Pediatric Asthma: Where Has Montelukast Gone?

At its introduction in the management of pediatric asthma, montelukast was regarded as a potentially revolutionary drug due to its mechanism of action and easy clinical applicability. Nevertheless, its use in daily practice and evidence from clinical trials have shown that, rather than a radical change in the approach to asthmatic children, montelukast more likely represents a second-line medication that is useful when inhaled steroids alone fail in providing adequate symptom control. Furthermore, increasingly reported side effects have raised concerns regarding its safety. In the last decade, several studies have tried to better define the strengths and drawbacks of montelukast both in preschool wheezing and school-age asthma. The present review summarizes the literature published on this topic since 2010, highlighting the often-controversial results and the unanswered questions regarding the role of montelukast in pediatric asthma. Moreover, advances in the understanding of the mechanisms of action of montelukast are reported. The main finding emerging from the present analysis is that montelukast application is likely to be useful in a subset of asthmatic children rather than in large groups of patients. Future studies should focus on the identification of biomarkers able to predict which patients will benefit from montelukast to achieve a more tailored prescription.

Incomplete Kawasaki Disease with Peripheral Facial Nerve Palsy and Lung Nodules: A Case Report and Literature Review.

The diagnosis of Kawasaki disease (KD) is challenging and often delayed mainly in case of young infants and in presence of an incomplete disease and atypical features. Facial nerve palsy is one of the rare neurologic symptoms of KD, associated with a higher incidence of coronary arteries lesions and may be an indicator of a more severe disease. Here, we describe a case of lower motor neuron facial nerve palsy complicating KD and perform an extensive literature review to better characterize clinical features and treatment of patients with KD-associated facial nerve palsy. The patient was diagnosed at the sixth day of disease and presented extensive coronary artery lesions. A prompt treatment with intravenous immunoglobulins, aspirin and steroids obtained a good clinical and laboratory response, with resolution of facial nerve palsy and improvement of coronary lesions. The incidence of facial nerve palsy is 0.9-1.3%; it is often unilateral, transient, more frequent on the left and seemingly associated with coronary impairment. Our literature review showed coronary artery involvement in the majority of reported cases (27/35, 77%) of KD with facial nerve palsy. Unexplained facial nerve palsy in young children with a prolonged febrile illness should prompt consideration of echocardiography to exclude KD and start the appropriate treatment.

Seizures in Children with SARS-CoV-2 Infection: Epidemiological, Clinical and Neurophysiological Characterization.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may present with a wide variety of symptoms, including neurological manifestations. We investigated clinical, demographic, laboratory, neurophysiological and imaging characteristics of SARS-CoV-2-positive children with seizures and analyzed differences between children admitted during the periods with prevalent circulation of the Alpha/Delta and Omicron variants, respectively. Patients' characteristics were analyzed according to the presence or absence of seizures and then according to the SARS-CoV-2 variants. Five-hundred and four SARS-CoV-2-positive patients were included: 93 (18.4%) with seizures and 411 (81.6%) without. Patients with seizures were older, had more commonly an underlying epilepsy and had more frequently altered C-reactive protein than those without seizures. Electroencephalography was abnormal in 5/38 cases. According to the SARS-CoV-2 variant, seizures were recorded in 4.7% of the total number of hospitalized patients during the Alpha/Delta period, and in 16.9% of patients admitted during the Omicron period. During the Alpha/Delta variants, seizures were more commonly observed in patients with epilepsy compared to those observed during the Omicron period. Our findings suggest that although SARS-CoV-2 may potentially trigger seizures, they are generally not severe and do not require intensive care admission.

MIS-C: A COVID-19-as sociated condition between hypoimmunity and hyperimmunity.

Multisystem inflammatory syndrome in children (MIS-C) is a rare, severe complication of COVID-19. A better knowledge of immunological, cellular, and genetic characteristics of MIS-C could help better understand the pathogenesis of the disease and contribute to identifying specific diagnostic biomarkers and develop targeted therapies. We studied 37 MIS-C children at hospital admission and 24 healthy controls analyzing serum cytokines (IFN-α, IFN-ß, IFN-γ, IL-6, IL-10, IL-17A, IL-12p70 and TNF), lymphocyte populations by flow cytometry and 386 genes related to autoimmune diseases, autoinflammation and primary immunodeficiencies by NGS. MIS-C patients showed a significant increase of serum IFNγ (despite a significant reduction of activated Th1) and ILs, even if with a great heterogeneity among patients, revealing different pathways involved in MIS-C pathogenesis and suggesting that serum cytokines at admission may help to select the inflammatory pathways to target in each patient. Flow cytometry demonstrated a relevant reduction of T populations while the percentage of B cell was increased in agreement with an autoimmune pathogenesis of MIS-C. Genetic analysis identified variants in 34 genes and 83.3% of patients had at least one gene variant. Among these, 9 were mutated in more patients. Most genes are related to autoimmune diseases like ATM, NCF1, MCM4, FCN3, and DOCK8 or to autoinflammatory diseases associated to the release of IFNγ like PRF1, NOD2, and MEF. Thus, an incomplete clearance of the Sars-CoV2 during the acute phase may induce tissue damage and self-antigen exposure and genetic variants can predispose to hyper-reactive immune dysregulation events of MIS-C-syndrome. Type II IFN activation and cytokine responses (mainly IL-6 and IL-10) may cause a cytokine storm in some patients with a more severe acute phase of the disease, lymphopenia and multisystemic organ involvement. The timely identification of such patients with an immunocytometric panel might be critical for targeted therapeutic management.

Immunophenotyping of peripheral blood cells allows to discriminate MIS-C and Kawasaki disease.

Background: The pathogenesis of the novel described multisystem inflammatory syndrome in children (MIS-C) and Kawasaki disease (KD) is still debated as it is not clear if they are the same or different nosological entities. However, for both the diseases a rapid and unequivocal diagnosis is mandatory to start the therapy before the onset of severe complications. In this study, we aimed to evaluate the white cell populations in MIS-C and KD as potential markers to discriminate between the two diseases. Methods: We studied white cell populations by flow cytometry in 46 MIS-C and 28 KD patients in comparison to 70 age-matched healthy children. Results: MIS-C patients had a significant lymphopenia that involved both B and T populations while KD patients showed a significant neutrophilia and thrombocythemia. Granulocyte/lymphocyte ratio helped to diagnose both MIS-C and KD with a high diagnostic sensitivity, while a multivariate analysis of granulocyte and T lymphocyte number contributed to discriminate between the two diseases. Conclusions: The relevant lymphopenia observed in MIS-C patients suggests that the disease would be a post-infectious sequel of COVID-19 immunologically amplified by a massive cytokine release, while the significant neutrophilia and thrombocythemia observed in KD confirmed that the disorder has the genesis of a systemic vasculitis. The analysis of a panel of circulating cells may help to early diagnose and to discriminate between the two diseases. Supplementary Information: The online version contains supplementary material available at 10.1186/s41231-022-00128-2.

Changing Epidemiology of Acute Viral Respiratory Infections in Hospitalized Children: The Post-Lockdown Effect.

Several reports highlighted how public health measures aimed at limiting severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) circulation have likely contributed to reducing the circulation of other respiratory viruses, particularly during the first year of the COVID-19 pandemic. We evaluated the epidemiology of acute respiratory infections in a large cohort of hospitalized children during the third year of the pandemic (2021-2022). We retrospectively analyzed data from the health records of children (<14 years) hospitalized for acute respiratory infections between 1 July 2021 and 31 March 2022. A total of 1763 respiratory panels were collected. Overall, 1269 (72%) panels hadpositive results for at least one pathogen. Most positive panels (53.8%) belonged to patients aged 1-12 months. The most detected pathogen was respiratory syncytial virus (RSV) (57.8% of positive panels). The RSV peak occurred in November 2021. Nine hundred and forty-five (74.5%) panels were positive for one pathogen while three hundred and twenty-four (25.5%) showed multiple infections. Patients with multiple infections were significantly older than those with a single infection. The 2021-2022 peak of RSV infection in Italy occurred earlier than in the previous pre-pandemic seasons. A high number of children have been hospitalized because of acute viral infections also due to less aggressive viruses.

Biomarkers of Endothelial Damage in Distinct Phases of Multisystem Inflammatory Syndrome in Children.

Endothelial hyperinflammation and vasculitis are known hallmarks of acute COVID-19 and multisystem inflammatory syndrome in children (MIS-C). They are due to the direct effect of the virus on endothelial cells enhanced by pro-inflammatory modulators and may cause venous/arterial thrombosis. Therefore, it is essential to identify patients with endothelial damage early in order to establish specific therapies. We studied the monocyte chemoattractant protein 1 (MCP-1), the perinuclear anti-neutrophil cytoplasmic antibodies (pANCA), and the vascular endothelial growth factor A (VEGF-A) in serum from 45 MIS-C patients at hospital admission and 24 healthy controls (HC). For 13/45 MIS-C patients, we measured the three serum biomarkers also after one week from hospitalization. At admission, MIS-C patients had significantly higher levels of MCP-1 and VEGF-A than the HC, but no significant differences were observed for pANCA. While after one week, MCP-1 was significantly lower, pANCA was higher and VEGF-A levels were not significantly different from the admission values. These findings suggest an involvement of epithelium in MIS-C with an acute phase, showing high MCP-1 and VEGF-A, followed by an increase in pANCA that suggests a vasculitis development. The serum biomarker levels may help to drive personalized therapies in these phases with anticoagulant prophylaxis, immunomodulators, and/or anti-angiogenic drugs.

Acute Kidney Injury in Children with Acute Appendicitis.

We hypothesized that-as in other common pediatric conditions-acute appendicitis (AA) could be complicated by acute kidney injury (AKI). We aimed to investigate the prevalence of, and the factors associated with AKI in a cohort of patients with AA. We retrospectively collected data of 122 children (63.9% of male gender; mean age 8.6 ± 2.9 years; range: 2.2-13.9 years) hospitalized for AA. AKI was defined according to the Kidney Disease/Improving Global Outcomes creatinine criteria. We considered a basal serum creatinine value as the value of creatinine estimated with the Hoste (age) equation, assuming that the basal estimated glomerular filtration rate (eGFR) was 120 mL/min/1.73 m2. Explorative univariate logistic regression analysis was used to explore the associations with AKI. Out of 122 patients, nine (7.4%) presented with AKI. One patient had stage two AKI and the remaining had stage one AKI. The maximum AKI stage was found at admission. The patients with AKI showed a higher prevalence of fever ≥ 38.5 °C (p = 0.02), vomiting (p = 0.03), ≥5% dehydration (p = 0.03), and higher levels of both C-reactive protein (CRP) (p = 0.002) and neutrophils (p = 0.03) compared with patients without AKI. Because all patients with AKI also presented with vomiting, an Odds Ratio (OR) for the vomiting was not calculable. The exploratory univariate logistic regression analysis confirmed that fever ≥ 38.5 °C (OR = 5.0; 95% CI: 1.2/21.5; p = 0.03), ≥5% dehydration (OR = 8.4; 95% CI: 1.1/69.6; p = 0.04), CRP (OR = 1.1; 95% CI: 1.05/1.2; p = 0.01), and neutrophil levels (OR = 1.1; 95% CI: 1.01/1.3; p = 0.04) were all predictive factors of AKI. AKI can occur in 7.4% of patients with AA. Particular attention should be paid to the kidney health of patients with AA especially in the presence of vomiting, ≥5% dehydration, fever ≥ 38.5 °C, and high CRP and neutrophils levels.

Distinctive Phenotype of Multisystem Inflammatory Syndrome in Children Associated with SARS-CoV-2 According to Patients' Age: A Monocentric Experience.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a disease temporally related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and it is characterized by fever, conjunctival injections, rash, gastrointestinal symptoms, and cardiovascular complications. We evaluated the clinical presentation, laboratory findings, imaging features, therapeutic interventions, and hospital course of a monocentric cohort, and we analyzed these findings according to two age groups. METHODS: Patients with MIS-C admitted to a Tertiary Care Pediatric Hospital from November 2020 to November 2021 were considered for the enrollment. RESULTS: Overall, 35 consecutive patients were included. Most of the children did not require intensive care unit at the admission. The clinical presentation of MIS-C slightly differs according to age groups. Mucocutaneus involvement was more frequent in younger patients, while abdominal symptoms were present in 54% of patients aged less than 5 years and in 95% of patients aged more than 5 years (p < 0.05). In addition, the number of cases with troponin above the normal reference value was significantly higher in older patients (77%) compared to younger cases (15%) (p < 0.01). CONCLUSIONS: MIS-C is a new emerging condition and represents a challenge to pediatricians due to the severity of presentation. Further studies to better characterize the long-term outcome of MIS-C patients are mandatory.

Liver and Pancreatic Involvement in Children with Multisystem Inflammatory Syndrome Related to SARS-CoV-2: A Monocentric Study.

Liver and pancreatic involvement in children with Multisystem Inflammatory Syndrome related to SARS-CoV-2 (MIS-C) has been poorly investigated so far. We reviewed a cohort of MIS-C patients to analyze the prevalence of acute liver injury (ALI) and pancreatic injury and their correlation with clinical outcomes. Demographic, clinical, laboratory and imaging features of children with MIS-C at admission and during hospital stay were prospectively collected. Fifty-five patients (mean age 6.5 ± 3.7 years) were included. At admission, 16 patients showed ALI and 5 had increased total serum lipase. During observation, 10 more patients developed ALI and 19 more subjects presented raised pancreatic enzymes. In comparison to those with normal ALT, subjects with ALI were significantly older (p = 0.0004), whereas pancreatic involvement was associated to a longer duration of hospital stay compared with patients with normal pancreatic enzymes (p = 0.004). Time between hospital admission and onset of ALI was shorter compared to the onset of raised pancreatic enzymes (3.2 ± 3.9 versus 5.3 ± 2.7 days, respectively; p = 0.035). Abdominal ultrasound showed liver steatosis in 3/26 (12%) and hepatomegaly in 6/26 (16%) patients with ALI; 2 patients presented enlarged pancreas. Although liver and pancreatic involvement is commonly observed in MIS-C patients, it is mild in most cases with a complete recovery.

Distinctive Phenotype of Multisystem Inflammatory Syndrome in Children Associated with SARS-CoV-2 According to Patients' Age: A Monocentric Experience

Background: Multisystem inflammatory syndrome in children (MIS-C) is a disease temporally related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and it is characterized by fever, conjunctival injections, rash, gastrointestinal symptoms, and cardiovascular complications. We evaluated the clinical presentation, laboratory findings, imaging features, therapeutic interventions, and hospital course of a monocentric cohort, and we analyzed these findings according to two age groups. Methods: Patients with MIS-C admitted to a Tertiary Care Pediatric Hospital from November 2020 to November 2021 were considered for the enrollment. Results: Overall, 35 consecutive patients were included. Most of the children did not require intensive care unit at the admission. The clinical presentation of MIS-C slightly differs according to age groups. Mucocutaneus involvement was more frequent in younger patients, while abdominal symptoms were present in 54% of patients aged less than 5 years and in 95% of patients aged more than 5 years (p < 0.05). In addition, the number of cases with troponin above the normal reference value was significantly higher in older patients (77%) compared to younger cases (15%) (p < 0.01). Conclusions: MIS-C is a new emerging condition and represents a challenge to pediatricians due to the severity of presentation. Further studies to better characterize the long-term outcome of MIS-C patients are mandatory.

Effects of Relaxed Lockdown on Pediatric ER Visits during SARS-CoV-2 Pandemic in Italy.

Previously, we demonstrated an 81% reduction in pediatric Emergency Room (ER) visits in Italy during the strict lockdown due to the SARS-CoV-2 pandemic. Since May 2020, lockdown measures were relaxed until 6 November 2020, when a strict lockdown was patchily reintroduced. Our aim was to evaluate the impact of the relaxed lockdown on pediatric ER visits in Italy. We performed a retrospective multicenter study involving 14 Italian pediatric ERs. We compared total ER visits from 24 September 2020 to 6 November 2020 with those during the corresponding timeframe in 2019. We evaluated 17 ER specific diagnoses grouped in air communicable and non-air communicable diseases. We recognized four different triage categories: white, green, yellow and red. In 2020 total ER visits were reduced by 51% compared to 2019 (16,088 vs. 32,568, respectively). The decrease in air communicable diseases was significantly higher if compared to non-air communicable diseases (-64% vs. -42%, respectively). ER visits in each triage category decreased in 2020 compared to 2019, but in percentage, white and red codes remained stable, while yellow codes slightly increased and green codes slightly decreased. Our results suggest that preventive measures drastically reduced the circulation of air communicable diseases even during the reopening of social activities but to a lesser extent with regard to the strict lockdown period (March-May 2020).

Brugada Pattern in a Child with Severe SARS-CoV-2 Related Multisystem Inflammatory Syndrome.

This report presents the first case of Brugada pattern complicated by a supraventricular arrhythmia in a child with SARS-CoV-2 related Multisystem Inflammatory Syndrome in Children (MIS-C). A 7-year-old boy came to our Emergency Department with 7 days of abdominal pain and fever. MIS-C was diagnosed on the basis of the clinical, laboratory and instrumental tests. On admission, ECG showed type 1 Brugada pattern in the right precordial leads. During hospitalization the onset of supraventricular arrhythmias complicated the clinical picture. This case underlines management complexity of supraventricular arrhythmic events, different from atrial fibrillation, in patients with Brugada pattern in the context of a systemic inflammatory condition with significant cardiac involvement. All potential therapeutic choices should be considered to ensure the best outcomes.

Infection control strategy and primary care assistance in Campania region during the national lockdown due to COVID-19 outbreak: the experience of two tertiary emergency centers.

BACKGROUND: COVID-19 pandemic has markedly affected emergency care, due to sudden limitation of health care capacity by general practitioners (GP) and urgent need for infection control strategies. We evaluated the activity of the Emergency Department (ED) during the national lockdown (March 8-April 30), as well as the outcomes of our infection control strategy. RESULTS: Despite a reduction in access by one fifth, a proportion of febrile patients comparable to 2019 was seen (829/2492, 33.3% vs 4580/13.342, 34.3%, p = 0.3). Diagnostic swab for COVID-19 was performed in 25% of patients, especially in subjects with co-morbidities or multiple access. Six infected cases were identified, all presenting with febrile disease. Only two positive patients fulfilled the criteria for diagnostic swab provided by the Italian Health Authorities, because of close contact with suspected or confirmed cases. The rate of admission for febrile or respiratory conditions was higher than the same period of 2019 (33.4% vs 25.9%, p < 0.0001). None of the 105 health-care professionals working during the study time lapse exhibited anti-SARS-CoV-2 seroconversion. Among the 589 patients with information available, 54.9% declared no medical consultation at all prior to coming to ED, while only 40 (of which 27 with fever) had been examined by their GP before coming to ED. Nevertheless, 35.6% of the cases were already taking medications. None of the 9 patients requiring intensive care reported recent pediatric consultation, despite symptoms duration up to 30 days. CONCLUSION: Our results provide evidence that the reduced capacity of primary care facilities during the national lockdown may have caused a high rate of self-medication as well as a delayed provision of care in some patients. Identification of pediatric patients affected with SARS-CoV-2 infection remains a challenge because of the absence of reliable predictive factors. Finally, the use of specific triage centers, with dedicated pathways to diagnose SARS-CoV-2 infection, trace contacts and allow adequate care after swabs, is effective in preventing spreading of the infection.

SARS-CoV-2 Pandemic Impact on Pediatric Emergency Rooms: A Multicenter Study.

From 9 March to 3 May 2020, lockdown was declared in Italy due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Our aim was to evaluate how the SARS-CoV-2 pandemic and related preventive strategies affected pediatric emergency rooms (ERs) during this period. We performed a retrospective cohort multicenter study, comparing the lockdown period to the corresponding period in 2019. We examined 15 Italian pediatric ERs in terms of visit rates, specific diagnoses (grouped as air communicable diseases and non-air communicable diseases), and triage categories. During the lockdown period, ER admissions decreased by 81% compared to 2019 (52,364 vs. 10,112). All ER specific diagnoses decreased in 2020 and this reduction was significantly higher for air communicable diseases (25,462 vs. 2934, p < 0.001). Considering the triage category, red codes remained similar (1% vs. 1%), yellow codes increased (11.2% vs. 22.3%), and green codes decreased (80.3% vs. 69.5%). We can speculate that social distancing and simple hygiene measures drastically reduced the spread of air communicable diseases. The increase in yellow codes may have been related to a delay in primary care and, consequently, in ER admissions.