Successful treatment with Omalizumab of a child affected by Systemic Mastocytosis: clinical and biological implications.

BACKGROUND: Pediatric Mastocytosis is a rare and heterogeneous disease, characterized by accumulation of mast cells in the skin (Cutaneous Mastocytosis) and/or, less frequently, in other organs, mainly liver, spleen, bone marrow, lymph nodes and gastrointestinal tract (Systemic Mastocytosis). Patients affected by Systemic Mastocytosis show symptoms caused by  a massive release of mast cell mediators: itching, flushing, abdominal pain, generalized weakness, fatigue and neuropsychiatric disorders. Moreover, children with Systemic Mastocytosis are at greater risk of anaphylactic/anaphylactoid reactions, often poorly controlled by the conventional therapy with antihistamines, mast cells stabilizers and steroids. As a result, children affected by Systemic Mastocytosis have a poor quality of life and suffer the consequence of prolonged steroidal treatment. CASE PRESENTATION: A child with Systemic Mastocytosis and severe symptoms, refractory to symptomatic and steroidal therapy, has been successfully treated with Omalizumab, an anti-IgE monoclonal antibody usually employed in allergic patients with severe asthma and orticaria. The onset of clinical benefit of Omalizumab therapy was extraordinarily rapid, but proved to be strictly dependent on drug administration. The child has become completely and steadily asymptomatic. No other anaphylactic episodes have been reported. Steroid treatment could be definitively withdrawn after the second dose of Omalizumab, and all the other medications were later reduced. Twenty months after beginning, Omalizumab therapy is still ongoing with good symptomatology control; no side effects have been observed so far. CONCLUSIONS: In our experience, Omalizumab is an effective treatment for children affected by Systemic Mastocytosis not responding to conventional medical treatments. The main strengths of this therapy are its rapid and extraordinary efficacy to control the severe mast cells mediator-related symptoms, the lack of side effects and its steroid-sparing effect. However, more extensive and controlled studies in pediatric patients affected by Systemic Mastocytosis are needed to substantiate these promising findings.

Intrapartum use of zidovudine in a large cohort of pregnant women living with HIV in Italy.

BACKGROUND: Intravenous administration of zidovudine (ZDV) during labour is a key step for vertical HIV transmission (VT) prevention, but there is no evidence of benefit when maternal HIV-RNA at delivery is <50 copies/mL. The aim of this study is evaluating the appropriateness of intrapartum ZDV use in Italy. METHODS: Observational study including mother-infant pairs with perinatal HIV exposure during 2002-2019, enrolled in the Italian Register for HIV Infection in Children. Univariable and multivariable logistic regression were used to evaluate factors associated with VT. RESULTS: A total of 3,861 infants, born from 3,791 pregnancies were included. The frequency of ZDV use was 79.9%, 92.1%, 93.7% and 92.8% when HIV-RNA was not available, ≥400 copies, between 50 and 399 copies, and <50 copies/mL. Thirty-three out of 3861 (0.85%) infants were subsequently diagnosed with HIV, 25/3861 (0.6%) of them born to mothers receiving intrapartum ZDV, and 31 (93.9%) to mothers with HIV-RNA ≥50 copies/mL or not available. In women with HIV-RNA < 50 copies/mL, ART discontinuation during pregnancy was the strongest risk factor for VT (odds ratio, OR, 23.1, 95%CI 2.4-219.3), while a higher gestational age (OR 0.6, 95%CI 0.4-0.8) and PEP administration to the newborn (aOR 0.004, 95%CI <0.0001-0.4) were protective factors. Intrapartum ZDV administration did not influence the final outcome in this group. CONCLUSIONS: In ART era, more transmission events may occur in utero, limiting value of intrapartum ZDV, particularly for women with suppressed HIV-RNA load. More attention to the HIV-RNA testing of mothers before delivery may avoid unnecessary ZDV use.

Clinical and Epidemiological Features of Pediatric Patients with COVID-19 in a Tertiary Pediatric Hospital.

BACKGROUND: Coronavirus disease 2019 (COVID-19) affects people of any age with high mortality and morbidity in adults older than 65 years. Reports on pediatric cases highlighted those children generally develop milder symptoms than adults or are asymptomatic. We aimed to assess the epidemiological and clinical data of children and adolescents with SARS-CoV-2 infection to improve pediatric COVID-19. METHODS: We retrospectively analyzed clinical and epidemiological features of patients with SARS-CoV-2 infection hospitalized at the Pediatric Hospital of Pavia, Italy, between February 1, 2020, to April 30, 2021. RESULTS: 71 patients aged 0-16 years were included; 33 (46%) females and 38 (54 %) males. Thirty-three (46%) patients had comorbidities, such as obesity and hematological diseases. Thirty-one children (44%) were exposed to COVID-19-positive household members. Nine (12.7 %) patients were asymptomatic, whereas 57 (80.3%) had a mild-moderate disease. Only five (7%) showed a severe or critical disease, and two patients required ICU admission. The most frequent symptoms were fever (76%), loss of appetite (26%), gastrointestinal symptoms (19%), and cough (19%). Chest X-ray was performed in 42 patients showing lung abnormalities in more than half of symptomatic patients. The most common laboratory features were lymphopenia and eosinopenia associated with high levels of inflammation markers. CONCLUSIONS: This study confirmed that COVID-19 has a mild course in children compared to adults. Most of the enrolled children were asymptomatic or had a mild-moderate disease. Patients with comorbidities were more prone to develop clinical complications.

Efficacy of Anakinra on Multiple Coronary Arteries Aneurysms in an Infant with Recurrent Kawasaki Disease, Complicated by Macrophage Activation Syndrome.

Kawasaki disease (KD) is rare in infants less than 3 months of age, and its recurrence is exceptional. Infants with KD are at higher risk of severe clinical presentation, therapy failure, complications and coronary aneurysms (CAAs), and this is the reason they deserve more aggressive therapy and a strict clinical follow-up. We report a 2-month-old male with KD, complicated by Macrophage Activation Syndrome (MAS). Despite timely and aggressive therapy with immunoglobulins, steroids and aspirin, multiple CAAs developed. Two-month therapy with anakinra completely reverted all the aneurysms. After six months, the infant experienced KD relapse and was successfully re-treated with immunoglobulins, steroids and aspirin. A strict echocardiographic follow-up did not show recurrence of aneurysms. Two years later, the child is healthy, without cardiac sequelae. In our experience, anakinra was effective in reverting multiple aneurysms and its effect proved to be long-lasting, even in front of KD recurrence. Based on this evidence, it seems reasonable to hypothesize not to limit the use of anakinra as rescue therapy for complicated or refractory KD, but to consider the possibility of adding it to first-line therapies for some subgroups of very-high-risk patients, in order to strengthen the prevention of CAAs.

Epidemiology and Management of Acute Hematogenous Osteomyelitis, Neonatal Osteomyelitis and Spondylodiscitis in a Third Level Paediatric Center.

Acute hematogenous osteomyelitis (AHOM) is a rare pathology in pediatric population. The aim of this study is to analyse the epidemiological data and the management, compared to European Society for Paediatric Infectious Disease (ESPID, European Society for Pediatric Infectious Diseases) guidelines 2017 of 216 children with AHOM, divided in three cohorts (neonatal-onset osteomyelitis, those with vertebral involvement and other types of osteomyelitis). We conducted a retrospective single center study, evaluating data from all the children (aged 0-18 years) consecutively admitted to the Meyer Children's Hospital, during a period of ten years (1 January 2010-31 December 2019). Isolation of pathogen was possible in 65 patients and S. aureus was the most frequently involved (43/65 children). Magnetic Resonance Imaging (MRI, magnetic resonance imaging) was performed in 201/216 cases and was compatible with osteomyelitis in 185/201 of these children (92.03%). In the neonatal-onset osteomyelitis group the percentage of diagnostic ultrasound for osteomyelitis was 36.36% significantly higher than the other groups. The median duration of total antibiotic therapy was 37.5 days. In total, 186/199 children recovered without complications. The present study delineates three heterogeneous cohorts of patients. S. aureus is confirmed as the first pathogen for isolation in all three groups analysed. MRI represent a gold standard for diagnosis. Longer duration of antibiotics treatment was performed in neonatal and spondylodiscitis group, compared to the other types of osteomyelitis.

Cerebral Toxocariasis as a Cause of Epilepsy: A Pediatric Case.

Toxocarosis is the consequence of human infection by Toxocara spp. larvae and is one of the most common ascarioses, not only in developing countries, but also in the European region, where its prevalence reaches 14%. Due to their particular behavior, children are at higher risk of this parasitic infection, whose clinical features depend on the localization of the Toxocara larvae. Neurotoxocariasis is very uncommon in children and may take different forms depending on the underlying physiopathologic process: immune reaction against the parasite antigens, vasculitis, treatment complications, or, very rarely, brain localization of Toxocara spp. larvae. The association between neurotoxocariasis and the onset of childhood epilepsy has been postulated but is still debated. Moreover, a Toxocara spp. abscess causing epileptic seizures in children has been rarely described, especially in western countries. Hereby we present a 9-year-old patient with a new diagnosis of epilepsy definitely secondary to brain abscess due to the localization of Toxocara canis larvae. Diagnosis was confirmed by neuroimaging and serological test. The successful treatment with albendazole and steroids was documented with a close and long-term clinical and neuroradiological follow-up. Our experience confirms that every case of cryptogenetic epilepsy in children deserves a neuroimaging study and, in case of cystic images, Toxocara serology is mandatory to avoid further unnecessary invasive diagnostic investigations and to set the specific drug therapy.

Timely adaptation of a Pediatric Unit to COVID-19 emergency in Northern Italy: the experience of Fondazione IRCCS Policlinico San Matteo in Pavia.

Italy is one of the most exposed countries worldwide to COVID-19, and Lombardy is the most affected region in Italy. In this context, Fondazione IRCCS Policlinico San Matteo in Pavia, one of the largest University hospitals in the region, has been involved in the management of the outbreak since its inception. Immediately after the communication of the first Italian COVID-19+ patient, the Pediatric Unit has been completely reorganized to face the approaching outbreak. The optimization of the Pediatric Unit resources for COVID-19 emergency is reported as an example to safely preserve health activity during the pandemic.

Disseminated Mycobacterium Avium Infection in a Child with Complete Interferon-γ Receptor 1 Deficiency due to Compound Heterozygosis of IFNGR1 for a Subpolymorphic Copy Number Variation and a Novel Splice-Site Variant.

Complete interferon-γ receptor 1 deficiency is a monogenic primary immunodeficiency caused by IFNGR1 germline defects, with autosomal dominant or recessive inheritance, which results in invasive mycobacterial diseases with varying degrees of severity. Most of the autosomal recessive IFNGR1 mutations are homozygous loss-of-function single-nucleotide variants, whereas large genomic deletions and compound heterozygosity have been very rarely reported. Herein we describe the clinical presentation, diagnosis, and successful treatment with hematopoietic stem cell transplantation of a child with disseminated Mycobacterium avium infection due to compound heterozygosity for a subpolymorphic copy number variation and a novel splice-site variant.

Telangiectasia macularis eruptiva perstans: a neglected type of mastocytosis with exclusively cutaneous involvement? A case series.

Telangiectasia macularis eruptiva perstans (TMEP) is a rare form of cutaneous mastocytosis (CM). Although TMEP has been traditionally thought to be restricted to the skin, a recent retrospective multicentric study established a diagnosis with systemic involvement of mastocytosis in 47% patients affected by TMEP and aggressive systemic mastocytosis in 9%. To evaluate systemic involvement in patients affected by TMEP. We conducted a retrospective monocentric study among patients affected by TMEP visited in our dermatology clinic. Data regarding gender, age at diagnosis, duration of the disease before diagnosis, topography, clinical features, presence of extra-cutaneous symptoms, serum tryptase levels, and histopathological and bone marrow biopsy features were analysed. Among 119 patients classified with mastocytosis, eight patients (six males, two females) with TMEP and one female patient affected by mastocytosis in the skin, a TMEP variant, were retrospectively studied. The mean diagnostic delay was two years (range: 8-26 months). In two patients (25%), bone marrow involvement was identified and osteoporosis and hepatosplenomegaly were also found. The two patients with systemic involvement exhibited a statistically significant increase in serum tryptase levels (p < 0.05). The detection of KIT gene mutation in skin specimens revealed a somatic mutation, KITD816 V, only in these two patients. TMEP is a rare form of CM, often neglected. A correct and early diagnosis of TMEP is important to rule out systemic involvement of the disease. Detection of serum tryptase levels may be a useful, rapid, and non-invasive marker of systemic involvement.

Immunophenotype Anomalies Predict the Development of Autoimmune Cytopenia in 22q11.2 Deletion Syndrome.

BACKGROUND: Patients with 22q11.2 deletion syndrome (22q11.2DS) may develop severe thrombocytopenic purpura and hemolytic anemia. There are no reliable predictors for the development of hematologic autoimmunity (HA) in these patients. OBJECTIVE: To describe the peculiar B and T subpopulation defects in patients with 22q11DS who have developed HA and test if these defects precede the development of HA. METHODS: We performed a case-control multicenter study. Patients with HA were compared with a control population of 22q11.2DS without HA (non-HA). A complete immunological evaluation was performed at diagnosis and at the last follow-up including extensive T and B phenotypes. RESULTS: Immunophenotype at the last follow-up was available in 23 HA and 45 non-HA patients. HA patients had significantly decreased percentage of naïve CD4+ cells (26.8% vs 43.2%, P = .003) and recent thymic emigrants (48.6% vs 80.5%, P = .046); decreased class-switched B cells (2.0% vs 5.9%, P = .04) and increased naive B cells (83.5% vs 71.4%, P = .02); increased CD16+/56+ both in absolute number (312 vs 199, P = .009) and percentage (20.0% vs 13.0%, P = .03). Immunophenotype was performed in 36 patients (11 HA and 25 non-HA) at diagnosis. Odds ratio (OR) of immune cytopenia were estimated for both CD4 naïve ≤30% (OR 14.0, P = .002) and switched memory B cells ≤2% (OR 44.0, P = .01). The estimated survival curves reached statistical significance, respectively, P = .0001 and P = .002. CONCLUSIONS: Among patients with 22q11.2DS, those with HA have characteristic lymphocyte anomalies that appear considerably before HA onset. Systematic immunophenotyping of patients with 22q11.2DS at diagnosis is advisable for early identification of patients at risk for this severe complication.

The Italian Mastocytosis Registry: 6-year experience from a hospital-based registry.

AIM: We collected 'real-life' data on the management of patients with mastocytosis in the Italian Mastocytosis Registry. METHODS: Six hundred patients diagnosed with mastocytosis between 1974 and 2014 were included from 19 centers. RESULTS: Among adults (n = 401); 156 (38.9%) patients were diagnosed with systemic mastocytosis. In 212 adults, no bone marrow studies were performed resulting in a provisional diagnosis of mastocytosis of the skin. This diagnosis was most frequently established in nonhematologic centers. In total, 182/184 pediatric patients had cutaneous mastocytosis. We confirmed that in the most patients with systemic mastocytosis, serum tryptase levels were >20 ng/ml and KIT D816V was detectable. CONCLUSION: The Italian Mastocytosis Registry revealed some center-specific approaches for diagnosis and therapy. Epidemiological evidence on this condition is provided.

Kawasaki disease: guidelines of Italian Society of Pediatrics, part II - treatment of resistant forms and cardiovascular complications, follow-up, lifestyle and prevention of cardiovascular risks.

This second part of practical Guidelines related to Kawasaki disease (KD) has the goal of contributing to prompt diagnosis and most appropriate treatment of KD resistant forms and cardiovascular complications, including non-pharmacologic treatments, follow-up, lifestyle and prevention of cardiovascular risks in the long-term through a set of 17 recommendations.Guidelines, however, should not be considered a norm that limits the treatment options of pediatricians and practitioners, as treatment modalities other than those recommended may be required as a result of peculiar medical circumstances, patient's condition, and disease severity or individual complications.

Kawasaki disease: guidelines of the Italian Society of Pediatrics, part I - definition, epidemiology, etiopathogenesis, clinical expression and management of the acute phase.

The primary purpose of these practical guidelines related to Kawasaki disease (KD) is to contribute to prompt diagnosis and appropriate treatment on the basis of different specialists' contributions in the field. A set of 40 recommendations is provided, divided in two parts: the first describes the definition of KD, its epidemiology, etiopathogenetic hints, presentation, clinical course and general management, including treatment of the acute phase, through specific 23 recommendations.Their application is aimed at improving the rate of treatment with intravenous immunoglobulin and the overall potential development of coronary artery abnormalities in KD. Guidelines, however, should not be considered a norm that limits treatment options of pediatricians and practitioners, as treatment modalities other than those recommended may be required as a result of peculiar medical circumstances, patient's condition, and disease severity or complications.

Pediatric Old World cutaneous leishmaniasis treated with oral fluconazole: A case series.

BACKGROUND: Cutaneous leishmaniasis has an incidence of 0.7-1.2 million cases per year and represents a growing concern in the outpatient dermatologic practice in Europe because of imported cases due to increased travel to risk areas and to immigration phenomena. When dealing with children, the treatment can be challenging because of side effects and pain of classic antimonial therapy leading to poor rates of course completion and requirement of sedation for several children. METHODS: We retrospectively studied three cases of cutaneous leishmaniasis in pediatric patients, between the ages of 3 and 6 years of age, treated with oral fluconazole. We examined the efficacy, the tolerability, the safety profile and the cosmetic result of fluconazole at a dose of 6 mg/kg/daily for 6 weeks. RESULTS: The patients had a complete resolution of their lesions with minimal scarring. No adverse effect was reported. The leishmaniasis species identified were L. major or L. tropica. CONCLUSION: Considering sides effects and the parents' and the clinician's concern for systemic treatment in the pediatric population, fluconazole represents a valid, safe and easily manageable option for Old World cutaneous leishmaniasis in pediatric outpatients caused by L. major or L. tropica.

Risk factors associated with complications/sequelae of acute and subacute haematogenous osteomyelitis: an Italian multicenter study.

BACKGROUND: Acute/subacute haematogenous osteomyelitis (AHOM/SAHOM) are potentially devastating diseases. Updated information about the epidemiology, management and outcome of AHOM/SAHOM is needed to minimize the risk of complications and sequelae. METHODS: A multicenter study was performed to evaluate retrospectively the management and outcome of AHOM/SAHOM in Italy. Data from children aged >1 month, and hospitalized between 2010 and 2016, in 19 pediatric centers, were analyzed. RESULTS: 300 children with AHOM and 98 with SAHOM were included. Median age was 6.0 years (IQR: 2.0-11.0). No clinical difference was observed with the exception of fever at onset (63.0% vs. 42.9%; P < 0.0001), and a more common spinal involvement in SAHOM (6.7% vs 20.4%; P < 0.001). Fifty-Eight Staphylococcus aureus strains were isolated; 5 (8.6%) were MRSA. No Kingella kingae infection was documented. No different risk for complication/sequela was observed between AHOM and SAHOM (38.3% vs. 34.7%; OR:0.85; 95%CI: 0.53-1.38; P = 0.518). Duration and type of antibiotic therapy were not associated with risk of complication/sequelae. CONCLUSION: AHOM and SAHOM displayed some differences, however occurrence and risk factors for complications and sequelae are similar, and the same empiric treatment might be recommended.

Altered natural killer cell cytokine profile in type 2 autoimmune hepatitis.

Type 2 autoimmune hepatitis (AIH-2) is a rare disease presenting in early childhood. The immunopathogenetic mechanisms are poorly characterized, although a defect of regulatory T cells (Treg) has been shown. There is virtually no information on innate immune responses and natural killer (NK) cells in particular. We have performed an extended immunophenotypic and functional analysis of NK cells in children with AIH-2. We show that NK cell frequency is reduced in this setting and that the balance between NK activating and inhibitory receptors is skewed toward activation. More importantly, NK cells display an altered cytokine pattern characterized by increased IFNγ and reduced IL2 production which could contribute to impaired Treg function. Exposure of mononuclear cells to IL2 resulted in normalization of NK IFNγ production. Thus, our findings support treatment of AIH-2 with low-dose IL2, which would result in normalization of NK cell function and expansion of the Treg cell subset.

An immune-molecular hypothesis supporting infectious aetiopathogenesis of Kawasaki disease in children.

The competitive binding between CpG-ODN (single-stranded DNA from pathogens) and HLA-B and HLA-A ligands for the inhibitory Killer Immunoglobulin-like Receptors (KIR)3DL1/2 may lead to possible hypo-sensing of pathogens and ineffective clearance. We observed an overabundance of HLA ligands for inhibitory KIR with three domains in KD subjects.

Atypical clinical presentation and successful treatment with oral cholic acid of a child with defective bile acid synthesis due to a novel mutation in the HSD3B7 gene.

We report definitive diagnosis and effective treatment with oral cholic acid in one Italian male child affected by 3ß-hydroxy-Δ5-C27-steroid dehydrogenase (3ß-HSD) deficiency. He presented with failure to thrive, hepatomegaly and multiple cystic images in kidneys; no biochemical evidence of cholestasis. Large amounts of bile acid metabolites was detected in urine by fast atom bombardment ionization mass spectrometry (FAB-MS). HSDH3B7 gene analysis identified one mutation in intron 4, at nucleotide 432, G>A substitution that has never been reported before.The replacement therapy with oral cholic acid started early after the diagnosis and is still ongoing. Three years later hepatomegaly is no longer evident, liver function is normal and the child is growing regularly. In our experience, clinical features of 3ß-HSD deficiency can be very poor and even cholestasis can lack at diagnosis. Early replacement therapy with cholic acid is safe and leads to clinical and biochemical control of the disease.