Case series of secondary thrombotic microangiopathy in children with multisystem inflammatory syndrome associated with COVID-19

Background

In 2020, one child with hemolytic uremic syndrome (HUS) received treatment in the pediatric ICU of the Khimki Regional Hospital. In January-May 2021, the admission diagnosis of HUS was established in 7 children. Therefore, in recent months, a 7-fold increase in the hospital admission rate of children with HUS clinical presentations was reported. This phenomenon occurred during the COVID-19 outbreak in the Russian Federation. As a result, an association between COVID-19 and HUS was established. The COVID-19 infection in children is less common than in adults (1-5% and 8.4% of all laboratory-confirmed cases globally and in Russian Federation, respectively) [1]. Moreover, 82.2% are asymptomatic or have mild disease [2]. Nevertheless, multisystem inflammatory syndrome in children (MIS-C), a severe COVID-19 in children or its complication, is reported worldwide [3]. In a study of children with MIS-C, the incidence of this condition in persons younger than 21 years was 2 per 100,000. Meanwhile, the incidence of SARS-CoV-2 infection in age-matched individuals was 322 per 100,000 [4].

MIS-C is a new disease firstly described in 2020. It is associated with a previous infection caused by SARS-CoV-2. Severe endothelial damage involving at least two organ systems underlies MIS-C [5]. Severe intoxication, fever, and increased D-dimer and ferritin levels are common to MIS-C.

Diagnostic criteria for MIS-C:

– severe patient condition requiring hospitalization;

– fever (body temperature >38°C) persisting at least 24 h;

– increased levels of inflammation markers (C-reactive protein/CRP, fibrinogen, procalcitonin, D-dimer, erythrocyte sedimentation rate/ESR);

– multisystem inflammation involving at least two organ systems;

– less than 21 years of age;

– laboratory-confirmed COVID-19 infection: positive oral (throat)/nasal swab PCR test for SARS-CoV-2 RNA, or positive SARSCoV-2 IgG/IgM blood tests, or epidemic medical history (contact with a person with confirmed COVID-19 infection within the last month) [6].

In analyzing MIS-C cases, we recognized changes in its clinical presentations in various periods of the COVID-19 pandemic. During the first wave, rash and hepatosplenomegaly (Kawasaki-like disease) were mainly reported [7]. During the second wave, gastrointestinal (GI) disorders manifested with diarrhea and vomiting prevailed. In January-May 2021, children with predominant kidney disease have been reported.

The pathogenic mechanisms of MIS-C associated with SARS-CoV-2 currently remain elusive. However, the COVID-19 infection is characterized by coagulopathy, including thrombotic microangiopathy [8].

Pulse steroid therapy and long-term treatment with peroral dexamethasone are effective for MIS-C. High-dose (2 g/kg per a 3-5-day course) immunoglobulins and anticoagulants also demonstrate good results in these patients [4, 6].

We describe several children with MIS-C and predominant kidney disease.

Case reports

Seven children with MIS-C received treatment in the intensive care unit of the Khimki Regional hospital. Anemia, thrombocytopenia, hyperbilirubinemia, and kidney disease of varying severity were reported in all children.

None of the children had a medical history of the established COVID-19 infection. All children underwent the PCR test for SARS-CoV-2 detection. Results were negative. Six children underwent the COVID-19 IgG/IgM antibody test (see Table 1). Antibodies against SARS-CoV-2 were detected in 5 of 6 children. In 3 children, antibody inversion was reported during the in-hospital stay, thereby demonstrating the development of this condition during the early convalescence stage of the COVID-19.

Given the association between the COVID-19 infection and immune abnormalities in MIS-C, this condition is regarded as a secondary thrombotic microangiopathy (TMA).

All children had a history of fever, more common low-grade one (see Table 2). In most children, the disease starts with GI disorders, i.e., vomit and diarrhea. The children were admitted to the hospital with suspected intestinal infection. Only one girl complained of myalgia without the intestinal syndrome. Hemorrhagic rash was detected in one child.

Complete blood test revealed anemia (hemoglobin 65–105 g/l, mean level 85.8 g/l) and thrombocytopenia (PLT count 47-136 10⁹/l, mean count 85 10⁹/l).

Blood biochemistry revealed high bilirubin, mostly due to indirect bilirubin (total bilirubin 24–115 mcmol/l), ASAT (6/7), LDH (463-12,000 U/l, mean level 4,980 U/l), and CPK (204-3,729.9 U/l, mean level 949 U/l).

Markers of systemic inflammation were detected in all children, i.e., ESR 18–54 mm/hour, CRP no more than 5 norms, ferritin 307–648 mcg/l, D-dimer 3.24–8 mcg/ml in FEU.

Low urine output (anuria in two children) was reported in all children. Lab tests detected kidney damage in all children. Urinalysis revealed macro- or microhematuria, minimal leucocyturia, proteinuria (0.1–6.0 g/l), cylinduria, and (in a half of children) ketonuria and urobilinogenuria. Azotemia was reported in all children, i.e., urea was 12.7–65.3 mmol/l (on average, 34 mmol/l) and creatinine was 135.8–1450.2 mmol/l (1.4to 27.8 times higher than normal). Low glomerular filtration rate (GFR) calculated using the Schwartz formula was reported in all children (1.7–58.1 ml/min/1.73 m²). In 5 children, GFR was less than 15 ml/min/1.73 m², thereby indicating total loss of nephron function. GFR was below the norm by 2.2–56.4 times.

Lab tests (see Table 3) have demonstrated that all children had the classic triad of HUS, i.e., anemia, thrombocytopenia, and acute kidney failure. Meanwhile, liver damage (the severity of cytolysis) and an increase in inflammation markers, which are not typical for HUS but are a signature of MIS-C associated with SARS-CoV-2 were detected.

Abdominal ultrasound (US) revealed polyserositis (ascites, pleural effusion, hydropericardium) and hepatosplenomegaly in all children.

At admission, renal Doppler ultrasound revealed enlarged kidneys (in 5 of 7 children) and decrease in cortical blood flow (in all children). After treatment, blood flow improved within a week in all children.

Therefore, clinical and lab tests revealed both signs of thrombotic microangiopathy typical for HUS and the COVID-19 infection and signs of systemic inflammation typical for MIS-C. Additionally, SARS-CoV-2 infection (history or early convalescence phase) was verified by lab tests in all children. Hence, the above establishes an association between HUS-like kidney disease and SARS-CoV-2-associated MIS-C.

Five children underwent renal replacement therapy/RRT (1 to 7 procedures of hemodiafiltration, an average, 2.14 procedures). Atypical HUS was suspected in 2 children who underwent therapeutic plasma exchange. Given an increase in systemic inflammation markers (ESR, CRP, ferritin, D-dimer), all children received systemic steroids. Improvement in kidney functions and hematological parameters secondary to steroids without extracorporeal treatment was reported in 2 children. Additionally, all children received antibiotics, infusions, and anticoagulants (dalteparin sodium). All children were discharged with clinical recovery. In 5 children, minimal and moderate proteinuria persisted in urinalysis.

Discussion

In children, the COVID-19 infection is initially characterized by a milder (often asymptomatic) course than in adults, being under the mask of ARI. However, blood coagulation abnormalities, vascular lesions, and systemic inflammation affecting several organs and systems triggered by SARS-CoV-2 require pediatricians to be aware of establishing an association between the COVID-19 infection and somatic diseases emerging after recovery.

All children presented with acute kidney injury (AKI) as evidenced by low urine output and elevated creatinine levels . The KDIGO (Kidney Disease: Improving Global Outcomes) classification includes three graded stages of AKI [10]. GFR was also low in all children.

Meanwhile, in our view, this syndrome cannot be regarded as typical (STEC-HUS) or atypical HUS. Instead, we should rather consider secondary thrombotic microangiopathy (TMA) with the primary kidney injury secondary to the prior COVID-19 infection and MIS-C. This phenomenon has been described earlier in HIV, influenza, malignancies, etc. [11].

TMA may develop in children with SARS-CoV-2-associated MIS-C and adults with severe COVID-19 infection [12]. Some authors have assessed TMA severity based on measuring blood sC5b9 levels in children with mild and severe COVID-19 infection and MIS-C. The most severe TMA and elevated sC5b9 levels were found in children with severe COVID-19 and MIS-C being correlated with kidney failure signs [13]. In our study, principal manifestations were kidney failure, anemia, and thrombocytopenia. Additionally, other organ lesions (gastrointestinal disorders, polyserositis, and rash) have been reported.

All children received hormones, anticoagulants, antibiotics, and RRT as indicated. This treatment regimen is recommended for MIS-C. We suggest that in secondary TMA, one should proceed to the treatment for MIS-C as the primary disease and enhance it with RRT as indicated. In our study, the key indications for RRT were low urine output and azotemia based on the KDIGO guidelines (stage 3 was reported in 3 children and stage 2 in 2 children) [10]. Hyperkalemia requiring RRT was not reported.

Conclusions

We have previously described toxic kidney-like renal failure in MIS-C, which was relieved by managing the underlying disease [7]. These case reports demonstrate a 7-fold increase in the number of patients with clinical signs of HUS within a year, as reported by a pediatric ICU in the Moscow Region. In 5 of 7 patients, AKI was associated with prior COVID-19 infection. These findings suggest secondary TMA in MIS-C associated with SARS-CoV-2. To our knowledge, this is the first study of that type published in the Russian Federation.

A pathogenic basis for HUS is TMA of the renal vessels. Secondary TMA with predominant impairment of renal vessels can also develop in multisystem inflammatory syndrome associated with SARS-CoV-2. In the lack of adequate lab tests, it is rather challenging to determine the primary cause of renal disorders. In the COVID-19 pandemic, it is essential to establish the association between TMA and prior COVID-19 in children to adjust therapy and follow them after discharge.

About the authors:

Dmitry V. Novikov — Head of the Department, anesthesiologist-resuscitator of the Department of Anesthesiology and Resuscitation for Children, Khimki Regional Hospital; 11, Kurkinskoe Highway, Khimki, 141407, Russian Federation; ORCID iD 0000-0001-8622-2998.

Tatiana S. Sabinina — anesthesiologist-resuscitator of the Department of Anesthesiology and Resuscitation for Children, Khimki Regional Hospital; 11, Kurkinskoe Highway, Khimki, 141407, Russian Federation; ORCID iD 0000-0001-9896-1798.

Tatiana V. Shalbarova — Laboratory Assistant Researcher of the Clinical Department of Infectious Pathology, Central Research Institute of Epidemiology of the Russian Federal Service for Supervision of Consumer Rights Protection and Human Well-Being; 3A, Novogireevskaya str., Moscow, 111123, Russian Federation; ORCID iD 0000-0003-3659-3592.

Olga L. Chugunova — Dr. Sc. (Med.), Professor of the Department of Hospital Pediatrics named after V.A. Tabolin, Faculty of Pediatrics, Pirogov Russian National Research Medical University: 1, Ostrovityanova str., Moscow, 117997, Russian Federation; ORCID iD 0000-0003-1547-0016.

Elena V. Melekhina — Dr. Sc. (Med.), Associate Professor in Pediatrics, Leading Researcher of the Clinical Department of Infectious Pathology, Central Research Institute of Epidemiology of the Russian Federal Service for Supervision of Consumer Rights Protection and Human Well-Being; 3A, Novogireevskaya str., Moscow, 111123, Russian Federation; ORCID iD 0000-0002-9238-9302.

Contact information: Tatyana S. Sabinina, e-mail: tanuwok@mail.ru.

Financial Disclosure: no authors have a financial or property interest in any material or method mentioned.

There is no conflict of interests.

Received 02.09.2021.

Revised 27.09.2021.

Accepted 20.10.2021.

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