ABSTRACT
Background: COVID-19 vaccination has been suggested as very effective in patients with Inflammatory Bowel Disease (IBD), but most studies assess antibody levels within a few weeks after vaccination and do not use the most recent recommendations as seroconversion cut-off. The objective of VACOVEII study is to evaluate the antibody response to vaccination at 6 months using these recommendations, the improvement after a booster dose and the effect of the immunosuppressive therapy (IST). We present the intermediate results of the study. Method(s): Spanish multicentre, prospective and case-control study. 18 years or older IBD patients fully vaccinated against COVID-19 were included. Those with previous COVID infection were not included, but not excluded for the next analyses if the infection was subsequent. Main outcomes were anti-SARS-CoV-2 spike protein antibody (anti S) concentrations and rate of seroconversion (defined above the protection threshold of 260 BAU/mL), measured 6 months after vaccination at a single centralized laboratory. The effect of IST on the main outcomes was analysed, adjusted by age, vaccine type and COVID infection. Groups of treatment considered for the analysis were: Patients without IST (without treatment or under salicylates alone), anti-TNF in combination with immunomodulators (IMM), anti-TNF in monotherapy, IMM in monotherapy, ustekinumab and anti-integrin. Result(s): We included 313 patients with IBD (46.5% ulcerative colitis and 52.3% Crohn's disease, median age 49 years) vaccinated either with non-mRNA vaccines (14%) or mRNA vaccines (86%). Baseline therapy was: 124 patients without IST, 21 with anti-TNF plus IMM, 67 with anti-TNF in monotherapy, 54 with IMM in monotherapy, 28 with ustekinumab and 19 with anti-integrin. Mean anti S concentrations were significant lower in patients with anti-TNF compared with patients without IST (Figure 1). In multivariable analysis, lower antibody concentrations were independently associated with anti-TNF treatment, non-mRNA vaccines and older age. Within the patients with no COVID infection during the follow-up, we found very low rates of seroconversion in patients with anti-TNF (14.1%), ustekinumab (30.8%) and IMM in monotherapy (34.9%), compared with patients without IST (51.5%) (Table 1). In multivariable analysis, anti-TNF treatment, non-mRNA vaccines and older age were independently associated with lower rates of seroconversion, as well as ustekinumab and IMM in monotherapy (Table 2). Conclusion(s): COVID-19 vaccine-induced antibody seroconversion in patients with IBD, measured at 6 months and according to >260 BAU as protection threshold, is clearly lower than previously reported, with a profound impact by some IST therapies, mainly anti-TNF, besides age and type of vaccine.
ABSTRACT
Background: Azathioprine is a purine analog metabolized to 6- mercaptopurine (6-MP) utilizing glutathione. Its high oral bioavailability and longer duration of action make it viable as a treatment for ulcerative colitis or as an anti-rejection medication for renal transplant patients. Specific experience in overdose with this agent is limited although toxicity mimics 6-MP including hepatotoxicity, delayed leukopenia, and acute interstitial nephritis. Case report: A 46 year old female (64 kg) with a history of ulcerative colitis, migraines, and anxiety presented with a selfreported intentional ingestion of 1000mg azathioprine and presented to care approximately 8 h post-ingestion. Her compliance with azathioprine preceding the ingestion was unclear. She reported taking her other medications as prescribed (tadalafil, sulfasalazine, fioricet, alprazolam) the day prior to presentation. Other than one episode of emesis without pill fragments, myalgias, headache she had no other symptoms. Her presenting vital signs were HR 84, RR 22, BP 90/63, T 36.2 degreeC. Initial labs included a normal chemistry profile, undetectable serum acetaminophen and salicylates, an ethanol level of 50 mg/dL and venous lactate of 1.6mmol/L. She received a total of 3 L of crystalloid IV fluids with improvement in blood pressure to 125/66 and was transferred for higher level of care. Due to the delay in presentation and well appearance, activated charcoal and hemodialysis were considered but deferred. While inpatient she had laboratory evaluation including CBC and differential every 8 h. In the ED she developed a fever, 38.1 degreeC. PCR testing for COVID-19 was negative. Whole blood thiopurine metabolites (Prometheus Biosciences, Test 3200) were sent approximately 33 h from time of ingestion. 6-thioguanine levels were 108 pmol/8x10degree8 RBC, below the therapeutic reference range (230-400 pmol/8x10degree8 RBC). 6-methylmercaptopurine metabolites were below the lower limit of quantification (761pmol/8x10degree8 RBC). Genetic testing for thiopurine S-methyltransferase was declined by the patient. She was hospitalized for 4 days and did not develop any substantial vital sign abnormalities or creatinine elevation. Her absolute neutrophil count dropped to 500/mm3 approximately 76 h post-ingestion, but started to improve 84 h post-ingestion and granulocyte-macrophage colony-stimulating factor was deferred. Her peak AST was 113 IU/L, approximately 46 h post-ingestion and returned to normal (16 IU/L) upon follow-up 7 days postingestion. White blood cell count 7 days post-ingestion was 4.3 K/mm3. Discussion(s): Azathioprine overdose is rarely reported in the literature. Case reports describe delayed leukopenia and hepatotoxicity from repeat supratherapeutic ingestions, however, based upon limited experience serious toxicity from single acute ingestions appears rare. A report of a single acute ingestion of 7500mg of azathioprine resulted in moderate leukopenia (4.1 K/ mm3) 3 days post-ingestion. Peak immunosuppressive effects can take up to 2 weeks from initiation or change in dose. Symptoms in this case are consistent with effects from azathioprine including vomiting, transient hypotension, and myalgias. Conclusion(s): Intentional ingestions of azathioprine are infrequently reported and can result in serious delayed myelosuppression. We report a case of a single acute ingestion of >15 mg/kg resulting in delayed myelosuppression managed conservatively.
ABSTRACT
Background This study aimed to compare the risk of COVID-19 in patients with IBD versus the general population, and to evaluate predictors of infection acquisition, progression to severe forms, and risk of developing persistent COVID-19. We also assess the differences between cases across the different COVID-19 pandemic waves in our target population. Methods This single-center prospective, cohort study included consecutive IBD patients diagnosed of COVID-19 either by a positive polymerase chain reaction test and/or antigen test in nasopharyngeal swabs, or by anti-SARS-CoV-2 antibodies, and that they had a followup of at least 4 months. Using logistic regression, we evaluated cases versus IBD controls included in the IBD Unit database for predictors of COVID-19 acquisition. COVID-19 cases were distributed according to pandemic waves. Cox regression analysis was used for predictors of severe and persistent COVID-19. Results By May 31, 2021, 160 out of 1911 IBD patients (8.3%) were diagnosed with COVID-19. IBD patients had a similar adjusted incidence of COVID-19 (OR 0.94;95% CI 0.86-1.02;P=0.42), and a similar associated mortality ratio (OR 0.83;95% CI 0.6-1.06;P=0.48), compared to the general population. In multivariable analysis, treatment with biologics was associated with a higher risk (OR 2.22, 95% CI 1.54-3.2, P<0.001), and treatment with salicylates with a lower risk (OR 0.71, 95% CI 0.50-0.99, P=0.048) of contracting COVID-19. Sixty-two COVID-19 cases were diagnosed during the first wave of pandemic (until the end of June 2020), and 54 and 44 cases during the second and third waves (until the end of December 2020 and May 2021, respectively). (Figure 1) In multivariate analysis, first wave cases were associated with a higher risk of progression to severe forms of infection (OR 4.76, 95% CI 1.83-12.37, P= 0.001), and development of persistent COVID-19 (OR 2.4, 95% CI 1.16-4.95, P=0.018). Twenty-nine patients (18.1%) required hospitalization and were classified as severe COVID- 19, which was associated in multivariable analysis with age>48 (HR 3.68, P=0.007), cases diagnosed in the first wave (HR 6.04, P<0.001), and comorbidities (evaluated with Duke Severity of Illness Checklist [DUSOI], P<0.001). (Table 1) During a median follow-up of 8.4 months, 68 patients (42.5%) were diagnosed with persistent COVID-19. Multivariable analysis identified UC (OR 2.00, 95% CI 0.99-4.03, P=0.053), comorbidities (P=0.090), and being diagnosed during the first wave (OR 2.48, 95% CI 1.23-5.00, P=0.011) as risk factors for persistent COVID-19. Conclusion IBD patients have a similar risk of COVID- 19 and associated mortality as the general population. Cases diagnosed during the first wave of the pandemic had severe and persistent forms of COVID-19 more frequently. Age and comorbidity were the main risk factors for severe forms of the disease. (Figure Presented) (Table Presented)
ABSTRACT
Background: The severe acute respiratory syndrome coronavirus, 2 (SARS-COV-2) infection may lead to the development of the novel coronavirus disease, 2019 (COVID-19). Currently, little to no data is available regarding safety and efficacy of SARS-COV-2 vaccination in Inflammatory Bowel Disease (IBD) patients, which may present differences between subgroups, as these patients may exhibit impaired innate and adaptive immune system responses. Lower immunological response could, in this specific population, require an additional booster injection. Methods: We conducted a prospective study including adult patients with Crohn's disease (CD) and Ulcerative Colitis (UC) who have undergone complete vaccination against SARS-COV-2 infection with BioNTech® vaccine. Patients with previous SARS-COV-2 infection were excluded. Medical data regarding age, sex, IBD classification and current medication for IBD were collected. A control group with healthy individuals matched for age and sex was also analyzed. Blood samples were collected, 30 days after complete vaccination to quantify IgG antibody titers for SARS-COV-2 in both groups (IBD and non-IBD). Results: Our final sample included, 81 IBD and, 32 non-IBD patients, 55 (48.7%) of them females, with a mean age of, 40.2±13.0 years. From the IBD patients, 58(71.6%) had CD and, 23(28.4%) had UC. IBD patients had significantly lower anti-SARS-COV-2 IgG levels when compared to the control group (8950±9366 vs, 14834±11679 AU/mL;p=0.003). Regarding IBD medication, significant lower levels of SARS-COV-2 IgG antibodies when compared to control patients were found in patients under thiopurines (9074±9779 AU/mL;p=0.011);methotrexate (1987±2568 AU/mL;p=0.002);infliximab (7208±7276 AU/ mL;p=0.001);and corticosteroids (1065±933 AU/mL;p=0.001). Additionally, patients under combined therapy (infliximab plus thiopurines) presented with significantly lower antibodies titers when compared to patients treated with thiopurines in monotherapy (8130±11048 vs, 10563±5680 AU/mL;p=0.039). No significant differences were found in IBD patients under salicylates (10195±7371 AU/mL;p=0.226);adalimumab (15644±21467 AU/mL;p=0.336);vedolizumab (10464±9087 AU/mL;p=0.286) and ustekinumab (11366±10016 AU/mL;p=0.390). Conclusion: IBD patients presented with significantly lower anti- SARS-COV-2 IgG levels, 1 month after complete vaccination against SARS-COV-2 infection compared to healthy controls. Thiopurines, methotrexate, infliximab and corticosteroid treatment were associated with significantly lower antibodies levels. These findings may express the benefit of an additional booster injection in this population.
ABSTRACT
Background: This study aimed to compare the risk of COVID-19 in patients with IBD versus the general population, and to evaluate predictors of infection acquisition, progression to severe forms, and risk of developing persistent COVID-19. We also assess the differences between cases across the different COVID-19 pandemic waves in our target population. Methods: This single-centre prospective, cohort study included consecutive IBD patients diagnosed of COVID-19 either by a positive polymerase chain reaction test and/or antigen test in nasopharyngeal swabs, or by anti-SARS-CoV-2 antibodies, and that they had a follow-up of at least 4 months. Using logistic regression, we evaluated cases versus IBD controls included in the IBD Unit database for predictors of COVID-19 acquisition. COVID-19 cases were distributed according to pandemic waves. Cox regression analysis was used for predictors of severe and persistent COVID-19. Results: By May 31, 2021, 160 out of 1911 IBD patients (8.3%) were diagnosed with COVID-19. IBD patients had a similar adjusted incidence of COVID-19 (OR 0.94;95% CI 0.86-1.02;P=0.42), and a similar associated mortality ratio (OR 0.83;95% CI 0.6-1.06;P=0.48), compared to the general population. In multivariable analysis, treatment with biologics was associated with a higher risk (OR 2.22, P<0.001), and treatment with salicylates with a lower risk (OR 0.71, P=0.048) of contracting COVID-19.(Table 1) 62 COVID-19 cases were diagnosed during the first wave of pandemic (until the end of June 2020), and 54 and 44 cases during the second and third waves (until the end of December 2020 and May 2021, respectively).(Figure 1) In multivariate analysis, first wave cases were associated with a higher risk of progression to severe forms of infection (OR 4.76, 95% CI 1.83-12.37, P=0.001), and development of persistent COVID-19 (OR 2.4, 95% CI 1.16-4.95, P=0.018). 29 patients (18.1%) required hospitalisation and were classified as severe COVID-19, which was associated in multivariable analysis with age>48 (HR 3.68, P=0.007), cases diagnosed in the first wave (HR 6.04, P<0.001), and comorbidities (evaluated with Duke Severity of Illness Checklist [DUSOI], P<0.001).(Table 2) During a median follow-up of 8.4 months, 68 patients (42.5%) were diagnosed with persistent COVID-19. Multivariable analysis identified UC (P=0.053), comorbidities (P=0.090), and being diagnosed during the first wave (P=0.011) as risk factors for persistent COVID-19.(Table 3) Conclusion: IBD patients have a similar risk of COVID-19 and associated mortality as the general population. Cases diagnosed during the first wave of the pandemic had severe and persistent forms of COVID-19 more frequently. Age and comorbidity were the main risk factors for severe forms of the disease.
ABSTRACT
We report the design and synthesis of a series of new 5-chloropyridinyl esters of salicylic acid, ibuprofen, indomethacin, and related aromatic carboxylic acids for evaluation against SARS-CoV-2 3CL protease enzyme. These ester derivatives were synthesized using EDC in the presence of DMAP to provide various esters in good to excellent yields. Compounds are stable and purified by silica gel chromatography and characterized using 1H-NMR, 13C-NMR, and mass spectral analysis. These synthetic derivatives were evaluated in our in vitro SARS-CoV-2 3CLpro inhibition assay using authentic SARS-CoV-2 3CLpro enzyme. Compounds were also evaluated in our in vitro antiviral assay using quantitative VeroE6 cell-based assay with RNAqPCR. A number of compounds exhibited potent SARS-CoV-2 3CLpro inhibitory activity and antiviral activity. Compound 9a was the most potent inhibitor, with an enzyme IC50 value of 160 nM. Compound 13b exhibited an enzyme IC50 value of 4.9 µM. However, it exhibited a potent antiviral EC50 value of 24 µM in VeroE6 cells. Remdesivir, an RdRp inhibitor, exhibited an antiviral EC50 value of 2.4 µM in the same assay. We assessed the mode of inhibition using mass spectral analysis which suggested the formation of a covalent bond with the enzyme. To obtain molecular insight, we have created a model of compound 9a bound to SARS-CoV-2 3CLpro in the active site.