| 1. |
- Bastard, Paul, et al.
(författare)
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Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1.
- 2021
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Ingår i: The Journal of experimental medicine. - 1540-9538. ; 218:7
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Tidskriftsartikel (refereegranskat)abstract
- Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range of autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These auto-Abs were recently reported to account for at least 10% of cases of life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients from 21 kindreds in seven countries, aged between 8 and 48 yr and infected with SARS-CoV-2 since February 2020. The 21 patients tested had auto-Abs neutralizing IFN-α subtypes and/or IFN-ω; one had anti-IFN-β and another anti-IFN-ε, but none had anti-IFN-κ. Strikingly, 19 patients (86%) were hospitalized for COVID-19 pneumonia, including 15 (68%) admitted to an intensive care unit, 11 (50%) who required mechanical ventilation, and four (18%) who died. Ambulatory disease in three patients (14%) was possibly accounted for by prior or early specific interventions. Preexisting auto-Abs neutralizing type I IFNs in APS-1 patients confer a very high risk of life-threatening COVID-19 pneumonia at any age.
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| 2. |
- Cooray, S., et al.
(författare)
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Anti-tumour necrosis factor treatment for the prevention of ischaemic events in patients with deficiency of adenosine deaminase 2 (DADA2)
- 2021
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Ingår i: Rheumatology. - : Oxford University Press (OUP). - 1462-0324 .- 1462-0332. ; 60:9, s. 4373-4378
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Tidskriftsartikel (refereegranskat)abstract
- Objective To evaluate the impact of anti-Tumour Necrosis Factor-alpha (anti-TNF) treatment on the occurrence of vasculitic ischaemic events in patients with deficiency of adenosine deaminase 2 (DADA2). Methods A retrospective analysis of DADA2 patients referred from six centres to Great Ormond Street Hospital for Children was conducted. Ischaemic events, vasculitic disease activity, biochemical, immunological, and radiological features were compared, before and after anti-TNF treatment. Results A total of 31 patients with genetically confirmed DADA2 were included in the study. The median duration of active disease activity prior to anti-TNF treatment was 73months (inter-quartile range [IQR] 27.5-133.5months). Twenty seven/31 patients received anti-TNF treatment for a median of 32months (IQR 12.0-71.5months). The median event rate of central nervous system (CNS) and non-CNS ischemic events before anti-TNF treatment was 2.37 per 100 patient-months (IQR 1.25-3.63); compared with 0.00 per 100 patient-months (IQR 0.0-0.0) post-treatment (p< 0.0001). Paediatric vasculitis activity score (PVAS) was also significantly reduced: median score of 20/63 (IQR 13.0-25.8/63) pre-treatment vs. 2/63 (IQR 0.0-3.8/63) following anti-TNF treatment (p< 0.0001), with mild livedoid rash being the main persisting feature. Anti-TNF treatment was not effective for severe immunodeficiency or bone marrow failure, which required haematopoietic stem cell transplantation (HSCT). Conclusion Anti-TNF treatment significantly reduced the incidence of ischaemic events and other vasculitic manifestations of DADA2, but was not effective for immunodeficiency or bone marrow failure.
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| 3. |
- Horne, A., et al.
(författare)
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Efficacy of Moderately Dosed Etoposide in Macrophage Activation Syndrome-Hemophagocytic Lymphohistiocytosis
- 2021
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Ingår i: Journal of Rheumatology. - : The Journal of Rheumatology. - 0315-162X .- 1499-2752. ; 48:10, s. 1596-1602
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Tidskriftsartikel (refereegranskat)abstract
- Objective. Macrophage activation syndrome (MAS) constitutes 1 subtype of the hyperinflammatory syndrome hemophagocytic lymphohistiocytosis (HLH), and the term MAS-HLH was recently proposed for HLH with underlying autoimmune/autoinflammatory conditions. The mortality of MAS-HLH has been estimated at 5-10%. Here we report our experiences with moderately dosed etoposide in severe MAS-HLH; the objective was to effectively reduce severe hyperinflammatory activity with limited side effects. Methods. In addition to conventional antiinflammatory treatment, moderately dosed etoposide was administered to 7 children affected by rapidly progressing MAS-HLH with central nervous system (n = 5) and/ or pulmonary (n = 5) involvement. Three had underlying systemic juvenile idiopathic arthritis (sJIA), 2 had atypical sJIA (no arthritis at diagnosis), and 2 had systemic lupus erythematosus. We performed lymphocyte cytotoxicity analyses in all 7 and genetic analyses in 6. Results. All children promptly responded to moderately dosed etoposide (50-100 mg/m(2Y) once weekly), added to conventional MAS-HLH treatment that was considered insufficient. The mean accumulated etoposide dose was 671 mg/m(2) (range 300-1050 mg/m(2)) as compared to 1500 mg/m(2) recommended in the first 8 weeks of the HLH-94/HLH-2004 protocols. One child developed neutropenic fever and another neutropenic sepsis (neutrophils 0.3 x 10(9)/L at therapy onset). Five of 7 children had low percentages (< 5%) of circulating natural killer (NK) cells prior to or in association with diagnosis; NK cell activity was pathologically low in 2 of 5 children studied. Disease-causing variants in HLH-associated genes were not found. All children were alive at latest follow-up (2-9 yrs after onset); neurological symptoms had normalized in 4 of 5 affected children. Conclusion. Moderately dosed etoposide may be beneficial in severe and/or refractory MAS-HLH.
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| 4. |
- Kahn, Robin, et al.
(författare)
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Population-based study of multisystem inflammatory syndrome associated with COVID-19 found that 36% of children had persistent symptoms
- 2022
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Ingår i: Acta Paediatrica, International Journal of Paediatrics. - : Wiley. - 0803-5253 .- 1651-2227. ; 111:2, s. 354-62
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Our aim was to describe the outcomes of multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19. Methods: This national, population-based, longitudinal, multicentre study used Swedish data that were prospectively collected between 1 December 2020 and 31 May 2021. All patients met the World Health Organization criteria for MIS-C. The outcomes 2 and 8weeks after diagnosis are presented, and follow-up protocols are suggested. Results: We identified 152 cases, and 133 (87%) participated. When followed up 2weeks after MIS-C was diagnosed, 43% of the 119 patients had abnormal results, including complete blood cell counts, platelet counts, albumin levels, electrocardiograms and echocardiograms. After 8weeks, 36% of 89 had an abnormal patient history, but clinical findings were uncommon. Echocardiogram results were abnormal in 5% of 67, and the most common complaint was fatigue. Older children and those who received intensive care were more likely to report symptoms and have abnormal cardiac results. Conclusion: More than a third (36%) of the patients had persistent symptoms 8weeks after MIS-C, and 5% had abnormal echocardiograms. Older age and higher levels of initial care appeared to be risk factors. Structured follow-up visits are important after MIS-C.
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| 5. |
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| 6. |
- Rydenman, Karin, 1982, et al.
(författare)
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Epidemiology and clinical features of PFAPA: a retrospective cohort study of 336 patients in western Sweden
- 2022
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Ingår i: Pediatric Rheumatology. - : Springer Science and Business Media LLC. - 1546-0096. ; 20
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Tidskriftsartikel (refereegranskat)abstract
- Background: Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome is generally regarded as the most common autoinflammatory disease, but the epidemiology of the disease is largely unknown. The objectives of this study were to estimate the annual incidence and describe the clinical features of PFAPA in a large cohort from western Sweden. Methods: The study retrospectively included children < 18 years of age diagnosed with PFAPA between 2006 and 2017 at three hospitals: NU Hospital Group, Skaraborg Hospital and Queen Silvia Children’s Hospital. Patients were identified by searching for relevant diagnostic ICD-10 codes in the comprehensive electronic medical records and data were retrieved by reviewing case records. To estimate incidence, patients with symptom onset from January 1, 2006, to December 31, 2016, were included. Population data for the study area during this period were retrieved from Statistics Sweden. Results: In this study, 336 patients with PFAPA were identified. Of these, 156 (46%) were girls and 180 (54%) were boys. Almost 90% of the children with PFAPA (291 patients) experienced their first symptoms before the age of 5 years and fewer than 3% presented at ages above 10 years. Pharyngitis was the most common symptom during febrile episodes, followed by cervical adenitis and aphthous stomatitis. Fourteen percent of the patients displayed atypical features, of which skin rash was the most common. To calculate incidence, 251 patients with symptom onset during the study period were identified. The mean annual incidence was estimated at 0.86/10,000 for children < 18 years of age and 2.6/10,000 for children < 5 years of age. Conclusions: This study adds to the understanding of the epidemiology of PFAPA syndrome by presenting incidence rates based on a large cohort and in different age groups in a population-based setting. It also shows the distribution of age of onset of PFAPA, with a peak in 1-year-olds and waning at older ages. Signs and symptoms of PFAPA syndrome were similar in children with symptom onset before vs. after 5 years of age.
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| 7. |
- Rydenman, Karin, 1982, et al.
(författare)
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Tonsillectomy reduces the family impact of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome and improves health-related quality of life in affected children
- 2023
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Ingår i: Orphanet Journal of Rare Diseases. - 1750-1172. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome is an autoinflammatory disorder that primarily affects young children, and typically gives rise to fever episodes that recur monthly for several years. This study investigated the impact of PFAPA syndrome on the families of affected children, the health-related quality of life (HRQOL) of children with the syndrome, and how these factors were influenced by tonsillectomy. Methods: This prospective cohort study included 24 children with typical PFAPA syndrome that were referred for tonsillectomy, of whom 20 underwent the procedure. The control group consisted of randomly selected children from the general population. Family impact and HRQOL were measured using the standardized, validated questionnaires Pediatric Quality of Life Inventory™ (PedsQL™) Family Impact Module (FIM) and PedsQL™ 4.0 Generic Core Scales (GCS). Parents to children with PFAPA completed the questionnaires before and 6 months after their child underwent tonsillectomy, and HRQOL was measured both between and during PFAPA episodes. The Wilcoxon signed-rank test was used to compare data before and after tonsillectomy in the patient group, while the Mann–Whitney test was used for comparison of the patient and control groups. Results: Before tonsillectomy, children with PFAPA had significantly lower scores than the control group on the PedsQL™ FIM and the PedsQL™ 4.0 GCS during fever episodes. After tonsillectomy, all patients improved with diminished febrile episodes, which resulted in significantly higher scores regarding both family impact and HRQOL at the time of follow-up. HRQOL of in children with PFAPA improved after tonsillectomy even when compared to afebrile intervals before the procedure. The differences between PFAPA patients and controls were eliminated after tonsillectomy. Conclusion: PFAPA syndrome has a profound negative impact on the families of affected children. Tonsillectomy that leads to cessation or reduction of fever episodes eases the impact of the disease on the family. HRQOL in children with PFAPA is low during febrile episodes and similar to healthy controls in between episodes. The improvement of HRQOL in patients with PFAPA after tonsillectomy compared to the afebrile intervals before tonsillectomy highlights that the constantly recurring fevers may affect the children’s well-being even between fever episodes.
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| 8. |
- Sansone, M., et al.
(författare)
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Severe multisystem inflammatory syndrome (MIS-C/A) after confirmed SARS-CoV-2 infection: a report of four adult cases
- 2022
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Ingår i: Infectious Diseases. - : Informa UK Limited. - 2374-4235 .- 2374-4243. ; 54:5, s. 378-383
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Tidskriftsartikel (refereegranskat)abstract
- Background: Multisystem inflammatory syndrome (MIS) triggered by a recent SARS-Cov-2 infection has been recognised worldwide. Although predominantly affecting children (MIS-C), similar presentations have been reported among adults (MIS-A). Method: A retrospective case series describing four critically ill patients with MIS-C/A diagnosed between January and April 2021 at Sahlgrenska University Hospital, Gothenburg, Sweden. Clinical presentation, laboratory and radiological findings, treatment and outcome are reported. Results: Cases occurred in previously healthy patients with a history of laboratory-confirmed mild SARS-CoV-2 infection four to seven weeks earlier. The median age was 24 years (range 19–43) and 3/4 were male. All fulfilled suggested MIS-C/A criteria according to the US Centre for Disease Control and all required care at an intensive care unit. Treatment was initiated with intravenous immunoglobulin, interleukin-1-receptor antagonists, and pulse steroids in 3/4 cases which resulted in rapid clinical improvement. No severe complications were noticed in any case during a three-month follow-up period. Conclusion: MIS-C/A should be considered, irrespective of age, in patients with fever, hyperinflammation and multiple organ system involvements emerging weeks after COVID-19. Previously suggested treatment regimens for MIS-C seem to be applicable also for MIS-A. © 2022 Society for Scandinavian Journal of Infectious Diseases.
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| 9. |
- Sundqvist, Martina, et al.
(författare)
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Severe chronic non-bacterial osteomyelitis in combination with total MPO deficiency and responsiveness to TNFα inhibition
- 2023
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Ingår i: Frontiers in Immunology. - : FRONTIERS MEDIA SA. - 1664-3224. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- We describe a female patient suffering from severe chronic non-bacterial osteomyelitis (CNO) with systemic inflammation and advanced malnutrition and complete deficiency of myeloperoxidase (MPO). CNO is a rare autoinflammatory bone disorder associated with dysregulation of the innate immune system. MPO deficiency is a genetic disorder with partial or complete absence of the phagocyte peroxidase MPO. MPO deficiency has no established clinical phenotype but reports indicate increased susceptibility to infection and chronic inflammation. The patient’s symptoms began at 10 years of age with pain in the thighs, systemic inflammation and malnutrition. She was diagnosed with CNO at 14 years of age. Treatment with nonsteroidal anti-inflammatory drugs, corticosteroids, bisphosphonates or IL1-receptor antagonists (anakinra) did not relieve the symptoms. However, the patient responded instantly and recovered from her clinical symptoms when treated with TNFα blockade (adalimumab). Three years after treatment initiation adalimumab was withdrawn, resulting in rapid symptom recurrence. When reintroducing adalimumab, the patient promptly responded and went into remission. In addition to clinical and laboratory profiles, neutrophil functions (reactive oxygen species, ROS; neutrophil extracellular traps, NETs; degranulation; apoptosis; elastase activity) were investigated both in a highly inflammatory state (without treatment) and in remission (on treatment). At diagnosis, neither IL1β, IL6, nor TNFα was significantly elevated in serum, but since TNFα blockade terminated the inflammatory symptoms, the disease was likely TNFα-driven. All neutrophil parameters were normal both during treatment and treatment withdrawal, except for MPO-dependent intracellular ROS- and NET formation. The role of total MPO deficiency for disease etiology and severity is discussed.
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