To assess the prevalence of and factors associated with post-coronavirus disease 2019 (COVID-19) syndrome 6 months after the onset.
A bidirectional prospective study. Interviews investigated symptoms ...potentially associated with COVID-19 6 months after the disease onset of all consecutive adult inpatients and outpatients with COVID-19 attending Udine Hospital (Italy) from March to May 2020. IgG antibodies against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) were also evaluated 6 months after the onset of symptoms, at the time of the interview.
A total of 599 individuals were included (320 female, 53.4%; mean age 53 years, SD 15.8) and interviewed 187 days (22 SD) after onset. The prevalence of post-COVID-19 syndrome was 40.2% (241/599). The presence of IgG antibodies was significantly associated with the occurrence of post-COVID-19 syndrome (OR 2.56, 95% CI 1.48–4.38, p 0.001) and median SARS-CoV-2 IgG titres were significantly higher in patients with post-COVID-19 syndrome than in patients without symptoms (42.1, IQR 17.1–78.4 vs. 29.1, IQR 12.1–54.2 kAU/L, p 0.004). Female gender (OR 1.55, 95% CI 1.05–2.27), a proportional increase in the number of symptoms at the onset of COVID-19 (OR 1.81, 95% CI 1.59–2.05) and ICU admission OR 3.10, 95% CI 1.18–8.11) were all independent risk factors for post-COVID-19 syndrome. The same predictors also emerged in a subgroup of 231 patients with the serological follow-up available at the time of the interview alongside the proportional increase in anti-SARS-CoV-2 IgG (OR 1.01, 95% CI 1.00–1.02, p 0.04).
Prospective follow-up could be offered to specific subgroups of COVID-10 patients, to identify typical symptoms and persistently high anti-SARS-CoV-2 IgG titres as a means of early detection of post-COVID-19 long-term sequelae.
Inflammatory bowel disease(IBD) is a group of chronic multifactorial disorders. According to a recent study,the number of IBD association loci is increased to 201,of which 37 and 27 loci contribute ...specifically to the development of Crohn’s disease and ulcerative colitis respectively. Some IBD associated genes are involved in innate immunity,in the autophagy and in the inflammatory response such as NOD2,ATG16L1 and IL23 R,while other are implicated in immune mediated disease(STAT3) and in susceptibility to mycobacterium infection(IL12B). In case of early onset of IBD(VEO-IBD) within the 6th year of age,the disease may be caused by mutations in genes responsible for severe monogenic disorders such as the primary immunodeficiency diseases. In this review we discuss how these monogenic disorders through different immune mechanisms can similarly be responsible of VEO-IBD phenotype. Moreover we would highlight how the identification of pathogenic genes by Next Generation Sequencing technologies can allow to obtain a rapid diagnosis and to apply specific therapies.
As the outbreak of the new coronavirus (SARS-CoV-2) infection is spreading globally, great effort is being made to understand the disease pathogenesis and host factors that predispose to disease ...progression in an attempt to find a window of opportunity for intervention. In addition to the direct cytopathic effect of the virus, the host hyper-inflammatory response has emerged as a key factor in determining disease severity and mortality. Accumulating clinical observations raised hypotheses to explain why some patients develop more severe disease while others only manifest mild or no symptoms. So far, Covid-19 management remains mainly supportive. However, many researches are underway to clarify the role of antiviral and immunomodulating drugs in changing morbidity and mortality in patients who become severely ill. This review summarizes the current state of knowledge on the interaction between SARS-CoV-2 and the host immune system and discusses recent findings on proposed pharmacologic treatments.
Off-label use of medications is still a common practice in pediatric rheumatology. JAK inhibitors are authorized in adults in the treatment of rheumatoid arthritis, psoriatic arthritis and ulcerative ...colitis. Although their use is not authorized yet in children, JAK inhibitors, based on their mechanism of action and on clinical experiences in small series, have been suggested to be useful in the treatment of pediatric interferon-mediated inflammation. Accordingly, an increased interferon score may help to identify those patients who might benefit of JAK inhibitors. We describe the clinical experience with JAK inhibitors in seven children affected with severe inflammatory conditions and we discuss the correlation between clinical features and transcriptomic data. Clinical improvements were recorded in all cases. A reduction of interferon signaling was recorded in three out of seven subjects at last follow-up, irrespectively from clinical improvements. Other signal pathways with significant differences between patients and controls included upregulation of DNA repair pathway and downregulation of extracellular collagen homeostasis. Two patients developed drug-related adverse events, which were considered serious in one case. In conclusion, JAK inhibitors may offer a valuable option for children with severe interferon-mediated inflammatory disorders reducing the interferon score as well as influencing other signal pathways that deserve future studies.
Systemic auto-inflammatory disorders (SAIDs) are a heterogeneous group of monogenic diseases sharing a primary dysfunction of the innate immune system. More than 50% of patients with SAID does not ...show any mutation at gene(s) tested because of lack of precise clinical classification criteria and/or incomplete gene screening. To improve the molecular diagnosis and genotype interpretation of SAIDs, we undertook the development of a next-generation sequencing (NGS)-based protocol designed to simultaneous screening of 10 genes.
Fifty patients with SAID, already genotyped for the respective causative gene(s), were massively sequenced for the coding portions of MEFV, MVK, TNFRSF1A, NLRP3, NLRP12, NOD2, PSTPIP1, IL1RN, LPIN2 and PSMB8. Three different bioinformatic pipelines (Ion Reporter, CLC Bio Genomics Workbench, GATK-based in-house workflow) were compared.
Once resulting variants were compared with the expected mutation list, no workflow turned out to be able to detect all the 79 variants known in the 50 DNAs. Additional variants were also detected, validated by Sanger sequencing and compared to assess true and false positive detection rates of the three workflows. Finally, the overall clinical picture of 34 patients was re-evaluated in the light of the new mutations found.
The present gene panel has resulted suitable for molecular diagnosis of SAIDs. Moreover, genotype-phenotype correlation has confirmed that the interpretation of NGS data in patients with an undefined inflammatory phenotype is remarkably difficult, thus supporting the need of evidence-based and validated clinical criteria to be used concurrently with the genetic analysis for the final diagnosis and classification of patients with SAIDs.
Interferonopathies are rare genetic conditions defined by systemic inflammatory episodes caused by innate immune system activation in the absence of pathogens. Currently, no targeted drugs are ...authorized for clinical use in these diseases. In this work, we studied the contribution of sulforaphane (SFN), a cruciferous-derived bioactive molecule, in the modulation of interferon-driven inflammation in an immortalized human hepatocytes (IHH) line and in two healthy volunteers, focusing on STING, a key-component player in interferon pathway, interferon signature modulation, and GSTM1 expression and genotype, which contributes to SFN metabolism and excretion. In vitro, SFN exposure reduced STING expression as well as interferon signature in the presence of the pro-inflammatory stimulus cGAMP (cGAMP 3 h vs. SFN+cGAMP 3 h p value < 0.0001; cGAMP 6 h vs. SFN+cGAMP 6 h p < 0.001, one way ANOVA), restoring STING expression to the level of unstimulated cells. In preliminary experiments on healthy volunteers, no appreciable variations in interferon signature were identified after SFN assumption, while only in one of them, presenting the GSTM1 wild type genotype related to reduced SFN excretion, could a downregulation of STING be recorded. This study confirmed that SFN inhibits STING-mediated inflammation and interferon-stimulated genes expression in vitro. However, only a trend towards the downregulation of STING could be reproduced in vivo. Results obtained have to be confirmed in a larger group of healthy individuals and in patients with type I interferonopathies to define if the assumption of SFN could be useful as supportive therapy.
SARS-CoV-2 occurs in the majority of children as COVID-19, without symptoms or with a paucisymptomatic respiratory syndrome, but a small proportion of children develop the systemic Multi Inflammatory ...Syndrome (MIS-C), characterized by persistent fever and systemic hyperinflammation, with some clinical features resembling Kawasaki Disease (KD).
With this study we aimed to shed new light on the pathogenesis of these two SARS-CoV-2-related clinical manifestations.
We investigated lymphocyte and dendritic cells subsets, chemokine/cytokine profiles and evaluated the neutrophil activity mediators, myeloperoxidase (MPO), and reactive oxygen species (ROS), in 10 children with COVID-19 and 9 with MIS-C at the time of hospital admission.
Patients with MIS-C showed higher plasma levels of C reactive protein (CRP), MPO, IL-6, and of the pro-inflammatory chemokines CXCL8 and CCL2 than COVID-19 children. In addition, they displayed higher levels of the chemokines CXCL9 and CXCL10, mainly induced by IFN-γ. By contrast, we detected IFN-α in plasma of children with COVID-19, but not in patients with MIS-C. This observation was consistent with the increase of ISG15 and IFIT1 mRNAs in cells of COVID-19 patients, while ISG15 and IFIT1 mRNA were detected in MIS-C at levels comparable to healthy controls. Moreover, quantification of the number of plasmacytoid dendritic cells (pDCs), which constitute the main source of IFN-α, showed profound depletion of this subset in MIS-C, but not in COVID-19.
Our results show a pattern of immune response which is suggestive of type I interferon activation in COVID-19 children, probably related to a recent interaction with the virus, while in MIS-C the immune response is characterized by elevation of the inflammatory cytokines/chemokines IL-6, CCL2, and CXCL8 and of the chemokines CXCL9 and CXL10, which are markers of an active Th1 type immune response. We believe that these immunological events, together with neutrophil activation, might be crucial in inducing the multisystem and cardiovascular damage observed in MIS-C.
The story of antimalarials as antinflammatory drugs dates back several centuries. Chinin, the extract of the Cinchona bark, has been exploited since the 18th century for its antimalarial and ...antifebrile properties. Later, during the Second World War, the broad use of antimalarials allowed arguing their antirheumatic effect on soldiers. Since then, these drugs have been broadly used to treat Systemic Lupus Erythematosus, but, only recently, have the molecular mechanisms of action been partly clarified. Inhibitory action on vacuole function and trafficking has been considered for decades the main mechanism of the action of antimalarials, affecting the activation of phagocytes and dendritic cells. In addition, chloroquine is also known as a potent inhibitor of autophagy, providing another possible explanation of its antinflammatory action. However, much attention has been recently devoted to the action of antimalarials on the so-called cGASSTING pathway leading from the sensing of cytoplasmic nucleic acids to the production of type I interferons. This pathway is a fundamental mechanism of host defence, since it is able to detect microbial DNA and induce the type I interferon-mediated immune response. Of note, genetic defects in the degradation of nucleic acids lead to inappropriate cGAS-STING activation and inflammation. These disorders, called type I interferonopathies, represent a valuable model to study the antinflammatory potential of antimalarials. We will discuss possible development of antimalarials to improve the treatment of type I interferonopathies and likely multifactorial disorders characterised by interferon inflammation, such as Systemic Lupus Erythematosus.
H Syndrome is a rare genetic condition caused by biallelic pathogenic variants in the SLC29A3 gene. It is characterized by a wide range of clinical manifestations, many of which are related to the ...immune-rheumatological field. These include scleroderma-like skin changes, deforming arthritis, and enlarged lymph nodes. The condition also features cardiac and endocrine defects, as well as hearing loss, for which the immune pathogenesis appears less clear. Immunomodulatory medications have been shown to improve many symptoms in recent experiences.
A 21-year-old girl was referred to our institute after being diagnosed with H syndrome. Her medical history was characterized by the development of finger and toe deformities, which developed since the first years of life and progressively worsened with clinodactyly. At 6 years of age, she was diagnosed with diabetes mellitus without typical autoantibodies and with bilateral sensorineural hearing loss. She also complained of frequent episodes of lymphadenopathy, sometimes with colliquation and growth retardation due to pancreatic insufficiency. It wasn't until the genetic diagnosis of H syndrome that the continual increase in acute phase reactants was noticed, suggesting that an immunological pathogenesis may be the source of her problems. During her visit to our institute, she reported serious pain in both feet and hands and difficulty walking due to knee arthritis and muscle contractures. Conventional therapy with steroid injection in affected joints and methotrexate only led to partial improvement. After a thorough assessment of her inflammatory profile showing a high interferon score, the girl received treatment with baricitinib. Furthermore, based on recent data showing that SLC29A3 deficiency results in interferon production because of Toll-like Receptor 7 activation in lysosomes, hydroxychloroquine was also added. The combination of the two drugs resulted for the first time in a rapid and persistent normalization of inflammatory markers, paralleled by a dramatic improvement in symptoms.
We describe the results of inhibiting IFN inflammation in H syndrome and discuss how JAK inhibitors and antimalarials might represent a mechanistically based treatment for this orphan drug disorder.
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