Convergence and divergence in Kawasaki disease and multisystem inflammatory syndrome in children: results from the COVASAKI survey.

OBJECTIVES: To compare Kawasaki disease (KD) and multisystem inflammatory syndrome (MIS-C) in children. METHODS: Prospective collection of demographics, clinical and treatment data. Assessment of type 1 interferon (IFN) score, CXCL9, CXCL10, Interleukin (IL)18, IFNγ, IL6, IL1b at disease onset and at recovery. RESULTS: 87 patients (43 KD, 44 MIS-C) were included. Age was higher in MIS-C compared to KD group (mean 31±23 vs. 94±50 months, p<0.001). Extremities abnormalities (p=0.027), mucosal involvement (p<0.001), irritability (p<0.001), gallbladder hydrops (p=0.01) and lymphadenopathy (p=0.07) were more often recorded in KD. Neurological findings (p=0.002), gastrointestinal symptoms (p=0.013), respiratory involvement (p=0.019) and splenomegaly (p=0.026) were more frequently observed in MIS-C. Cardiac manifestations were higher in MIS-C (p<0.001), although coronary aneurisms were more frequent in KD (p=0.012). In the MIS-C group, the multiple linear regression analysis revealed that a higher IFN score at onset was related to myocardial disfunction (p<0.001), lymphadenopathy (p=<0.001) and need of ventilation (p=0.024). Both CXCL9 and CXCL10 were related to myocardial disfunction (p<0.001 and p=0.029). IL18 was positively associated to PICU admission (0.030) and ventilation (p=004) and negatively associated to lymphadenopathy (0.004). IFNγ values were related to neurological involvement and lymphadenopathy (p<0.001), IL1b to hearth involvement (0.006). A negative correlation has been observed between IL6 values, heart involvement (p=0.013) and PICU admission (p<0.001). CONCLUSIONS: The demographic and clinical differences between KD e MIS-C cohorts confirm previous reported data. The assessment of biomarkers levels at MIS-C onset could be useful to predict a more severe disease course and the development of cardiac complications.

Mycophenolate mofetil-induced hypogammaglobulinemia and infectious disease susceptibility in pediatric patients with chronic rheumatic disorders: a monocentric retrospective study.

Mycophenolate mofetil (MMF) is an immunosuppressive drug used for the treatment of autoimmune rheumatological diseases. To test the risk of hypothetical drug-induced hypogammaglobulinemia, the aim of this study was to report the trend of the immunoglobulin (Ig) values and of the infectious diseases in children treated with MMF. This study retrospectively evaluated demographic, clinical, and laboratory data of a cohort of patients affected by a chronic rheumatic disease receiving MMF, followed at the Rheumatology Unit of Meyer Children Hospital, Florence. A total of 29 pediatric patients were enrolled. In patients with normal values of immunoglobulins at the baseline, treatment with MMF resulted in a statistically significant reduction of the IgG levels (p = 0.0058) and in a decrease of IgM levels not reaching statistical significance. The levels of IgA were not affected. During the follow-up, seven patients developed an humoral immune defect. The univariate analysis did not identify any risk factors related to the iatrogenic hypogammaglobulinemia. The infection rate during MMF therapy was significantly higher than the 12-month period before therapy (p = 0.006), while the severe infections did not significantly increase (p = 0.1818), even considering only the patients with hypogammaglobulinemia. CONCLUSION: In pediatric patients with chronic rheumatic diseases, immunological first level tests and serological analyses to screen the protection against the common childhood pathogens are suggested before starting an immunosuppressive drug. These patients should also complete the vaccination schedule. In patients treated with MMF a strict monitoring of Ig is required during treatment and after discontinuation of the drug. WHAT IS KNOWN: • MMF is an immunosuppressive drug initially used for the treatment of the graft-versus-host disease. • Mycophenolic acid is an inhibitor of inosine-5'-monophosphate dehydrogenase, expressed in lymphocytes; therefore, MMF could impair the immune system function. WHAT IS NEW: • MMF resulted in a reduction of IgG and an increase of not severe infection rate. • Immunological first level tests, including Ig, lymphocyte subpopulations, and antibody response to vaccines, are suggested in pediatric patients before starting MMF; a strict monitoring of Ig is important before, during, and after MMF treatment.

Alagille Syndrome and Chronic Arthritis: An International Case Series.

We describe 10 children with Alagille syndrome and inflammatory arthritis. In our centers, the prevalence of chronic arthritis in patients with Alagille syndrome is approximately 50 times higher compared with the general population. Arthritis was refractory to most treatment. Patients with Alagille syndrome should routinely be screened for musculoskeletal symptoms.

Chronic non-bacterial osteomyelitis: a retrospective international study on clinical manifestations and response to treatment.

OBJECTIVES: Chronic non-bacterial osteomyelitis (CNO) is a rare non-infectious bone inflammatory disorder; when multifocal, it is referred to as Chronic Recurrent Multifocal Osteomyelitis (CRMO). This study evaluates the demographic, clinical and radiological characteristics of a multi-centre cohort of patients with CNO/CRMO. METHODS: Demographic and clinical data of patients with an established diagnosis of CNO/CRMO followed at paediatric rheumatology centres across Europe (Italy, France, Slovenia) and India were retrospectively collected. RESULTS: There were no demographic differences across countries, but time to diagnosis was significantly longer in India (p=0.041). Pain was almost invariably present at disease onset; functional impairment was more frequent among Italian and Slovenian patients (p=0.001). The number of sites of bone involvement was similar between genders and countries, with long bone metaphises being the most common site. Raised acute phase reactants, detected in >50% of patients, were not associated with clinical manifestations or response to treatment. Comorbidities, evinced in 37% of patients, were equally distributed between genders and nationalities. Imaging approach was similar across countries, without any association between radiological findings and clinical manifestations. NSAIDs were almost invariably used as first-line treatment, but response rate was significantly lower in Italy (p=0.02). Methotrexate was used in 28% of case, with an overall rate of response of 82%. Health conditions and rate of permanent deformities were similar across different countries. CONCLUSIONS: The differences in clinical presentation, radiological features and response to treatment described in this multinational cohort of CNO/CRMO might provide novel insights into this still elusive disease.

Prevalence of cranial involvement in a cohort of Italian patients with chronic non-bacterial osteomyelitis.

OBJECTIVES: Chronic non-bacterial osteomyelitis (CNO) is a non-infectious inflammatory disease characterised by uni- or multi-focal bone lytic lesions. CNO mainly affects metaphysis of long bones, pelvis and shoulder girdle. Neurocranium lesions are extremely rare. The objective of the study is to describe the prevalence and clinical manifestations of CNO patients with neurocranium involvement in an Italian cohort of CNO patients. METHODS: This is a retrospective study. Medical records of patients with CNO admitted to eight paediatric rheumatology centres were reviewed. RESULTS: Among 86 patients with CNO enrolled in the study, three of them were female and presented neurocranium involvement - multifocal lesions. Two out of the 3 patients were completely asymptomatic for cranial involvement, while one of the 3 complained of cranial bossing. Cranial involvement was detected with bone scintigraphy and then confirmed by magnetic resonance imaging and/or computed tomography. Two patients presented fever and two with skin manifestations. Laboratory inflammatory markers were increased in two of them. All patients underwent bone biopsy confirming the diagnosis. They all received NSAIDs. Two patients received corticosteroids and then methotrexate and achieved clinical remission, while one patient received pamidronate. CONCLUSIONS: This is the first report of neurocranium involvement in a cohort of patients affected by CNO. In our cohort no patient showed significant signs attributable to cranial involvement.

Evidence-Based Treatment for Uveitis.

BACKGROUND: Uveitis is an inflammatory disorder of the uveal tract of the eye that can affect both adults and children. Non-infectious uveitis can be an expression of a systemic autoimmune condition, or it can be idiopathic. It is a serious disease, associated with possible severe complications leading to visual impairment and blindness. For this reason, a prompt diagnosis and assessment of an appropriate treatment, with the collaboration of specialists such as ophthalmologists and rheumatologists, are extremely important. Many treatment options may be associated to side effects; therefore, clinicians should follow a stepladder approach starting with the least aggressive treatments to induce remission of inflammation. In this review, we reported the current evidence-based treatments for non-infectious uveitis in pediatric and adult patients with particular attention to the biologic response modifier treatment options. Important multicenter studies have demonstrated the efficacy of adalimumab, both in adults (VISUAL I, VISUAL II, VISUAL III) and in children (SYCAMORE, ADJUVITE), while for other agents data are still scarce.

Clinical Use and Molecular Action of Corticosteroids in the Pediatric Age.

Corticosteroids are the mainstay of therapy for many pediatric disorders and sometimes are life-saving. Both endogenous and synthetic derivatives diffuse across the cell membrane and, by binding to their cognate glucocorticoid receptor, modulate a variety of physiological functions, such as glucose metabolism, immune homeostasis, organ development, and the endocrine system. However, despite their proved and known efficacy, corticosteroids show a lot of side effects, among which growth retardation is of particular concern and specific for pediatric age. The aim of this review is to discuss the mechanism of action of corticosteroids, and how their genomic effects have both beneficial and adverse consequences. We will focus on the use of corticosteroids in different pediatric subspecialties and most common diseases, analyzing the most recent evidence.

Chronic nonbacterial osteomyelitis may be associated with renal disease and bisphosphonates are a good option for the majority of patients.

AIM: The aim of this Italian study was to describe the clinical features, treatment options and outcomes of a cohort of patients with chronic nonbacterial osteomyelitis (CNO). METHODS: This was a retrospective cohort study. Laboratory data, diagnostic imaging, histological features and clinical course are reported. RESULTS: We enrolled 47 patients diagnosed with CNO. Bone pain was the leading symptom, and multifocal disease was present in 87% of the patients. The majority of the bone lesions were located in the appendicular skeleton (58%). Extraosseous manifestations were present in 34% of the patients, and renal involvement was detected in four patients. Inflammatory indices were increased in 80%, and bone x-rays were negative in 15% of the patients. Nonsteroidal anti-inflammatory drugs (NSAIDs) were the first therapy for all patients, achieving clinical remission in 27%. A good response to NSAIDs was significantly associated with a better prognosis. Bisphosphonates were used in 26 patients, with remission in 73%. Only six patients (13%), all with spine involvement, developed sequelae. CONCLUSION: We found a possible association between CNO and renal disease. Bisphosphonates were more likely to lead to clinical remission when NSAIDs and corticosteroids had failed. Vertebral localisation was the only risk factor for potential sequelae.

Does Teno Torque Virus Induce Autoimmunity After Hematopoietic Stem Cell Transplantation? A Case Report.

Teno Torque virus, member of the family of Anelloviridae, has been associated with many autoimmune diseases such as idiopathic hepatitis, systemic lupus erythematosus, and multiple sclerosis. Its viral load tends to be higher in the bone marrow and in tissues with high turnover rate. We report here a case of an 11-month-old infant affected by acute myeloid leukemia who underwent hematopoietic stem cell transplantation, and after 6 months had autoimmune hepatitis and atopic dermatitis. Extremely high-cytokine IP-10 and eotaxin levels were found in her sera, and serological tests and RT-PCR for viruses showed positive results exclusively for Teno Torque virus.

Hematopoietic stem cell transplantation effects on spinal cord compression in Hurler.

Hurler syndrome type 1 (MPS-1) is an autosomal recessive lysosomal disorder due to the deficiency of the enzyme alpha-L-iduronidase which is necessary for the degradation of dermatan and heparan sulfate. It is characterized by deposit of glycosaminoglycans in tissues, progressive multisystem dysfunction, and early death. HSCT for children with MPS-I is effective, resulting in increased life expectancy and improvement of clinical parameters. The spinal MRI performed on a female 10 yr old undergoing HSCT at the age of 18 months and receiving ERT revealed a considerable decrease in soft tissue around the tip of odontoid causing a significant reduction in spinal cord compression. In light of this result, we suppose that combined ERT and HSCT are successful in Hurler I disease.

A comparison of three scales for measuring pain in children with cognitive impairment.

AIM: Pain is a neglected problem in children with cognitive impairments, and few studies compare the clinical use of specific pain scales. We compared the Non-Communicating Children's Pain Checklist Postoperative Version (NCCPC-PV), the Echelle Douleur Enfant San Salvador (DESS) and the Children's Hospital of Eastern Ontario Pain Scale (CHEOPS). The first two were developed for children with cognitive impairment, and the third is a more general pain scale. METHODS: Two external observers and the child's caregiver assessed 40 children with cognitive impairment for pain levels. We assessed inter-rater agreement, correlation, dependence on knowledge of the child's behaviour, simplicity and adequacy in pain rating according to the caregiver for all three scales. RESULTS: The correlation between the NCCPC-PV and the DESS was strong (Spearman correlation coefficient = 0.76) and better than between each scale and the CHEOPS. Although the DESS showed better inter-rater agreement, it was more dependent on familiarity with the child and was judged more difficult to use by all observers. The NCCPC-PV was the easiest use and the most appropriate for rating the child's pain. CONCLUSION: The NCCPC-PV was the easiest to use for pain assessment in cognitively impaired children and should be adopted in clinical settings.

A precordial rub in a boy with a severe attack of ulcerative colitis.

A case of a pneumomediastinum mimicking a pericarditis in a boy with an occult perforation due to ulcerative colitis is reported. Pneumomediastinum is a rare complication of severe attacks of ulcerative colitis, with or without the previous development of a toxic megacolon, that should be considered in the differential diagnosis.

Acquired long QT syndrome: a focus for the general pediatrician.

Acquired long QT syndrome (LQTS) is a disorder of cardiac repolarization most often due to specific drugs, hypokalemia, or hypomagnesemia that may precipitate torsade de pointes and cause sudden cardiac death. Common presentations of the LQTS are palpitations, presyncope, syncope, cardiac arrest, and seizures. An abnormal 12-lead electrocardiogram obtained while the patient is at rest is the key to diagnosis. The occurrence of drug-induced LQTS is unpredictable in any given individual, but a common observation is that most patients have at least 1 identifiable risk factor in addition to drug exposure. The cornerstone of the management of acquired LQTS includes the identification and discontinuation of any precipitating drug and the correction of metabolic abnormalities, such as hypokalemia or hypomagnesemia. Most of the episodes of torsade de pointes are short-lived and terminate spontaneously. We propose a management protocol that could be useful for the daily practice in the emergency pediatric department to reduce the risk of acquired QT prolongation.

Treatment Options in Pediatric Behçet's Disease.

Behçet's disease is a rare and poorly understood vasculitis affecting blood vessels of all types and sizes. Uveitis and oral and genital ulcers represent the typical clinical triad. Populations along the ancient trading route connecting the Mediterranean basin with the Middle and Far East are most affected. Up to a quarter of the cases has a pediatric onset, typically around puberty. The aim of the treatment is early intervention to control inflammation, with symptom relief and prevention of relapses, damage, and complications. The heterogeneous clinical presentation often requires a multidisciplinary and tailored approach. Ocular, neurological, gastrointestinal, and vascular involvement is associated with a worse prognosis and needs more aggressive treatments. In young patients with expected prolonged disease, treatment should also focus on preventive measures and lifestyle advice. In recent years, the pharmacological armamentarium has grown progressively, although only a limited number of drugs are currently authorized for pediatric use. Most evidence for these drugs still derives from adult studies and experience; these are prescribed as off-label medications and are only available as adult formulations. Corticosteroids frequently represent the mainstay for the management of the initial acute phases, but their potential serious adverse effects limit their use to short periods. Different conventional disease-modifying anti-rheumatic drugs have long been used. Many other biologic drugs targeting different cytokines such as interleukin-1, interleukin-6, and interleukin-17 and treatments with small molecules including the phosphodiesterase 4 and Janus kinase inhibitors are emerging as novel promising therapeutic agents. In recent years, a growing interest has developed around anti-tumor necrosis factor agents that have often proven to be effective in severe cases, especially in those with a gastrointestinal and ocular involvement.

Biphasic Hormetic-like Effect of Lebecetin, a C-type Lectin of Snake Venom, on Formalin-induced Inflammation in Mice.

BACKGROUND: Integrins, important extracellular matrix (ECM) receptor proteins, are affected by inflammation and can participate in the maintenance of many painful conditions. Although they are ubiquitous and changeable across all cell types, the roles of these cell adhesion molecules in pathological pain have not been fully explored. OBJECTIVE: We evaluated the effects of the subcutaneous injection of lebecetin, a C-type lectin isolated from Macrovipera lebetina snake venom, previously reported to inhibit α5ß1 and αv integrin activity, on different components of inflammation induced by the formalin administration in the hind paw of mice. METHODS: The formalin-induced nocifensive behavior, edema, and histopathological changes in the hind paw associated with cytokine, iNOS, and COX2 expression, nociceptive-specific neuron activity, and microglial activation analysis in the spinal cord were evaluated in mice receiving vehicle or lebecetin pretreatment. RESULTS: Lebecetin inhibited the nocifensive responses in the formalin test, related edema, and cell infiltration in the injected paw in a biphasic, hormetic-like, and dose-dependent way. According to that hormetic trend, a reduction in pro-inflammatory cytokines IL-6, IL-8, and TNF-alpha and upregulation of the anti-inflammatory cytokine IL-10 in the spinal cord were found with the lowest doses of lebecetin. Moreover, COX2 and iNOS expression in serum and spinal cord followed the same biphasic pattern of cytokines. Finally, nociceptive neurons sensitization and activated microglia were normalized in the dorsal horn of the spinal cord by lebecetin. CONCLUSION: These findings implicate specific roles of integrins in inflammation and tonic pain, as well as in the related central nervous system sequelae.

Acute Arthritis in Children: How to Discern between Septic and Non-Septic Arthritis?

The term septic arthritis refers to an infection of the synovial space. This is an infrequent condition in healthy children, but it should be considered a medical emergency potentially leading to irreversible articular damage. Therefore, prompt diagnosis and antimicrobial treatment play a crucial role in improving the prognosis. Although septic arthritis is the most common cause of acute arthritis, many other diseases may mimic a similar clinical picture, constituting a diagnostic challenge for the clinician who first approaches the patient. Herein we analyze the main features of septic arthritis, offering an overview of the main conditions involved in the differential diagnosis and suggesting a diagnostic workup plan.

Conjunctival lymphangiectasia in a pediatric patient with neurofibromatosis type 1.

Conjunctival lymphangiectasia, a rare condition characterized by dilated lymphatic channels in the bulbar conjunctiva, generally develops as a consequence of a local lymphatic scarring or distal mechanical outflow obstruction following surgery, radiotherapy, neoplastic disease, or other disease processes. The actual cause often remains unknown. We report a case of a unilateral conjunctival lymphangiectasia in a 7-year-old girl with neurofibromatosis type 1 (NF-1) and discuss a possible association between the two entities.