ABSTRACTImportanceRecurrent respiratory tract infection (RRTI) is common in children. Inappropriate RRTI treatment will lead to asthma and other diseases, thereby seriously affecting the growth and physical health of children. Immune function modulation can prevent and alleviate childhood RRTI. Yupingfeng (YPF), a patented traditional Chinese medicine (TCM), has immunomodulatory effects and is widely used in China to treat children with RRTI.ObjectiveTo evaluate the safety and efficacy of YPF monotherapy in treating children with RRTI.MethodsThis multicenter, randomized, double‐blind, double‐simulation, noninferiority clinical trial was conducted from January 2015 to August 2017, with an 8‐week treatment period and 52‐week follow‐up after the drug withdrawal. Children aged 2–6 years with RRTI meeting the inclusion and exclusion criteria were enrolled in 13 hospitals in China and divided randomly into three groups (2:2:1 ratio) to receive YPF, pidotimod, or placebo. The primary outcome was the proportion of RRTI returning to normal standard level during the follow‐up. The secondary outcomes were reduction in the number of RRTI recurrences, effect on clinical symptoms (in accord with TCM practice), effect per symptom, and safety. The trial was registered at the Chinese Clinical Trials Registry (www.chictr.org.cn) under the unique identifier ChiCTR‐IPR‐15006847.ResultsThree hundred and fifty‐one children were enrolled and randomly assigned to 3 groups; 124, 125, and 61 children in the YPF, pidotimod, and placebo groups, respectively, had completed the trial. During the follow‐up, the proportion of RRTI returning to normal standard level was 73.13%, 67.15%, and 38.81% with YPF, pidotimod, and placebo, respectively (P < 0.0001). The proportion of cases who returned to normal standard level in the YPF group was 34.32% higher than that in the placebo group. The safety profile did not significantly differ among the groups.InterpretationYPF granules were noninferior to the active control drug pidotimod oral solution for the treatment of RRTI in children, and were superior to placebo, with a high safety profile.

ABSTRACTIntroductionCoronavirus disease‐2019 (COVID‐19) presents with a variety of symptoms, but rhabdomyolysis has rarely been reported in children.Case presentationWe report a 10‐year‐old girl who presented with fever, myalgia, and limping. The patient was tested positive for severe acute respiratory syndrome coronavirus‐2. On admission, creatine kinase (CK) level was 13 147 units per liter and the patient was diagnosed with rhabdomyolysis. She was treated with intravenous fluids, which resulted in CK levels decrease. There are currently seven case reports of children with rhabdomyolysis associated with acute COVID‐19 infection and two reports with the multisystemic inflammatory syndrome.ConclusionChildren presenting with muscle pain and weakness in the acute phase or following COVID‐19 infection, should alert physicians of the possibility of rhabdomyolysis.

To the editor: A 2-month-old boy presenting with left foot swollen for four days was admitted to our hospital. The temperature was normal. There was no vomit, seizure or diarrhea. Left foot abscess incision drainage was given 2 days prior to presentation. He had no history of skin rash or joint swelling. His birth weight was 3.7 kg with born full-term. The perinatal period was normal. The weight was 5.2 kg and height was 61 cm on initial assessment. Physical examination revealed mild jaundice and left foot abscess drainage incision. The other evaluation was normal. After laboratory examination, complete blood count showed hemoglobin 6.8 g/dL, white blood cell count 25.9 × 109/L (neutrophils 60.7%, lymphocytes 32.3%, monocytes 6.3%) and platelets 133 × 109/L, and biochemistry revealed abnormal liver function (elevated indirect bilirubin and normal liver enzyme). The coagulation profile was prominently disturbed (prothrombin time 106 s and International Normalized Ratio 9.3). Initial assessment of immune function was normal. Two sets of blood cultures on admission were positive for penicillin-sensitive Streptococcus pneumoniae (SP) (serotype 6B). Left foot abscess culture was also positive for penicillin-sensitive SP (serotype 6B). A next generation sequencing analysis for left foot abscess was also suggestive of SP infection. Anti-pneumococcal therapy was adjusted to ceftriaxone over 14 days with good recovery of foot abscess. A magnetic resonance imaging (MRI) showed lesions in the shrunken liver and no enhancement in abnormal signals of liver (Figure 1A). Liver stiffness measurement was 19.8 Kpa. The presence of specific antibodies (positive IgM and IgG), blood cytomegalovirus (CMV) load (500 copies/mL) and urine CMV viral load (7000 copies/mL) confirmed the diagnosis of CMV infection. Then he was treated with intravenous ganciclovir. High serum methionine (109 μmol/L) and tyrosine (724 μmol/L) with the α-fetoprotein level (45 389 ng/mL) and persistent coagulopathy despite treatment with fresh frozen plasma and vitamin K, suggested tyrosinaemia. Whole-exome sequencing identified compound heterozygous variants in fumarylacetoacetate hydrolase (FAH, NM_000137), including a known pathogenic maternal nonsense variant c.520C>T (p.R174*) and a paternal missense variant c.742G>A (p.G248R) in the proband (Figure 1B). The paternal missense variant was predicted to be likely pathogenic by SIFT and Polyphen. Mutations in the FAH gene have been attributed to hereditary tyrosinemia type 1 (HT1). So this patient was diagnosed as HT1. Fortunately, his sister did not carry these variants (Figure 1B). In the 3rd month of life the patient was discharged from hospital with liver function and coagulation function improved, having been on a diet restricted in phenylalanine, methionine and tyrosine. The patient died a year after discharge because of severe liver damage without compliance to dietary restrictions. HT1 is an autosomal recessive disorder of tyrosine metabolism and is caused by deficiency FAH, resulting in accumulation of the intermediate toxic metabolite fumarylacetoacetate released into the circulation and thus can be measured for diagnosis.1 These are several reports of invasive pneumococcal disease (IPD) with HT1. Wabitsch et al2 reported a severely ill 2-month-old female infant with meningitis and septicaemia caused by SP and HT1. Gill and Lipscomb3 reported a 3-month-old, previously healthy girl diagnosed with primary pneumococcal peritonitis associated with HT1. At present, no study has been conducted on the correlation between the pathogenesis of IPD and HT1. Georgouli et al4 reported a 5-month-old boy with HT1 presented with Escherichia coli sepsis and severe coagulopathy due to liver dysfunction. To our knowledge, this is the first reported case of SP sepsis and left foot abscess with CMV infection and HT1. For our patient, persistent coagulopathy during SP sepsis and foot abscess is indicative of tyrosinemia, especially with abnormal liver function. This work was supported by the Special Fund of the Pediatric Medical Coordinated Development Center of Beijing Hospitals Authority (No. XTZD20180501) and Beijing Hospitals Authority “Dengfeng” Talent Training Plan (DFL 20181201). Consent was obtained from the patient’s parents. The authors declare no competing interests.

ABSTRACTHost immune responses to severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), especially in children, are still under investigation. Children with coronavirus disease 2019 (COVID‐19) constitute a significant study group of immune responses as they rarely present with severe clinical manifestations, require hospitalization, or develop complications such as multisystem inflammatory syndrome in children (MIS‐C) associated with SARS‐CoV‐2 infection. The deciphering of children’s immune responses during COVID‐19 infection will provide information about the protective mechanisms, while new potential targets for future therapies are likely to be revealed. Despite the limited immunological studies in children with COVID‐19, this review compares data between adults and children in terms of innate and adaptive immunity to SARS‐CoV‐2, discusses the possible reasons why children are mostly asymptomatic, and highlights unanswered or unclear immunological issues. Current evidence suggests that the activity of innate immunity seems to be crucial to the early phases of SARS‐CoV‐2 infection and adaptive memory immunity is vital to prevent reinfection.

ABSTRACTImportanceIn cases of epiblepharon with lower eyelid retraction secondary to glaucoma, correcting epiblepharon alone is ineffective. Combined surgery should be performed to obtain satisfactory outcomes.ObjectiveTo investigate outcomes after surgery to correct epiblepharon with lower eyelid retraction secondary to buphthalmos in children.MethodsA retrospective analysis of six eyes in four patients was performed included lower lid retractor recession combined with marginal rotation with tarsal fixation. The margin reflex distance‐2, lagophthalmus, resolution of clinical symptoms, and complications were assessed during 6 to 12 months of follow‐up.ResultsIn all cases, epiblepharon and lagophthalmus were corrected, symptoms of photophobia and epiphora were relieved, and the corneal epithelium was repaired. The margin reflex distance‐2 decreased and remained normal during the follow‐up period, but slightly regressed within 6 months postoperatively.InterpretationEpiblepharon caused by buphthalmos in children is often associated with lower eyelid retraction. Lower lid retractor recession combined with marginal rotation with tarsal fixation fundamentally solves the problems of high eyelid tension, lower eyelid retraction, and epiblepharon and reduces the recurrence rate.

ABSTRACTImportanceFirst branchial cleft anomalies (FBCAs) are rare congenital malformations, accounting for < 8% of all branchial cleft anomalies. However, little is currently known about the cause of FBCAs at the molecular level.ObjectiveTo identify genomic alterations related to the genetic etiology of FBCAs in Chinese children.MethodsWe performed whole‐exome sequencing of samples from 10 pediatric patients with FBCAs. Data analysis was carried out using the Burrow‐Wheeler Alignment software package, and the dbSNP database for comparisons. Rare variants were further validated by Sanger sequencing. Insertion/deletions (indels) were examined using the Genome Analysis Toolkit.ResultsWe identified 14 non‐synonymous mutations in seven potential FBCA‐susceptibility genes (TRAPPC12, NRP2, NPNT, SH3RF2, RHPN1, TENM4, and ARMCX4). We also detected 133 shared small indels in 125 genes. Gene Ontology analysis indicated that most of the identified genes played critical roles in development and differentiation pathways involved in regulating organ development.InterpretationWe characterized the mutational landscape in pathways involved in development and differentiation in Chinese children with FBCA. The results identified potential pathogenic genes and mutations related to FBCA, and provide molecular‐level support for the branchial theory of FBCA pathogenesis.

ABSTRACTImportanceHypervirulent variants of Klebsiella pneumoniae (hvKp) are capable of causing life‐threatening pyogenic liver abscesses (PLAs), but hvKp caused PLAs was seldom reported in pediatric populations. Hence, there is an urgent need to raise our awareness of this phenomenon in pediatric populations.ObjectiveThis study aimed to report the clinical characteristics of hvKp that caused fatal PLA complicated by bacteremia in an adolescent and further identify the microbiological and genomic features of the causative strain.MethodsA 14‐year‐old boy with diabetes mellitus was admitted to our hospital with a diagnosis of PLA complicated by bacteremia. A hypermucoviscous hvKp strain, KPN_19‐106, was isolated from the drainage fluid present within the liver abscess cavity and blood. The hypermucoviscosity phenotype of the causative strain was determined by string test. Its virulence was measured using serum resistance assay and Galleria mellonella larvae‐killing assay. Antimicrobial susceptibility was determined by broth microdilution method. Genetic information was obtained by whole‐genome sequencing and bioinformatics analysis.ResultsKPN_19‐106 belonged to sequence type 380 and serotype K2 and exhibited stronger serum resistance and higher in vivo lethality than the well‐characterized hvKp NTUH‐K2044 strain. Although KPN_19‐106 is susceptible to most antibiotics, no sign of improvement was observed during treatment with such drugs. Whole‐genome sequencing revealed that the isolate had integrated multiple mobile genetic elements related to virulence.InterpretationAntibiotic‐susceptible hvKp can cause fatal PLA complicated by bacteremia in adolescents, with no improvement during antimicrobial therapy. The causative strain in this case had integrated multiple virulence genes and thus exhibited higher virulence both in vitro and in vivo when compared with NTUH‐K2044.

To the editor: A 9-month-old girl presented with multiple hypomelanotic macules that had been present since birth. Previously, she had been diagnosed with nevus depigmentosus and treated with intermittent topical emollient and sun protective measures; however, she exhibited no improvement. One week prior to presentation in our clinic, the patient’s mother had observed a shagreen patch on the patient’s back, as well as more than 10 new hypomelanotic macules on her trunk and extremities. The parents recalled no history of infantile spasms or seizures. Physical examination revealed multiple depigmented or hypopigmented polygonal or guttate macules, measuring 0.2 to 2.0 cm in diameter, over the patient’s trunk and limbs (Figure 1A). No fluorescence reaction was observed under Wood’s lamp examination. A shagreen patch with a pigskin-like surface was found on the patient’s torso (Figure 1B, black arrow). The patient’s mother also noted the presence of similar lesions on the patient’s trunk and lumbosacral area (Figure 2A); multiple dome-shaped, pink-tan papules (facial angiofibromas) on her cheeks (Figure 2B); and ash leaf macules on her neck (Figure 2C, red arrow). However, the patient’s mother could not remember when those symptoms had initially occurred, so their duration could not be determined. Echocardiography revealed multiple irregular abnormal echoes in the left and right ventricle and right ventricular outflow tract (Figure 1C), which had previously been detected on prenatal ultrasound at 24 weeks’ gestation; subsequently, they had not been further investigated. After getting ethical approval from the Beijing Children’s Hospital, next-generation sequencing was performed by using the patient’s peripheral blood and Sanger sequencing was performed by using her parents’ blood. The results revealed a known heterozygous frameshift mutation (c.3691_3694delCTGT, p.S1232Tfs*92) in TSC2 in both the patient and her mother (Figure 1D).1 Mutations in the TSC1 and TSC2 genes have been attributed to tuberous sclerosis complex (TSC). Therefore, a diagnosis of TSC was made in this family, based on the clinical and genetic findings. TSC is an autosomal dominant neurocutaneous congenital disorder of cellular differentiation and proliferation that affects multiple organ systems including the skin, brain, kidneys, and heart; it also involves hamartoma formation.2 Major cutaneous features in patients with TSC include hypomelanotic macules, typically the only cutaneous finding at birth; shagreen patch and facial angiofibromas, first observed at the ages of 2–8 years; and periungual fibromas, which develop later in childhood (after 4 years of age) and continue to form throughout adulthood. Because most major TSC criteria comprise cutaneous features in childhood, especially in a neonate, a thorough dermatologic examination frequently helps to establish the diagnosis.3 Hypomelanotic macules or patches are the earliest sign of TSC and are present from birth in up to 90% of pediatric patients; three or more of these macules or patches (≥5 mm in diameter) are regarded as a major criterion for diagnosis. Hypomelanotic macules of TSC should be distinguished from nevus depigmentosus, nevus anemicus, post-inflammatory hypopigmentation, tinea versicolor, and vitiligo. Shagreen patch, a type of collagenoma, is another characteristic feature of TSC that very rarely appears before 1 year of age.4 Because seizures and cardiac rhabdomyomas occur in the majority of affected infants, systemic examinations for asymptomatic infants with skin lesions alone should be performed. Notably, our patient presented with hypopigmented macules and shagreen patch; it was highly unusual for a neonate of this age with TSC to exhibit a complete spectrum of cutaneous presentations. Our patient received regular echocardiography follow-up; spontaneous resolution of cardiac rhabdomyomas was observed 2 years later. Consent was obtained from the patient’s parents. None.