The systemic autoinflammatory diseases are characterized by seemingly unprovoked inflammation, without major involvement of the adaptive immune system. This review focuses mainly on a subset of these ...illnesses, the hereditary recurrent fevers, which include familial Mediterranean fever, the tumor necrosis factor receptor-associated periodic syndrome, the hyperimmunoglobulinemia D with periodic fever syndrome, and cryopyrin-associated periodic syndromes. This review elucidates how recent advances have impacted diagnosis, pathogenesis, and treatment.
More than 170 mutations have been identified in the four genes underlying the six hereditary recurrent fevers. Genetic testing has broadened the clinical and geographic boundaries of these illnesses, given rise to the concept of the cryopyrin-associated periodic syndromes as a disease spectrum, and permitted diagnosis of compound heterozygotes for mutations in two different hereditary recurrent fever genes. Genetics has also advanced our understanding of amyloidosis, a complication of the hereditary recurrent fevers, and suggested a possible role for common hereditary recurrent fever variants in other inflammatory conditions. Recent advances in molecular pathophysiology include the elucidation of the N-terminal PYRIN domain in protein-protein interactions, the description of the NALP3 (cryopyrin) inflammasome as a macromolecular complex for interleukin-1beta activation, and the identification of signaling defects other than defective receptor shedding in patients with tumor necrosis factor receptor-associated periodic syndrome. These molecular insights form the conceptual basis for targeted biologic therapies.
Advances in molecular genetics extend our ability to recognize and treat patients with systemic autoinflammatory diseases and inform our understanding of the regulation of innate immunity in humans.
To validate the Auto-Inflammatory Diseases Activity Index (AIDAI) in the four major hereditary recurrent fever syndromes (HRFs): familial Mediterranean fever (FMF), mevalonate kinase deficiency ...(MKD), tumour necrosis factor receptor-associated periodic syndrome (TRAPS) and cryopyrin-associated periodic syndromes (CAPS).
In 2010, an international collaboration established the content of a disease activity tool for HRFs. Patients completed a 1-month prospective diary with 12 yes/no items before a clinical appointment during which their physician assessed their disease activity by a questionnaire. Eight international experts in auto-inflammatory diseases evaluated the patient's disease activity by a blinded web evaluation and a nominal group technique consensus conference, with their consensus judgement considered the gold standard. Sensitivity/specificity/accuracy measures and the ability of the score to discriminate active from inactive patients via the best cut-off score were calculated by a receiver operating characteristic analysis.
Consensus was achieved for 98/106 (92%) cases (39 FMF, 35 CAPS, 14 TRAPS and 10 MKD), with 26 patients declared as having inactive disease and 72 as having active disease. The median total AIDAI score was 14 (range=0-175). An AIDAI cut-off score ≥9 discriminated active from inactive patients, with sensitivity/specificity/accuracy of 89%/92%/90%, respectively, and an area under the curve of 98% (95% CI 96% to 100%).
The AIDAI score is a valid and simple tool for assessing disease activity in FMF/MKD/TRAPS/CAPS. This tool is easy to use in clinical practice and has the potential to be used as the standard efficacy measure in future clinical trials.
To report on the demographic data from the first 18 months of enrollment to an international registry on autoinflammatory diseases in the context of the Eurofever project.
A web-based registry ...collecting baseline and clinical information on autoinflammatory diseases and related conditions is available in the member area of the PRINTO web-site. Anonymised data were collected with standardised forms.
1880 (M:F=916:964) individuals from 67 centers in 31 countries have been entered in the Eurofever registry. Most of the patients (1388; 74%), reside in western Europe, 294 (16%) in the eastern and southern Mediterranean region (Turkey, Israel, North Africa), 106 (6%) in eastern Europe, 54 in Asia, 27 in South America and 11 in Australia. In total 1049 patients with a clinical diagnosis of a monogenic autoinflammatory diseases have been enrolled; genetic analysis was performed in 993 patients (95%): 703 patients have genetically confirmed disease and 197 patients are heterozygous carriers of mutations in genes that are mutated in patients with recessively inherited autoinflammatory diseases. The median diagnosis delay was 7.3 years (range 0.3-76), with a clear reduction in patients born after the identification of the first gene associated with autoinflammatory diseases in 1997.
A shared online registry for patients with autoinflammatory diseases is available and enrollment is ongoing. Currently, there are data available for analysis on clinical presentation, disease course, and response to treatment, and to perform large scale comparative studies between different conditions.
The syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is the most common periodic fever disease in children. However, the pathogenesis is unknown. Using a ...systems biology approach we analyzed blood samples from PFAPA patients whose genetic testing excluded hereditary periodic fevers (HPFs), and from healthy children and pediatric HPF patients. Gene expression profiling could clearly distinguish PFAPA flares from asymptomatic intervals, HPF flares, and healthy controls. During PFAPA attacks, complement (C1QB, C2, SERPING1), IL-1-related (IL-1B, IL-1RN, CASP1, IL18RAP), and IFN-induced (AIM2, IP-10/CXCL10) genes were significantly overexpressed, but T cell-associated transcripts (CD3, CD8B) were down-regulated. On the protein level, PFAPA flares were accompanied by significantly increased serum levels of chemokines for activated T lymphocytes (IP-10/CXCL10, MIG/CXCL9), G-CSF, and proinflammatory cytokines (IL-18, IL-6). PFAPA flares also manifested a relative lymphopenia. Activated CD4âº/CD25⺠T-lymphocyte counts correlated negatively with serum concentrations of IP-10/CXCL10, whereas CD4âº/HLA-DR⺠T lymphocyte counts correlated positively with serum concentrations of the counterregulatory IL-1 receptor antagonist. Based on the evidence for IL-1β activation in PFAPA flares, we treated five PFAPA patients with a recombinant IL-1 receptor antagonist. All patients showed a prompt clinical and IP-10/CXCL10 response. Our data suggest an environmentally triggered activation of complement and IL-1β/-18 during PFAPA flares, with induction of Th1-chemokines and subsequent retention of activated T cells in peripheral tissues. IL-1 inhibition may thus be beneficial for treatment of PFAPA attacks, with IP-10/CXCL10 serving as a potential biomarker.
The sequela of COVID-19 include a broad spectrum of symptoms that fall under the umbrella term post-COVID-19 condition or syndrome (PCS). Immune dysregulation, autoimmunity, endothelial dysfunction, ...viral persistence, and viral reactivation have been identified as potential mechanisms. However, there is heterogeneity in expression of biomarkers, and it is unknown yet whether these distinguish different clinical subgroups of PCS. There is an overlap of symptoms and pathomechanisms of PCS with postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). No curative therapies are available for ME/CFS or PCS. The mechanisms identified so far provide targets for therapeutic interventions. To accelerate the development of therapies, we propose evaluating drugs targeting different mechanisms in clinical trial networks using harmonized diagnostic and outcome criteria and subgrouping patients based on a thorough clinical profiling including a comprehensive diagnostic and biomarker phenotyping.
Diagnosis of Periodic Fever, Aphthous stomatitis, Pharyngitis and Cervical Adenitis (PFAPA) syndrome is currently based on the modified Marshall's criteria, but no validated evidence based ...classification criteria for PFAPA has been established so far.
A multistep process, based on the Delphi and Nominal Group Technique was conducted. After 2 rounds of e-mail Delphi survey involving 21 experts in autoinflammation we obtained a list of variables that were discussed in an International Consensus Conference. Variables reaching the 80% of consensus between participants were included in the new classification criteria. In the second phase the new classification criteria and the modified Marshall's criteria were applied on a cohort of 80 pediatric PFAPA patients to compare their performance.
The Delphi Survey was sent to 22 participants, 21 accepted to participate. Thirty variables were obtained from the survey and have been discussed at the Consensus Conference. Through the Nominal Group Technique we obtained a new set of classification criteria. These criteria were more restrictive in respect to the modified Marshall's criteria when applied on our cohort of patients.
Our work led us to identify a new set of classification criteria for PFAPA syndrome, but they resulted to be too restrictive to be applied in daily clinical practice for the diagnosis of PFAPA.
Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystemic disease characterized by a complex, incompletely understood etiology. Methods: To facilitate ...future clinical and translational research, a multicenter German ME/CFS registry (MECFS-R) was established to collect comprehensive, longitudinal, clinical, epidemiological, and laboratory data from adults, adolescents, and children in a web-based multilayer-secured database. Results: Here, we present the research protocol and first results of a pilot cohort of 174 ME/CFS patients diagnosed at two specialized tertiary fatigue centers, including 130 (74.7%) adults (mean age 38.4; SD 12.6) and 43 (25.3%) pediatric patients (mean age 15.5; SD 4.2). A viral trigger was identified in 160/174 (92.0%) cases, with SARS-CoV-2 in almost half of them. Patients exhibited severe functional and social impairment, as reflected by a median Bell Score of 30.0 (IQR 30.0 to 40.0) and a poor health-related quality of life assessed with the Short Form-36 health survey, resulting in a mean score of 40.4 (SD 20.6) for physical function and 59.1 (SD 18.8) for mental health. Conclusions: The MECFS-R provides important clinical information on ME/CFS to research and healthcare institutions. Paired with a multicenter biobank, it facilitates research on pathogenesis, diagnostic markers, and treatment options. Trial registration: ClinicalTrials.gov NCT05778006.
This review summarizes current knowledge on post-acute sequelae of COVID-19 (PASC) and post-COVID-19 condition (PCC) in children and adolescents. A literature review was performed to synthesize ...information from clinical studies, expert opinions, and guidelines. PASC also termed Long COVID — at any age comprise a plethora of unspecific symptoms present later than 4 weeks after confirmed or probable infection with severe respiratory syndrome corona virus type 2 (SARS-CoV-2), without another medical explanation. PCC in children and adolescents was defined by the WHO as PASC occurring within 3 months of acute coronavirus disease 2019 (COVID-19), lasting at least 2 months, and limiting daily activities. Pediatric PASC mostly manifest after mild courses of COVID-19 and in the majority of cases remit after few months. However, symptoms can last for more than 1 year and may result in significant disability. Frequent symptoms include fatigue, exertion intolerance, and anxiety. Some patients present with postural tachycardia syndrome (PoTS), and a small number of cases fulfill the clinical criteria of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). To date, no diagnostic marker has been established, and differential diagnostics remains challenging. Therapeutic approaches include appropriate self-management as well as the palliation of symptoms by non-pharmaceutical and pharmaceutical strategies.
Conclusion
: PASC in pediatrics present with heterogenous severity and duration. A stepped, interdisciplinary, and individualized approach is essential for appropriate clinical management. Current health care structures have to be adapted, and research was extended to meet the medical and psychosocial needs of young people with PASC or similar conditions.
What is Known:
• Post-acute sequelae of coronavirus 2019 (COVID-19) (PASC) — also termed Long COVID — in children and adolescents can lead to activity limitation and reduced quality of life.
• PASC belongs to a large group of similar post-acute infection syndromes (PAIS). Specific biomarkers and causal treatment options are not yet available.
What is New:
• In February 2023, a case definition for post COVID-19 condition (PCC) in children and adolescents was provided by the World Health Organization (WHO), indicating PASC with duration of at least 2 months and limitation of daily activities.
PCC can present as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
• Interdisciplinary collaborations are necessary and have been established worldwide to offer harmonized, multimodal approaches to diagnosis and management of PASC/PCC in children and adolescents.
Zusammenfassung
Hintergrund
Multimodale Schmerztherapien erfolgen üblicherweise im Rahmen von mehrwöchigen Gruppentherapien und basieren auf einem generell aktivierenden Ansatz. Durch die ...Besonderheit einer Belastungsintoleranz mit postexertioneller Malaise (PEM) bei Patient:innen mit postviralen Syndromen muss in diesen Fällen eine körperliche sowie psychische Überlastung dringend vermieden werden. Diese Aspekte können in gängigen schmerzmedizinischen Therapiekonzepten jedoch nur unzureichend berücksichtigt werden.
Methodik
Zusammenfassung der aktuellen Literatur und Darstellung klinischer Besonderheiten sowie Vorstellung eines therapeutischen Modellprojekts für eine interdisziplinäre multimodale Schmerztherapie bei postviralen Syndromen mit PEM.
Modellkonzept
Das vorgestellte Modellkonzept beschreibt ein der individuellen Belastbarkeit angepasstes tagesklinisches Behandlungssetting für die multimodale Schmerztherapie mit Minimierung des Risikos einer belastungsinduzierten Zustandsverschlechterung.
Multimodal pain therapy usually take place in the context of group therapy lasting several weeks and is based on a generally activating approach. Due to the specificity of stress intolerance with ...postexertional malaise (PEM) in patients with postviral syndromes, physical as well as psychological overload must be urgently avoided in these cases; however, these aspects can only be insufficiently considered in current medical pain therapy concepts.
Summary of the current literature and presentation of clinical characteristics as well as presentation of a model project for a multimodal pain therapy in postviral syndromes with PEM.
The presented model project describes a day clinic treatment setting for interdisciplinary multimodal pain therapy adapted to the individual resilience with minimization of the risk of strain-induced deterioration of the condition.
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