Anakinra and hepatotoxicity in pediatric rheumatology: a case series.

BACKGROUND: Anakinra is a recombinant interleukin-1 (IL-1) receptor antagonist used in systemic juvenile idiopathic arthritis (sJIA), refractory Kawasaki disease (KD) and cryopyrin-associated autoinflammatory syndrome (CAPS). Anakinra associated hepatotoxicity, while rare, has been described in several cases in daily practice. ​In this case series the authors describe three pediatric patients with this side effect in the setting of severe macrophage activation syndrome (MAS) in KD and sJIA. CASE PRESENTATION: The first patient was a 12-year-old boy who presented with fever, maculo-papular exanthema and polyarthralgia. Tonsillitis, distal limb induration and tender cervical lymph nodes were observed. Erythrocyte-sedimentation rate (ESR), C-reactive protein (CRP), ferritin (11,975 ng/mL), D-dimers (5,98 mg/L FEU) and soluble CD25 (3645 pg/mL) levels were elevated. Exclusion of sepsis / toxic shock syndrome warranted introduction of IV methylprednisolone and immunoglobulin (IG IV), with partial response. A MAS secondary to KD was assumed, and anakinra 2 mg/kg/day was introduced. Twenty days later he developed new-onset nausea and severe cyto-cholestasis, normalizing after 2 months of drug discontinuation. Posterior onset of polyarthritis and evanescent lead to a final diagnosis of sJIA. The second patient was a 2-year-old boy with a 10-day history of fevers, generalized rash, hepatosplenomegaly and strawberry tongue. Leucocytosis with neutrophilia and elevated CRP were observed. Initial treatment with IVIG in the setting of incomplete KD was ineffective. Mild anaemia, leukopenia and very high serum ferritin (maximum 26,128 ng/mL) ensued. Presumptive sJIA associated MAS was treated with IV methylprednisolone and anakinra 2 mg/kg/day, with prompt response. Four weeks later transaminitis was detected, and temporary anakinra suspension led to normalisation of laboratorial values. The third case related to a 4-year-old boy presenting with fever, maculopapular rash and cervical lymphadenopathy. CRP and ESR were elevated, and KD was diagnosed. IVIG and methylprednisolone were initiated with clinical worsening, warranting for anakinra introduction at 2 mg/kg/day. After three weeks, liver enzymes progressively elevated, resolving on 2 weeks of anakinra discontinuation. CONCLUSIONS: To the best of our knowledge, this is the first case series describing anakinra associated hepatotoxicity in pediatric patients with rheumatic diseases other than sJIA, bringing additional insight to therapeutic monitoring in patients undergoing this treatment.

Microbiome in Nasal Mucosa of Children and Adolescents with Allergic Rhinitis: A Systematic Review.

The human upper respiratory tract comprises the nasal cavity, pharynx and larynx regions and offers distinct microbial communities. However, an imbalance and alterations in the nasal mucosa microbiome enhance the risk of chronic respiratory conditions in patients with allergic respiratory diseases. This is particularly important in children and adolescents once allergic rhinitis (AR) is an inflammatory disorder of the nasal mucosa, often associated with an increase in pulmonary allergic inflammation. Therefore, this systematic review aimed to collect scientific data published concerning the microbial community alterations in nasal mucosa of children and adolescents suffering from AR or in association with adenotonsillar hypertrophy (AH) and allergic rhinoconjunctivitis (ARC). The current study was performed using the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Publications related to microbiome alterations in the nasal mucosa in pediatric age, studies including next-generation sequencing platforms, and studies exclusively written in the English language were some of the inclusion criteria. In total, five articles were included. Despite the scarcity of the published data in this research field and the lack of prospective studies, the genera Acinetobacter, Corynebacterium, Dolosigranulum, Haemophilus, Moraxella, Staphylococcus and Streptococcus dominate the nares and nasopharyngeal microbiome of the pediatric population regardless of their age. However, an imbalance in the resident bacterial community in the nasal mucosa was observed. The genera Acinetobacter, and Pseudomonas were more abundant in the nasal cavity of AR and AH children, while Streptococcus and Moraxella were predominant in the hypopharyngeal region of AR infants. An abundance of Staphylococcus spp. was also reported in the anterior nares and hypopharyngeal region of children and adolescents suffering from AR passive smoke exposure and ARC. These records suggest that different nasal structures, ageing, smoke exposure and the presence of other chronic disorders shape the nasal mucosa microbiome. Therefore, the establishment of adequate criteria for sampling would be established for a deeper understanding and a trustworthy comparison of the microbiome alterations in pediatric age.