Multisystem Inflammatory Syndrome in Adult (MIS-A)

Abstract

Multisystem Inflammatory Syndrome (MIS) is a severe medical condition that can develop following a COVID-19 infection. It is characterized by widespread tissue inflammation, affecting various organs such as the heart, lungs, kidneys, brain, skin, eyes, and gastrointestinal system. A new medical condition emerged in children during the early stages of the COVID-19 pandemic. This condition necessitated intensive care due to symptoms like fever, abdominal pain, heart failure, and shock, which could lead to fatal outcomes. This condition bore some similarities to Kawasaki disease and was named ‘Multisystemic Inflammatory Syndrome in Children (MIS-C)’ by the Centers for Disease Control and Prevention (CDC) in April 2020. Subsequently, similar clinical conditions were reported in adults in June 2020, and this condition in adults was defined as ‘MIS-A.’ MIS-A primarily affects individuals aged 21 and older. It is characterized by persistent fever, multi-organ involvement, elevated markers of systemic inflammation, a history of exposure to SARS-CoV-2, and the absence of an alternative diagnosis. Early diagnosis of MIS-A is crucial, as a delayed diagnosis can be life-threatening.

1. Introduction

In December 2019, an outbreak of pneumonia with an unidentified cause emerged in Wuhan, China [1]. Subsequently, it was determined that a novel coronavirus was responsible for the disease, leading to its designation as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). This disease became known as Coronavirus Disease 2019 (COVID-19). The virus swiftly spread globally, prompting the World Health Organization (WHO) to declare it a global pandemic on March 11, 2020 [2].

SARS-CoV-2 is an enveloped, single-stranded positive RNA virus belonging to the beta coronavirus family. Its spike (S) glycoprotein binds to angiotensin-converting enzyme 2 (ACE2), a transmembrane protein highly expressed in vascular endothelial cells within the lungs and other organs. This interaction facilitates the virus’s entry into host cells, triggering an immune response that includes the production of proinflammatory cytokines [3]. This immune response can sometimes lead to severe conditions such as acute respiratory distress syndrome (ARDS), multi-organ failure, and even death in infected individuals [4].

COVID-19 presents with a range of symptoms, varying from asymptomatic or mild to severe. Common symptoms include dry cough, sore throat, fever, shortness of breath, fatigue, sputum production, dyspnea, conjunctivitis, myalgia, and loss of taste or smell [5]. The severity of the disease is categorized as mild, moderate, severe, or critical. COVID-19 progresses through three stages: early infection with the viral invasion of host cells, a pulmonary phase characterized by lung tissue damage due to immune activation and proinflammatory cascades, and the most dangerous phase, the inflammatory cell overactivation period known as the cytokine storm [6]. This phase can result in respiratory distress, oxygen desaturation, respiratory failure, and an increased risk of venous thromboembolism [7].

In children, COVID-19 generally follows a milder course compared to adults, and many children may remain asymptomatic [8]. However, in April 2020, a new condition characterized by severe inflammation, like Kawasaki disease and toxic shock syndrome, was observed in previously healthy children who had recently been infected with SARS-CoV-2 [9]. Affected children displayed symptoms such as high fever, abdominal pain, hypotension, myocardial dysfunction, multi-organ failure, and the need for intensive care. Epidemiological analysis revealed a delay of several weeks between the peak of COVID-19 cases in the community and the highest number of MIS-C cases. This suggests a potential link to post-infection immune responses [10].

The first reports of these cases in Europe came from the UK, and this new condition was temporarily named Pediatric Inflammatory Multisystem Syndrome temporally associated with SARS-CoV-2 (PIMS-TS) by the Royal College of Pediatrics and Child Health (RCPCH). Subsequently, similar case reports emerged from the United States, leading to the CDC and WHO defining it as Multisystem Inflammatory Syndrome in Children (MIS-C) in April 2020 [11].

As the COVID-19 pandemic continued, similar clinical findings were reported in adults who had previously been infected with SARS-CoV-2. In June 2020, this condition seen in adults was defined as MIS-A [12, 13].

2. MIS-A pathophysiology

MIS-A is a rare complication of COVID-19, and its pathophysiology is not yet fully understood, but it can be potentially life-threatening. Clinically, the disease most commonly manifests itself 2–6 weeks after infection, especially affecting young and middle-aged patients [14]. The clinical course of the disease is highly variable, with fever being the most important clinical sign and the most observed symptom. Additionally, widespread organ involvement and signs of shock can occur due to systemic inflammation [15].

The exact pathophysiology of MIS-A remains uncertain, but it is suggested to result from a delayed and irregular immune response that occurs weeks after recovery from COVID-19 infection. In most cases of SARS-CoV-2 infection, there is an inflammatory immune response that activates both the innate and acquired immune systems. However, during the recovery period, an irregular immune response, possibly contributed to by macrophage activation, can lead to hyperinflammation. This results in the reactivation of both the innate and acquired immune systems, involving B cells and T cells, along with high levels of proinflammatory production. Cytokines and antibodies play a role in this process. These inflammatory cytokines lead to a multisystem inflammatory response and contribute to the development of MIS-A [16, 17].

The exact cause of this irregular immune response that develops after recovering from COVID-19 infection is not known, but it is believed to be related to persistent viral antigens and autoantibodies [18].

3. Clinical symptoms of MIS-A

In MIS-A, there is a severe systemic inflammatory response accompanied by multi-organ dysfunction, including the heart, lungs, kidneys, brain, skin, eyes, or gastrointestinal system, along with elevated proinflammatory markers. Symptoms can often appear 2–6 weeks after SARS-CoV-2 virus infection. The most common symptom and clinical finding in MIS-A patients is fever. Unlike most infectious diseases, MIS-A patients typically have persistent and prolonged fever. In addition to fever, clinical symptoms observed in MIS-A can include abdominal pain, vomiting, diarrhea, various skin lesions, non-purulent conjunctivitis (bloodshot eyes), shortness of breath, myalgia (muscle pain), headache, encephalopathy, newly developed epileptic seizures, dizziness, and clinical symptoms of hypotension and shock. In the case of the series, it has been reported that 100% of patients had a fever (fever being a prerequisite for diagnosis), and skin rash was seen in 57.8% of cases. Diarrhea (51.6%) and abdominal pain (40.6%) were also noted as the most common gastrointestinal symptoms in MIS-A [14, 15, 17].

Characteristics of organ involvement in MIS-A include:

Multi-Organ Involvement: MIS-A can affect various organs, including the heart, lungs, kidneys, gastrointestinal system, and skin. Patients may experience symptoms related to dysfunction in these organs, such as chest pain, shortness of breath, abdominal pain, diarrhea, and skin rashes [18].

Heart: Cardiac involvement is common in MIS-A and is among the main causes of mortality and morbidity. The most common cardiac abnormalities observed include myocarditis (inflammation of the heart muscle), pericarditis (inflammation of the lining around the heart), pericardial effusion, coronary artery dilatation or aneurysm, echocardiographic findings indicating left or right ventricular dysfunction, elevated levels of troponin and BNP (B-type Natriuretic Peptide), various arrhythmic electrocardiogram abnormalities such as second and third-degree atrioventricular (A-V) block, ventricular tachycardia, along with hypotension or cardiogenic shock. Patients may also present with chest pain, and symptoms related to hypotension or cardiac shock can be observed. Additionally, in previously reported cases, cardiac involvement in MIS-A has been observed to be reversible, with improved heart function seen in follow-up assessments [17, 19].

Skin: The skin is one of the most affected organs in MIS-A. Skin rashes are typically widespread and may have a maculopapular and/or polymorphic character. Patients may experience non-exudative conjunctivitis, periorbital edema, mucositis, subcutaneous edema, palmar erythema, and petechial rashes. Vesicular rashes are not expected in the MIS-A [17, 18, 20].

Gastrointestinal system: Gastrointestinal symptoms in MIS-A can include abdominal pain, vomiting, or diarrhea. In the reported case series, diarrhea (51.6%) and abdominal pain (40.6%) were noted as the most common gastrointestinal symptoms. While gastrointestinal symptoms tend to be dominant in MIS-C patients, traditional Kawasaki disease (KD) symptoms like vomiting and diarrhea are rare [18, 21].

Brain: Neurological symptoms and signs may include newly developed headaches, encephalopathy, meningeal signs, epileptic seizures, or peripheral neuropathy. Newly developed Guillain-Barré syndrome is also considered one of the peripheral neurological findings in the MIS-A [16, 17]. These features, along with multi-organ dysfunction and elevated proinflammatory markers, contribute to the serious systemic inflammatory response seen in MIS-A.

It’s important to note that the observed findings in MIS-A are not specific and can also occur in other infectious diseases and inflammatory conditions. The heterogeneity of clinical symptoms in MIS-A can make diagnosis challenging for clinicians. In a patient suspected of having a multisystemic inflammatory disease with persistent high fever and a history of exposure to the SARS-CoV-2 virus, advanced investigations are recommended if at least two of the listed findings are present to establish the diagnosis of MIS-A [15, 17].

It’s clear from the various studies and reports you have mentioned that MIS-A (Multisystem Inflammatory Syndrome in Adults) is a complex and serious condition associated with previous COVID-19 infection. Here are some key findings from the literature:

1. CDC report (2020):

   • In 2020, the CDC (Centers for Disease Control and Prevention) reported 27 cases that met the criteria for MIS-A.

   • The patients’ ages ranged from 21 to 50 years.

   • Common symptoms included fever, gastrointestinal symptoms, and ground-glass images in some cases.

   • All patients showed increased inflammatory markers, cardiac involvement, and positive PCR or antibody tests indicating prior COVID-19 infection.

   • Nine patients had no underlying medical conditions, while others had comorbidities like obesity, diabetes mellitus type 2, hypertension, and obstructive sleep apnea.

   • Some patients had negative PCR but positive antibody tests.

   • Most patients survived, but many required intensive care [6].

2. Belay et al. study:

   • The median age of 35 years in their case series.

   • 65% of the patients were male.

   • Most patients had a preceding COVID-19-like illness about a month before MIS-A onset [22].

3. Kunal S et al. study:

   • The review included 79 cases from 53 articles.

   • Most patients were male (73.4%) with a mean age of 31.67 years.

   • Fever was the most common symptom, followed by skin rash.

   • The cardiovascular system was most frequently involved, followed by the gastrointestinal system and mucocutaneous.

   • Decreased left ventricular ejection fraction was observed in many patients.

   • The mean time from symptom onset to hospital admission was about 5.84 days.

   • Comorbidities like hypertension and obesity were common.

   • The mean time to symptom onset before MIS-A in patients with previous COVID-19 infection was around 31.61 days [18].

4. Patel et al. review:

   • A review of 221 MIS-A patients worldwide.

   • MIS-A typically develops about 4 weeks after acute COVID-19 infection.

   • The mean age was 21 years, with 70% being male, and 58% had no other comorbidities.

   • Common symptoms included fever, hypotension, cardiac dysfunction, dyspnea, and diarrhea.

   • Many patients required intensive care and respiratory support.

   • The mortality rate was 7% [15].

These findings collectively highlight the diverse clinical presentations and outcomes associated with MIS-A, emphasizing the importance of timely recognition and management of this condition, especially in individuals with a recent history of COVID-19. Further research is needed to better understand the underlying mechanisms and improve clinical management strategies [14].

4. Laboratory findings

The laboratory findings associated with MIS-A (Multisystem Inflammatory Syndrome in Adults) typically reveal a significant increase in various inflammatory markers. Here are some key laboratory findings mentioned in the provided information:

1. Inflammatory markers:

   • C-reactive protein (CRP): Elevated in most cases.

   • Ferritin: Elevated.

   • Interleukin 6 (IL-6): Elevated.

   • Erythrocyte Sedimentation Rate: Elevated.

   • Procalcitonin (PCT): Elevated.

   • Fibrinogen: Elevated.

   • D-dimer: Elevated.

   • Lactate Dehydrogenase (LDH): Elevated.

   • Lymphopenia: Reduced lymphocyte count.

   • Thrombocytopenia: Reduced platelet count [17, 18].

2. Cardiac evaluation:

   • Electrocardiogram (ECG): Recommended for cardiac assessment.

   • Cardiac enzymes:

     • Troponin: Elevated in many cases.

     • B-type Natriuretic Peptide (BNP) /N-terminal-prohormone of brain Natriuretic Peptide (NT-pro BNP): Elevated.

   • Echocardiography (ECHO): Recommended for assessing cardiac function.

   • Left Ventricular Ejection Fraction (LVEF): Reduced in a significant percentage of cases (LVEF<50%).

   • Right Ventricular Dysfunction: Present in some cases.

   • Cardiac Magnetic Resonance (CMR): Myocardial edema and pericardial effusion were observed in some cases [15, 18].

3. SARS-CoV-2 testing:

   • RT-PCR: Positive in some patients.

   • Serology: Positive in most patients [17, 23].

These findings emphasize the importance of conducting thorough laboratory assessments and cardiac evaluations when diagnosing and managing MIS-A. Elevated inflammatory markers, cardiac involvement, and history of COVID-19 infection (PCR or antibody positivity) are common features in MIS-A patients. Additionally, coagulopathy and abnormalities in inflammatory parameters are frequently observed, underlining the systemic nature of this condition. Early diagnosis and appropriate management are crucial for improving patient outcomes [6, 23].

5. Case definition

The MIS-A (Multisystem Inflammatory Syndrome in Adults) case definition developed by the CDC (Centers for Disease Control and Prevention) in 2021 outlines the criteria that a patient must meet to be diagnosed with MIS-A. To be classified as a MIS-A case, a patient must:

1. Be 21 years of age or older.

2. Have an illness that resulted in hospitalization for 24 hours or longer or led to death.

3. Meet the following clinical and laboratory criteria, with alternative diagnoses ruled out:

   • Experience subjective fever lasting for ≥24 hours or documented fever (≥ 38.0°C) within the first 3 days before or after hospitalization. If we assume the admission date as day 0, these criteria must be met by the end of the third day.

   • Exhibit at least three of the following clinical criteria, with at least one being a primary clinical criterion:

   • Primary clinical criteria:

     1. Severe cardiac illness, including myocarditis, pericarditis, coronary artery dilatation/aneurysm, or new-onset right or left ventricular dysfunction (LVEF<50%), 2nd/3rd-degree atrioventricular (A-V) block, or ventricular tachycardia (cardiac arrest alone does not meet this criterion).

     2. Rash AND non-purulent conjunctivitis.

   • Secondary clinical criteria:

     1. New-onset neurologic signs and symptoms, including encephalopathy in a patient without prior cognitive impairment, seizures, meningeal signs, or peripheral neuropathy (including Guillain-Barré syndrome).

     2. Shock or hypotension not explained by medical therapy (e.g., sedation, renal replacement therapy).

     3. Abdominal pain, vomiting, or diarrhea.

     4. Thrombocytopenia (platelet count <150,000/microliter).

4. Provide laboratory evidence of inflammation AND SARS-CoV-2 infection, which includes:

   • Elevated levels of at least two of the following: C-reactive protein (CRP), ferritin, IL-6, erythrocyte sedimentation rate, and procalcitonin (PCT).

   • A positive SARS-CoV-2 test result for current or recent infection by RT-PCR (reverse transcription-polymerase chain reaction), serology, or antigen detection [24].

This case definition helps healthcare professionals identify and diagnose MIS-A in adults while excluding other potential diagnoses. It focuses on clinical symptoms, laboratory markers, and the presence of SARS-CoV-2 infection to establish the MIS-A diagnosis [16].

6. Differential diagnosis

MIS-A can share many clinical features with other diseases such as Kawasaki Disease (KD), Toxic Shock Syndrome (TSS), Macrophage Activation Syndrome (MAS), and septic shock. Therefore, among adult patients who exhibit unexplained shock, heart failure, and/or gastrointestinal symptoms, MIS-A should be considered for diagnosis, even if there is no confirmed history of COVID-19 [23, 25].

Especially in children, MIS-C (Multisystem Inflammatory Syndrome in Children) shares similarities with Kawasaki Disease [8].

7. Kawasaki disease

Kawasaki disease is a condition that typically affects children under the age of 5 and is characterized by clinical symptoms such as fever, rash, conjunctivitis, swelling of the hands and feet, swollen neck lymph nodes, and inflammation of the mouth, lips, and throat.

According to the CDC, the diagnostic criteria for Kawasaki disease include:

1. Rash

2. Cervical lymph node enlargement (at least 1.5 cm in diameter)

3. Conjunctival inflammation in both eyes

4. Changes in oral mucosa

5. Changes in peripheral extremities

The diagnosis of Kawasaki disease is made when at least four of these five criteria are present along with fever. Two or three of the five main features, along with fever, are referred to as “incomplete Kawasaki [26].

Although Kawasaki Disease is generally a self-limiting condition, serious complications such as coronary artery aneurysms, myocardial dysfunction, and thrombotic events may develop in some children. Therefore, children diagnosed with Kawasaki Disease are typically treated with standard methods such as intravenous immunoglobulin and aspirin [27].

8. Differences between KD and MIS-C

When we compare Kawasaki disease (KD), which affects children and is extremely rare in adults, with MIS-C, we find several differences. In MIS-C cases, the average age is higher (with average ages of 8.5 for MIS-C and 3 for KD). While both diseases share fever as a common symptom and sign, there are variations in other aspects [6]:

1. Skin Rash: Skin rashes are slightly more common in MIS-C compared to KD.

2. Gastrointestinal Symptoms: Gastrointestinal symptoms such as vomiting, abdominal pain, and diarrhea tend to be more dominant in MIS-C, whereas, in traditional KD, gastrointestinal involvement is rare.

3. Inflammatory Markers: MIS-C is associated with higher levels of inflammatory markers such as C-reactive protein (CRP), ferritin, and D-dimer. Additionally, MIS-C patients often exhibit more lymphopenia and thrombocytopenia.

4. Cardiac Involvement: MIS-C typically has more severe cardiac involvement. High troponin levels, BNP (B-type natriuretic peptide), and EKG (electrocardiogram) changes are more common in MIS-C. Hypotension and shock are also more frequent in MIS-C.

5. Myocardial Edema: In KD, myocardial edema is often observed without ischemia, whereas MIS-C can lead to more severe myocardial involvement.

6. Mortality Rate: The mortality rate for MIS-C is higher (around 2%) compared to KD (around 0.17%) [6].

9. Differences between MIS-A and MIS-C

These distinctions are important for healthcare professionals when evaluating and diagnosing children with these conditions to ensure appropriate management and care. MIS-C and MIS-A are similar in many ways. However, MIS-C is more common than MIS-A. Accompanying comorbidities, the severity of cardiac dysfunction, incidence of thrombosis, shock, and mortality rate higher in MIS-A (Table 1) [6, 17].

Phenotype	MIS-A	MIS-C
Prevalence	Less common	More Common
Myocarditis	54%	29%
Cardiac dysfunction	30%	15%
Arterial thrombosis, pulmonary embolism, and/or deep venous thrombosis	5%	1%
Dermatologic findings	46%	76%
Hospital stays	~ 8 days	~ 5 days
Ventilation	25%	9%
Sex	70% male	60% male
Mortality	7%	1%

Table 1.

Differences between MIS-A and MIS-C.

Summarizing differences between MIS-A and MIS-C [6].

MIS-A shares various clinical features with other diseases such as sepsis, septic shock, or toxic shock syndrome, making its diagnosis challenging and potentially leading to delayed or missed appropriate treatment [17]. Bacterial sepsis is a significant concern in patients presenting with fever, shock, and elevated inflammatory markers. To differentiate MIS-A from bacterial sepsis, blood cultures should be obtained from all patients with suspected serious MIS-A, and empirical antibiotics should be administered while awaiting culture results. Some clinical characteristics may aid in distinguishing MIS-A from bacterial sepsis. For instance, cardiac involvement, especially coronary artery involvement, is rare in bacterial sepsis. Additionally, microbiological tests (SARS-CoV-2 antigen/antibody/RT-PCR tests, bacterial cultures) are necessary for differentiation [14, 17].

We had mentioned earlier that MIS-A shares various clinical features with other diseases such as sepsis, septic shock, or toxic shock syndrome [14, 25]. This makes diagnosis difficult and can lead to delayed or missed appropriate treatment. A comprehensive history, physical examination, and laboratory investigation are necessary [14, 15]. Exposure to water sources and animals should be questioned to assess the risk of these diseases. Bacterial infections (such as staphylococcus, streptococcus, leptospirosis, and rickettsia) can cause toxic shock syndrome or septic shock. Therefore, these should also be considered in the differential diagnosis. Among common viral infections, viruses that can cause multi-system organ involvement, such as enteroviruses, adenoviruses, parvovirus, rotavirus, and Epstein-Barr virus (EBV), should be particularly kept in mind during differential diagnosis. Additionally, drug-induced hypersensitivity syndrome (DIHS) and macrophage activation syndrome (MAS), which can lead to a similar clinical picture, should also be considered [6, 28].

High inflammatory markers and systemic involvement should also be particularly considered in the differential diagnosis of acute COVID-19 with systemic manifestations. This is because distinguishing MIS-A with multi-organ involvement, which can have both acute and biphasic courses, from both acute COVID-19 and the acute sequelae of SARS-CoV-2 infection can be challenging [14, 17]. While there are some clinical similarities in terms of symptoms and signs between MIS-A and COVID-19, rashes and gastrointestinal symptoms are more commonly seen in MIS-A, whereas upper respiratory symptoms such as cough and runny nose are more pronounced in COVID-19. Since the treatment for these two diseases is different, making the correct differentiation is of vital importance [14].

Due to the severity of the disease and the possibility of rapid progression, the cornerstone of successful treatment for the patient lies in suspecting MIS-A based on the medical history (especially recent recovery from COVID-19) and clinical symptoms, excluding alternative diagnoses, and making an early diagnosis [14].

10. Treatment

MIS-A therapy is generally adapted from the treatment guidelines developed for MIS-C. There is no uniform treatment strategy for MIS-A. Treatment largely focuses on immunosuppression using steroids or other immunomodulators, and supportive therapies (such as fluid resuscitation, inotropic support, and respiratory support) are used in most cases [29]. From a clinical point of view, undetected MIS-A has a high mortality rate [14]. The prognosis of the disease depends on early recognition of the condition and prompt administration of immunomodulatory therapy, which reduces the risk of developing life-threatening complications [6, 30]. The published literature on MIS-A is limited to small case series and a single observational epidemiological study that provides little data to guide treatment decisions for MIS-A patients. Therefore, MIS-A treatment is usually adapted from the treatment guidelines developed for MIS-C [31]. No randomized controlled trials have compared different treatment approaches for MIS-C. However, data from descriptive and observational comparative efficacy studies are available to guide MIS-C treatment [31]. This section summarizes the recommendations of the COVID-19 Treatment Guidelines Panel (NIH, July 21, 2023) for the therapeutic management of pediatric patients with multisystem inflammatory syndrome in children (MIS-C). Includes individuals <21 years of age, according to the Centers for Disease Control and Prevention (CDC) MIS-C case definition [31].

Children with MIS-C are recommended to be treated in centers where a multidisciplinary team consisting of experts in cardiology, hematology, infectious diseases, intensive care, and rheumatology is available when immunomodulatory therapy is applied. Based on previously reported cases, intravenous immunoglobulin (IVIG) and glucocorticoids are the most used immunomodulatory treatments in children with MIS-C. The American College of Rheumatology recommends the combination of IVIG and glucocorticoids as the first-line immunomodulatory treatment for hospitalized children with MIS-C. The NIH (COVID-19 Treatment Guidelines Panel) the panel also suggests the combined use of IVIG and low to moderate-dose glucocorticoids in children hospitalized with MIS-C. The glucocorticoid dose considered low to moderate is typically 1 to 2 mg/kg/day of methylprednisolone or an equivalent dose of another glucocorticoid [31].

The IVIG dose should be administered at a dose of 2 g/kg based on the ideal body weight and should not exceed a maximum total dose of 100 g. During the patient’s IVIG infusion, heart function and fluid status should be monitored, and in cases where there is a risk of developing fluid-related issues, the IVIG dose can be divided into 1 g/kg doses based on the ideal body weight and spread over 2 days. When clinical improvement occurs in the patient, glucocorticoid doses should be gradually reduced [31].

In children with MIS-C, the absence of fever, a decrease in inflammatory parameters in laboratory measurements (especially C-reactive protein, CRP, IL-6, sedimentation rate, etc.), and the improvement of end-organ dysfunction are considered as signs of clinical improvement. Studies have shown that the combined use of IVIG and glucocorticoids provides additional benefits compared to monotherapy with glucocorticoids or IVIG alone. Therefore, the NIH recommends IVIG monotherapy as the initial treatment only when steroids are contraindicated, while glucocorticoid monotherapy is recommended in cases where IVIG is not available or contraindicated [31].

10.1 Hospitalized children with treatment-resistant MIS-C may require intensified immunomodulatory therapy

In general, children hospitalized with MIS-C tend to respond well to initial immunomodulatory treatment, with clinical improvement often seen on the first day of treatment. However, some children may not show this clinical improvement and may experience worsening organ dysfunction alongside persistent fever and increased inflammatory markers. In cases where children with MIS-C do not respond to treatment within 24 hours of the initial immunomodulatory therapy, the NIH recommends transitioning to intensified therapy. Response to treatment is considered as the resolution of fever, a decrease in inflammatory markers, and improvement in end-organ dysfunction [31].

For children with NIH-defined treatment-resistant MIS-C, the NIH recommends additional immunomodulatory therapy with anakinra, high-dose glucocorticoids, or infliximab. There is insufficient evidence to determine which of these agents is superior for intensified therapy in treatment-resistant MIS-C. Therefore, they are recommended in alphabetical order [31].

In cases of severe disease resistance, combination therapy with high-dose glucocorticoids and anakinra or high-dose glucocorticoids and infliximab can be used for intensified treatment. However, anakinra and infliximab should not be used in combination. In cases of treatment-resistant MIS-C, intensified therapy with a second dose of IVIG is not recommended by the NIH, especially for cases that did not respond to initial treatment. The NIH emphasizes the high risk of IVIG resistance, concerns about fluid overload, and the potential for rapid disease progression in such cases [31].

Patients receiving immunosuppressive treatment are at a higher risk of infections. The NIH emphasizes that the risks and benefits of using these agents should be evaluated individually for each patient, especially in immunocompromised MIS-C patients, as there is an increased risk of secondary infections with immunomodulatory therapy [31].

In the case of MIS-C, positive results have been observed in patients treated with Intensified Immunomodulatory Therapy using High-Dose Glucocorticoids. High-dose glucocorticoid therapy is defined as the intravenous (IV) administration of 10 to 30 mg/kg/day of methylprednisolone or an equivalent corticosteroid. After 1 to 3 days of high-dose glucocorticoids, the treatment is transitioned to low to moderate doses (1–2 mg/kg/day) [31].

10.2 Anakinra

Anakinra has been used successfully in the treatment of IVIG-resistant Kawasaki disease and is commonly used in other hyperinflammatory syndromes like macrophage activation syndrome in pediatric patients. Anakinra has a good safety record and is the most used biological agent for the treatment of MIS-C in children in the United States. An advantage of anakinra is its short half-life (4–6 hours), allowing it to be quickly discontinued when necessary. High-dose anakinra (5–10 mg/kg/day) is recommended for MIS-C patients based on its proven efficacy in macrophage activation syndrome. The duration of treatment can vary but it has been noted that it can be used as a long-term steroid-sparing agent for up to 2 weeks [31].

NIH recommends Infliximab as an option for intensified treatment in hospitalized MIS-C patients. A single dose of IV Infliximab (5–10 mg/kg) is suggested [31].

Furthermore, there is a consensus among the panel that low-dose aspirin should be given as antithrombotic therapy to MIS-C patients without bleeding risk. It is also noted that antiviral treatment is not expected to be beneficial since MIS-C is thought to develop because of a disrupted immune response weeks after the primary SARS-CoV-2 infection [31].

MIS-C patients are at an increased risk of developing shock, and shock management is recommended to follow the Pediatric Septic Shock Management Guidelines [31].

According to the analysis results by Kunal et al., who investigated the treatment of MIS-A in a total of 79 patients, steroids (60.2%) and intravenous immunoglobulins (37.2%) were most often used in the treatment. Only about 10% of patients required biological treatment [18].

According to Patel’s study, which included 221 patients, anticoagulant treatment was used in 110 of 193 patients receiving MIS-A treatment, corticosteroids were used in 152 of 205 patients, and IVIG treatment was used in 112 of 205 patients. Immunomodulators were used in 42 of 203 patients. Shock or hypotension developed in 51% of the patients, 115 of the 201 patients were admitted to the intensive care unit, and 15 of the patients (7%) died [15].

11. Conclusion

Multisystem inflammatory syndrome in adults (MIS-A) is a rare and not fully understood post-infection complication of COVID-19, potentially life-threatening, and has been reported in a limited number of cases worldwide. From a clinical perspective, undiagnosed MIS-A has a high mortality rate. The prognosis of the disease relies on early recognition of the condition and the immediate application of immunomodulatory treatments (such as steroids, immunoglobulins, etc.) that reduce the risk of life-threatening complications. Due to the risk of rapidly developing decompensation and critical illness, patients require urgent medical intervention. MIS-A should be considered in cases of sudden cardiac symptoms of unknown cause. Therefore, increasing awareness among clinicians about this emerging disease is essential. More research is needed to better understand the pathophysiology of the multisystem inflammatory syndrome and optimize its treatment.