**4. Clinical manifestation**

#### **4.1 Signs and symptoms**

As described above, the onset of symptoms occurs weeks after exposure to the virus. During this period, the child is usually asymptomatic. When the disease manifests clinically, it starts with general symptoms that are not very specific. Fever is present and is one of the main criteria for diagnosing the syndrome. It is presented in all cases, being a requirement in all published clinical criteria. For CDC criteria fever >38°C must be at least 24 hrs., for WHO on the other hand it must be at least 3 days. Regardless of the criteria used, fever is a cardinal sign. The average duration is between 4 and 6 days. The early gastrointestinal symptoms are frequent to find, the series describe it in more than 60%. These include diffuse abdominal pain, vomiting, and diarrhea. Many of the children consult emergency services even with clinic suggestive of acute abdomen. Up to this point, the disease can mimic any common febrile gastrointestinal infection or can be similar to appendicitis. The involvement of skin is also frequent, and it is described between 45 and 75% of cases. It includes rash which is usually non-specific and generalized and swelling of the palms and hands with edema [14]. Another frequent clinical finding is the involvement of mucous membranes, which can vary between 30 and 75%, which includes inflammation of the labial mucosa presenting with edematous and reddened lips, and inflammation of lingual mucosa with a strawberry tongue, that resembles a Kawasaki Disease (KD)

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

[45, 46]. Ocular involvement can vary from 30 to 80% of cases, usually presenting as bilateral no purulent conjunctivitis. Other general symptoms may be present but in a low percentage. Neurocognitive involvement includes headache, lethargy, confusion, or irritability, which is described in less than 50% of cases [46]. Respiratory symptoms are rare during MIS-C, but may be present as a history of upper respiratory infection weeks prior to the onset of MIS-C symptoms. Lymphadenopathy is usually rare to find [47].

#### *4.1.1 Severe presentation*

So far, many children may express the disease with mild symptoms meeting the diagnostic criteria for CVC and WHO, but without cardiovascular compromise. The major problem is the group of patients who develops cardiovascular involvement. It is this involvement that reflects the severity of multisystemic inflammation and poses a potential life-threatening risk to affected pediatric population. These group of patient will need a pediatric critical care unit. It usually presents as shock, meeting most of the surviving sepsis campaign criteria, being difficult to differentiate it initially from a sepsis or a toxic shock since MIS-C usually is accompanied by cutaneous manifestations. Many children may show cardiovascular involvement due to cardiac dysfunction with or without coronary involvement. Coronary disease seems to be present more frequently than in KD. Arrhythmia is described but it is a less common presentation. Respiratory illness is rare in these critically ill patients and the need for invasive ventilatory support is often necessary for the management of pediatric shock and not for inflammation, damage or lung infection. The dysfunction of other organs is less frequent, but as it is generalized inflammatory multisystemic disease, there may be diffuse inflammation. This inflammation may present as serositis like pleurisy, pericardial effusion, and/or ascites. The liver can also be affected. There may be an increase in transaminases or even hepatitis. This condition is rare and fluctuates between 5 and 20% of cases. A neurologic clinic of mild symptoms was previously described at the beginning of symptoms; however when MIS-C is severe, it can severely compromise the central nervous system. The disease may present with encephalopathy, meningeal inflammation, and seizures [48].

#### *4.1.2 Presentation phenotypes*

The spectrum of the disease ranges from mild to severe as described above. MIS-C is new, so the factors that cause a child to evolve from mild-to-severe disease with cardiovascular involvement are still unknown. It is likely that laboratory tests that show a greater range of general inflammation are more frequently present in cases that are going to evolve to severe (3.2 laboratory tests); however, the severity of the disease is determined by cardiovascular involvement and presence of shock rather than by the results of laboratory tests [49]. What has been seen is that there are phenotypes resulting from associations combining the severity of the clinical presentation, the KD criteria, and the presence of shock. Then, we could classify the phenotype in three main forms: MIS-C phenotype KD without shock; MIS-C phenotype shock/myocarditis (with or without KD); and MIS-C phenotype without KD or shock.

MIS-C phenotype KD without shock. This is a group of children who, regardless of age, meet the WHO or CDC criteria for MIS-C, in which the clinical presentation fully or partially fulfills the diagnostic criteria for KD. These patients may have clinical and laboratory signs of general inflammation and even organ dysfunction or cardiac inflammation, but do not present with hypotension or signs of shock. Their laboratory tests show general and non-specific inflammation, but show no evidence of hypoperfusion.

MIS-C phenotype shock/myocarditis (with or without KD). These patients, who meet WHO and CDC criteria for MIS-C, show hypotension or evidence of shock regardless of the KD criteria. Then, we can have patients in shock with mucosal and cutaneous involvement like KD, but also patients in shock who do not show any Kawasaki signs. In them, the cardiovascular compromise can manifest as shock, by the criteria of the surviving sepsis campaign, or as myocarditis. Laboratory tests appear to show higher ranges of generic and cardiac inflammation. It is important to recognize this group of patients since they are children who require advanced monitoring and management of shock in an Intensive Care Unit (ICU).

MIS-C phenotype without KD or shock. These children also meet WHO and CDC criteria for MIS-C, but they have no clinical criteria for KD or clinical or laboratory evidence of hypoperfusion, shock or myocarditis. These patients, like the previous ones, present multisystem inflammation and organ systems involved, but without cardiovascular involvement.

All the groups have in common a generalized systemic inflammation, initiated as fever and gastrointestinal symptoms, defining their phenotypes in a few days. It is important to note that coronary alterations can be present in any of the groups. Coronary alterations are rare to observe in children, so it denotes severity of the disease, independent of filling the KD criteria and even without hypotension or shock. In summary, the clinical presentation of MIS-C can be very variable. Most children have a mild multisystemic inflammatory compromise without shock; however, the recognition of cardiovascular involvement is critical. Children with Shock (with or without KD criteria) are the group of patients that will require advanced critical care support, including advanced monitoring and in some cases connection to invasive mechanical ventilation. The pediatric population with an clinical presentation of shock are the children with the highest risk of morbidity and mortality.

#### **4.2 Laboratory test**

Laboratory tests reflect children's severe inflammatory involvement. Abnormal level of blood cell counts is one of the most frequent findings. The blood count shows elevation of white blood cells of neutrophilic predominance; however, the presence of lymphopenia is described as even more frequent, up to 80–95% of cases. Moderate anemia and thrombocytopenia can be observed in many cases and can be seen in 70 to 80%. The elevation of inflammatory parameters is relevant when making the diagnosis of MIS-C and is present in the diagnostic criteria of all clinical guidelines. There is an elevation of general inflammatory parameters and also of specific cardiac parameters. The rise of C-reactive protein (CRP) into bacterial range occurs up to 90–100%. Erythrocyte sedimentation rate (ESR) is another result that is elevated up to 80%. Procalcitonin also rises up in bacterial ranges [9, 47]. Elevation of other acute phase reactants such as ferritin, dimer D, and fibrinogen also occurs in 60 to 80% of MIS-C. Hypoalbuminemia is a common finding. As stated, when signs and symptoms were described, MIS-C can present with or without shock. Patients with shock have a greater elevation of inflammatory parameters compared to children without shock, so it could be assumed that these elevated parameters are related to the severity of the disease [50, 51]. Regarding interleukins, in MIS-C there is a severe elevation of Interleukin (IL) 6. It is interesting to note that although the elevation of IL6 is severe


#### **Table 1.**

*Tests required in MIS-C.*

due to the large systemic inflammatory process that occurs in MIS-C, when compared to the IL6 measurements of pediatric septic shock, the latter are greater. This suggests that although the pathophysiological basis of MIS-C is immune-mediated, it is likely that IL6 is not the main interleukin mediating the disease [52]. Elevated cardiac inflammatory parameters seem to be important when making the diagnosis of pediatric inflammatory syndrome associated with COVID-19, since the heart is one of the main organs affected. Between 60 and 90% of patients with MIS-C can elevate troponins and/or pro BNP. As in general inflammatory parameters, cardiac laboratory elevation is greater in patients with shock than without it. The laboratory tests requested in children with MIS-C are shown in **Table 1**.

#### **4.3 Images**

There are no specific altered images in MIS-C. Chest X-ray shows no specific findings. Although infiltrates, consolidation or atelectasis may be observed, most of the patients have no acute respiratory clinic, so the most frequent finding is a normal chest X-ray. If X-ray shows pulmonary alteration, it may be a consequence of the SARS-CoV2 infection that occurred prior to MIS-C. It is rare to see a patient with an altered chest X-ray who is simultaneously in a multisystem inflammatory process, since MIS-C occurs weeks after the respiratory infection as explained above. It is possible to find pleural effusion as part of the inflammatory disease. One of the initial symptoms of the disease is abdominal pain that can even mimic an acute abdomen, so abdominal ultrasound is a study frequently requested. Like chest X-ray, abdominal images are non-specific for the disease, showing alterations that are mainly a consequence of a diffuse inflammatory process. It can observe ascites, free fluid, ileitis, and mesenteric adenopathy/adenitis. Chest or abdomen computed tomography (CT) does not show specific alterations. The most altered image study is echocardiography. There is no specific finding in cardiac ultrasound, being able to find multiple alterations alone or associated. Left ventricle (LV) dysfunction can be found up to 40% of patients with MIS-C. If the disease presents clinically as shock, depression of LV function is more frequent, being present in up to 60% of these severe cases. Heart valve diseases such as mitral or tricuspid regurgitation also may be found. Pericardial effusion can be seen, and as well as pleural effusion and ascites, it is due to a generalized inflammatory process with serositis. One of the most important findings of the disease is the alteration of the coronary arteries (CA). This type of alteration is very rare in children, with KD being one of the few pediatric diseases in which it is present. CA abnormalities include dilation or aneurysm. This alteration may be present up to 25% of mild cases and even up to 50% in severe cases with shock. CA assessment is based on Z-scores used in KD [53–55]. Performing cardiac nuclear magnetic resonance imaging (MRI) is rare, but when it has been done, myocardial edema and abnormal strain is described, compatible with a generalized cardiac inflammatory process [56].
