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Well-known symptoms, new disease – a case of SARS-CoV-2 infection in an eight-year-old boy

Paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 infection (PIMS-TS) is a new disease in children, connected with the COVID-19 pandemic. The main cause of this disease is dysregulation of the immune homeostasis. We report the first case of PIMS-TS in the Polish Mother’s Memorial Hospital Research Institute in Lodz. Many non-specific symptoms presented by the patient were the cause of the primary care physician’s therapeu-tic failure, which resulted in the boy being transferred to the district hospital and then to the institute in Lodz. During the complex diagnostic process anti-SARS-CoV-2 antibodies in the IgM and IgG classes were detected. The initial diagnosis of PIMS-TS was made, and treatment with immunoglobulins and acetylsalicylic acid was initiated. The patient’s condition improved the following day. The aim of this report is to emphasize that typical symptoms do not always determine known disease entities, and to point out the need to constantly improve one’s knowledge.


INTRODUCTION
Paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 infection (PIMS-TS) is a new disease in children. The first reported case of PIMS-TS occurred in the USA on 7 April 2020 [1], while in Poland that novel diagnosis was confirmed almost a month later in a 2-year-old boy. Research shows that PIMS-TS is more prevalent in school-aged children with the median age of 9 years and occurs about 4 weeks after COVID-19 infection. The main cause of this disease is dysregulation of immune homeostasis. Clinical presentations include fever, cardiac involvement, gastro-intestinal symptoms, mucocutaneous manifestations, haematological features, or other organ dysfunctions.

CASE REPORT
We report an 8-year-old boy with allergy to dust mites, with no other chronic diseases, weight at the 25 th percentile, and height at the 75 th percentile for age. He was vaccinated in accordance with Polish recommendations.
The history of our patient starts at the primary care physician, where he reported with abdominal pain (without abnormal masses, exacerbate during movement) and 38-40ºC fever lasting for 4 days, of unknown origin. There he was treated with trimethoprim/sulfamethoxazole without result and then referred to the district hospital. The following treatment (ceftriaxone, fluconazole, ibuprofen, paracetamol) was administered with no improvement. Additionally, a generalized rash occurred, which was the reason for his transfer the patient to the Polish Mother's Memorial Hospital Research Institute in Lodz.
On admission the patchy and itchy rash (especially on the chest, lumbar area, and extremities), swelling and redness of the scrotum, auricles, and lips, "strawberry" tongue, bilateral non-purulent conjunctivitis, and enlarged anterior cervical lymph nodes were observed. The boy was weak and without appetite.
Laboratory tests showed high inflammatory markers, neutrophilia, hypoalbuminaemia, hiperferritinaemia, LDH, D-dimers, prolonged PT and INR, and high NT-proBNP. Interleukin 6 level (as an indicator of the risk of a cytokine storm) proved to be elevated (Tables 1 and 2).
Initially, the treatment was based on third-generation cephalosporin, antipyretic drugs, and intravenous fluids.
The following day, oliguria appeared. Daily protein loss in urine (1800 mg) met the criteria for nephrotic proteinuria. Systematic measurements of body weight, vital parameters, and daily fluid balance were carried out. According to the boy's increase of weight, the decision about fluid deprivation was made.
Thoracic ultrasonography revealed features of pneumonia and pleuritis with collection of fluid (55 ml) in the right pleural cavity. Echocardiography showed decreased ejection fraction of the left ventricle (56-58%). During hospitalization the boy's blood pressure was measured regularly; the lowest level was 87/44 mmHg.
Anti-Sars-CoV-2 antibodies in the IgM and IgG classes were detected.
Clinical features, laboratory results, and imaging studies led to a diagnosis of PIMS-TS.
The treatment with 2 g/kg intravenous immunoglobulins in 2 divided doses were initiated in premedication with clemastine and methylprednisolone. Acetylsalicylic acid was added. After modifying the treatment, the patient's condition improved the next day. Diuresis increased from 200 ml to 1800 ml per day (weight decreased by 1.1 kilograms). The fever, abdominal pain, and rash gradually normalized.
Due to the negative bacterial cultures, ceftriaxone was discontinued. The control echocardiography did not show significant changes. The patient was discharged from hospital after 11 days in good general condition with the following recommendations: • acetylsalicylic acid until the control echocardiography and until the further decision of paediatric cardiologist; • cardiological reassessments after 2-3 months; • probiotic; • reduction of physical activity for 2 months; • influenza vaccination; • control visit in the clinic after one month, with daily urine collection.

DISCUSSION
The pathogenesis of PIMS-TS is not fully clear, but it seems to be related with immune response dysregulation. Available research indicates a hyperinflammatory state presented by patients with that entity. Elevated levels of cytokines, such as interleukin 18 and interleukin 6 (IL-18 and IL-6), markers of lymphocytic and myeloid activation and peripheral chemotaxis are observed. Patients also present features of activation of natural killer cells, T cells, monocytes, and dendritic cells. Moreover, researchers have shown the presence of autoantibodies against endothelial, gastrointestinal, and immune system cells [2,3].
The pro-inflammatory status of PIMS-TS patients has common features with other conditions; however, differences in T-cell subsets and the cytokine profile suggest that the hyperinflammation in PIMS-TS can be placed between Kawasaki disease (KD) and acute SARS-CoV-2 infection in adults and children. KD is characterized by higher levels of arteritis and coronary artery disease markers than PIMS-TS, which suggest less severe endothelium involvement in the latter disease. Furthermore, analyses showed that pathogenesis of KD, but not of PIMS-TS, is strongly associated with interleukin 17A (IL-17A), which suggests that IL-17A blocking agents, such as secukinumab, will not be useful in the treatment of this new condition [4].
On the other hand, scientific data elevate the possible role of interleukin 6 (IL-6) in the aetiopathogenesis of PIMS-TS. An elevated level of this substance after interaction with IL-6 receptor leads to enhanced production of other inflammatory cytokines and consequently to initiation of the disease process. The mentioned biological phenomenon resembles the cytokine storm connected with, among others, SARS-CoV-2 infection in adults [5]. This observation suggests that IL-6 or IL-6 receptor are possible targets of severe PIMS-TS treatment, in addition to standard therapy.
However, the treatment of PIMS-TS is not yet conclusively established due to relatively little experience and ongoing research in this field.  • Fever occurs every day in the afternoon and evening hours, and responds poorly to antipyretic drugs • Salmon-coloured rash accompanies episodes of temperature increases, usually on the trunk and extremities • Joint pain or arthritis is most severe at the peak of the fever • Laboratory abnormalities are not specified and no indicator is present in this disease pathognomonic Acute rheumatic fever

• Occurs usually 2-3 weeks after a throat infection with group A Streptococcus
• Symptoms of cardiovascular system are pancarditis: pericarditis, myocarditis, endocarditis, including valvular inflammation, heart failure • Common symptoms of the other organs are arthritis, involvement of the brain (chorea), and skin (erythema marginatum, subcutaneous nodules) In accordance with the current state of knowledge, first-line treatment is intravenous infusion of immunoglobulins (IVIG) in total dose 2 g/kg. If the patient presents no improvement after administration, a second infusion of IVIG is not recommended [6]. Intravenous immunoglobulins have multiple functions that modulate and reduce inflammatory reactions. By blocking Fcγ receptors -proteins on the surface of the immune cells -IVIG contributes to impairment of the activation of the innate immune system. IVIG can also block interactions of receptors with target cells, affect lymphocyte differentiation and maturation, and cause cytokine dysfunction [7,8].
The second-line treatment, applied with IVIG in some conditions or when IVIG is not available or cannot be used, are glucocorticosteroids. Experts suggest starting the therapy with methylprednisolone (2 mg/kg, in 2 doses) and then changing it to oral medication, because CRP will reach the normal range.
Third-line treatment includes biological therapy: IL-1 antagonists (anakinra), IL-6 receptor blockers (tocilizumab), and anti-TNF agents (infliximab) [9]. Thrombocytopaenia is often observed at the end of therapy and requires modification of the ASA treatment. The dose (anti-platelet or anti-inflammatory) depends on the clinical manifestation of the disease.
A characteristic manifestations of PIMS-TS is cardiac dysfunction, including coronary artery dilatation or aneurysms, myocarditis, pericardial effusion, dysfunction of the left ventricle, or even shock. In all children suspected for PIMS-TS, electrocardiogram and echocardiography must be performed. The patients often have elevated levels of troponin and NT-pro-BNP -markers of heart failure, myocardial ischaemia, and damage. Most children with cardiac involvement require paediatric intensive care unit admission and administration of inotropic drugs. The fact that sudden deaths in that group of patients were also documented mean that PIMS-TS should be perceived as a serious and potentially life-threatening condition [10,11].
Other clinical symptoms include persistent fever, abdominal pain, skin and mucosal involvement, and respiratory or nervous dysfunctions (Table 2).