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Background: The clinical course of coronavirus disease-2019 (COVID-19) varies from those who are asymptomatic, experience mild symptoms such as fever, cough, and dyspnea, to more severe outcomes including acute respiratory distress, pneumonia, renal failure, and death. Early reports suggested severe outcomes in patients with primary immunodeficiency (PID), particularly those with type 1 interferon signalling defects. This prompted a rigid approach to social distancing to protect this patient population, particularly children. To date, real-world data describing the course and outcome of COVID-19 in paediatric PID patients remains scarce. Method(s): In this retrospective case series, we describe the clinical course of 36 paediatric patients with underlying primary immunodeficiency (PID) followed by SickKids Hospital (Toronto, Canada) who were symptomatic and tested positive for SARS-CoV-2 infection between October 2020 to November 2022. Result(s): Our cohort consisted of patients with combined immunodeficiency (66.7%), antibody deficiency (22.2%), neutrophil dysfunction (8.3%), and immune dysregulation (2.8%). The median age was 7.5 years (range: 8 months - 17 years), with 21 male and 15 female patients. Three (8.3%) patients were post-hematopoietic stem cell transplant (HSCT) and 12 (33%) patients were on immunoglobulin replacement. Nine (25%) patients had underlying lung problems including bronchiectasis (1), interstitial lung disease on home oxygen therapy (1), and underlying asthma (7). Most patients had mild clinical course and were managed at home. The most common symptoms were fever (80%), cough (75%) and other upper respiratory tract symptoms (72%). Nineteen (52.7%) patients experienced other symptoms which included headache, lethargy, or gastrointestinal upset. At the time of the infection, 13 patients (36.1%) had received 2 doses of a SARS-CoV-2 vaccine, 5 patients (13.9%) had received 1 dose, and 18 (50%) were not vaccinated. None of the patients received antiviral or monoclonal antibody as prophylaxis or treatment. Only 1 patient required hospital admission out of precaution given the close proximity to HSCT. All patients recovered without complications. Conclusion(s): The paediatric patients with PID followed by our centre experienced mild to moderate COVID-19 symptoms and recovered fully without complications. These findings support the return of much needed social interactions among children, which were impacted severely during the COVID-19 pandemic.Copyright © 2023 Elsevier Inc.
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We conducted a retrospective study in the adult primary immunodeficiency clinic at UAB examining COVID-19 infection and COVID-19 antibody response from vaccination, natural infection, and immunoglobulin replacement from February 2021 to November 2022. Our goal was to determine if nucleocapsid and spike antibodies could be found in our PID patients and if these antibodies could be derived from natural infection, vaccination, or antibody replacement exclusively or combinatory. We hypothesized that increasing antibodies would be detected in our population as the COVID period extended. Two hundred and forty-five subjects were tracked over 336 clinic visits during this period. Our PID population included subjects with CVID, XLA, thymoma, hypogammaglobulinemia, IgA deficiency, IgG subclass deficiency, specific antibody deficiency, Down syndrome, IgM deficiency, and patients with recurrent sinopulmonary infections. We had 196 females and 45 males in our study. In our patient population, 47% of our patient had known COVID-19 infection. Of those 47%, 21% of those infected patients had COVID-19 at least twice. Of those infected, three did not have COVID-19 spike antibodies and chose not to get vaccinated either. Two of those patients were not on IVIG and one was on Pangyza. Of those infected, 70% (n = 80) were on IgG infusions compared to those uninfected, 77% (n = 96) were on IgG infusions. Of interest, we had three XLA patients and all three had COVID-19 infection in the summer 2021. Two of them tested positive for nucleocapsid and spike antibodies in high titers and they were receiving Gammagard or Gamunex infusions, suggesting that these immunoglobulin preparations contain COVID-19 antibodies. We are still in the process of analyzing our data to see if diagnosis, IgG preparations, date of testing, B cell numbers, and drugs play a role in producing nucleocapsid antibodies and high spike antibody titers.Copyright © 2023 Elsevier Inc.
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Currently, 640 million cases of coronavirus disease 2019 (COVID-19) and 6.6 million deaths have been reported world-wide. Risk factors for severe COVID-19 are known, including those with compromised immunity. Among patients with inborn errors of immunity (IEI), early reports of severe outcomes lead to strict masking and social distancing measures. While this resulted in relatively low infection rates among those with IEI, real-world data describing the clinical course of COVID-19 in this patient population have remained limited. We performed a retrospective study of adult IEI patients followed by our center in which a positive test (rapid antigen or PCR) for COVID-19 was determined between November 2021-November 2022. Medical charts were reviewed, and patient interviews conducted. All patients provided informed consent. Twenty-nine patients were enrolled (22 females, 7 males), aged between 18-69 years (median: 20-29 years). The cohort included those with antibody deficiencies (41.37%), combined immunodeficiencies (34.48%;HIES, CARD11, STAT1-GOF), immune dysregulation disorders (20.69%;LRBA deficiency, AIRE deficiency) and phagocyte defect (3.45%;CGD). The duration of symptoms ranged between 3 days-4 weeks (median: < 1 week). Upper respiratory symptoms (including sore throat, congestion) were reported in 97% while fever was present in 41% of patients. Prior to infection, 14 (48%) patients had underlying asthma or bronchiectasis - 2 subsequently experienced shortness of breath and were treated with inhalers or Sotrovimab, respectively. No treatment was required in 65.5% of cases. The remaining received Paxlovid (10.3%), Sotrovimab (13.79%), or antibiotics (10.3%). Of the 2 patients with STAT1-GOF, one tested positive during a repeat episode of febrile neutropenia which required hospitalization. No other patients were hospitalized or needed ICU admission. No deaths were recorded. In light of these favourable outcomes, patients with IEI can gradually and safely return to normal activities.Copyright © 2023 Elsevier Inc.
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Background: Intravenous (IV) and subcutaneous (SC) Immunoglobulin G (IG) replacement products are in wide use in patients with primary antibody deficiency syndrome (PAD). There is limited data on the levels of anti-SARS-CoV-2 spike antibodies in IG products or their ability to neutralize emerging SARS-CoV-2 variants. There is lack of data on the impact of IG therapy on serum anti-SARS-CoV-2 spike or neutralizing antibody titers in PAD patients. Method(s): We measured anti-SARS-CoV-2 anti-spike antibody levels and neutralizing titers against historical (WA1/2020) and variant (B.1.617.2 [Delta] and BA.1 [Omicron]) strains in 158 lots of 6 different IG products, collected between August 2021 to April 2022 and manufactured between December 2019 to December 2021. IG products were compared to serum from 20 healthy donors vaccinated with 2 doses of Pfizer-BioNTech mRNA vaccine. Serum anti-spike antibody level and SARS-CoV-2 neutralization activity were measured in 27 PAD patients treated with the tested IG products. Result(s): Anti-spike antibody titers started to increase in products manufactured in March 2021 and reached peak level, comparable to vaccinated healthy donors, in products manufactured in August 2021 (Fig. 1). The neutralization activity against WA1/2020 and Delta strains showed a similar pattern (Fig. 2). However, 95% of the tested products had no neutralization activity against Omicron. Until November 2021, IVIG products infused to patients in the study had anti-spike titers comparable to unvaccinated healthy donors (Fig. 3). Beginning in February 2022, IVIG products had anti-spike titers comparable to vaccinated healthy controls. Concurrent with a rise in anti-spike antibodies in IG products, PAD patients showed an increase in serum levels of anti-spike antibody and neutralizing activity against WA1/202 and Delta but not against Omicron variants. Testing of immunoglobulin replacement products neutralization activity against emerging variants BQ.1 and BQ.1.1 is underway.[Formula presented][Formula presented][Formula presented] Conclusion(s): The anti-SARS spike antibody and neutralization activity of IVIG products lags after the emergence of COVID-19 variants and currently have poor activity against Omicron strain. Because of the protracted manufacturing process, this is expected to be an ongoing challenge. As variants emerge, clinicians should consider additional means of protection for PAD patients such as vaccination, or prophylaxis with monoclonal antibodies.Copyright © 2023 Elsevier Inc.
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Background: The disparity in COVID-19 disease burden between European, Asian, and African countries is notable, with considerably higher morbidity and mortality in many European countries as well as the U.S. Dietary differences between regions could play a role in differential COVID-19 pathogenesis, as Western diets high in fat and sugar have been implicated in enhancing gut damage and pathogenesis during viral infections. Here we investigate the effect of diet on gut immunity and SARS-CoV-2 infection. Method(s): Six pigtail macaques were fed a commercial monkey chow diet, then transitioned to a high fat and sugar chow diet (HFD) for approximately two months prior to infection with Delta strain SARS-CoV-2. Animals were sampled prior to HFD initiation, during HFD administration but prior to infection, and for approximately one month post-infection. HFD was maintained following infection and animals were euthanized at the study conclusion. Result(s): Viral RNA was detected for up to 28 days post-infection in nose swabs, with peak viral load at day 2 at a mean of 8.2x109 copies/mL of swab fluid. Subgenomic RNA (sgRNA, indicating viral replication) decayed more rapidly, with all animals having undetectable sgRNA by day 21, and a lower peak of 2.6x109 copies/mL swab fluid on day 2. Viral RNA load was approximately 3.5 logs greater and sgRNA load approximately 3 logs higher at day 2 than in rhesus macaques infected with WA2020 SARS-CoV-2 and fed standard monkey chow. Mucosal rectal biopsies indicated significantly lower B cell frequencies from baseline to approximately two months following HFD administration (p=0.04, Dunn's), and frequencies had not recovered approximately one month postinfection. GI tract-resident IgG+ B cells were nearly absent at necropsy, with mean frequency 0.03% of total B cells. B cell loss was coupled with modest T cell expansion during HFD administration, though frequencies declined following infection. Furthermore, NK cell frequencies tended to decline from baseline throughout HFD administration, and were further depleted at necropsy one month post-infection. Conclusion(s): SARS-CoV-2 infection can induce lymphopenia, and our sampling of gut mucosal tissue indicates B cell depletion and NK cell loss with a HFD that is further exacerbated by SARS-CoV-2 infection. Excess dietary fat and sugar may disrupt gut barrier integrity and immunity, in turn predisposing the tissue to pathology of viral infection.
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Background: There is little information in the literature on primary immunodeficiency (PID) or innate immune error (IEI) as a risk factor for severe COVID-19 disease. Our aim is to detail the course of COVID-19, especially in patients with PID who predominantly have antibody deficiencies. Method(s): In this cross-sectional retrospective study, we included 18 cases (12 males, 6 females) of our 120-patient IEI group, aged between 30 months and 32 years, predominantly with antibody deficiencies. Their mean age was 12.2 (3-32) years. This study retrospectively evaluated IEI patients between February 2020 and February 2022 to determine the prevalence of COVID-19. Assays used: Polymerase chain reaction (PCR) tests from nasopharyngeal swab were positive for SARS-CoV- 2. This study was approved by the Turkish Ministry of Health. Written consent was obtained from all patients or their parents. Sakarya University Ethics Committee was also applied to. Result(s): All of our patients had a benign course, suggesting a possible protective factor related to young age despite IEI. In our patients, there was no other comorbidity other than bronchiectasis in 1 patient. A total of 18/120 (15%) PID patients aged 30 months to 32 years tested positive for SARS-CoV- 2. All patients were on routine monthly IVIG or SCIG replacement therapy at the time of virus detection. In addition, 9/18 patients received intermediate-dose IVIG treatment. Also, 2/18 patients were completely asymptomatic, but 16 out of 18 patients were symptomatic. As a result, none of the patients showed any serious illness, and none even required supplemental oxygen and/or intensive care unit admission. Except for the intermediate dose IVIG treatment, 1 patient was treated with hydroxychloroquine, 1 patient with favipiravir, and 4 patients with ceftriaxone antibiotic treatment. Conclusion(s): If we look at the clinical course and outcome of COVID 19 disease in our patients, all of our patients showed a benign course as well as better results.
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Background: Congenital/primary immunodeficiency (PID) affects about 6 million people worldwide, about 50% of whom are antibody deficient. During the COVID-19 pandemic, these people are at special risk because they have inborn errors of immunity and immune defense against infections. A number of immune mediators, in particular serum levels of interleukin 6 (IL-6), are closely correlated with severity and mortality from COVID-19. Method(s): The clinical course of COVID-19 and IL-6 levels in 14 patients with PID were studied. The age of patients ranged from 18 to 46 years. Among 14 patients with PID, 5 were diagnosed with common variable immunodeficiency (CVID), 4 with IgG4 deficiency, 4 with X-linked agammaglobulinemia (XLA), and 1 with WHIM syndrome. All patients with PID received replacement immunoglobulin therapy. The control group was randomly selected from 25 patients with COVID-19 without immune deficiency disease. The level of IL-6 was determined by ELISA. Result(s): Among 14 patients with PID, 10 patients (71.4%) had mild COVID-19 and 4 patients (28.57%) had moderate COVID-19. Importantly, all 4 patients with IgG4 deficiency, 1 patient with WHIM syndrome, 3 out of 5 patients with CVID, and 2 out of 4 patients with XLA had mild COVID-19. It should be noted that the clinical course and level of IL-6 in all patients with PID and control group did not differ statistically. Conclusion(s): More than 70% of patients with congenital antibody deficiencies had a mild form of COVID-19. The predominantly mild course of COVID-19 confirms the important role of cellular immunity in protecting against SARS Cov-2. Interestingly, all patients with XLA experienced mild or moderate COVID-19 without elevated IL-6 levels likely due to decreased activity of Bruton tyrosine kinase, which mediates development of a cytokine storm through activation of NF-kappabeta. Mild forms of COVID-19 in XLA may reflect a decrease in cytokine storm, in particular IL-6 production.
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Background: Treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in immuno-compromised patients with complete B cell depletion can be really challenging due to the lack of seroconversion and long-lasting disease. Case Report: We describe a case of long-lasting coronavirus disease (COVID-19) in a fe-male patient with rheumatoid arthritis who was treated with rituximab and continued to show B-cell depletion. An ongoing replication of SARS-CoV-2 was demonstrated for a period of 8 months when nasopharyngeal swabs were tested. She was treated once with remdesivir but without lasting resolution, and she was then treated with convalescent plasma but with a sim-ilar effect. Only with a combination of both treatments was clinical resolution achieved. The patient's lack of seroconversion and the prolonged course of the disease illustrate the im-portance of humoral immunity in resolving SARS-CoV-2 infection. This case report high-lights challenges in managing immunocompromised hosts, who may act as persistent shed-ders and sources of transmission. Conclusion(s): The combination of remdesivir and convalescent plasma resulted in successful-ly achieving clinical resolution of SARS-CoV-2 infection in our patient.Copyright © 2023 Bentham Science Publishers.
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Vaccines having aided in escaping the majority of the population from immunological naïvety, our strategies are now shifting towards an increased focus on identifying and protecting the extremely vulnerable. We here describe the results of testing 12 patients, those with lymphoid malignancies having been targeted their B-cells for therapy with rituximab-containing regimens or a Bruton tyrosine kinase inhibitor, for anti-SARS-CoV-2 spike antibodies after receiving the BNT162b2 mRNA vaccine doses. The interval from last dosing of B-cell depletion therapy to SARS-CoV-2 vaccination was at median 5.3 (range 3.1–6.6) months. Using the ‘seroprotection' threshold of 775 [BAU/mL] for the anti-spike antibody titer, our finding points out the crucial unresponsiveness of the targeted population with 0/12 (0%) achieving ‘seroprotection'. Although IgG seroconversion was observed in 4/12 (33%), supporting the overall benefit of vaccination, the figures still point out a potential need for optimization of practice. IgA was further less responsive (unsuccessful ‘seroconversion' in 11/12 (92%)), implicating an underlying class switch defect. Those with depletion on B-cells are caught at a dilemma between, being too early and too late on receiving SARS-CoV-2 vaccines. They wish to get over their immunological naïvety at the earliest, while, in order to assure quality immune memory, are also required to hold the patience for their B-cells to repopulate. Although it remains an issue whether intensified vaccine schedules and/or regimens will lead to stronger immunogenicity or more effective boosters for non-responders, we shall take advantage of every increasing evidence in order to optimize current options. © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases
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Background. The COVID-19 pandemic has been marked by long-term persistence of SARS-CoV-2 in immunocompromised patients receiving B-cell-depleting therapies, with many individuals experiencing fatal COVID-19. Methods. We report an individual treated with rituximab who survived persistent COVID-19 over 9 months. SARS-CoV-2 positive RNA samples were sequenced using targeted amplicon NGS sequencing with backup sequencing on a nanopore platform. The resulting sequences were analyzed for genomic variance over time at the consensus and sub-consensus level. Results. An individual with rheumatoid arthritis (RA) treated with azathioprine and rituximab (last dose in May 2020) was diagnosed with COVID-19 in July 2020 and admitted with pneumonia. After initial incomplete recovery, the patient had persistent infection through March 2021 and received both remdesivir and convalescent plasma (January 2021). The patient received three doses of mRNA vaccine (Pfizer BioNTech) in December 2020, April 2021, and November 2021, but was seronegative for nucleocapsid IgG in both January 2021 and March 2021;positive spike IgG developed by September 2021 (512 AU/ml) and December 2021 (621 AU/ml) (Figure 1). The patient recovered with new oxygen dependence (2-3L) and manages RA off B-cell depletion;they required an extended corticosteroid taper to manage organizing pneumonia and treatment for several opportunistic infections. Viral sequencing over the course of illness indicated a persistent infection with a lineage B.1.585.3 virus that accumulated 14 mutations throughout the infection. Two mutations (S494P, S D737Y) are associated with therapy resistance and are similar to those found in other immunocompromised individuals with persistent COVID-19. Additional mutations were of unknown consequence Conclusion. SARS-CoV-2 was able to establish persistent infection and accumulated mutations associated with therapeutic resistance;repeated vaccination was associated with successful resolution following repeated vaccination after stopping rituximab. Cessation of B-cell-depleting therapy was likely the critical factor in the patient's recovery, but repeated vaccination was associated with a delayed seroconversion in this patient with reversibly immunosuppression.
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Introduction: Patients with multiple sclerosis (MS) are commonly treated with B-cell depletion therapies (BCDTs). Reduced seroconversion following COVID-19 vaccination in patients receiving certain BCDTs has been reported, however the immune response following natural infection is poorly understood. Objective(s): This study aimed to evaluate COVID-19 antibody responses after vaccination and natural infection in BCDT-treated patients. This single-centre study evaluated COVID-19 seroconversion and spike protein antibody titres for double-vaccinated MS or neuroinflammatory disease patients treated with BCDT (n=33) with confirmed COVID-19 infection (n=16) or uninfected by COVID-19 (control;n=17). Method(s): We performed a retrospective review of patients at the Yale MS Center who had systematically checked COVID-19 spike antibody levels among patients treated with BCDTs (ocrelizumab [OCR], n=24;rituximab [RTX], n=5;ofatumumab [OFT], n=4). Data were collected from Mar 2020 to Feb 2022. All patients had received >=2 doses of FDA-approved COVID-19 vaccine. Qualitative spike antibody seropositivity was determined based on test-specific lab reference ranges. For a subset of patients (n=18), quantitative spike antibody levels were assessed via DiaSorin Liaison chemiluminescence assay (positive titre of >=13;OCR, n=13;RTX, n=3;OFT, n=2). Vaccination and COVID-19 infection dates were also recorded. Patients were monitored for health effects following COVID-19. Result(s): Overall,16/33 (48%) patients seroconverted post full vaccination. After COVID-19 infection, 15/16 (94%) seroconverted, while 7/17 (41%) of uninfected patients seroconverted after vaccination. For the 18 patients with quantitative COVID-19 spike antibody titres, mean titres post-vaccination were 37.38. Mean antibody titres were significantly higher after COVID-19 infection;540.32 vs 20.1 in the control group (p<0.05). Of the 16 infected patients, 15 had mild COVID-19 symptoms and 1 was asymptomatic. No hospitalizations or deaths were reported. Conclusion(s): This study reports that COVID-19 spike antibody titres in fully vaccinated, BCDT-treated patients were significantly increased post-infection compared to the control group. BCDT-treated patients infected with COVID-19 displayed mild infection or were asymptomatic, with no hospitalizations or deaths. These results provide reassurance that BCDTs in doublevaccinated MS patients do not preclude an appropriate COVID-19 antibody response post infection.
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Introduction: Booster vaccination against SARS-CoV-2 is recommended for patients with multiple sclerosis (pwMS), usually six months after the last vaccination. Objectives and aims: To investigate humoral response after SARS-CoV-2 booster vaccination in pwMS compared to healthy controls (HC), as well as the role of the third vaccination in the primarily seronegative and therefore more vulnerable group of treated pwMS (S1PMs, anti-CD20 mAbs). Method(s): In this prospective multicenter study on 292 pwMS and 46 HC, who had all received two vaccinations, SARS-CoV-2 IgG response was measured in the month before and 2-4 months after booster vaccination. PwMS were categorized as follows: untreated (N-DMT, n=32), receiving disease-modifying therapy (DMT) with expected humoral response (er-DMT: interferon-beta preparations, glatiramer acetate, dimethyl fumarate, teriflunomide, natalizumab, cladribine, alemtuzumab;n=120) or no expected humoral response (nr-DMT: S1PMs, CD20mAb;n=140). Result(s): PwMS on nr-DMT had significantly lower median antibody levels before (12.1 U/ml [0.4-2500]) and after booster vaccination (305 U/ml [0.4-2500]) in comparison to other groups (p<0.001). We did not find differences in antibody levels after homologous (n=281;2500 [0.4-2500]) and heterologous (n=57;2500 [0.4-2500]) vaccination regime regardless of the DMT group. The DMT group (= -0.16;95% CI -34.88, -5.08;p=0.009) were associated with antibody levels after booster vaccination, while time to revaccination(6 months [1-13]) was not. After booster vaccination, seropositivity was reached in 75.8% and 82.2% of pwMS on anti-CD20 mAbs and S1PMs, respectively. Complete B-cell depletion significantly decreased the probability of seroconversion even after the third vaccination (OR 0.14;p=0.021), whereas time interval to last DMT intake and time to revaccination did not. Twenty-three patients reported a SARSCoV- 2 infection (3 N-DMT, 10 er-DMT, 10 nr-DMT), one being asymptomatic and the rest having a mild course. Conclusion(s): Humoral response to SARS-CoV-2 booster vaccination in pwMS is excellent. While reduced by S1PMs and CD20mAb, protective response is still expected in the majority of patients.
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Introduction: MS patients on highly-active disease-modifying treatment develop no or insufficient amounts of protective antibodies after vaccination against SARS-CoV-2, a matter of general concern. Besides the humoral response, the development of cellular vaccine response has not been reported. Aim(s): To assess SARS-CoV-2 spike protein-specific cellular immunity in those multiple sclerosis (MS) patients who remain seronegative in response to vaccination. Method(s): In our centre, patients with no antibodies against the Spike-protein after two oder three doses of a SARS-CoV-2 vaccine were offered additional testing with a commercially available SARS-CoV-2 Elispot assay. Result(s): All patients had been vaccinated using two or three doses of mRNA vaccines, according to national and international recommendations. To date, 10 patients on sphingosin-1 phosphate receptor modulators (S1PRM) were seronegative;none of these had SARS-CoV-2 specific T-cell reactivity. 12 patients on B cell depleting therapy were seronegative;in contrast to S1PRM treated patients, seronegative patients on B-cell depleting therapy showed a measurable T-cell based vaccine response. Conclusion(s): In patients on S1PRM, absence of mRNA-vaccine induced SARS-CoV-2 antibodies corresponds to a lack of cellular response, while on B cell depletion, seronegativity provides only partial assessment of vaccine response. Analyses in patients who decide to get a booster vaccination are ongoing. The differential cellular response in MS patients on DMT targeting trafficking of all lymphocytes (S1PRM) vs depleting select lymphocyte populations might be expected.
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Preeclampsia (PE), new onset hypertension (HTN) during pregnancy, is associated with placental ischemia and chronic inflammation that includes increased CD4+ T cells, B cells secreting agonistic autoantibodies against the angiotensin II type 1 receptor (AT1AA), and activation of the complement system. Previous studies have shown AT1-AA is produced in patients with COVID-19 infection. Interestingly, having had COVID-19 during pregnancy is associated with increased incidence of developing a PE phenotype during pregnancy. We have previously shown an important role for B cell depletion or AT1AA inhibition to attenuate HTN in rat models of PE. Collectively, this data suggests B cells contribute to PE development and that B cells may increase incidence of PE in patients with a history (Hx) of COVID-19 during pregnancy through production of the AT1AA. We hypothesize B cells from PE or CV Hx PE patients produce AT1AA resulting in HTN and complement activation in pregnancy. Placental B cells were isolated from normal pregnant (NP), PE, normotensive (NT) CV Hx, or PE CV Hx patients at delivery. B cells were transferred i.p. into pregnant athymic rats at gestation (GD) 12. On GD18, carotid catheters were inserted. On GD19, blood pressure was measured and tissues collected. PE B cell recipients had increased Mean Arterial Pressure (MAP) (115+/-3 mmHg n=6) compared to NP B cell recipients (97+/-4 mmHg n=6 p<0.05). PE B cell recipients had increased AT1AA (20+/-2 DELTABPM n=4) compared to NP B cell recipients (6+/-1 DELTABPM n=4 p<0.05). PE B cell recipients had increased markers of complement activation such as reduced plasma C4 (1302+/-169 mug/mL n=4) and C3 (516+/-45 mug/mL n=4) compared to recipients of NP B cells (2348+/-338 mug/mL n=4 p<0.05) and (790+/-66 mug/mL n=4 p<0.05) respectively. CV Hx PE B cell recipients had elevated MAP (108+/-3 mmHg n=4) compared to CV Hx NT B cell recipients (101+/-7 mmHg n=4) and increased AT1AA (24+/-3 DELTABPM n=3) compared to CV Hx NT B cell Recipients (4+/-1 DELTABPM n=4 p<0.05). Collectively, this study demonstrates an important role for B cells to cause HTN during pregnancy;and indicates that B cells contribute to a higher incidence of PE in women with a Hx of CV infection during pregnancy possibly by secreting AT1-AA.
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SESSION TITLE: Pulmonary Manifestations of Infections SESSION TYPE: Case Reports PRESENTED ON: 10/17/2022 03:15 pm - 04:15 pm INTRODUCTION: Diffuse alveolar hemorrhage (DAH) due to an undiagnosed autoimmune condition is rare and can be life-threatening. Veno-venous extracorporeal membrane oxygenation (VV-ECMO) has been described as a viable rescue therapy in severe cases, providing time to establish a diagnosis and begin remission induction therapy (1). We report a patient who presented during the Omicron surge with hypoxemic respiratory failure due to pulmonary hemorrhage ultimately diagnosed with antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) who was supported with VV-ECMO without systemic anticoagulation. CASE PRESENTATION: A 46-year-old woman presented with subacute fatigue and two days of cough and brown sputum. She was found to have normocytic anemia (hemoglobin 3.5 g/dL), renal failure (serum creatinine 17.4 µmol/L), and bilateral pulmonary infiltrates on chest roentgenogram. Though vaccinated, nasal molecular testing detected SARS-CoV-2. She was intubated for progressive hypoxic respiratory failure and bronchoalveolar lavage fluid was consistent with DAH. She received empiric antibiotics, remdesivir, and pulse dose intravenous methylprednisolone as well as continuous renal replacement therapy and plasma exchange. Due to refractory hypoxemia she was cannulated for VV-ECMO. Systemic anticoagulation was deferred due to concerns that it may exacerbate her underlying pathology and due to a small subcortical bleed seen on computed tomography of the head. Perinuclear ANCA (titer >1:1280) was confirmed by immunofluorescence analysis with elevated myeloperoxidase serologies and cyclophosphamide was initiated. Glomeruli with cellular crescent formation consistent with AAV was later identified on renal biopsy. Her course was complicated by recurrent DAH while tapering steroids and an iliac vein thrombus, extracted during decannulation. Her respiratory failure resolved and she was discharged to rehab. DISCUSSION: Traditionally, VV-ECMO obligates systemic anticoagulation to prevent circuit thrombosis, however this may be viewed as a barrier to its use in patients with prohibitive bleeding risk and may contribute to the therapy's overall morbidity. Some institutions have begun to demonstrate the safety of ECMO with low- or prophylactic doses of anticoagulation (2), but this practice remains controversial. Detection of SARS-CoV-2 posed diagnostic and management challenges and its significance to this case remains uncertain. There are many past examples of infectious triggers for both DAH and AAV, and there is emerging evidence for an association between SARS-CoV-2 and ANCA (3). Concerns regarding the risk of B-cell depletion influenced the selection of remission induction therapy. CONCLUSIONS: In the case described, a patient with severe DAH was successfully supported with VV-ECMO. Withholding systemic anticoagulation did not prevent recurrent bleeding and may have contributed to a deep vein thrombosis. Reference #1: Arnold S, Deja M, Nitschke M, Bohnet S, Wallis S, Humrich JY, Riemekasten G, Steinhoff J, Lamprecht P. Extracorporeal membrane oxygenation in ANCA-associated vasculitis. Autoimmun Rev. 2021 Jan;20(1):102702. doi: 10.1016/j.autrev.2020.102702. Epub 2020 Nov 11. PMID: 33188916. Reference #2: Kurihara C, Walter JM, Karim A, et al. Feasibility of Venovenous Extracorporeal Membrane Oxygenation Without Systemic Anticoagulation. Ann Thorac Surg. 2020;110(4):1209-1215. doi:10.1016/j.athoracsur.2020.02.011 Reference #3: Kadkhoda, K., Laurita, K. Antineutrophil cytoplasmic antibodies and their association with clinical outcomes in hospitalized COVID-19 patients. Cell Death Discov. 7, 277 (2021). DISCLOSURES: No relevant relationships by Nathaniel Nelson No relevant relationships by Radu Postelnicu no disclosure on file for Antonio Velez;
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Background: Immunodeficient (ID) patients are among risk groups for severe disease after SARS-CoV2 (CoV2) infection. Despite high population immunity, ID patients remain difficult to medically advice due to their impaired immunity during an evolving CoV2 strains pandemic. Aim: We examined if durable immunisation to CoV2 infection or vaccination is developed. Serology cannot answer this since IgG replacement therapy now contains CoV2 antibodies. Instead, a cellular diagnostic test for patients' CoV2 memory T cells was used Methods: We included 13 ID patients (aged 34-78;7 female) who were vaccinated against CoV2 or previously infected: 5 with common variable immunodeficiency (CVID) and 8 with B cell deficiency (BCD) due to anti-CD20 or BTK inhibition therapy. Peripheral blood mononuclear cells isolated from whole blood were cultured with CoV2 spike protein or peptides for 7 days, then measured for T cell activation markers by flow cytometry. Results: CoV2 spike specific CD4 or CD8 T cells were detectable in 7/8 BCD and all CVID patients. However, only 3/5 CVID and 6/8 BCD patients had both CD4 and CD8 T cell responses. Conclusion: Genuine CoV2 T cell responses are detectable with a cellular diagnostic test in CVID and BCD patients after immunisation. As ID patients are heterogenous, a diagnostic test for memory T cells against CoV2 gives clinicians evidence of a patient's own immune response beyond passive IgG replacement therapy. This aids in consulting advice for infection avoidance strategies and indication for urgent treatment with monoclonal antibodies against CoV2.
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Background: Rituximab (RTX) achieved high remission-induction and sustained maintenance rates for patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) [1], [2]. However, RTX is an expensive medication, which may potentially lead to serious side effects. Defning the best dose regimen for maintenance in AAV is still an unmet need. Objectives: The aim of the present study is to compare the effects of ultra-low dose RTX (500 mg or 1000 mg once per year) to standard low dose RTX (500 or 1000 mg twice per year) as remission-maintenance therapy in AAV patients. Methods: We included consecutive AAV patients (classifed as GPA and MPA [3]) referring to four different Rheumatology centers in Italy. We assessed all AAV patients who successfully achieved disease remission (BVASv3=0) with conventional RTX or cyclophosphamide regimens and have been subsequently treated with RTX for maintenance of remission. All included patients received at least three maintenance infusions with either 1000 mg or 500 mg, twice per year (standard low dose) or once per year (ultra-low dose). After a period of 18 months, we assessed the remission rate, damage (VDI), glucocorticoids intake, ANCA status, B-cells depletion and serum IgG levels. Results: From January 2011 to December 2021, 83 AAV patients (mean age 51±16, 49.4% female, 95.2% ANCA positive, 65.8% anti PR3, 34.2% anti MPO), 61 classifed as GPA and 22 MPA, achieved complete disease remission with conventional RTX induction regimen. After 7 [6-9] months, 29.9% patients started maintenance treatment with ultra-low dose RTX (once per year), while 70.1% patients with standard low dose (twice per year), for 18 months. No signifcant differences at baseline were noted between patients receiving ultra-low dose when compared to those treated with conventional low-dose. At the end of observation period, a disease fare was observed in 22.7% of the low-dose group, and 21.2% in those treated with the standard dose (p=0.881). Relapse-free survival was comparable between the two group (log-rank p=0.818, Figure 1). When comparing AAV patients treated with ultra-low dose regimen to those treated with low-dose, no differences were noted in negative ANCA rate (72.2% vs 67.1%, p=0.262), ANCA titer (0 [0-7.8] vs 0 [0-50] UI/mL, p=0.232), B-cells depletion rate (70.6% vs 75%, p=0.725), mean serum IgG (811 [146-922] vs 680 [429-861] mg/dL, p=0.367), mean daily glucocorticoid dosage (2.5 [0-5] vs 3.75 [0-5] mg/d, p=0.647), VDI (4 [1-5] vs 2 [1-4], p=0.098), hypogammaglobulinaemia rate (31.8% vs 36.5%, p=0.697) and deaths (4.5% vs 5.8%, p=0.831). Although not signifcant, patients treated with ultra-low dose had lower severe infection rate (10.5% vs 26.8%, p=0.154). Notably, in the all cohort 5 deaths were related to COVID19 pneumonia. Conclusion: Reduced exposure to RTX was not associated with an impaired efficacy of maintenance therapy in patients with AAV. Remission maintenance with ultra-low dose RTX is a safe and more cost-effective option.
ABSTRACT
Background: Immunocompromised patients are considered high-risk and prioritized for vaccination against COVID-19 (1). Furthermore, vaccination-induced CD4 and CD8 T-cell responses have been suggested to have a protective role in COVID-19 (2). If T-cell responses are diminished after vaccination in immuno-compromised individuals is not known to date. Objectives: To investigate cellular immunity following mRNA vaccination against COVID-19 in healthy individuals and patients undergoing B-cell depletion therapy. Methods: In this interim analysis of the CoVVac study (NCT04858607), we analyzed T-cell responses in autoimmune patients treated with B-cell depleting therapy (BD, n=41) and age-matched healthy controls (HCs, n=50) 3-4 weeks after the second dose of mRNA vaccination against COVID-19. Therefore, we isolated PBMCs and stimulated them with a peptide pool covering the spike protein in vitro. Reactive CD4 and CD8 T-cells were determined by staining for IFNg, TNFa, IL-2 and GzmB by fow cytometry. Anti-SARS-CoV-2 antibody assays targeting the receptor-binding domain (RBD) or trimeric S protein (TSP) were performed to elucidate concomitant B-cell responses. Results: We observed signifcant alterations in anti-SARS-CoV-2 antibody responses in our cohort, the frequency of IFNg+ and IL-2+ CD4 and CD8 T-cells was similar in BD patients and controls. On the other hand, TNFa+ CD4 T-cells were signifcantly enriched in healthy controls versus BD patients (p=0.017) and correlated signifcantly with antibody titres (p=0.003). Similarly, GzmB+ CD8 T-cells were signifcantly diminished in our patient cohort (p<0.001) and also showed a signifcant correlation with antibody titres (p<0.001). Overall, the frequency of GzmB+ CD8 T-cells correlated very well with reactivity of T-cell subsets for other cytokines. This effect, however, is lost in the BD cohort. No difference was observed in the frequency of TNFa+ CD8 T-cells between the groups. Only 21 (42%) healthy individuals and 14 (34%) patients showed reactive T-cells for all the cytokines tested. This observation is mainly explained by a lack of cytokine production of CD8 T-cells in 26 (52%) HCs and 27 (66%) BD patients. In turn, 22 (44%) HCs and 17 (42%) patients didn't show any IL-2 producing CD8 cells. Of note, only 2 (4%) of HCs showed no GzmB+ CD8 T-cells whereas the number increased to 15 (37%) of BD individuals (p<0.001). In contrast, 42 (84%) HCs as well as 32 (78%) of patients showed production of all IFNg, TNFa and IL-2 in CD4 T-cells. Conclusion: Our data suggest that most patients with B-cell depleting therapy are able to mount T-cell responses similar to those of healthy individuals while a minority of these patients did not show complete immunity against SARS CoV-2. Further analyses are needed to better understand a possible link of B-cell depletion therapy and CD8 T-cell responses.
ABSTRACT
Background: At the beginning of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease 2019 (COVID-19) pandemic, the influence of anti-infammatory therapy on the course of SARS-CoV-2 infection in patients with infammatory rheumatic diseases (IRD) was unknown. In the meantime, several data indicate an association of severe courses of COVID-19 with the use of ritux-imab (RTX). Objectives: To gather further knowledge about SARS-CoV-2 infections in RTX-treated IRD patients, data from the German COVID-19-IRD-registry were analysed. Methods: Hospitalisation was used as a surrogate of COVID-19 severity. Baseline characteristics, disease features, medication and outcome of COVID-19 were compared in RTX-treated inpatients and outpatients. Results: In total, 3592 cases were reported in the registry, which included 130 RTX patients (3.6%) for our analysis. RTX-treated inpatients were older than RTX-treated outpatients (median age 63 y vs 56 y, p=0.007). Patients with granulomatosis with polyangiitis treated with RTX (n=32) showed a significant higher COVID-19 related hospitalisation rate (33% vs 11%, p=0.005), which was not the case for patients with rheumatoid arthritis (49% vs 50%). Cardiovascular comorbidities were reported more frequently in hospitalised RTX-treated patients (20% vs. 6%, p=0.032). More than 50% of the RTX-treated inpatients developed COVID-19 related complications, e.g. acute respiratory distress syndrome. The median time period between the last RTX treatment and SARS-CoV-2 infection was shorter in inpatients than in non-hospitalised patients (3 (range 0-17) vs. 4 months (range-29), p=0.039). The COVID-19 related mortality rate was 14% (n=19) in RTX-treated IRD patients. In RTX-treated inpatients and outpatients, there were no relevant differences with respect to the use of concomitant glucocor-ticoids or other disease modifying anti-rheumatic drugs, disease activity, median last RTX dose or median number of immunomodulatory drugs prior to RTX treatment. Conclusion: In addition to general risk factors, such as age and comorbidities, it is already known that IRD patients treated with RTX show a higher rate of severe COVID-19. In our registry, RTX-treated patients with granulomatosis with polyangiitis appear to be at even higher risk to develop severe COVID-19 compared to other IRD. Moreover, the shorter the time since the last RTX treatment, the higher seems to be the risk of developing severe COVID-19. This might be explained by a more profound B-cell depletion in the frst weeks after RTX treatment warranting further studies.
ABSTRACT
Background: As rituximab (RTX) is a B-cell depleting agent, there are concerns regarding its safety during the COVID pandemic. Data from registries during pre-vaccination period reported increased risk of poor outcomes in RTX-treated patients vs TNFi. However, registry data could be limited by reporting bias in determining true incidence. There are also limited data on breakthrough infections following COVID vaccination. Objectives: To assess the incidence of breakthrough infections and predictors of severe COVID outcomes in RTX-treated autoimmune rheumatic diseases (ARDs) with a view to establishing a treatment algorithm for safe RTX administration. Methods: An observational cohort study was undertaken in the frst consecutive 300 ARD patients in a single centre between index date 01/09/2019 (i.e. 6 months prior to pandemic) and 31/01/2022. Only PCR positive cases were included. COVID outcomes were categorised as Mild (i.e. not hospitalised) or Moderate/Severe (i.e. hospitalised and requiring at least oxygenation or death). Predictors of moderate/severe outcomes were analysed using Cox-regression proportional hazard. Results: Mean (SD) at index date was 59 (14) years, 226/300 (75%) patients were female and 254 (85%) were Caucasians. The diagnoses were RA=212 (71%), SLE=33 (11%), AAV=26 (9%), Sjogren=9 (3%), IIM=8 (3%) and others=12 (4%). Therapy included concomitant DMARDs = 205 (68%) and oral prednisolone = 84 (28%). Median (range) no. of previous RTX courses was 4 (0-19). 534 RTX courses were administered. Of 294 patients with available vaccine data, 17 (6%) were unvaccinated, 4 (1%) had a single dose, 47 (16%) were double-vaccinated, 217 (74%) triple-vaccinated and 9 (3%) quadruple-vaccinated. Of those who were vaccinated, for the frst dose, 11% were given within 12 weeks post-RTX, 15% within 26 weeks and 74% were >26 weeks post-RTX. The rate of overall COVID and moderate/severe infections were 11.2/100 PYs and 2.6/100 PYs respectively. Vaccinated patients had lower rate of moderate/severe infection (2.6/100 PYs) vs unvaccinated (18.6/100 PYs) [Table 1]. Over 650.7 PY follow-up, 17/300 patients (5.7%) had moderate/severe COVID including 2 deaths. Factors associated with time-to-infection in imputed multivariable analysis were number of comorbidities [HR 1.46 (95% CI 1.05-2.04)] and low IgG (<6g/L) [6.15 (1.95-19.41)]. A history of COVID vaccination reduced risk [HR 0.13 (0.03-0.51)]. Demographics including concomitant predni-solone, RTX-and vaccine-associated factors (e.g. RTX dose, time from RTX to vaccine, vaccine mode, peripheral B-cell depletion) were not predictive. Conclusion: The rate of moderate/severe COVID infection in this cohort is comparable to the pre-pandemic severe infection rate in rituximab trials in RA. The high vaccination uptake in our cohort was effective in preventing severe infection despite the termination of national shielding programme in March 2021 and the spread of the Delta and Omicron variants. Individualised risk-beneft assessment should be undertaken in those with comorbidities, low IgG and unvacci-nated when scheduling rituximab therapy.