IL-1 antagonists such as anakinra, rilonacept, and canakinumab. Other immunotherapies such as azathioprine and methotrexate have been sparingly used in the treatment of IP in children, relative to adults.²⁴ Data regarding the use of IV immunoglobulin (IVIG) are limited to an array of case reports and case series.³⁷ However, most patients in these reports were not diagnosed with idiopathic or viral etiologies of pericarditis, such that the external validity of the data is less applicable.

Most of the data discussing the experience of using anakinra to treat recurrent IP in children consist of case reports or case series.^8,38–41 In the majority of these reports, most patients were adolescents (age range, 12–14 years) and were receiving corticosteroids for initial acute IP episode. When corticosteroids were tapered, patients experienced a relapse in pericarditis symptoms and laboratory manifestations, which was documented in all of the cases. Upon initiation of anakinra (dosing range, 0.7–1.25 mg/kg/day), clinical improvement (i.e., chest pain symptoms), normalization of laboratory parameters including acute phase reactants (i.e., CRP), and resolution of echocardiographic features (i.e., pericardial effusion) occurred within a few days. Most patients were also retained on corticosteroid therapy, colchicine, and/or ASA or NSAIDs, with tapering of corticosteroids and/or colchicine over a period of weeks to months. However, upon discontinuing anakinra, recurrence or relapse of pericarditis occurred within weeks to months and anakinra was subsequently restarted. Follow-up ranged from several months to about 3 years, and most patients did not report any relapses while anakinra monotherapy was restarted either daily or on alternating days of administration.^38–41

While anakinra is the immunotherapy associated with the most numerous available data for treating recurrent IP in children, there are several issues to be considered. First, more robust data are needed to solidify a cause and effect relationship between anakinra and decreased risk of recurrence in children diagnosed with recurrent IP. Currently, there is only 1 available randomized, double-blind, placebo-controlled trial studying anakinra in patients with IP.⁸ The authors compared outcomes in 11 patients receiving anakinra versus 10 receiving placebo; they found that anakinra reduced the risk of recurrence over a 14-month period, and most patients receiving anakinra had transient skin reactions. However, this study only included 1 child. Secondly, standardized definitions for recurrence, incessancy, and relapses need to be incorporated into a study in order to streamline the internal validity of studies. Moreover, more relevant endpoints, such as recurrence rate, cardiac tamponade, resolution of symptoms, and time to recurrence, need to be incorporated. Finally, many reports used varying types of pharmacotherapy as initial treatment (i.e., corticosteroid first, corticosteroid plus an NSAID); a study design using colchicine and NSAIDs as first-line—corticosteroid, colchicine, plus NSAID if combination therapy with colchicine and NSAID is ineffective—would be helpful in truly ascertaining the role of anakinra added to second-line treatment of recurrent IP.

Rilonacept, an interleukin-1a and -1B cytokine trap, is a newer IL-1 antagonist that has demonstrated benefit in treating recurrent pericarditis. A phase-3, double-blinded, randomized withdrawal trial evaluated the use of rilonacept for recurrent pericarditis in 86 patients; however, only 7 patients <18 years of age were enrolled.⁴² In this trial, rilonacept was administered via a 12-week run-in period; a loading dose of 320 mg or 4.4 mg/kg for patients <18 years of age was administered subcutaneously, followed by a weekly subcutaneously maintenance dose of 160 mg or 2.2 mg/kg for patients <18 years of age. The 12-week run-in period included 1 week of stabilization, 9 weeks of weaning off of background pericarditis therapy, and 2 weeks of rilonacept monotherapy. With the limited number of patients of appropriate age to receive the weight-based dosing, it may be difficult to extrapolate these results to younger children. Rilonacept has a FDA-labeled indication to treat and prevent recurrent pericarditis in children and adolescents >12 years of age.⁴³ The authors reported a reduction in recurrence of pericarditis with rilonacept, with the ability to completely wean off background pericarditis therapies (i.e., corticosteroids, colchicine, and NSAIDs) and improved quality of life; however, these findings should also be interpreted with caution owing to the small sample size of the study and limited follow-up time.

Canakinumab, a monoclonal antibody IL-1 antagonist, is another immunotherapy option for recurrent IP. Canakinumab has shown benefit in many proinflammatory disease states, including cryopryrin-associated and tumor necrosis factor receptor–associated periodic syndromes, and more recently has shown positive results with use in atherosclerotic disease owing to its anti-inflammatory mechanism.⁴⁴ These findings suggest that canakinumab could potentially be beneficial in treating pericarditis; however, its use in pediatric pericarditis is limited to case reports, and not all have shown success.^45,46 There is currently 1 case report that describes using canakinumab to successfully treat recurrent IP in a 6.5-year-old male who had previous anaphylaxis with anakinra.⁴⁵ Canakinumab was dosed at 5 mg/kg subcutaneously monthly for 1 year, followed by alternating monthly dosing for an additional year. The patient did not have any recurrent pericarditis episodes or ADEs during this 2-year period.⁴⁵ However, there have also been 2 documented cases of failure with canakinumab in patients with recurrent pericarditis.⁴⁶ In case 1, a 10-year old female who had an allergic reaction to anakinra was initiated on canakinumab 4 mg/kg every 4 weeks, later changed to every 3 weeks. Over a 6-month period, the patient had 4 relapses, each time when steroids were tapered to below 0.25 mg/kg/day. In case 2, the therapy for an 11-year-old female was changed to canakinumab owing to poor compliance with daily anakinra injections. She experienced a relapse in her pericarditis course 10 days after receiving 1 canakinumab dose of 2.5 mg/kg; canakinumab was not re-initiated. While the infrequent dosing interval is advantageous over that of other IL-1 antagonist options, more studies are needed before canakinumab should be routinely considered a treatment option for pediatric IP.

Interleukin-1 antagonists are generally well tolerated by patients receiving them for IP, with the most common ADE being injection site reactions.⁴⁷ Table 5 provides information on dosing, ADEs, and clinical pearls for the IL antagonists. With anakinra, there have also been some reports of elevated LFT results, and therefore these should be routinely monitored throughout therapy.⁸ Other common anakinra ADEs include GI intolerances, headache, and arthralgia.³⁶ For rilonacept specifically, sinusitis, as well as increased low-density lipoprotein and triglyceride concentrations, have been noted.⁴² For all IL-1 therapies, owing to the immunosuppressive mechanism, these therapies should not be used in patients with an active infection, and signs and symptoms of infection should be closely monitored during therapy, because they increase the risk for infection. Owing to the risk of neutropenia, baseline as well as routine monitoring of neutrophil counts should be performed.³⁶ Vaccine administration is another important consideration for patients receiving IL-1 antagonists, especially in children who may be receiving routine immunizations. Administration of live vaccines should be performed prior to IL-1 therapy and should be avoided during therapy. These therapies may also decrease the effectiveness of inactivated vaccines if given concomitantly.³⁶

The 2015 ESC guidelines provide a class IIb level C recommendation for use of anti–IL-1 drugs and state that they may be considered in children with recurrent pericarditis, especially in children who are corticosteroid dependent (Table 2).¹ At the time the 2015 ESC guidelines were published, anakinra was the only anti–IL-1 medication that had been studied in IP. Rilonacept may be considered a third-line option for children with elevated CRP concentrations who have experienced failure of first-line combination therapy with colchicine and an NSAID, as well as second-line therapy with colchicine, NSAIDs, plus corticosteroids, and when attempts to wean a patient off corticosteroids result in relapsing of pericarditis signs and/or symptoms. Anakinra may be considered if rilonacept is too costly or is not tolerated; caution should be used with canakinumab given its limited data in children.

Intravenous immunoglobulin is another immunotherapy strategy for treating recurrent IP. It is hypothesized that IVIG affects recurrent IP by inhibiting leukocyte action such as phagocytosis, ameliorating production of inflammatory cytokines, downregulating chemokines and chemokine receptor expression, as well as neutralizing autoantibodies. In children, much of the experience of using IVIG for treatment of recurrent pericarditis is within the scope of pericarditis secondary to known etiologies (i.e., post-pericardiectomy or secondary to infections).^37,48 Data consist of case reports and cohorts of children with varying disease durations (range, 1–2160 days) and number of recurrences prior to IVIG administration (range, 1–15). Most children were not initially administered combination therapy with anti-inflammatory therapy plus colchicine. IVIG regimens ranged from 0.4 to 1 g/kg/day for 2 to 5 consecutive days, to 2 g/kg as 1 single dose. Patients received as many as 5 cycles of IVIG to complete treatment. Overall, the majority did not experience a recurrence after IVIG administration. It should be noted, however, that follow-up data were either not available or discordant amongst children treated with IVIG for recurrent pericarditis.^37,48

The use of IVIG for the treatment of recurrent pericarditis should be extrapolated carefully. Not only does the literature include discordant dosing, monitoring, and follow-up data, but also many of the patients treated with IVIG did not have viral or idiopathic etiologies of pericarditis, making it nebulous to extrapolate these findings to idiopathic or viral etiologies of pericarditis. Furthermore, compared with anakinra, IVIG is relatively more cumbersome to administer and has more serious ADEs.⁴³ While most patients treated with IVIG were provided with IV administration, IVIG can also be administered either subcutaneously or intramuscularly. Table 5 provides information on dosing, ADEs, and clinical pearls. Depending on the formulation, IVIG may have to be administered over 24 hours (e.g., IV), necessitating a longer clinic or hospital stay in some cases.⁴³ Moreover, the type of administration may also be associated with specific ADEs. For example, in patients who receive IVIG, AKI may manifest with certain formulations, whereas thrombosis may occur with any IVIG formulation.⁴³

The use of immunotherapy for treatment of IP in children is a novel frontier, especially for treatment of recurrent IP. While the most robust evidence relates to using either IL-1 blockade or IVIG, other pharmacotherapeutic options have been investigated, albeit based on limited data. Limited literature consists of data including patients receiving immunotherapies such as azathioprine, hydroxychloroquine, methotrexate, cyclosporine, and mycophenolate mofetil. However, data are primarily based on cohort studies.²² Overall, immunotherapies in children should be considered for patients with recurrent pericarditis, specifically for those who have had relapsing signs and/or symptoms, despite treatment with an NSAID plus colchicine and corticosteroids, which cannot be successfully tapered.

Summary

Idiopathic (viral) pericarditis is associated with a significant morbidity burden in children. Similar to adults, recurrence rates are relatively high and pharmacotherapy should be used to decrease rates of recurrence and decrease pericarditis-related chest pain in children.¹⁰ Clinicians should consider using combination therapy with NSAIDs plus colchicine for first-line therapy.¹ Attack doses of NSAIDs should be used within the first week. Relatively larger doses of NSAIDs should be used to rapidly elicit the anti-inflammatory properties associated with improving symptoms of pericarditis.¹⁴ Treatment doses of ASA should not be routinely used in patients <12 years or any child with a concurrent viral infection owing to the relative risk for development of Reye syndrome.¹⁶ Attack dosing may be used for at least 1 week, with hs-CRP monitoring at baseline, then at the end of the week of attack dosing.¹⁸ If hs-CRP is not reduced after 1 week of attack dosing, the clinician should extend attack dosing until hs-CRP is decreasing. Typically, the NSAID should be used for 3 to 4 weeks, tapering the dose and/or frequency every 1 to 2 weeks, and monitoring for laboratory and clinical improvement of signs and symptoms of pericarditis.^11,18 Gastrointestinal protective therapy should be used for the duration of NSAID therapy to decrease the incidence of NSAID-related GI ADEs.¹ Choice of NSAID should be dictated by cost, tolerability, and ADEs.¹⁴ Attack doses may be considered with colchicine in the hospital setting, although it should be noted that not all patients were administered attack doses both in adult and pediatric studies. In adults, colchicine reduces the risk of recurrence and improves symptoms related to pericarditis, when combined with an NSAID, while data in children are conflicting.^1,2–7,22 The dosing of colchicine in the United States should be extrapolated from dosing in the landmark studies, using the US tablet or oral solution formulations of colchicine.²⁸ As noted, the oral solution is not available as a generic, so the increased costs compared with the tablets should be considered. Colchicine should be dose adjusted in renal and hepatic impairment, and clinicians should screen for relevant drug-drug interactions prior to initiation. Regular laboratory monitoring to identify or prevent ADEs is warranted, as colchicine is usually used for 3 months in acute pericarditis, and at least 6 months in patients with recurrence.²⁸ Pending no contraindications or intolerances, clinicians should concomitantly start an NSAID with colchicine therapy.

Corticosteroids should be considered last-line in the treatment of acute pericarditis in children.^1,2 Corticosteroids have been shown to increase the risk of recurrence in patients with idiopathic or viral etiologies of pericarditis.² Therefore, they should only be used in patients with intolerances or contraindications to NSAIDs for the treatment of acute idiopathic or viral etiologies of pericarditis.¹ Corticosteroids may also be used for the treatment of recurrent pericarditis in patients who present with signs of relapsing pericarditis, despite adherence to combination therapy with NSAIDs and colchicine.¹ However, in studies that include corticosteroids as a treatment option for children with pericarditis, corticosteroids are often not the primary therapy being evaluated, which results in lack of availability of sufficient data, including, for example, specific corticosteroid dosing regimens. Additionally, because corticosteroids need to be used for up to several months, after a slow taper, ADEs (associated with both short- and long-term use) are common and may affect adherence and subsequently the efficacy of corticosteroid therapy in the treatment of idiopathic or viral etiologies of pericarditis. If corticosteroids are selected, relatively small doses (0.25–0.5 mg/kg/day; maximum of 60 mg/day of prednisone equivalents) should be used with tapering; laboratory and clinical improvement should be monitored, and corticosteroids should be the first medication tapered off.^30,31

Immunotherapies may be considered in patients with multiple recurrences, despite use of NSAIDs, colchicine, and/or corticosteroid therapy.¹ Rilonacept has the advantage of less frequent dosing, but anakinra could be considered instead if cost is an issue or ADEs occur with rilonacept.^36,42 However, drug-disease interactions should be considered prior to choosing any immunotherapy.³⁶ Most studies involving anakinra or rilonacept tapered-off corticosteroids first, followed by NSAID and/or colchicine therapy.^{8,17,36,38–42} The majority continued treatment with anakinra as monotherapy, even after resolution of relapse. Although there are no landmark trials evaluating pharmacotherapy in children with IP, previous epidemiologic studies have described similar benefits to using the aforementioned pharmacotherapy when compared with adults.^10,22,24 Furthermore, the 2015 ESC guidelines provide recommendations for IP treatment in children.¹ Careful attention should be taken to avoid ADEs. Similar to adults, diligent monitoring should be implemented to prevent drug-drug interactions, drug-disease interactions, and/or ADEs in such a vulnerable patient population.

ABBREVIATIONS

ADEs

adverse drug events

AKI

acute kidney injury

ASA

aspirin

AUC_0–24 hr

area under the curve

CRP

C-reactive protein

CYP

cytochrome

ECG

electrocardiogram

ESC

European Society of Cardiology

FDA

US Food and Drug Administration

FMF

familial Mediterranean fever

GI

gastrointestinal

H₂RA

histamine 2 receptor antagonist

HPA

hypothalamic-pituitary-adrenal

hs-CRP

high-sensitivity CRP

IL-1

interleukin 1

IP

idiopathic (viral) pericarditis

IV

intravenous

IVIG

intravenous immunoglobulin

LFTs

liver function tests

NSAIDs

non-steroidal anti-inflammatory drugs

p-gp

p-glycoprotein

Funding Statement

Disclosures. Dr Schwier is a paid consultant and serves on the advisory board of Kiniksa Pharmaceuticals. No financial incentive was provided to Dr Schwier in the preparation of this manuscript. Kiniksa Pharmaceuticals was not involved in the preparation of this manuscript.