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The immune system of neonates is immature and therefore knowledge of possible early-life protection against SARS-CoV-2 infection, such as breastfeeding, is of great importance. Few studies have investigated the presence and duration of SARS-CoV-2 antibodies in breastmilk in relation to the trimester of maternal infection during pregnancy, and none with successful participation from all three trimesters. This study has dual objectives (1) in relation to the trimester of infection to examine the frequency, concentration and duration of IgA and IgG antibodies in breastmilk and blood serum in the third and sixth month post-partum in former SARS-CoV-2-infected mothers and (2) to examine the association in pediatric emergency admission of children within the first six months of life compared to children of non-SARS-CoV-2-infected women. The first objective is based on a prospective cohort and the second is based on a nested case-control design. The study participants are women with a former SARS-CoV-2 infection during pregnancy, whose serology IgG tests at delivery were still positive. Maternal blood and breastmilk samples were collected at three and six months postpartum. Serum IgA frequency three months pp was 72.7% (50%, 90% and 60% in the first, second and third trimester) and 82% six months pp (67%, 91% and 82% in the first, second and third trimester). Breastmilk IgA frequency three months pp was 27% (16.6%, 36% and 20% in first, second and third trimester) and 28% six months pp (0%, 38% and 28% in the first, second and third trimester). The highest IgA concentration in breastmilk was found six months post-partum with infection in the third trimester. Serum IgA was detectable more than 400 days post infection, and serum IgG above threshold was found 430 days after date of infection. We found no correlation between serum IgA and breastmilk IgA, nor between serum IgG and breastmilk IgA regardless of the trimester of infection.
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COVID-19 , Recém-Nascido , Gravidez , Humanos , Feminino , Criança , Masculino , SARS-CoV-2 , Leite Humano , Estudos Prospectivos , Período Pós-Parto , Anticorpos Antivirais , Imunoglobulina G , Mães , Imunoglobulina ARESUMO
BACKGROUND: Our study investigated the rate of breakthrough SARS-CoV-2 infection and clinical outcomes in a cohort of multiple sclerosis (MS) patients who were treated with the anti-CD20 monoclonal antibody (Ab), ocrelizumab, before first, second and third BNT162b2 mRNA vaccinations. To correlate clinical outcomes with the humoral and cellular response. METHODS: The study was a prospective non-randomised controlled multicentre trial observational study. Participants with a diagnosis of MS who were treated for at least 12 months with ocrelizumab prior to the first BNT162b2 mRNA vaccination were prospectively followed up from January 2021 to June 2022. RESULTS: Out of 54 participants, 32 (59.3%) developed a positive SARS-CoV-2 PCR test in the study period. Mild infection was observed in all infected participants. After the third vaccination, the non-infected participants had higher mean Ab levels compared to the infected participants (54.3 binding antibody unit (BAU)/mL vs 26.5 BAU/mL, p=0.030). The difference in reactivity between spike-specific CD4+ and CD8+ T lymphocytes in the two groups was not significant. CONCLUSION AND RELEVANCE: The study results demonstrate rates of 59% in breakthrough infections after the third SARS-CoV-2 mRNA vaccination in ocrelizumab-treated patients with MS, without resulting in critical disease courses. These findings suggest the need for continuous development of prophylactic treatments when proved important in the protection of severe breakthrough infection.
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COVID-19 , Esclerose Múltipla , Humanos , COVID-19/prevenção & controle , Vacina BNT162 , SARS-CoV-2 , Esclerose Múltipla/complicações , Esclerose Múltipla/tratamento farmacológico , Estudos Prospectivos , Anticorpos Monoclonais Humanizados/uso terapêutico , Infecções Irruptivas , Progressão da Doença , RNA Mensageiro , Anticorpos Antivirais , Vacinas de mRNARESUMO
OBJECTIVES: To investigate the humoral immune response and risk of disease flare in systemic lupus erythematosus (SLE) patients following three-doses of SARS-CoV-2 vaccines. METHODS: In adult patients with SLE, we measured SARS-CoV-2 spike IgG in blood samples drawn three weeks after the 1st dose (baseline), four and eight weeks after the 2nd dose and after the 3rd dose. A sufficient antibody response was ≥54BAU/mL. SLEDAI-2K, SLAQ and SDI were assessed at baseline and eight weeks after the 2nd dose along with adverse events. Demographic and treatment data were collected from hospital records. RESULTS: Of 123 patients, 115 (93.5%) received the BNT162b2 vaccine, the remaining received the 1st dose of ChAdOx-1 followed by a 2nd and 3rd dose of mRNA-1273. After the 2nd dose 102 (83%) patients had a sufficient antibody response (median 559.2, IQR 288.8-1180.5 BAU/mL), increasing to 115 (93.5%) (median 2416.9, IQR 1289-4603.8 BAU/mL) patients after the 3rd dose. Eight weeks after the 2nd dose patients treated with high dose prednisolone (p=0.034) and DMARDs (p<0.001) had significantly lower antibodies; however, this difference was not significant following the 3rd dose. Disease activity and damage were stable during the study period. Adverse events were more frequent in patients with a sufficient response. Breakthrough infections were reported in 39 (31.7%) patients; all with mild symptoms. CONCLUSIONS: A 3rd dose improved the humoral response to SARS-CoV-2 vaccines in patients with SLE to the level of healthy individuals. Vaccination did not affect SLE disease activity. Subsequent breakthrough infections were mild and did not require hospitalisation.
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Vacinas contra COVID-19 , COVID-19 , Lúpus Eritematoso Sistêmico , Adulto , Humanos , Anticorpos Antivirais , Vacina BNT162 , Infecções Irruptivas , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Imunoglobulina G , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Estudos Prospectivos , SARS-CoV-2 , Exacerbação dos Sintomas , Vacinação/efeitos adversosRESUMO
BACKGROUND: Studies presenting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) for healthy individuals are warranted. We estimate IFR by age and comorbidity status using data from a large serosurvey among Danish blood donors and nationwide data on coronavirus disease 2019 (COVID-19) mortality. METHODS: Danish blood donors aged 17-69 years donating blood October 2020-February 2021 were tested with a commercial SARS-CoV-2 total antibody assay. IFR was estimated for weeks 11 to 42, 2020 and week 43, 2020 to week 6, 2021, representing the first 2 waves of COVID-19 epidemic in Denmark. RESULTS: In total, 84944 blood donors were tested for antibodies. The seroprevalence was 2% in October 2020 and 7% in February 2021. Among 3898039 Danish residents aged 17-69 years, 249 deaths were recorded. The IFR was low for people <51 years without comorbidity during the 2 waves (combined IFR=3.36 per 100000 infections). The IFR was below 3 for people aged 61-69 years without comorbidity. IFR increased with age and comorbidity but declined from the first to second wave. CONCLUSIONS: In this nationwide study, the IFR was very low among people <51 years without comorbidity.
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Anticorpos Antivirais/sangue , Doadores de Sangue , COVID-19/diagnóstico , SARS-CoV-2/isolamento & purificação , Adolescente , Adulto , Idoso , COVID-19/sangue , COVID-19/epidemiologia , Comorbidade , Dinamarca/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Soroepidemiológicos , Adulto JovemRESUMO
Catastrophic antiphospholipid syndrome (CAPS) is a multisystem autoimmune disease with widespread thrombotic events. In this case report, we present a young man with primary antiphospholipid syndrome (PAPS) admitted to the hospital with abdominal pain and vomiting. Abdominal computed tomography showed pneumoperitoneum and acute explorative laparotomy revealed small intestinal necrosis indicating small vessel thrombosis without involvement of large intestine. "Triple therapy" was initiated after surgery and the patient was treated in an intensive care unit for 72 days before being discharged to a rehabilitation clinic. A review of the literature regarding CAPS affecting small intestine shows it is extremely rare and may be associated with higher mortality.
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Síndrome Antifosfolipídica , Lúpus Eritematoso Sistêmico , Trombose , Síndrome Antifosfolipídica/complicações , Síndrome Antifosfolipídica/diagnóstico , Doença Catastrófica , Humanos , Intestino Delgado , Lúpus Eritematoso Sistêmico/complicações , Masculino , Necrose , Trombose/diagnóstico por imagem , Trombose/tratamento farmacológico , Trombose/etiologiaRESUMO
BACKGROUND: The pandemic due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has tremendous consequences for our societies. Knowledge of the seroprevalence of SARS-CoV-2 is needed to accurately monitor the spread of the epidemic and to calculate the infection fatality rate (IFR). These measures may help the authorities make informed decisions and adjust the current societal interventions. The objective was to perform nationwide real-time seroprevalence surveying among blood donors as a tool to estimate previous SARS-CoV-2 infections and the population-based IFR. METHODS: Danish blood donors aged 17-69 years giving blood 6 April to 3 May were tested for SARS-CoV-2 immunoglobulin M and G antibodies using a commercial lateral flow test. Antibody status was compared between geographical areas, and an estimate of the IFR was calculated. Seroprevalence was adjusted for assay sensitivity and specificity taking the uncertainties of the test validation into account when reporting the 95% confidence intervals (CIs). RESULTS: The first 20â 640 blood donors were tested, and a combined adjusted seroprevalence of 1.9% (95% CI, .8-2.3) was calculated. The seroprevalence differed across areas. Using available data on fatalities and population numbers, a combined IFR in patients <70 years is estimated at 89 per 100â 000 (95% CI, 72-211) infections. CONCLUSIONS: The IFR was estimated to be slightly lower than previously reported from other countries not using seroprevalence data. The IFR is likely severalfold lower than the current estimate. We have initiated real-time nationwide anti-SARS-CoV-2 seroprevalence surveying of blood donations as a tool in monitoring the epidemic.
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Doadores de Sangue , COVID-19 , Adolescente , Adulto , Idoso , Anticorpos Antivirais , Humanos , Pessoa de Meia-Idade , SARS-CoV-2 , Estudos Soroepidemiológicos , Adulto JovemRESUMO
BACKGROUND: It is currently not well described if a two-dose regimen of a Covid-19 vaccine is sufficient to elicit an immune response in solid organ transplant (SOT) recipients. RESULTS: A total of 80 SOT recipients completed a two-dose regimen with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA vaccine. Only 35.0% (n = 28) were able to mount a positive IgG immune response 6 weeks after the second dose of vaccine. CONCLUSION: This emphasizes that SOT recipients need continued use of personal protective measures. Future studies need to closely examine the cellular immune response in patients with compromised antibody response to Covid-19 vaccination.
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Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Imunogenicidade da Vacina/imunologia , RNA Mensageiro/imunologia , SARS-CoV-2/imunologia , Transplantados , COVID-19/epidemiologia , Vacinas contra COVID-19/genética , Humanos , Imunogenicidade da Vacina/genética , Transplante de Órgãos , RNA Mensageiro/genética , SARS-CoV-2/genéticaRESUMO
Aim: This Danish national guideline describes the treatment of adult patients with Clostridioides (formerly Clostridium) difficile (CD) infection and the use of faecal microbiota transplantation (FMT). It suggests minimum standard for implementing an FMT service.Method: Four scientific societies appointed members for a working group which conducted a systematic literature review and agreed on the text and recommendations. All clinical recommendations were evalluated for evidence level and grade of recommendation.Results: In CD infection, the use of marketed and experimental antibiotics as well as microbiota-based therapies including FMT are described. An algorithm for evaluating treatment effect is suggested. The organisation of FMT, donor recruitment and screening, laboratory preparation, clinical application and follow-up are described.Conclusion: Updated evidence for the treatment of CD infection and the use of FMT is provided.
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Clostridioides difficile , Infecções por Clostridium , Adulto , Clostridioides , Infecções por Clostridium/terapia , Dinamarca , Transplante de Microbiota Fecal , HumanosRESUMO
Worldwide, there is a rising demand for thoroughly screened, high-quality fecal microbiota transplantation (FMT) products that can be obtained at a reasonable cost. In the light of this evolving therapeutic area of the intestinal microbiota, both private and public stool banks have emerged. However, some of the larger difficulties when establishing stool banks are caused by the absence of or international disagreement on regulation and legislative formalities. In this context, the establishment of a stool bank within a nonprofit blood and tissue transplant service has several advantages. Especially, this setting can ensure that every step of the donation process, laboratory handling, and donor-traceability is in agreement with the current expert guidelines and meets the requirements of the European Union's regulative directives on human cells and tissues. Although safety and documentation are the top priority of the stool bank setup presented here, cost-effectiveness of the production is possible due to a high donor screening success rate and the knowhow, infrastructure, facilities, personnel, and laboratory- and quality-management systems that were already in place. Overall, our experience is that a centralized, nonprofit, blood and tissue transplant service is an ideal and safe facility to run a stool bank of high quality FMT products that are based on stool donations from volunteer, unpaid, healthy, blood donors.
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Bancos de Espécimes Biológicos , Transplante de Microbiota Fecal , Fezes , HumanosRESUMO
The role of CXCL13 as a marker of Lyme neuroborreliosis (LNB) is under investigation, and CXCL13 is not part of routine diagnostics in suspicion of LNB. Our aim was to find the optimal cut-off value of CXCL13 for LNB in a Danish population and to investigate the role of CXCL13 both in early LNB and as a discriminatory marker between LNB and other neuroinflammatory disorders. We conducted a retrospective cross-sectional study including all patients with a cerebrospinal CXCL13 test performed at the Department of Clinical Immunology, Odense University Hospital, Denmark, between 1 January 2015 and 31 December 2018. We included 619 patients, of which 51 had definite LNB, 14 patients had possible LNB with neurological symptoms suggestive of LNB and pleocytosis but no intrathecal Borrelia antibodies, eight patients had prior LNB and 546 had no LNB. With an optimal CXCL13 cut-off of 49 ng/L we found a sensitivity of 100% and specificity of 94% (AUC 0.988, 95% CI 0.980-0.996) when patients treated with antibiotics prior to lumbar puncture were excluded (n = 130). All patients with possible LNB had a CXCL13 value above the cut-off value; 18/546 patients (3.3%) without LNB had a CXCL13 value ≥ 50 ng/L. While CXCL13 cannot be used as a stand-alone test, it can be used as a reliable additional marker in treatment-naive patients suspected of LNB. CXCL13 can be used to monitor treatment response in LNB patients.
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Quimiocina CXCL13/líquido cefalorraquidiano , Neuroborreliose de Lyme/diagnóstico , Adolescente , Adulto , Biomarcadores/líquido cefalorraquidiano , Borrelia/isolamento & purificação , Criança , Estudos Transversais , Dinamarca , Testes Diagnósticos de Rotina , Feminino , Humanos , Neuroborreliose de Lyme/líquido cefalorraquidiano , Neuroborreliose de Lyme/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sensibilidade e Especificidade , Adulto JovemAssuntos
Autoanticorpos/líquido cefalorraquidiano , Borrelia burgdorferi/isolamento & purificação , Neuroborreliose de Lyme/líquido cefalorraquidiano , Neuroborreliose de Lyme/diagnóstico , Receptores de N-Metil-D-Aspartato/metabolismo , Índice de Gravidade de Doença , Adulto , Reações Falso-Positivas , Feminino , HumanosRESUMO
INTRODUCTION: Small-cell lung cancer (SCLC) may be associated with neuronal autoantibodies and paraneoplastic neurological syndromes. It has been suggested that neuronal autoantibodies, especially antineuronal nuclear antibody type 1 (Hu) autoantibodies, are associated with longer survival of patients with SCLC. The objective of this study was to determine the frequency and distribution of neuronal autoantibodies at the time of diagnosis of SCLC patients and assess survival rates in relation to autoimmunity. METHODS: In this retrospective study, serum from 40 patients with biopsy-proven SCLC at the time of diagnosis was studied prior to treatment. The sera originated from a cancer registry at the Oncology Department, Vejle Hospital from 2007 to 2010. The sera were analyzed blindly to clinical status for the presence of neuronal autoantibodies. Medical records were reviewed for neurological symptoms. RESULTS: Neuronal autoantibodies were detected in 22/40 (55%) of the SCLC patients. A broad range of neurological symptoms was recorded in 28/40 (70%) patients, of which 14/28 (50%) were positive for neuronal autoantibodies. The most frequently detected autoantibodies were Hu (7/40, 17.5%) followed by GAD65 (6/22, 15.0%). Striational and P/Q- or N-type voltage-gated calcium channel antibodies were less common, with each found in five patients (12.5%). Eight patients (20%) had coexisting autoantibodies. Autoantibody-positivity was not associated with survival. CONCLUSION: Neuronal autoantibodies were at time of diagnosis found in approximately half of the treatment-naïve SCLC patients. Neither autoantibody positivity at diagnosis nor neurological manifestations correlated with survival and their clinical importance requires further studies in larger, prospective cohorts.
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Autoanticorpos , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Masculino , Feminino , Autoanticorpos/sangue , Autoanticorpos/imunologia , Carcinoma de Pequenas Células do Pulmão/imunologia , Carcinoma de Pequenas Células do Pulmão/mortalidade , Carcinoma de Pequenas Células do Pulmão/sangue , Idoso , Pessoa de Meia-Idade , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/imunologia , Estudos Retrospectivos , Idoso de 80 Anos ou mais , Adulto , Prognóstico , Neurônios/patologia , Neurônios/imunologiaRESUMO
Tick Borne Encephalitis (TBE) is endemic to an increasing number of countries and is a common cause of meningoencephalitis in Europe and Asia making any potential complications of the disease increasingly relevant to clinicians. We present, what is to our knowledge, the second reported case of N-methyl-d-aspartate receptor (NMDAR) encephalitis following Tick Borne Encephalitis (TBE) in a 47-year-old Lithuanian man. The case provides further evidence of TBE being a possible trigger of NMDAR encephalitis and highlights the importance of being aware of symptoms of autoimmune encephalitis in patients with infectious encephalitis.
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Encefalite Antirreceptor de N-Metil-D-Aspartato , Vírus da Encefalite Transmitidos por Carrapatos , Encefalite Transmitida por Carrapatos , Masculino , Humanos , Pessoa de Meia-Idade , Encefalite Transmitida por Carrapatos/epidemiologia , Encefalite Antirreceptor de N-Metil-D-Aspartato/complicações , Europa (Continente)/epidemiologia , ÁsiaRESUMO
OBJECTIVES: The gut microbiota can mediate both pro and anti-inflammatory responses. In patients with psoriatic arthritis (PsA), we investigated the impact of faecal microbiota transplantation (FMT), relative to sham transplantation, on 92 inflammation-associated plasma proteins. METHODS: This study relates to the FLORA trial cohort, where 31 patients with moderate-to-high peripheral PsA disease activity, despite at least 3 months of methotrexate treatment, were included in a 26-week, double-blind, randomised, sham-controlled trial. Participants were allocated to receive either one gastroscopic-guided healthy donor FMT (n=15) or sham (n=16). Patient plasma samples were collected at baseline, week 4, 12 and 26 while samples from 31 age-matched and sex-matched healthy controls (HC) were collected at baseline. Samples were analysed using proximity extension assay technology (Olink Target-96 Inflammation panel). RESULTS: Levels of 26 proteins differed significantly between PsA and HC pre-FMT (adjusted p<0.05), of which 10 proteins were elevated in PsA: IL-6, CCL20, CCL19, CDCP1, FGF-21, HGF, interferon-γ (IFN-γ), IL-18R1, monocyte chemotactic protein 3, and IL-2. In the FMT group, levels of 12 proteins changed significantly across all timepoints (tumour necrosis factor (TNF), CDCP1, IFN-γ, TWEAK, signalling lymphocytic activation molecule (SLAMF1), CD8A, CD5, Flt3L, CCL25, FGF-23, CD6, caspase-8). Significant differences in protein levels between FMT and sham-treated patients were observed for TNF (p=0.002), IFN-γ (p=0.011), stem cell factor (p=0.024), matrix metalloproteinase-1 (p=0.038), and SLAMF1 (p=0.042). FMT had the largest positive effect on IFN-γ, Axin-1 and CCL25 and the largest negative effect on CCL19 and IL-6. CONCLUSIONS: Patients with active PsA have a distinct immunological plasma protein signature compared with HC pre-FMT. FMT affects several of these disease markers, including sustained elevation of IFN-γ. TRIAL REGISTRATION NUMBER: NCT03058900.
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Artrite Psoriásica , Humanos , Artrite Psoriásica/terapia , Artrite Psoriásica/etiologia , Transplante de Microbiota Fecal/efeitos adversos , Interleucina-6 , Resultado do Tratamento , Inflamação/etiologia , Fator de Necrose Tumoral alfa , Antígenos de Neoplasias , Moléculas de Adesão CelularRESUMO
Diagnosis of paraneoplastic neurologic syndromes (PNS) requires an understanding of the clinical, immunologic and oncologic heterogeneity. The 2004 PNS criteria were partially outdated due to advances in the field, and updated consensus criteria for PNS have been proposed in 2021, including the PNS-Care score for assessment of PNS probability. Furthermore, knowledge on the limitations of autoantibody testing is crucial to ensure accurate interpretation. This review presents the updated diagnostic criteria for PNS, in a Danish context.
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Síndromes Paraneoplásicas do Sistema Nervoso , Síndromes Paraneoplásicas , Humanos , Síndromes Paraneoplásicas do Sistema Nervoso/diagnóstico , AutoanticorposRESUMO
The heterogeneity of autoantibody targets in autoimmune encephalitides presents a challenge for understanding cellular and humoral pathophysiology, and the development of new treatment strategies. Thus, current treatment aims at autoantibody removal and immunosuppression, and is primarily based on data generated from other autoimmune neurological diseases and expert consensus. There are many subtypes of autoimmune encephalitides, which now entails both diseases with autoantibodies targeting extracellular antigens and classical paraneoplastic syndromes with autoantibodies targeting intracellular antigens. Here, we review the current knowledge of molecular and cellular effects of autoantibodies associated with autoimmune encephalitis, and evaluate the evidence behind the proposed pathophysiological mechanisms of autoantibodies in autoimmune encephalitis.
Assuntos
Doenças Autoimunes do Sistema Nervoso , Encefalite , Doença de Hashimoto , Humanos , Autoanticorpos , ConsensoRESUMO
BACKGROUND: Antineuronal antibodies can cause psychotic symptoms, particularly NMDAR antibodies; however, studies on the prevalence of antineuronal antibodies in cerebrospinal fluid (CSF) and serum of patients with psychotic disorders compared to matched healthy controls are sparse. METHODS: We included 104 patients with a first-time diagnosis of a psychotic disorder within one year prior to inclusion (50 % outpatients) and 104 individually matched healthy controls, all without any known immunological conditions. CSF and serum were tested for IgG antibodies (Abs) against NMDAR NR1-subunit, GAD65, LGI1, CASPR2, AMPAR1, AMPAR2 and GABAb-receptor B1/B2 using commercial fixed cell-based assays (CBAs) (Euroimmun). Positive samples were retested with CBA twice, and tested with tissue-based assays (TBA). Primary outcomes were the presence of any of the seven anti-neuronal antibodies in CSF or serum. Secondarily, we analyzed the prevalence of each autoantibody. RESULTS: No antineuronal IgG antibodies were consistently found in any CSF sample and NMDAR-antibodies were not consistently present in any of the 208 participants, neither in CSF nor serum. CASPR2-Abs were consistently found in the serum of one patient and one control, and one healthy control, without diabetes, was seropositive for GAD65-Abs. CASPR2 borderline seropositivity was additionally found in one patient and two controls. All samples positive on CBA were negative on TBA. CONCLUSIONS: We found no significant differences between patients and controls. Antineuronal IgG antibodies are very rare when screening a broad group of individuals with recent-onset psychotic disorders without other indications of autoimmune encephalitis. Thus, much larger studies are needed to conclude on potential contrasts in prevalence compared to healthy controls.
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Encefalite , Doença de Hashimoto , Transtornos Psicóticos , Humanos , Autoanticorpos , Imunoglobulina GRESUMO
No large studies have investigated the prevalence of cerebrospinal fluid antineuronal autoantibodies in isolated depression. In this case-control study comparing 106 patients with isolated depression (ICD-10 code F32) with 106 healthy control subjects, cerebrospinal fluid and serum samples were tested for 7 immunoglobulin G autoantibodies using commercial fixed cell-based assays. To explore validity of methods, positive samples were retested twice by cell-based assays and once by tissue-based assays (monkey cerebellum). The prevalence of any of the antineuronal autoantibodies in cerebrospinal fluid was 0.0% in both groups and the seroprevalence was 0.9% in both groups, based on consistent findings in cell-based assays. However, all samples were negative by the tissue-based assay. Evaluation of antineuronal autoantibodies in cerebrospinal fluid cannot be recommended routinely for patients with isolated depression of moderate severity. Future studies of isolated depression should consider much larger sample sizes and evaluation of antineuronal autoantibodies using modalities other than commercial kits.
RESUMO
Disease mechanisms underlying neurological and neuropsychiatric symptoms after coronavirus disease 2019 (COVID-19), termed neuro-COVID, are poorly understood. Investigations of the cerebrospinal fluid (CSF) for the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and antibodies, as well as autoantibodies against neuronal surface antigens, could improve our understanding in that regard. We prospectively collected CSF and blood from patients investigated by lumbar puncture for neurological or neuropsychiatric symptoms during or after COVID-19. Primary outcomes were the presence of (i) SARS-CoV-2 RNA in CSF via polymerase chain reaction (PCR), (ii) SARS-CoV-2 immunoglobulin G (IgG) anti-S receptor-binding-domain antibodies via the Euroimmun and Wantai assays and (iii) IgG autoantibodies against neuronal surface antigens using commercial cell- and tissue-based assays (Euroimmun). Secondary outcomes were (i) routine CSF investigations and (ii) correlation between SARS-CoV-2 antibody levels in CSF with serum levels, blood-brain barrier permeability and peripheral inflammation. We obtained CSF from 38 COVID-19 patients (mean age 56.5 ± 19.2 years, 53% women) who developed neurological and neuropsychiatric symptoms. CSF pleocytosis (>5 cells) was observed in 9/38 patients (23.7%), elevated CSF protein (>0.50â g/L) in 13/38 (34.2%) and elevated CSF/serum albumin ratio in 12/35 (34.3%). PCR for SARS-CoV-2 RNA in CSF was negative in all. SARS-CoV-2 CSF antibodies were detected in 15/34 (44.1%; Euroimmun assay) and 7/31 (22.6%; Wantai assay) individuals, but there were no signs of intrathecal SARS-CoV-2 IgG production. SARS-CoV-2 CSF antibodies were positively correlated with serum levels (R = 0.93, P < 0.001), blood-brain barrier permeability (R = 0.47, P = 0.006), peripheral inflammation (R = 0.51, P = 0.002) and admission to the intensive care unit [odds ratio (OR) 17.65; 95% confidence interval (CI) 1.18-264.96; P = 0.04; n = 15]. Cell-based assays detected weakly positive NMDAR, LGI1 and CASPR2 antibodies in serum of 4/34 (11.8%) patients but not in CSF. The tissue-based assay showed anti-neuronal fluorescence in CSF from one individual, staining for Purkinje cells. In summary, whereas we did not detect active SARS-CoV-2 infection in the CSF, SARS-CoV-2 antibodies were prevalent. The absence of intrathecal antibody production points towards blood-brain barrier impairment as the origin of CSF SARS-CoV-2 antibodies. In contrast, CSF autoantibodies against neuronal surface antigens were rare. There was no evidence for a clinical correlate of these antibodies. We conclude that, rather than specific autoimmune neuronal injury, non-specific effects of critical illness including an impaired blood-brain barrier are more likely to contribute to neuro-COVID.