Journal of Clinical Immunology https://doi.org/10.1007/s10875-021-01078-4 ORIGINAL ARTICLE Atypical Inflammatory Syndrome Triggered by SARS‑CoV‑2 in Infants with Down Syndrome Louise Malle1,2,3,4,5 · Paul Bastard6,7,8 · Andrea Martin‑Nalda9,10 · Taya Carpenter11 · Douglas Bush2 · Roosheel Patel1,2,3,4,5 · Roger Colobran12,13 · Pere Soler‑Palacin9,10 · Jean‑Laurent Casanova6,7,8,14 · Melissa Gans11,15,16 · Jacques G. Rivière9,10 · Dusan Bogunovic1,2,3,4,5 Received: 19 March 2021 / Accepted: 25 May 2021 © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021 Abstract While adults with Down syndrome (DS) are at increased risk of severe COVID-19 pneumonia, little is known about COVID- 19 in children with DS. In children without DS, SARS-CoV-2 can rarely cause severe COVID-19 pneumonia, or an even rarer and more typically pediatric condition, multisystem inflammatory syndrome in children (MIS-C). Although the underlying mechanisms are still unknown, MIS-C is thought to be primarily immune-mediated. Here, we describe an atypical, severe form of MIS-C in two infant girls with DS who were hospitalized for over 4 months. Immunological evaluation revealed pronounced neutrophilia, B cell depletion, increased circulating IL-6 and IL-8, and elevated markers of immune activation ICAM1 and FcɣRI. Importantly, uninfected children with DS presented with similar but less stark immune features at steady state, possibly explaining risk of further uncontrolled inflammation following SARS-CoV-2 infection. Overall, a severe, atypical form of MIS-C may occur in children with DS. Keywords Down syndrome · COVID-19 · MIS-C · inborn errors of immunity 10 * Dusan Bogunovic Infection in Immunocompromised Pediatric Patients Dusan.Bogunovic@mssm.edu Research Group, Vall D’Hebron Institut de Recerca (VHIR), Hospital Universitari Vall D’Hebron (HUVH), Vall d’Hebron 1 Center for Inborn Errors of Immunity, Icahn School Barcelona Hospital Campus, Barcelona, Catalonia, Spain of Medicine At Mount Sinai, New York, NY, USA 11 Department of Pediatrics, Maria Fareri Children’s Hospital 2 Department of Pediatrics, Icahn School of Medicine At At Westchester Medical Center, Valhalla, NY, USA Mount Sinai, New York, NY, USA 12 Immunology Division, Hospital Universitari Vall D’Hebron 3 Mindich Child Health and Development Institute, Icahn (HUVH), Diagnostic Immunology Research Group, Vall School of Medicine At Mount Sinai, New York, NY, USA D’Hebron Institut de Recerca (VHIR), Vall D’Hebron 4 Barcelona Hospital Campus, Department of Cell Biology, Precision Immunology Institute, Icahn School of Medicine Physiology and Immunology, Universitat Autònoma de At Mount Sinai, New York, NY, USA Barcelona (UAB), Barcelona, Catalonia, Spain 5 Department of Microbiology, Icahn School of Medicine At 13 Genetics Department, Hospital Universitari Vall D’Hebron Mount Sinai, New York, NY, USA (HUVH), Vall D’Hebron Barcelona Hospital Campus, 6 Laboratory of Human Genetics of Infectious Diseases, Barcelona, Catalonia, Spain Necker Branch, INSERM U1163, Necker Hospital for Sick 14 Howard Hughes Medical Institute, New York, NY, USA Children, Paris, France 15 7 Division of Pediatric Pulmonology, Allergy and Immunology University of Paris, Imagine Institute, Paris, France and Sleep Medicine, Boston Children’s Health Physicians, 8 St. Giles Laboratory of Human Genetics of Infectious Valhalla, NY, USA Diseases, Rockefeller Branch, The Rockefeller University, 16 New York Medical College, Valhalla, NY, USA New York, NY, USA 9 Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall D’Hebron (HUVH), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Catalonia, Spain 13 Vol.:(0123456789) Journal of Clinical Immunology Introduction generalized maculopapular erythematous rash with peripheral desquamation, edematous hands, vomiting, persistent fever, and While adults have suffered the highest rates of morbidity eventually coronary dilatation. She received lopinavir/ritonavir, and mortality from COVID-19 pneumonia, children are rela- hydroxychloroquine, high-dose intravenous immunoglobulin tively spared from this manifestation of SARS-CoV-2 infec- (IVIG), corticosteroids, and azithromycin. She was diagnosed tion and account for < 1.5% of hospitalizations [1]. From with MIS-C with myocarditis signs and coronary dilatation. the age of 5 years onward, the risk of severe COVID-19 Despite requiring a 4-month hospitalization in the PICU com- doubles about every 5 years [2, 3]. A small subset of children plicated by multiple catheter-related bloodstream infections, the develops multisystem inflammatory syndrome in children final outcome was favorable. Blood samples were obtained in (MIS-C) around a month after exposure to SARS-CoV-2 July 2020, while the patient was afebrile but still in the PICU. [4–6].The prevalence of MIS-C is unknown but estimated to be less than 1 in 50,000 [7]. This severe inflammatory Patient 2 condition is primarily characterized by fever, rash, shock, and cardiac, respiratory, and/or gastrointestinal involvement. An 8-month-old Hispanic girl with DS, atrioventricular canal MIS-C affects children with a median age of 8.3 years and defect status post repair, pulmonary hypertension with chronic usually has favorable outcomes after a median hospital stay oxygen dependence, and nasogastric tube feed dependence was of 7 days [4, 8, 9]. Risk factors predisposing children to admitted to the PICU for respiratory failure secondary to RT- develop MIS-C include being Black and Hispanic [4, 7]. PCR positive COVID-19 pneumonia in October 2020. She was MIS-C pathogenesis is thought to be primarily immune- treated with remdesivir, COVID-19 convalescent plasma, and mediated. Children with MIS-C have evidence of broad corticosteroids and had waxing and waning respiratory distress immune cell activation (phospho-STAT signaling, upregu- and afebrile episodes that lasted up to 5 days. Two weeks after lation of ICAM1, FcγRI), elevated circulating cytokines initial onset of COVID-19 symptoms, her fever returned accom- (including IL-6, IL-8, and IL-18, among others), and the panied by elevated inflammatory markers, anemia, thrombocy- presence of autoantibodies both against known antigens and topenia, elevated ferritin, hypertriglyceridemia, low fibrinogen, novel candidates [6, 10–12]. and elevated liver function tests. Her respiratory condition wors- Individuals with Down syndrome (DS), or trisomy 21, ened, and she developed a diffuse blanching erythematous rash. show signs of immune dysregulation, including a higher A second RT-PCR test in December 2020 was negative. At this incidence of autoimmune and autoinflammatory diseases time, she was IgG positive. Hemophagocytic lymphohistiocy- such as autoimmune thyroid disease, autoimmune skin con- tosis (HLH) was initially considered as the patient had elevated ditions, celiac disease, and type I diabetes [13, 14]. At the IL-2 receptor and low natural killer cell function, but she had molecular level, they have elevated inflammatory markers normal perforin/granzyme B and her bone marrow aspiration and an exacerbated response to type I interferon [15, 16]. did not show hemophagocytosis. She was treated with IVIG, Somewhat paradoxically, they are also more susceptible higher dose corticosteroids, and Anakinra with no improvement to viral infections, as documented for respiratory syncy- in symptoms. She became critical with a prolonged hospitali- tial virus and influenza virus [17, 18]. While epidemio- zation complicated by multiple infections, multi-organ failure, logic studies of COVID-19 hospitalization in DS suggest and distributive shock requiring vasopressor support. Repeat increased rate, morbidity, and mortality in this population bone marrow aspiration revealed hemophagocytosis, so she [19], MIS-C has not yet been reported in individuals with was started on etoposide. With no improvement on etoposide, DS. Herein, we present cases of two unrelated infant girls emapalumab and ruxolitinib were trialed. The patient died in with DS who developed a clinical course characterized by April 2021 after succumbing to gram negative sepsis. Blood symptomatic COVID-19 followed by atypical MIS-C ill- samples were obtained in January 2021 while the patient was in ness requiring hospitalization of over 4 months. the PICU in critical condition on corticosteroids. Patient 1 Results A 6-month-old North African girl with DS and congenital heart disease had mild COVID-19 manifestations including fever, Whole blood immune phenotyping by mass cytometry revealed fatigue, and cough after her father had contracted COVID-19. neutrophilia and a profound decrease in total B cells in both She received a positive RT-PCR test in March 2020. Ten days patients compared to uninfected age-matched children with DS later, she was admitted to the pediatric intensive care unit (PICU) (p = 0.008) (who already had a decrease in total B cells com- due to heart dysfunction and distributive shock. She tested nega- pared to uninfected without DS, p = 0.002) (Fig. 1A,B). Within tive by RT-PCR at this time. During her stay, the patient had a total B cells, memory and plasma B cell subsets were decreased 13 Journal of Clinical Immunology in both patients compared to controls, while naïve B cells were Conclusion relatively increased (Fig. 1C). These findings in patients with DS months after onset of disease differed from patients without DS We show that severe, atypical MIS-C can occur in children with acute MIS-C which were reported previously, who had nor- with DS. These two patients fulfilled the clinical criteria for mal B cell counts [6, 11]. We also found a depletion of activated MIS-C diagnosis [9], and their immunological profile resem- ­(CD38+HLADR+) CD4 T cells in our patients, likely suggest- bled that of previously described children with MIS-C without ing extravasation to the affected tissues (Fig. 1D). Interestingly, DS, including neutrophilia, lymphopenia, elevated phospho- we found that activated (­ CD38+HLADR+) CD8 T cells were STAT3, ICAM-1, FcγRI, and circulating cytokines. By con- also depleted in P1, while they were elevated in P2 (Fig. 1E). trast, their significant B cell depletion, as well as their young Previous studies of non-DS patients with MIS-C report either age, prolonged hospital stay, and refractoriness to treatment in unchanged or elevated activated T cells [6, 11]. Importantly, P2, set them apart from children with MIS-C without DS. Of we confirm that the immune state of uninfected children with note, the patients’ samples were collected months after initial DS is significantly altered [20], including already decreased B onset while children with MIS-C were sampled within weeks cells, increased NK cells, and slightly elevated myeloid dendritic of onset. This study and a recent case report also describing cells (Fig. 1B). It remains unknown if these altered subsets con- severe disease after SARS-CoV-2 infection in two other chil- tributed to susceptibility to severe disease after SARS-CoV-2 dren [24] emphasize the notion that children with DS are at infection. unique risk of atypical disease presentation. Further research We then surveyed markers of inflammation and detected is needed to elucidate mechanisms underlying disease progres- increased STAT3 phosphorylation in most immune subsets sion and tailored treatment protocols in this patient population. in P1 and in C ­ D4+ TEMRA, NK cells, C ­ D16+ monocytes, This report suggests that vaccination should be considered in and eosinophils in P2, compared with uninfected controls children with DS for prevention of SARS-CoV-2 infection. with or without DS (Fig. 1F). This was similar to augmented Importantly, uninfected children with DS already had phospho-STAT3 in patients with acute MIS-C without DS elevated markers of immune activation at baseline, including [6]. Furthermore, intracellular interleukin-8 (IL-8) and ICAM1, FcγRI, and serums IL-6 and IL-8. Together with interleukin-1β (IL-1β), two pro-inflammatory mediators previously reported defects in immune activation in DS [16, that enhance neutrophil recruitment and cytokine release, 20, 22], our report highlights that DS should be considered respectively, were elevated in P1’s neutrophils and C ­ D16+ an inborn error of immunity, in the broad sense of the term, + and ­CD14 monocytes even after clinical signs of MIS-C not restricted to monogenic disorders. Although no clear had resolved (Fig. 1G,H) but not in P2. Discrepancies in mechanistic or epidemiologic links between DS and the pre- inflammatory markers between P1 and P2 may be due to the disposition to MIS-C have been reported yet, we describe a fact that P2 was on high-dose steroids at the time of sam- pre-existing inflammatory state in pediatric DS patients that pling. Additionally, clinical laboratory inflammatory markers could have contributed to the severe course of MIS-C in our including CRP, ferritin, procalcitonin, and LDH were highly two patients. As these first reports of severe autoinflamma- elevated in both patients (Table 1). Together, these data indi- tion brought on by SARS-CoV-2 in DS may indicate a larger cate a broad, nonspecific, immune activation in these two looming problem with novel syndromic features, we suggest patients with DS after SARS-CoV-2 infection compared with particular care should be taken to children with DS during age-matched uninfected individuals with or without DS. the COVID-19 pandemic. Interestingly, other markers of immune activation such as ICAM1/CD54 and FcɣRI/CD64 were found to be elevated in myeloid cells not only in P1 and P2, but also in uninfected Methods children with DS (Fig. 1I–L). This elevation was compara- ble to that in non-DS children with MIS-C. These markers Sample Collection were not detected in children without DS or MIS-C. ICAM1 mediates immune cell extravasation into tissues, and FcɣRI The study was approved under the protocols Mount Sinai can trigger potent inflammation upon antibody binding. Fur- Health System (MSHS) IRB-18-00,638 and Vall d’Hebron thermore, the two broad-acting pro-inflammatory cytokines Research Institute, Barcelona, Spain, PR(AG)198/2014. All interleukin-6 (IL-6) and IL-8 were elevated in the serum of P1 patient data were de-identified. Written informed consent and P2, as well as in uninfected children with DS (Fig. 1M,N). for all individuals in this study was provided in compliance This confirms cytokine dysregulation previously reported at with an institutional review board protocol. All uninfected baseline in children with DS [15, 23]. Collectively, these find- patient samples were drawn in the context of an outpatient ings suggest that children with DS are in a state of immune routine visit, and patients exhibited no signs of infection activation, even in the absence of a pathogen. (fever, runny nose, cough, sore throat). From each patient, 13 Journal of Clinical Immunology 13 Journal of Clinical Immunology ◂Fig. 1  Immune phenotyping by mass cytometry of peripheral blood a heparin-block were then performed to prevent non-specific from P1 and P2 and age-matched controls with or without DS. A binding. Cells were then incubated with an antibody cocktail Granulocyte cell type frequencies as percent of CD45 + cells (leu- kocytes). B Major cell type frequencies as percent of CD66b- cells for surface markers to identify major immune populations. All (nongranulocytes). C B cell, D CD4, and E CD8 T cell frequencies. F antibodies were purchased with pre-conjugated or conjugated STAT3 phosphorylation across immune cell subtypes. G,H Intracel- in-house with X8 MaxPar conjugation kits (Fluidigm). After lular IL-8, IL-1β, cytokine staining and I–L extracellular CD54, and surface staining, the samples were methanol-permeabilized, CD64 expression in neutrophils and monocyte subsets, color-coded by the mean log2 transformed signal intensity. Differences between washed, heparin-blocked, and stained with a cocktail of anti- groups were assessed in unpaired t tests. *p ≤ 0.05; **p ≤ 0.005; bodies against intracellular targets, including markers of phos- ***p ≤ 0.0005; ****p ≤ 0.00005. M,N IL-6 and IL-8 levels in patient phorylation and signaling. After washing, cells were then incu- serum. Differences between groups were assessed in unpaired t tests bated in freshly diluted 2.4% formaldehyde containing 125 nM of log10 values Ir Intercalator (Fluidigm), 0.02% saponin and 30 nM OsO4 (ACROS Organics) for 30 min at room temperature. Samples blood was drawn into a cell preparation tube with sodium were then washed and acquired immediately. heparin (BD Vacutainer). Plasma was isolated from using For acquisition, samples were washed with PBS + 0.2% Ficoll separation and stored at – 80 °C until use. Whole BSA, PBS, and then CAS buffer (Fluidigm). The final solu- blood was fixed using Proteomic Stabilizer PROT1 (Smart- tion in CAS buffer consisted of 1 million cells per mL and Tube) and frozen at – 80 °C. Controls range from 7 months a 1/20 dilution of EQ beads (Fluidigm). Following routine to 6 years old in immune phenotyping studies (Fig. 1A–E), instrument optimization, samples were acquired at a rate from 19 months to 2 years in inflammatory marker expres- of < 300 events per second on a Helios mass cytometer (Flui- sion analyses (Fig. 1F–I,K), and from 7 months to 19 years digm) with a modified wide-bore injector (Fluidigm). old in Luminex analyses (Fig. 1M,N). FCS files of acquired events were normalized and concat- enated with Fluidigm acquisition software and deconvoluted Mass Cytometry with a MATLAB-based debarcoding application, and resulting files were analyzed using Cytobank. Cell events were identified Frozen stabilized blood samples were thawed according to the as Ir191/193-positive and Ce140-negative events. Doublets were manufacturer’s recommended protocol and then washed with excluded on the basis of Mahalanobis distance and barcode sep- barcode permeabilization buffer (Fluidigm). Samples were aration and with the Gaussian parameters calculated by Helios uniquely barcoded with Cell-ID 20-Plex Pd Barcoding Kit CyTOF software. Downstream data analysis was performed on (Fluidigm) and washed and pooled together. An Fc-block and Cytobank, by biaxial gating of immune populations according Table 1  Clinical characteristics of P1, P2, and children with MIS-C or DS Children with MIS-C [4–9] Children with DS P1 P2 Age Median 8.3 years [4] N/A 6 months 8 months Evidence of SARS-CoV-2 Positive RT-PCR and/or Absent Positive RT-PCR Positive RT-PCR serology Negative serology Positive serology Clinical presentation COVID-19 symptoms Absent Absent Fever, fatigue, cough Fever, COVID-19 pneumonia MIS-C symptoms Fever, rash, shock, puffy Absent Fever, rash, shock, periph- Fever, rash, shock, respira- extremities, conjunctivitis, eral desquamation, puffy tory failure, elevated liver and/or mucocutaneous, hands, vomiting, cardio- enzymes gastrointestinal, cardiac, vascular abnormalities respiratory abnormalities Length of hospitalization Median 7 days (interquartile N/A 4 months 6 months range, 4 to 10 days) [4] Laboratory findings ↑↑ CRP, ESR, IL-6, procal- ↑ CRP, IL-6 [21] ↑↑ CRP, ferritin, IL-6, ↑↑ CRP, ferritin, IL-6, proc- citonin, ferritin, LDH Lymphopenia [22] procalcitonin, LDH alcitonin, LDH ↑↑ Fibrinogen and D-dimer ↑↑ Fibrinogen and D-dimer ↑↑ Fibrinogen and D-dimer Hypoalbuminemia Hypoalbuminemia Hypoalbuminemia ↑↑ Troponin ↑↑ Troponin Normal Troponin ↑ AST, ALT Lymphopenia, neutrophilia ↑ AST, ALT Lymphopenia, neutrophilia Lymphopenia, neutrophilia Immune activation ↑ phospho-STAT3 ↑ FcɣRI and ICAM1 on ↑ phospho-STAT3 ↑ FcɣRI and ICAM1 on ↑ FcɣRI and ICAM1 on neutrophils, mono- ↑ FcɣRI and ICAM1 on neutrophils, monocytes neutrophils, monocytes cytes neutrophils, monocytes ↑ IL-2R ↑ Serum IL-6, IL-8 ↑ Serum IL-6, IL-8 ↑ Serum IL-6, IL-8 ↑ Serum IL-6, IL-8 13 Journal of Clinical Immunology to the gating scheme outlined in Supplemental Fig. 1. 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