**5. Diagnosis**

#### **5.1 Case definition**

The CDC or WHO criteria are the most commonly used case definition. Regardless of the institution that defines the case, all definitions have some pillars to make the diagnosis. The first is a pediatric patient with fever. The second is to have inflammation of at least two systems, by clinical presentation or by laboratory test. The third is to have altered laboratory parameters that show a systemic and generalized process of inflammation. The fourth is to have ruled out any infection that is not COVID and finally any epidemiological association with SARS-CoV2 infection [7, 8]. Case definition criteria are shown in **Tables 2** and **3**.

The criteria can be modified over time as there is more knowledge of the syndrome. CDC will change the current case definition in 2023. Among main changes are fever lasting >24 hrs. Will be changed by subjective or documented fever >38.0°C. Illness requiring hospitalization will be changed for severe illness that requires hospitalization

*Multisystem Inflammatory Syndrome in Children (MIS-C) DOI: http://dx.doi.org/10.5772/intechopen.110684*


*BNP: B-type natriuretic peptide. PT: Prothrombin time. PTT: Partial thromboplastin time. ESR: Erythrocyte sedimentation rate. CRP: c-reactive protein. PCR: Polymerase chain reaction.*

#### **Table 2.**

*WHO MIS-C case definition (all criteria are required).*


*Health Alert Network (HAN) [8].*

*CRP: c-reactive protein, ESR: erythrocyte sedimentation rate, BNP: B-type natriuretic peptide, and PCR: polymerase chain reaction.*

#### **Table 3.**

*2020 CDC MIS-C case definition (all criteria are required).*

and may result in death. Laboratory makers of inflammation will be limited to just CRP >3 mg/dl. Shock will appear as a separate criterion of cardiac involvement. Coronary involvement will include coronary dilatation/aneurysm and left ventricular ejection <55%. Dermatological criteria will be more explicit: oral mucosal inflammation, conjunctivitis/conjunctival injection, or extremity findings (erythema, edema). Gastrointestinal criteria will be limited to abdominal pain, vomiting, or diarrhea. Renal, respiratory, and neurologic organ system involvement will be removed.

#### **5.2 Differential diagnosis**

Because it is a disease that can have many clinical presentations, there are many possible differential diagnoses but there are some of them that are essential to rule out. In many cases, the disease simulates sepsis or septic shock, both by its clinical presentation or by laboratory tests in ranges that simulate bacterial infection. The main difference is that in MIS-C there is no bacterial infectious focus and that no infectious agent is isolated. The association with SARS-CoV-2 as the only infectious agent it is absolutely necessary.

#### *5.2.1 Infectious inflammatory diseases*

Appendicitis: MIS-C may present as acute abdomen. Fever added to abdominal pain and tests in bacterial range make appendicitis difficult to rule it out. At the beginning of the pandemic, cases of children undergoing laparoscopies for suspected appendicitis were reported in which normal appendices were found. To dismiss the diagnosis of appendicitis, an abdominal image (ultrasound or CT) is required. In MIS-C, this image shows non-specific abdominal inflammatory findings but no inflammation of the cecal appendage.

Sepsis y Septic Shock: It is one of the main diagnoses to discard. Aforesaid, MIS-C simulates a bacterial infection, with fever and laboratory parameters in bacterial range, even in severe cases of MIS-C may show evidence of shock. That is why many established protocols suggest the initiation of antibiotics empirically and then suspend them once an infectious focus has been ruled out. Unlike septic shock, MIS-C does not have a specific infectious focus and bacterial infectious agents cannot be identified. It is necessary to take cultures to rule out the main bacterial pediatric infectious diseases. At least blood cultures are required to rule out bacteremia and complete urine with urine culture to rule out urinary focus. Other studies may be added depending on the clinical presentation. Intestinal pathogens can be searched if gastrointestinal clinic predominates. Study of cerebrospinal fluid can be studied if the predominant clinic is neurological. Other studies depend on each case. With negative cultures and once any clinical focus is dismissed, the bacterial cause of the inflammatory process should be ruled out.

Toxic Shock Syndrome (TSS): It has many similarities with MIS-C, since they share the multisystem inflammation, laboratory tests in similarly high ranges and the skin involvement. The main difference between both conditions is the presence of a clinical focus and the bacterial origin of the (TSS). Cultures are required to determine staphylococcal or streptococcal infection.

Other viral infections: There are viral pathogens that can cause systemic inflammation and skin involvement, including this adenovirus, cytomegalovirus, Epstein Barr virus, enterovirus, and parvovirus among others. Infection with these agents often occurs in immunosuppressed patients. In general, these viral infections do not produce an elevation of inflammatory parameters in bacterial range. If the suspicion exists, molecular study by polymerase chain reaction is necessary to confirm the presence of this viral infection.

#### *5.2.2 Immune-mediated inflammatory diseases*

Kawasaki disease: This is a challenge as they share a large number of clinical and laboratory elements. The situation becomes more difficult if the MIS-C does not meet all the KD criteria, with the incomplete Kawasaki being more difficult to distinguish from a MIS-C. The keys to differentiate them could be the gastrointestinal symptoms that are more frequent in MIS-C, cardiovascular dysfunction, and shock that are rare in KD (KD shock syndrome has an incidence rate of only 3.3–7% of KD cases) [57], high inflammatory parameters in laboratory tests associated with lymphopenia most common in MIS-C and the temporal association or evidence of exposure to SARS-CoV-2 [25].

Systemic lupus erythematosus (SLE): Like MIS-C, SLE is a multisystem immune process which can have skin involvement and that occurs with elevation of inflammatory parameters often in bacterial ranges. One of the elements to be taken into consideration to differentiate these diseases is age, being SLE more frequent in adolescent patients; female sex that is predominant in SLE, renal involvement that is much less frequent in MIS-C; and the neurological compromise that is most associated with SLE.

Hemophagocytic lymphohistiocytosis (HLH): Macrophage activation syndrome (MAS).

This disease shares characteristics with MIS-C, both in multiorgan involvement and in laboratory parameters. It usually occurs in patients with a history of immunerheumatologic diseases, but can also be triggered by viral or bacterial infectious diseases in previously healthy patients. There are diagnostic criteria published by the histiocyte society. Fever, high C-reactive protein, high ferritin, and thrombocytopenia are elements that it shares with MIS-C; however, the compromise of other lines of the blood count as well as the increase in triglycerides is not common in MIS-C. One of the most important tests for HLH/MAS is the elevation of soluble CD25, which does not occur in MIS-C.

## **6. Treatment**

Treatment has two goals. The first is to stop hyperinflammation and the second is to treat cardiovascular complications that could be associated in severe cases. At the time of this publication, there are no randomized controlled studies evaluating the treatment of MIS-C.

#### **6.1 Treatment of hyperinflammation**

Many ways to immunomodulate the disease are described, most of them initially borrowed from Kawasaki disease and other hyperinflammatory syndromes. They could be grouped into three approaches: the use of intravenous immunoglobulin (IVIG), the use of steroids, and the use of biological drugs.

#### *6.1.1 IVIG and steroids*

VIG is the most commonly used drug to modulate MIS-C followed by glucocorticoids. There are few comparative studies between the use of IVIG and steroids, and

their results are contradictory. On the one hand, some studies would suggest that the joint use of both therapies appears to have some impact on signs or symptoms, as well as in severe cardiovascular evolution (v/s IVIG alone). On the other hand, some publications suggest that patients who meet the WHO criteria for MIS-C are treated with glucocorticoids and they would have a possible benefit (v/s IVIG alone). Moreover, other studies show no difference between using IVIG alone, steroids alone, or the two therapies together. In view of the lack of evidence, but with the clarity that patients respond to immunomodulatory therapy, scientific societies have published treatment recommendations. American College of Rheumatology (ACR) recommends the use of IVIG as a first line in all patients with MIS-C with addition of glucocorticoids in the presence of shock, organ-threatening disease or refractory disease. There are countless protocols, adapted according to each local reality. The recommended doses of IVIG are 2gr/kg/day once. Methylprednisolone doses vary according to protocols between 2 and 10 mg/k/day for 3 days. In general, patients respond to the use of IVIG and steroids. Patients who maintain fever and elevated inflammatory parameters are considered refractory. In this type of patients, the use of biological drugs is considered [58].

#### *6.1.2 Biological drugs*

The use of biological therapy as rescue in patients refractory to IVIG/steroid treatment is described in many protocols. Like other therapies, these drugs were extrapolated from the treatment of KD and other diseases with systemic inflammatory processes. In order to block the effect of IL-1B, anakinra (an IL-1 receptor blocker) has been used. Another IL receptor blockade described is IL-6 by tocilizumab. Infliximab is another monoclonal antibody, used in refractory KD, to stop the effect of tumor necrosis factor alpha (TNFa) [59]. This drug is also described as a therapeutic tool in refractory MIS-C. As shown in **Figure 2**, the pathophysiology of MIS-C is complex,. Trying to stop an inflammatory cascade by blocking a single pathway seems unlikely. IL6 is elevated in both MIS-C and pediatric septic patients (both diseases with immune dysregulation). Septic patients have higher IL-6 plasmatic levels and have good outcomes without using interleukin blockade, suggesting that there is no clear role of some IL6 in the pathophysiology of MIS-C [52]. The use of biological drugs is continuously studied for this pathology.

#### **6.2 Treatment of cardiovascular complications**

Severe MIS-C can lead to severe cardiovascular dysfunction that can be life threatening for children. Endothelial involvement and cardiac dysfunction (with or without coronary alteration) can lead to hypotension, hypoperfusion, and dysfunction of other organs. It must be managed as shock, and in many cases it requires volume, vasoactive drugs, and even connection to mechanical ventilation as part of shock management. Due to the compromise of vascular tone, norepinephrine is indicated. If there is cardiac dysfunction, epinephrine should be associated. In the case of coronary alterations, anti-inflammatory and antiplatelet treatment with acetylsalicylic acid is used in MIS-C protocols. This management was extrapolated from KD protocols. Although abnormal coagulation parameters are frequently reported, thrombotic or embolic events were rare, in contrast to adult COVID-19 [59, 60]. Other management of vascular complications includes the possibility of thrombosis. High D-dimer is frequently found in this disease and could be associated with greater hypercoagulability,

which is why many protocols include the use of anticoagulation such as enoxaparin until the inflammatory process and D-dimer go down.
