Macrophage activation syndrome in neonatal lupus presenting with fever and rash.

Neonatal lupus can occur in infants born to mother with autoimmune disorders through transplacental auto-antibodies. Clinical manifestations in neonatal lupus include cutaneous lesions and hematologic or hepatobiliary findings resembling those seen in systemic lupus erythematosus. In autoimmune state, macrophage activation syndrome (MAS) represent a critical and potentially fatal complication that can result in mortality if not immediately identified and managed with the appropriate care. Here we present a 33-day-old girl diagnosed with neonatal lupus and serious MAS. She was delivered by a primipara mother who did not exhibit any autoimmune symptoms. The patient visited the hospital due to fever and pancytopenia. Laboratory data were compatible with MAS, including pancytopenia, high level of ferritin, soluble interleukin-2, and decreased natural killer cell activity. In addition, autoimmune study showed positive results for anti-nuclear antibody (ANA), anti-Sjogren syndrome antigen A (SSA), and SSB, The autoimmune study for mother also showed positive results for ANA, anti-SSA, and SSB. The patient recovered after she received high dose steroid and supportive care. Our case indicates that neonatal lupus should be taken into consideration when fever, erythematous skin rash, and pancytopenia are observed in infants, even if their mothers have no prior history of autoimmune conditions.

Comparison of COVID-19-associated multisystem inflammatory syndrome in children (MIS-C) and Kawasaki disease shock syndrome: case reports and literature review.

Multisystem inflammatory syndrome in children (MIS-C) is a serious post-infectious complication of COVID-19 characterized by hyperinflammation and multi-organ dysfunction including shock. Shock is also seen in a severe form of Kawasaki disease (KD) called KD shock syndrome (KDSS). Here, we present one MIS-C and one KDSS case and compare similarities and differences between them. Both MIS-C (case 1) and KDSS (case 2) showed hyperinflammation, KD-related features, gastrointestinal problems, hypotension, and coagulopathy. The extent of systemic inflammation and organ dysfunction was more severe in KDSS than in MIS-C. Case 1 was diagnosed as MIS-C because SARS-CoV-2 was confirmed, and case 2 was diagnosed as KDSS because no pathogen was identified in microbiological studies. We believe that the most important difference between MIS-C and KDSS was whether SARS-CoV-2 was identified as an infectious trigger. Organ dysfunction is a hallmark of MIS-C and KDSS, but not KD, so MIS-C shares more clinical phenotypes with KDSS than with KD. Comparison of MIS-C and KDSS will be an interesting and important topic in the field of KD-like hyperinflammatory disease research.

Similarities and Differences between Multisystem Inflammatory Syndrome in Children (MIS-C) and Kawasaki Disease Shock Syndrome.

This study aimed to investigate the characteristics of COVID-19-associated multisystem inflammatory syndrome in children (MIS-C) and Kawasaki disease shock syndrome (KDSS) and to compare the similarities and differences between the two diseases. The incidence of KDSS and MIS-C was also estimated. Medical records of patients diagnosed with MIS-C or KDSS at four hospitals from January 2013 to December 2022 were retrospectively reviewed. Thirty-one patients were enrolled in the study in either an MIS-C group (n = 22) or a KDSS group (n = 9). The incidence of KDSS in KD was 0.8% (9/1095) and the incidence of MIS-C versus KD was 10.2% (22/216). Compared with the MIS-C group, the KDSS group had longer hospital stays and more severe systemic inflammation (e.g., anemia, elevated C-reactive protein, hypoalbuminemia, and pyuria) and organ dysfunction (e.g., number of involved organs, shock, vasoactive infusion, and intensive care unit admission). All patients in the MIS-C group, but none in the KDSS group, including two patients during the COVID-19 pandemic, had laboratory evidence of SARS-CoV-2 infection. MIS-C and KDSS shared demographic, clinical, and laboratory characteristics; organ dysfunction; treatment; and outcomes. Overall severity was more severe in patients with KDSS than in those with MIS-C. The most important difference between MIS-C and KDSS was whether SARS-CoV-2 was identified as an infectious trigger.

Under-Recognized Macrophage Activation Syndrome in Refractory Kawasaki Disease: A Wolf in Sheep's Clothing.

Recognition of macrophage activation syndrome (MAS) in patients with refractory Kawasaki disease (KD) can be challenging. This study aimed to investigate the incidence of MAS in patients with refractory KD and to compare the characteristics of refractory KD and MAS. Medical records of 468 patients diagnosed with KD from January 2010 to December 2019 were retrospectively reviewed. Of the 468 KD patients, 63 were enrolled in the study as a refractory KD group (n = 59) and an MAS group (n = 4). The incidence of MAS was 0.8% (4/468) in patients with KD and 6.3% (4/63) in patients with refractory KD. Compared to the refractory KD group, the MAS group had higher frequencies of incomplete KD, hepatosplenomegaly, third-line treatment, and MAS screening, and showed lower levels of albumin. No significant differences were found in other clinical and laboratory findings. In addition to four patients with MAS, five patients with refractory KD who received third-line treatment showed severe systemic inflammation and organ dysfunction, but only one in five patients underwent MAS screening, including ferritin levels. In conclusion, given the relatively high incidence of MAS in children with refractory KD and the similar phenotype between refractory KD and MAS, we propose that MAS screening should be included in routine laboratory tests for refractory KD.

High-Concentration Intravenous Immunoglobulin May Influence the Course of Fever and Rate of Reported Treatment Resistance in Children With Kawasaki Disease: A Single-Center Retrospective Analysis.

BACKGROUND: Intravenous immunoglobulin (IVIG) resistance in patients with Kawasaki disease (KD) is defined as persistent or recrudescent fever ≥36 hours after IVIG infusion. We have experienced an increase in IVIG resistance in patients with KD since the substitution of 10% IVIG for 5% IVIG. This study aimed to determine the independent association between increased IVIG resistance and 10% IVIG therapy. METHODS: Medical records of pediatric patients with KD were retrospectively reviewed. Clinical and laboratory characteristics were compared between patients receiving 5% IVIG therapy and those receiving 10% IVIG therapy. Between IVIG-responsive and IVIG-resistant patients, a multivariate analysis was performed to determine the independent factors for IVIG resistance. RESULTS: A total of 119 patients were included in this study: 81 (68.1%) and 38 (31.9%) patients received 5% and 10% IVIG therapy, respectively. IVIG resistance was identified in 34 (28.6%) patients: 44.7% of patients receiving 10% IVIG therapy and 21.0% of patients receiving 5% IVIG therapy (p = 0.008). The clinical manifestations and outcomes were comparable between patients who received 5% IVIG therapy and those who received 10% IVIG therapy. IVIG resistance was significantly associated with fewer fever days at IVIG administration (p = 0.032), a higher percentage of neutrophils (p = 0.013), and 10% IVIG treatment (p = 0.004) in the multivariate analysis. CONCLUSION: 10% IVIG therapy was significantly associated with increased reporting of IVIG resistance. However, the increase in patients with fever patterns consistent with IVIG resistance seemed to represent adverse febrile reactions resulting from using high-concentration IVIG rather than increased severity of KD.

Catch-up growth of infants born to mothers with autoimmune rheumatic disorders.

BACKGROUND: In women with autoimmune rheumatic disorders (ARD), pregnancy complications or postpartum events are more frequent compared to the general population. Transplacental autoantibodies or cytokines influence various fetal and neonatal outcomes. We compared the growth patterns of babies born to mothers with ARD versus healthy mothers to assess the long-term growth outcomes of children born to women with ARD. METHODS: This was a retrospective age-matched cohort analyses of babies born to mothers with ARD from the hospitals belonging to the Catholic University of Korea between 2010 and 2017. Demographic and autoimmune laboratory test data of the mothers and newborns were assessed. Neonatal growth was measured in terms of height and weight, measured at birth and follow-up examinations. RESULTS: We enrolled 142 infants from mothers with ARD and 149 infants from healthy mothers. There was no significant difference between mothers with ARD and healthy mothers in terms of delivery age, parity, abortion, and premature delivery history. The mothers with ARD were diagnosed with systemic lupus erythematosus (81%), Sjogren syndrome (6%), and other autoimmune phenomena (11%). The groups were significantly different in terms of neonatal characteristics such as prematurity, gestational age, birth weight, and height, but not in Apgar score and delivery type. For most neonates, autoimmune laboratory results were normalized within 1 year, except for anti-La/SSB antibody, which remained high in some. The height and weight for age z-score were lower than the normal age groups at birth but showed catch-up growth by 2 years of age. CONCLUSIONS: Low birthweight and prematurity at birth for neonates born to mothers with ARD could be caught up by 2 years of age, and maternal ARD does not affect the growth of their offspring.

Juvenile Dermatomyositis.

Juvenile dermatomyositis (JDM) is a systemic capillary vasculopathy. Patients present with proximal muscle weakness, raised muscle enzymes, and pathognomic skin rashes such as heliotrope rash, Gottron's papules. Main complications are calcinosis, lipodystrophy, osteoporosis. Complement-mediated damage of vessels is a major mechanism. Magnetic resonance imaging is currently widely used to diagnosis of JDM. The goals of treatment are to control inflammatory myositis and prevent disease complication. Early, aggressive treatment of JDM associated with a better prognosis. High-dose corticosteroids in combination with methotrexate is the mainstay of treatment. The course of JDM is variable.

Ischemic Vaso-occlusive Retinopathy as Initial Presentation in Pediatric Systemic Lupus Erythematosus: A Case Report.

Ischemic vaso-occlusive retinopathy as an initial manifestation is rare in pediatric systemic lupus erythematosus (pSLE). A 13-year-old girl presented with two months' history of papules and crusts with fatigue, weight loss, and abrupt hair loss. Pancytopenia and findings compatible with SLE, including positive direct Coombs' test, antinuclear antibody (Ab), anti-double stranded DNA Ab, anti-Smith Ab, anti-ribonucleoprotein Ab, lupus anticoagulant, anti-ß2 glycoprotein Immunoglobulin G, and anti-cardiolipin Ab, were detected. Bi-nasal hemianopsia was detected. Initial visual acuity was hand motion in the right eye and 15/20 in the left. Fundoscopy showed massive exudation around the optic disc with macular edema, vascular sheathing with perivascular hemorrhage in the whole retina, and ghost vessels in the peripheral retina. Intravitreal triamcinolone injection and dexamethasone implant injection were administered. Visual symptoms improved but did not recover. Methylprednisolone therapy and photocoagulation improved visual acuity and fever. Early intervention for retinopathy in pSLE can help prevent vision-loss.

Etiological and pathophysiological enigmas of severe coronavirus disease 2019, multisystem inflammatory syndrome in children, and Kawasaki disease.

During the coronavirus disease 2019 (COVID-19) pandemic, a novel multisystem inflammatory syndrome in children (MIS-C) has been reported worldwide since the first cases were reported in Europe in April 2020. MIS-C is temporally associated with severe acute respiratory syndrome coronavirus 2 infection and shows Kawasaki disease (KD)-like features. The epidemiological and clinical characteristics in COVID-19, KD, and MIS-C differ, but severe cases of each disease share similar clinical and laboratory findings such as a protracted clinical course, multiorgan involvement, and similar activated biomarkers. These findings suggest that a common control system of the host may act against severe disease insult. To solve the enigmas, we proposed the protein-homeostasis-system hypothesis in that every disease involves etiological substances and the host's immune system controls them by their size and biochemical properties. Also, it is proposed that the etiological agents of KD and MIS-C might be certain strains in the microbiota of human species and etiological substances in severe COVID-19, KD, and MIS-C originate from pathogen-infected cells. Since disease severity depends on the amounts of inflammation-inducing substances and corresponding immune activation in the early stage of the disease, an early proper dose of corticosteroids and/or intravenous immunoglobulin (IVIG) may help reduce morbidity and possibly mortality among patients with these diseases. Corticosteroids are low cost and an analogue of host-origin cortisol among immune modulators. This study's findings will help clinicians treating severe COVID-19, KD, and MIS-C, especially in developing countries, where IVIG and biologics supplies are insufficient.

Effects of Antiviral Therapy and Glucocorticoid Therapy on Fever Duration in Pediatric Patients with Influenza.

Background and Objectives: Considering developing resistance against neuraminidase inhibitors (NAIs) and their adverse reactions, restricted use of NAIs and use of alternative drugs should be considered for treating influenza. Although glucocorticoids (GCs) have been used for severe influenza, their effects on non-severe influenza have rarely been evaluated. This study aimed to evaluate the clinical responses to NAI therapy and GC therapy in pediatric patients with non-severe influenza. Materials and Methods: A total of 601 pediatric patients (<19 years of age) diagnosed with non-severe influenza were retrospectively recruited to evaluate the effects of NAI therapy and GC therapy. Post-admission fever duration and hospitalization duration were compared among four patient groups divided by the administered treatment: No therapy (n = 52), NAI therapy (n = 154), GC therapy (n = 123), and Both therapies (n = 272). Results: In a multivariate analysis with adjustment for confounding variables, the post-admission fever duration was not significantly different among the four patient groups. The post-admission fever duration tended to shorten with increasing age, longer pre-admission fever duration, and incidence of influenza A virus infection and lower respiratory tract infection. The type of administered treatment showed no significant effects on the post-admission fever duration in any subgroups according to patient age, pre-admission fever duration, influenza virus subtype, and clinical diagnosis. Conclusions: Symptomatic treatment rather than antiviral or GC therapy seems to be sufficient for patients with non-severe influenza, although the effects of NAI therapy and GC therapy according to their administered time and dose should be further evaluated.

Application of a Multiplex Polymerase Chain Reaction Test for Diagnosing Bacterial Enteritis in Children in a Real-Life Clinical Setting.

This study aimed to determine the subjects for bacterial multiplex polymerase chain reaction (mPCR) testing and to interpret the mPCR test results based on patients' clinical symptoms and diagnoses. The medical records of 710 pediatric patients who underwent a bacterial mPCR test were retrospectively reviewed. Clinical characteristics and mPCR test results were compared between patients with positive (n = 199) and negative mPCR test results (n = 511) and between patients with invasive pathogens (n = 95) and toxigenic pathogens (n = 70). Positive mPCR test results were significantly associated with older age (p < 0.001), diagnosis of acute gastroenteritis (p = 0.021), presence of hematochezia (p < 0.001), and absence of cough (p = 0.004). The diagnosis of acute gastroenteritis (p = 0.003), presence of fever (p = 0.027) and diarrhea (p = 0.043), and higher C-reactive protein levels (p = 0.025) were significantly associated with the identification of invasive pathogens in patients with positive mPCR test results. Thus, selective bacterial mPCR testing should be performed based on the patients' clinical symptoms and diagnoses, and the results should be interpreted in consideration with identified pathogens.

Early Confirmation of Mycoplasma pneumoniae Infection by Two Short-Term Serologic IgM Examination.

The aim of the present study is to re-evaluate the clinical application of two-times serologic immunoglobulin M (IgM) tests using microparticle agglutination assay (MAA), an enzyme-linked immunosorbent assay (ELISA), and polymerase chain reaction (PCR) assay in diagnosing Mycoplasma pneumoniae (MP) infection. A retrospective analysis of 62 children with MP pneumonia during a recent epidemic (2019-2020) was conducted. The MAA and ELISA immunoglobulin M (IgM) and IgG measurements were conducted twice at admission and around discharge, and MP PCR once at presentation. Diagnostic rates in each test were calculated at presentation and at discharge. The seroconverters were 39% (24/62) of patients tested by MAA and 29% (18/62) by ELISA. At presentation, the diagnostic positive rates of MAA, ELISA, and PCR tests were 61%, 71%, and 52%, respectively. After the second examination, the rates were 100% in both serologic tests. There were positive correlations between the titers of MAA and the IgM values of ELISA. The single serologic IgM or PCR tests had limitations to select patients infected with MP in the early stage. The short-term, paired IgM serologic tests during hospitalization can reduce patient-selection bias in MP infection studies.

Clinical features and outcomes of influenza by virus type/subtype/lineage in pediatric patients.

BACKGROUND: Recently, four influenza viruses are circulating worldwide: A(H1N1)pdm09, A(H3N2), B/Victoria, and B/Yamagata. However, information on the clinical differences among pediatric patients infected with four recently circulating influenza viruses is sparse. METHODS: Medical records of pediatric patients (<20 years of age) diagnosed with influenza between the 2014-2015 and 2018-2019 influenza seasons were retrospectively reviewed. Clinical features were compared between (I) patients infected with influenza A (FluA) and influenza B (FluB) viruses, (II) patients infected with FluA when A(H1N1)pdm09 and A(H3N2) circulated dominantly, and (III) patients infected with FluB when B/Victoria and B/Yamagata circulated dominantly. RESULTS: A total of 1,588 patients infected with FluA and 964 patients infected with FluB were included in this study. Patients infected with FluB were older (P<0.001) and more likely to report sore throat (P=0.002) than those infected with FluA. Otherwise, there were no significant differences in the clinical symptoms, diagnoses, and outcomes between patients infected with FluA and FluB. Overall, clinical features of influenza patients were similar regardless of the dominantly circulated subtype and lineage of the virus. In children aged ≤2 years, patients infected with FluB were more like to experience lower respiratory tract infection (P=0.034) and hospitalization (P=0.001) than those infected with FluA. CONCLUSIONS: There were no significant clinical differences among pediatric patients infected with four recently circulating influenza viruses, except that FluB infection tended to be more severe than FluA infection in children aged ≤2 years.

Febrile urinary tract infection in children: changes in epidemiology, etiology, and antibiotic resistance patterns over a decade.

BACKGROUND: Understanding the epidemiology and prevalence of febrile urinary tract infection (fUTI) in children is important for risk stratification and selecting appropriate urine sample collection candidates to aid in its diagnosis and treatment. PURPOSE: This study aimed to analyze the epidemiology, etiology, and changes in antibiotic susceptibility patterns of the first fUTI in children. METHODS: This retrospective observational cohort study included children younger than 19 years of age who were diagnosed and treated for their first fUTI in 2006-2016. Electronic medical records were analyzed and radiologic images were evaluated. RESULTS: A total of 359 patients (median age, 5.1 months; interquartile range, 3.0-10.5 months) fit the inclusion criteria; of them, 78.0% (n=280) were younger than 12 months old. The male to female ratio was 5.3:1 for patients aged 0-2 months, 2.1:1 for those 3-5 months, and 1.6:1 for those 6-11 months. Beyond 12 months of age, there was a female predominance. Escherichia coli was the leading cause (83.8%), followed by Enterococcus species (6.7%), and Klebsiella pneumoniae (3.6%). Significant yearly increases in the proportions of multidrug-resistant strains (P<0.001) and extended-spectrum beta-lactamase (ESBL) producers (P<0.001) were observed. In patients with vesicoureteral reflux (VUR), the overall recurrence rate was 53.6% (n=15). A significantly higher recurrence rate was observed when the fUTI was caused by an ESBL versus non-ESBL producer (75.0% vs. 30.0%, P=0.03). CONCLUSION: fUTI was most prevalent in children younger than 12 months of age and showed a female predominance in patients older than 12 months of age. The proportion of ESBL producers causing fUTI is increasing. Carbapenems, rather than noncarbapenems, should be considered for treating fUTI caused by ESBL-producing enteric gram-negative rods to reduce short-term recurrence rates in children with VUR.

Impact of Antibiotic Prescribing Patterns on Susceptibilities of Uropathogens in Children below 24 Months Old.

Monitoring regional antibiotic resistance patterns of uropathogens are important for deciding suitable empirical antibiotics for urinary tract infections (UTIs) in children. This study aimed to investigate regional differences in antimicrobial susceptibility patterns of E. coli and Klebsiella spp. in children below 24 months old, diagnosed with their first episode of UTI, and to find factors associated with an increased risk for UTI caused by extended-spectrum ß-lactamase (ESBL)-producing uropathogens. This was a retrospective cohort study of children diagnosed between 2011 and 2017 in four different hospitals located in four different regions of South Korea; regions A, B, C, and D. The government's big data repository was used to acquire data on regional antibiotic prescriptions. The pooled antimicrobial susceptibilities of E. coli and Klebsiella spp. (n = 2044) were as follows: ampicillin-sulbactam (61.0%), 3rd generation cephalosporin (3C) (82.8%), and trimethoprim-sulfamethoxazole (72.0%). Multivariate analysis showed that children diagnosed at hospital A (OR, 1.8; 95% confidence interval [CI], 1.2-2.6; P = 0.002) and every year that increased in the study period (OR, 1.1; 95% CI, 1.1-1.2; P < 0.001) were factors associated with an increased risk for UTIs with ESBL-producers. Regions A and B had significantly higher amounts of oral 3Cs prescribed compared to regions C and D (P = 0.009), which correlate with hospitals in the regions that had higher proportions of UTIs with ESBL-producing uropathogens (A and B vs. C and D, P < 0.001). Therefore, children in certain regions are at a higher risk for UTIs caused by ESBL-producers compared to other regions, which correlate with regions that had higher amounts of oral 3Cs prescribed.

Epidemiology of Kawasaki Disease in South Korea: A Nationwide Survey 2015-2017.

BACKGROUND: This study aimed to investigate recent epidemiologic features of Kawasaki disease (KD) in South Korea. METHODS: The ninth triennial nationwide questionnaire survey collected data on the demographic findings, symptoms and signs, treatment patterns and coronary artery complications of acute-phase KD occurred in 2015-2017 from 98 hospitals with pediatric residency programs and 108 community hospitals without residency programs. RESULTS: We received data from 93 of the 98 hospitals (response rate: 94.9%) with residency programs and 75 of the 108 community-based children's hospitals (response rate: 69.4%) without residency programs. In the 3-year survey period, a total of 15,378 (5449 in 2015, 5171 in 2016 and 4758 in 2017) cases of KD were reported. The mean age at diagnosis was 33.0 ± 24.8 months (range: 0-205 months), and the male-to-female ratio was 1.41:1. The overall KD incidence was 196.9 (202.2 in 2015, 197.1 in 2016 and 191.0 in 2017) per 100,000 younger than 5 years population. Recurrent cases were 4.85%. KD occurred more frequently during winter (December-January) and late spring (May-June). Intravenous immunoglobulin (IVIG) was administered to 95% of the patients; nonresponder rate for the first IVIG was 14.8%. Coronary artery aneurysms and giant coronary artery aneurysms (internal diameter >8 mm) occurred in 1.7% and 19 patients, respectively. Two patients died due to multiorgan failure and hepatic encephalopathy. CONCLUSION: Peak incidence of KD in South Korea was 202.2 per 100,000 younger than 5 years population (2015), and the incidence of giant coronary artery aneurysm decreased to 0.09% (2017).

Immunopathogenesis of COVID-19 and early immunomodulators.

The novel coronavirus disease 2019 (COVID-19) is spreading globally. Although its etiologic agent is discovered as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), there are many unsolved issues in COVID-19 and other infectious diseases. The causes of different clinical phenotypes and incubation periods among individuals, species specificity, and cytokine storm with lymphopenia as well as the mechanism of damage to organ cells are unknown. It has been suggested that in viral pneumonia, virus itself is not a direct cause of acute lung injury; rather, aberrant immune reactions of the host to the insults from viral infection are responsible. According to its epidemiological and clinical characteristics, SARS-CoV-2 may be a virus with low virulence in nature that has adapted to the human species. Current immunological concepts have limited ability to explain such unsolved issues, and a presumed immunopathogenesis of COVID-19 is presented under the proteinhomeostasis-system hypothesis. Every disease, including COVID-19, has etiological substances controlled by the host immune system according to size and biochemical properties. Patients with severe pneumonia caused by SARS-CoV-2 show more severe hypercytokinemia with corresponding lymphocytopenia than patients with mild pneumonia; thus, early immunomodulator treatment, including corticosteroids, has been considered. However, current guidelines recommend their use only for patients with advanced pneumonia or acute respiratory distress syndrome. Since the immunopathogenesis of pneumonia may be the same for all patients regardless of age or severity and the critical immune-mediated lung injury may begin in the early stage of the disease, early immunomodulator treatment, including corticosteroids and intravenous immunoglobulin, can help reduce morbidity and possibly mortality rates of older patients with underlying conditions.