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1.
Mediterranean Journal of Infection, Microbes and Antimicrobials ; 11(1) (no pagination), 2022.
Article in English | EMBASE | ID: covidwho-2066934

ABSTRACT

Introduction: Severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) antibodies are produced in persons who have been infected by the virus or have received the vaccine. Many features of these antibodies, including their dynamics and neutralization capacities, are still unclear. Understanding the immune response of the host is very important for the development of appropriate treatment methods, vaccines, and epidemiological control strategies. The present study aimed to monitor the change in antibody levels over time in individuals diagnosed with SARSCoV- 2 infections and to determine their neutralization capacity. Material(s) and Method(s): Anti-nucleocapsid and anti-spike antibody titers were measured using different kits on monthly obtained serum samples of patients of patients with SARS-CoV-2 infection. The neutralizing antibodies were evaluated using a microneutralization assay. Result(s): A total of 134 serum samples taken from 43 patients with a mild-moderate disease course were analyzed. Anti-spike antibody positivity was detected on day seven at the earliest and day 334 at the latest following a positive polymerase chain reaction (PCR) test. The mean antibody levels were observed to increase gradually to a peak after three months, and then started to decrease after month six. Anti-nucleocapsid IgM and IgG antibodies were detected alone or in combination. The highest neutralizing antibody titer was 1/80 in the first month, which was seen to drop below 1/10 after four months. Conclusion(s): The combined use of kits for the detection of antibodies against different antigens or testing total antibodies would result in a more accurate and earlier detection of the antibodies that start to emerge on the seventh day and decrease six months after SARS-CoV-2 PCR positivity. In addition, the dramatic decrease in neutralizing antibody titers after four months may be one of the causes of early reinfections. Copyright © 2022 by the Infectious Diseases and Clinical Microbiology Specialty Society of Turkey.

2.
Journal of Clinical and Diagnostic Research ; 16(9):ED01-ED03, 2022.
Article in English | EMBASE | ID: covidwho-2067193

ABSTRACT

Sickle Cell Disease (SCD) is an inherited disorder with variable clinical presentation and low immunity. Coronavirus Disease-2019 (COVID-19)is a pandemic disease with a high-risk in chronic disease patients and older adults. SCD is widely distributed in Sudan;many SCD patients are infected with COVID-19. Despite this, no published data is available. This case report demonstrated the haematological and clinical course of a Sudanese sickle cell anaemia patient with COVID-19. A 20-year-old male patient was admitted to a hospital for 15 days. Demographic and clinical data were obtained from his medical records. A blood sample was taken at the time of admission and during hospitalisation. Tests were performed during admission, including Complete Blood Count (CBC), liver function test, renal function test, coagulation studies, viral screening, and urine general. The patient was diagnosed with COVID-19 using the Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) test based on the nasopharyngeal swab and COVID-19 IgG and IgM using Enzyme Linked Immunosorbent Assay (ELISA) for the previous infection. The patient received intravenous fluids, antibiotics, analgesia, oxygen supplementation, and blood transfusion two times during hospitalisation, and there was no need for Intensive Care Unit (ICU) admission. The patient's prognosis was good;he was discharged on day 16 with no symptoms and a negative result of the COVID-19 PCR test. A severe illness was expected because he was infected twice by COVID-19, the patient showed mild clinical symptoms with a good prognosis, so further studies are required to understand COVID-19 among Sudanese SCD patients.

3.
American Journal of Transplantation ; 22(Supplement 3):1059, 2022.
Article in English | EMBASE | ID: covidwho-2063485

ABSTRACT

Purpose: The purpose of this study was to evaluate long term humoral and cellular immunity generated following SARS-CoV-2 infection in solid organ transplant recipients (SOTR). Method(s): Patients included had an active graft of an organ transplant as an adult, a positive polymerase chain reaction nasopharyngeal swab for SARS-CoV-2 after transplant, and had not received convalescent plasma, vaccination, or monoclonal antibody for SARS-CoV-2. Whole blood was obtained 6 months (+/- 1 month) after infection. Serology measured IgG and IgM titer to the SARS-CoV-2 spike protein receptor binding domain, reported as signal/ cut-off ratio (s/co). CD4+ and CD8+ T-cell reactivity was measured by Activation Induced Marker assays following stimulation of peripheral blood mononuclear cells with SARS-CoV-2 peptide pools encompassing the SARS-CoV-2 spike protein. Result(s): Of 25 subjects, 19 (76.0%) were hospitalized, 4 (16.0%) developed hypoxia, but none required mechanical ventilation. Biopsy-proven graft rejection occurred in 3 (12.0%), but none had graft loss. At 6 months, 8 (16%) had persistent symptoms and 2 (4.0%) were re-infected within one year. In the immunity study, 22 (88.0%) had reactive IgG testing and 11 (44.0%) had reactive IgM testing. Median IgG titer was 3.68 s/co (range 0.19-36.44) and IgM titer was 0.79 s/co (range 0.02-16.41). Virus-specific CD4+ T-cell reactivity was noted in 23 (92%), but only 10 (40.0%) had reactive CD8+ T-cell testing. Moderate correlation was observed between IgG and IgM titer (r=.51, p= 0.009) and between IgG titer and percent virus-specific CD4+ T-cells (r=.46, p=0.02). CD8+ T-cell reactivity was correlated with greater illness severity (p=0.043). Use of Tacrolimus, mycophenolate, or corticosteroids at time of infection was not associated with T-cell or antibody reactivity. Conclusion(s): In summary, this cohort of SOTR evaluated six months after noncritical COVID-19 illness demonstrated robust IgG and CD4+ T-cell responses, and CD8+ T-cell reactivity was correlated with higher disease severity.

4.
American Journal of Transplantation ; 22(Supplement 3):709, 2022.
Article in English | EMBASE | ID: covidwho-2063451

ABSTRACT

Purpose: To determine if HLA allo-antibody levels are affected by COVID-19 in renal transplanted patients and to compare the immunoglobulin class and subclass profiles as well as the epitope binding patterns of anti-HLA and anti-SARS-CoV-2 antibodies. Method(s): A cross-sectional study of 46 kidney transplant recipients diagnosed with PCR+ SARS-CoV-2 infection was conducted. Serum samples were collected at the time of infection. For 21 patients, we obtained historical anti-HLA antibody information before COVID-19. Using a single-antigen bead Luminex assay, we determined IgG, IgG1/2/3/4, IgM, and IgA antibodies against Class I and Class II HLA, as well as against five SARS-CoV-2 (Wuhan strain) protein fragments: nucleocapsid, whole spike (S), spike S1, spike S2 and spike receptor binding domain (RBD). Result(s): 26/46 subjects had anti-HLA antibodies of which fourteen had donorspecific anti-HLA antibodies (DSA) compared with 45/46 had anti-SARS-CoV2 antibodies. The majority of DSA were specific to HLA-DQ (10/14), with a dominant IgG/IgG1/IgG3 subclass prevalence. Anti-SARS-CoV-2 antibodies exhibited stronger reactivity towards S and RBD and had increased IgM (38/43, 79%) and IgA (41/42, 85%) prevalence when compared to DSAs (5/14, 35% and 2/14, 14%, p<0.001).Out of 21 patients with pre-COVID-19 data available, calculated panel antibody reactivity (cPRA) levels did not change after COVID-19 in 14 cases (67%);cPRA increased in two cases (10%), both of them with allograft nephrectomy and immunosuppression discontinuation, and decreased in five patients (20%) (from 65.4+/-12.6% before COVID-19, to 29.4+/-33.6% after COVID-19) (Figure 1). Patients with DSA exhibited significantly lower anti-S IgG (9453+/-9945 vs 17975+/-12792;P=0.001), anti-RBD IgM (4464+/-3693 vs 8751+/-6468;P=0.03) and anti-nucleoprotein IgA (998+/-835 vs 5476+/-6895;P=0.001) anti-SARS-CoV2 antibody MFI values than patients without DSA. Conclusion(s): cPRA values did not increase following PCR confirmed COVID-19 diagnosis in renal transplant recipients and those subjects with pre-existing DSA had lower antibody strength directed at SARS-CoV-2 antigens. The lack of increase in alloantibody response is quite remarkable, since over 80% of the patients underwent either significant reduction or withdrawal of mycophenolate mofetil after COVID-19 diagnosis. (Figure Presented).

5.
American Journal of Transplantation ; 22(Supplement 3):908, 2022.
Article in English | EMBASE | ID: covidwho-2063434

ABSTRACT

Purpose: To determine if IgM has a direct effect in preventing SARS-CoV-2 replication in Vero E6 cells, and delaying or preventing disease in infected K18- hACE2 mice. Method(s): 1) Vero E6 cells, grown to confluence in 12 well plates, were used to test the effect of IgM in reducing the number of plaque-forming units (PFU).There were 4 groups: a) 25PFU WA-1 SARS-CoV-2 was combined with 20, 5 or 0.8mug IgM in growth medium, and incubated for 1hr in a final volume of 500ul. 100mul was added to Vero E6 cells in replicate wells and incubated for 1hr;b) 100mul of 20, 5 or 0.8mug IgM was added to Vero E6 cells and incubated. Media was aspirated and the cells were then inoculated with 25PFU WA-1 and incubated for 1hr;c) Virus control - as above, but with no IgM;d) No virus or IgM. FBS growth medium containing Avicel was overlain in the wells and incubated for 48 hours. Virus replication was stopped by incubating with 10% buffered formalin. Following removal of formalin, plates were stained with Giemsa violet, dried, and photographed. 2) A COVID -19 Spike- ACE2 binding assay kit was used to determine if IgM (2ug, 4.5ug, 20ug, 45ug IgM) inhibits the interaction between the Spike-receptor binding domain (S-RBD) and Angiotensin I ConvertingEnzyme 2 (ACE2) receptor. 3) K18-hACE2 mice were divided into 3 groups based on treatment regimen;Group 1: with IgM, No virus;2: with Saline, with virus;3: with IgM, with virus. 35ug IgM was injected intraperitoneal in a single dose, 2 days prior to infection. Mice were innoculated intranasally with 1250 pfu of HK SARS-CoV-2. Result(s): 1) Exposure of 25PFU SARS-CoV-2 to IgM (at all concentrations) prior to incubation with Vero E6 cells, inhibited its replication in Vero E6 cells. When Vero E6 cells were incubated with IgM prior to infection, no plaques were seen in wells with 20ug and 5ug IgM but were observed in wells with 0.8ug IgM. Plaques were also observed in the Virus alone group, but none were seen in the 'No IgM-No virus' group. 2) 45ug IgM/100uls inhibited the binding of S-RBD to ACE2 by ~94-100%, 20ug IgM/100uls inhibited it by ~80%, and 2 or 4.5ug/100ul by ~70-75%. Control without IgM did not inhibit the S-RBD-ACE-2 binding. 3) Pretreatment with a single low dose IgM injection delayed weight loss and mortality. Conclusion(s): IgM inhibits the replication of SARS-CoV-2 in Vero cells in vitro. It also inhibits the interaction between S-RBD that is present on the viral surface and the ACE2 receptor, by binding to S-RBD. A single low dose of IgM given prechallenge delayed disease in infected mice. The discovery that IgM interferes with the formation of the S-RBD-ACE2 complex, and that a single low dose can delay disease, indicates its translational potential as a vaccine/therapeutic to prevent or treat COVID-19.

6.
American Journal of Transplantation ; 22(Supplement 3):1072, 2022.
Article in English | EMBASE | ID: covidwho-2063406

ABSTRACT

Purpose: Data showed seroconversion after different SARS-CoV-2 vaccination platforms might yield diminished response in transplant recipients. However, it is unknown whether different vaccination platforms could offer a specific grade of protection against SARS-CoV-2. Method(s): we prospectively studied adult kidney & liver recipients who received who had no previous COVID-19 infection, and received either ChAdOx1 or BNT- 162b2 vaccines between January 2021 to September 2021, with an assessment of IgM/IgG spike (S) antibodies. Result(s): Our cohort is composed of kidney (n=235) or liver (n=217) patients, who have received either ChAdOx1 (N=157) or BNT-162b2 (n=295). The response was higher with mRNA vaccine. Unresponsiveness is found to be mainly linked to diabetes and older age. Side effects were similar to those reported in clinical trials. Conclusion(s): mRNA vaccines might elicit a higher humoral immunity response as compared with ChAdOx1 in immunosuppressed transplant patients.

7.
American Journal of Transplantation ; 22(Supplement 3):570, 2022.
Article in English | EMBASE | ID: covidwho-2063352

ABSTRACT

Purpose: Seroconversion after a 2 doses of mRNA COVID-19 vaccine in kidney transplant recipients (KTR) ranges between 30 and 50% in different series. We previously demonstrated that a substantial proportion of KTRs (35%) without a humoral response, develops a cellular response after the second dose assessed by the ELISpot technique. We aim to study the evolution of both humoral and cellular response in the same cohort before and 1 month after the administration of the third dose of mRNA-1273 COVID-19 vaccine. Method(s): We included in the final analysis KTRs without evidence of previous exposure to COVID-19 and who were not infected during the course of the study and with complete data in all the time-points (n=105). The four time-points studied were at baseline before the first dose (T1), after the second dose (T2, 2 months) and before (T3, 6 months) and after (T4, 7 months) the administration of the third dose of 100mcg mRNA-1273 COVID-19 vaccine. In all the time points, IgG and IgM titre against protein S assessed by Luminex technique and cellular immunity assessed by N- and S-protein specific ELISpot were studied. Result(s): The percentage of patients with a positive humoral or cellular immunity against the S-protein were 24.8% and 51.4% after the second dose (T2). This percentages changed to 54.3% and 48.6% at 6 months (T3), respectively for IgG and S-ELISpot, in the absence of proven COVID-19. After the administration of the 3rd dose (T4) these percentages increased to 75.2% for IgG and 61.0% of S-ELISpot respectively. At multivariate analysis, the only factor that was positively associated with IgG development at T4 was S-ELIspot positivity after the 2nd dose (T2) [OR(CI) 3.14[1.10-8.96], p=0.032). Factors negatively associated with seroconversion were being transplanted during the last year [OR(CI) 0.23[0.07-0.80], P=0.021] and previous transplantation [OR(CI) 0.22[0.06-0.78], P=0.020). Conclusion(s): After a 3 doses-course of mRNA-1273 COVID-19 vaccine, three quarters of kidney transplant recipients developed finally IgG against protein S. Developing a cellular response after the second dose was positively associated with the final seroconversion, while being transplanted previously or being vaccinated during the first year after KT impacted negatively on the vaccine outcome.

8.
American Journal of Transplantation ; 22(Supplement 3):458-459, 2022.
Article in English | EMBASE | ID: covidwho-2063349

ABSTRACT

Purpose: The diverse factors affecting the vaccine induced neutralizing antibody response in solid organ transplant recipients and their immunity against CoV2 variants are needed to be well characterize to understand how we improve the vaccine efficacy. Method(s): Anti-CoV2 receptor binding domain (RBD) plasma antibody response and their neutralization potency in 29 kidney and 22 heart transplant patients was determined with recombinant RBD protein binding ELISA and by calculating the 50% virus neutralization titer of the plasma antibody with ACE2-Hu-HeLa cell based pseudo virus neutralization assay against CoV2 wild type and delta variant. Result(s): We detected strong binding and protective neutralizing plasma antibody response in SOTR who were infected with CoV-2 either prior to or after the first dose of vaccine (n=8), who showed high median IC50 value > 10,000 against both the CoV2 wild type strain and the more transmissible delta variant. In contrast to this, the CoV2 uninfected and vaccinated SOTR ( naive vaccinees, n=43) had considerably lower anti-RBD plasma antibody binding titers, and only 19% of this population possessed minimally protective neutralizing antibody titer (IC50 >50) against the wild type CoV2 strain, which further decreased to 10% against the delta variant. While IgG and IgA were dominant isotypes of anti-RBD antibody induced by the CoV2 vaccines and correlated significantly (r=0.84, p=<0.001) with the CoV2 neutralization. The COV2 uninfected SOTR vaccinees who were within 1.5 years from transplantation or African American ethnicity were less likely to have detectable vaccine induced neutralizing antibody responses than the other populations. In the naive vaccinees, administration of corticosteroids in combination with calcineurin or mTOR inhibitors and antimetabolites also negatively affected the CoV2 antibody responses, while female and younger organ transplant recipients tended towards higher IgM and IgA titers. Kidney transplant recipients showed better IgG responses vs heart transplant recipients and elevated serum creatinine levels correlated with poorer antibody response to the vaccines in both kidney and heart transplant groups. Conclusion(s): These results suggest that in the absence of immunity due to CoV2 infection, vaccination in SOTRs induces much lower protective antibody levels than in healthy controls and identifies African-American ethnicity, less than 1.5 years post transplantation as additional risk factors that further exacerbate these effects. Poor kidney function negatively affected the vaccine induced antibody response.

9.
American Journal of Transplantation ; 22(Supplement 3):404-405, 2022.
Article in English | EMBASE | ID: covidwho-2063344

ABSTRACT

Purpose: Transplantation has been disrupted dramatically by COVID-19 due to reallocation of healthcare resources and concerns from early reports of increased mortality rates (20-30%) in solid organ transplant recipients. Across the transplant population, up to 90% of patients are several years post-transplant and managed by primary care practitioners. Hence, it is important to understand if transplantation truly conveys additional risk and to differentiate predictors of outcomes associated with COVID-19 disease. Method(s): The international COVID-19 transplant registry, www.c19txr.org, centralized global tracking of outcomes for transplant patients. COVID-19 cases were defined by positive PCR nasal swab. Seventeen countries and 57 centers participated (Jan 1-Dec 20, 2020). Data analysis was performed at two timepoints, differentiating global lockdowns. Result(s): There were 1619 kidney, 157 heart, 50 lung, 127 liver and 49 multi-visceral patients with COVID-19. Patient demographics are shown in Table 1. Of all cases, 8.7% required hospitalization, 3.9% required ventilation, and 2.2% of grafts failed (kidney only). Overall mortality was 7.1% at a median of 17.2 days after diagnosis. The risk of mortality in year 1 post-transplant was 34.3% (n=49) and 14.7% (n=21) within 90 days of T-cell depleting induction therapy. The need for dialysis led to 11% increase in mortality. A significant decrease in mortality rates was observed from 6.2% to 2.6% in patients with COVID-19 before and after July 2020 respectively;however, this differed by geographical location. Patients were asymptomatic in 19.7% of cases and 78.6% developed IgG and/or IgM antibodies (Table 2). Conclusion(s): Global registry data suggests overall risk of COVID-19, antibody response to infection and the associated mortality post-transplant mirror the general population. However, findings show higher risk of mortality within 90 days of T-cell depleting agents and within year 1 post-transplant, supporting modulation of immunosuppression during acute infection for these high-risk individuals. Racial data has shown disadvantaged groups experience higher mortality. The mortality data described here is consistent with geographical census statistics, with North and South America having a larger African population than Europe or Asia. (Table Presented).

10.
Chest ; 162(4):A2508-A2509, 2022.
Article in English | EMBASE | ID: covidwho-2060955

ABSTRACT

SESSION TITLE: Rare Cases with Masquerading Pulmonary Symptoms SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 01:35 pm - 02:35 pm INTRODUCTION: COVID vaccinations have been encouraged by many healthcare providers but many adverse effects have also been reported. The adverse effects of the vaccine can vary based on each individual. Common adverse effects of the vaccine included fatigue, fever, chills, sore throat, muscle pain, headache, rash at injection site. Pleurodynia, also known as Devil's Grip, is a viral myalgia which causes sharp chest pain or the sensation of a grip around one's chest. Pleurodynia treatment is mostly supportive like anti-inflammatories (NSAIDS), pain management, and antibiotics (if bacterial inflammation is suspected). CASE PRESENTATION: We present a case report of a 63-year-old female who presented with complaints of pleuritic chest pain worse with inspiration. She had a history of atrial fibrillation and HTN. Patient had received the Pfizer COVID booster vaccine a few days prior to onset of the pleuritic chest pain. She was obese and had a 40 pack year smoking history. She was on room air saturating 92% with no increased work of breathing. Lung sounds were diminished due to body habitus but clear. Chest x-ray showed low lung volumes with no evidence of acute pulmonary disease. Computed Tomography Angiography (CTA) chest showed no pulmonary embolism and small left partially loculated pleural effusion with peripheral airspace opacities abutting the pleura. Acute coronary syndrome was ruled out and other cardiac workup was negative. COVID PCR was negative. Patient was treated empirically for bacterial infection with ceftriaxone and azithromycin. She was given NSAIDS to decrease inflammation and pain. Patient's symptoms improved significantly with treatment. She was discharged on NSAIDS and advised to follow up outpatient with her primary care and pulmonology. DISCUSSION: Research studies have indicated that the COVID vaccines (like Pfizer) can cause exacerbation of inflammatory or autoimmune conditions. Multiple mechanisms may be responsible for myocarditis, pericarditis, and other inflammatory conditions post vaccines. One mechanism describes that lipid particles of SARS mRNA vaccines can induce inflammation by activating the NLR pyrin domain containing 3 inflammasome of mRNA which are recognized by toll like receptors and cytosolic inflammasome components leading to inflammation. Another mechanism explains that viral proteins can cause immune cross reactivity with self-antigens expressed in the myocardium leading to an inflammatory process. CONCLUSIONS: As per current literature review there are no case reports about pleurodynia post COVID vaccination but pericarditis and myocarditis have been described. Further research studies are indicated to assess the cause and pathophysiology of pleurodynia post COVID vaccine. Physicians should have a high index of clinical suspicion for pleurodynia when assessing a patient with pleuritic chest pain with a recent history of COVID vaccination. Reference #1: 1. Analysis of COVID 19 Vaccine Type and Adverse Effects Following Vaccination. Beatthy, A;Peyser, N;Butcher, X. AMA Netw Open. 2021;4(12):e2140364. doi:10.1001/jamanetworkopen.2021.40364 Reference #2: 1. Association of Group B Coxsackieviruses with Cases of Pericarditis Myocarditis, or Pleurodynia by Demonstration of Immunoglobulin M Antibody. Schmidt, N;Magoffin, R;& Lennette, E. Infection and Immunty Journal. 1973 Sep;8(3): 341–348. PMCID: PMC422854 Reference #3: 3. Autoimmune phenomena following SARS-CoV-2 vaccination. Ishay, Y;Kenig, A;Toren, T;Amer, R;et. al. International Journal of Immuno-pharmacology. 2021 Oct;99: 107970. DISCLOSURES: No relevant relationships by Olufunmilola Ajala No relevant relationships by Arij Azhar No relevant relationships by Louis Gerolemou No relevant relationships by Wael Kalaji No relevant relationships by Steven Miller No relevant relationships by Kunal Nangrani No relevant relationships by Gaurav Parhar No relevant relationships by iran Zaman

11.
Chest ; 162(4):A1804, 2022.
Article in English | EMBASE | ID: covidwho-2060865

ABSTRACT

SESSION TITLE: Lung Cancer Imaging Case Report Posters 1 SESSION TYPE: Case Report Posters PRESENTED ON: 10/17/2022 12:15 pm - 01:15 pm INTRODUCTION: Pulmonary alveolar proteinosis (PAP) is a lung condition that is caused by a build-up of proteins, fats, and other substances (collectively called surfactants) in the alveoli of the lungs. Here we describe a case of a 47-year-old female diagnosed with PAP, with radiologic features conflicting with Coronavirus Disease 19 (COVID-19) pneumonia. CASE PRESENTATION: The patient is a 47-year-old female with no significant medical history who presents to the outpatient pulmonology clinic for shortness of breath evaluation. She reported that for the past 3-4 months she has been having progressively worsening shortness of breath (SOB) associated with dry cough, and nasal congestion. She reports no recent illness, no history of COVID or COVID exposure, no second-hand smoke exposure, no toxin/chemical exposure, no pets/birds at home. Her SOB has been impacting her lifestyle. Pulmonary function tests showed no obstruction, moderate restriction, mildly decreased diffusion capacity. Computed tomography (CT) of the chest showed multiple ground-glass opacities with septal wall thickening (appears crazy paving pattern) - suggestive of infection or inflammatory process. Infectious/inflammatory work up with HIV, COVID-19, hypersensitivity pneumonitis (HP) panel, autoimmune panel, immunoglobulins, QuantiFERON gold, IgM mycoplasma antibodies was negative. Repeat CT chest in 6 weeks as per patient request, was unchanged from prior. A bronchoscopy was done, bronchoalveolar lavage (BAL) negative for infection - fungal, acid-fast bacilli, Mycobacterium tuberculosis;GMS (Grocott's methenamine silver) stain negative for fungus;negative PCP (Pneumocystis pneumonia);left upper lobe and left lung biopsy showed lung parenchyma with scant amorphous eosinophilic material in alveolar sacs, Periodic Acid-Schiff stain (PAS) stain was positive confirming PAP diagnosis. DISCUSSION: PAP is a rare disease, affecting about 1 person in 100,000 people worldwide, with fewer than 10,000 of them in the United States. The "crazy paving pattern" is characteristic of PAP but recently it has appeared in the list of radiologic findings for COVID 19 pneumonia1,2,3. In these COVID times, these kinds of interactions might make the decision tougher, often leading to misdiagnosis. The decision of diagnosis/treatment should be based on symptoms and their duration, medical history, previous tests, response to treatment. Given our patient never had a COVID infection in the past or current infection, CT chest was typical for PAP with a crazy-paving pattern, no significant subjective/radiological improvement lead us to the diagnosis of PAP with eventual work up with bronchoscopy. CONCLUSIONS: A high index of suspicion is needed for the diagnosis of such rare diseases as PAP, which can be misdiagnosed as COVID-19 pneumonia, given radiological similarities. Early diagnosis and treatment can improve morbidity and mortality of PAP. Reference #1: PAP with COVID-19 Radiology - Differential Diagnosis Discussion, PMID: 33646114 Reference #2: Proteinaceous Lung With COVID-19: The Mimicker, PMID: 34703683 Reference #3: COVID-19 pneumonia: the great radiological mimicker - https://insightsimaging.springeropen.com/articles/10.1186/s13244-020-00933-z DISCLOSURES: No relevant relationships by Ahmad Al-Alwan No relevant relationships by Arundhati Chandini Arjun No relevant relationships by Farhan Khalid no disclosure submitted for Boning Li;No relevant relationships by Rana Prathap Padappayil No relevant relationships by Raghu Tiperneni

12.
Chest ; 162(4):A1265, 2022.
Article in English | EMBASE | ID: covidwho-2060791

ABSTRACT

SESSION TITLE: Diagnosis of Lung Disease through Pathology Case Posters SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Usual interstitial pneumonia (UIP) is a histological term used to describe a pattern of interstitial fibrosis with alternating areas of the normal lung with temporal fibrosis and architectural alteration due to chronic scarring or honeycomb change. It is a subset of idiopathic interstitial pneumonias (IPF) that usually presents in the sixth and seventh decades of life with progressive dyspnea on exertion and productive cough. CASE PRESENTATION: We present a 46 y/o man with a history of thyroid disease, hypertension and a former smoker of 20 pack-year smoking. Presented to ED complaining of low oxygen saturation with pulse oximetry at home with readings between 60-80%. Accompanied with progressive dyspnea on exertion and unintentional weight loss of 80 pounds in the last year. Also referred productive cough of white sputum that was worse in the morning. Home nebulized Albuterol therapy did not provide improvement. Denied recent viral respiratory infections, night sweats, environmental exposures nor family history of lung disease. DISCUSSION: Physical exam demonstrated bilateral expiratory dry crackles and pulse oximetry oxygen saturation at room air of 78%. RBBB evidenced on EKG. Bloodwork showed polycythemia with hemoglobin of 17.8;ABG's with pH: 7.40, Pco2: 42.2, PO2: 59.8, HCO3: 26, O2 sat: 90.8 and ideal PO2: 85.6 consistent with metabolic alkalosis with BMP CO2 of 30, A/a gradient: 43.0. Mycoplasma IgM, Influenza A & B and COVID-19 antigen test were negative. CXR with increased vascular markings, chest CT demonstrated small pericardial effusion, bilateral coarse interstitial pulmonary markings and bronchiectasis suggestive of chronic interstitial lung disease with no specific pattern. Left heart catheterization revealed right ventricular hypertrophy, normal EF >55%, and no evidence of coronary disease. Alpha-1 antitrypsin: 158, EPO: 6.5, HIV, and hepatitis panel were all negative. Rheumatology work up with only an ANA antibody positive, with titer 1:160. Patient underwent VATS procedure with wedge biopsy of the right upper and middle lobe that revealed usual interstitial pneumonia pattern. Patient improved and was discharged on home oxygen 3L. At follow-up, treatment was started with Nintedanib and Sildenafil Citrate. He had clinical improvement and oxygen requirements decreased to intermittent oxygen. CONCLUSIONS: Patients with interstitial pulmonary fibrosis experience slow progressive decline with typical clinical presentation over 60 years of age. This case remarks the importance of the need for stratification of interstitial lung disease classification, when pattern and history are non specific, with the use of VATS procedure for early start of treatment. Our patient with no environmental exposure or connective tissue disease had an uncommon early presentation of usual interstitial pneumonia. Reference #1: Tibana, R.C.C., Soares, M.R., Storrer, K.M. et al. Clinical diagnosis of patients subjected to surgical lung biopsy with a probable usual interstitial pneumonia pattern on high-resolution computed tomography. BMC Pulm Med 20, 299 (2020). https://doi.org/10.1186/s12890-020-01339-9 DISCLOSURES: No relevant relationships by Jesse Aleman No relevant relationships by Carlos Martinez Crespí no disclosure submitted for Jean Ramos;No relevant relationships by Alexandra Rodriguez Perez No relevant relationships by Paola Vazquez No relevant relationships by Nahomie Veguilla Rivera

13.
Chest ; 162(4):A773-A774, 2022.
Article in English | EMBASE | ID: covidwho-2060686

ABSTRACT

SESSION TITLE: COVID-Related Critical Care Cases SESSION TYPE: Case Reports PRESENTED ON: 10/19/2022 11:15 am - 12:15 pm INTRODUCTION: We present a case of diffuse alveolar hemorrhage (DAH) secondary to Immune Thrombocytopenia (ITP) temporally related to SARS-CoV-2 (CoV) vaccine. CASE PRESENTATION: An 80-year-old female presented with dyspnea, hemoptysis, diffuse petechiae, and ecchymosis;no focal neurological deficits or hepatosplenomegaly. She had no history of bleeding or autoimmune disorders;no recent respiratory or gastrointestinal infections;but received Moderna CoV vaccine 4 weeks prior to presentation. Chest X-ray (CXR) and CTA of chest demonstrated multifocal bilateral patchy airspace opacities. Initial platelet was 1 x 109/L with normal morphology of platelet and WBC, and no schistocytes. Coagulation panel, LDH, haptoglobin, and bilirubin were all normal. CoV NAAT was negative. Dexamethasone and IVIG for high suspicion of ITP was initiated. Supportive care including platelet transfusion and oxygen via nasal cannula was maintained. Platelets were severely consumed in spite of treatment with platelets undetectable at nadir and rapid decrease of hemoglobin, approximately 6 g/dL, within 24 hours of admission. IgM and IgG plasma platelet autoantibodies returned positive, confirming ITP diagnosis. Additional workup was unremarkable for infections, rheumatologic disorders, and malignancy. Respiratory state rapidly declined with worsening hemoptysis and significant increase of bilateral airspace opacities on repeat CXR, indicative of DAH. Lung protective mechanical ventilation protocol was initiated on day 2 with medically induced deep sedation and paralysis to minimize hemorrhage exacerbation. Rituximab, romiplostim, and nebulized tranexamic acid were added for severe and refractory ITP, which eventually slowed platelet consumption, reduced pulmonary hemorrhage, and stabilized hemoglobin. Platelets recovered above 30 x 109/L on day 9, and subsequent bronchoscopy showed persistent blood on bronchoalveolar lavage. She was successfully extubated after prolonged 14-day intubation. Platelet normalized before discharge. DISCUSSION: Incidence of ITP related to CoV vaccine is approximately 0.8-0.9 case per million vaccinated. Most cases present with superficial bleeding and respond to first-line agents with rapid recovery. GI bleeding and intracranial hemorrhage, but not DAH, have been reported in several cases, requiring third-line agents to promote platelets recovery and achieve hemostasis. We report a case of DAH secondary to ITP following CoV vaccine. Temporal relationship and severe presentation are consistent with other reports of ITP with life-threatening internal bleeding probably secondary to CoV vaccine. CONCLUSIONS: When DAH is suspected, rapid escalation of treatment to include third-line agents is desired. If intubated, lung protective ventilation with paralysis is preferred to minimize further lung injury due to DAH. Reference #1: Lee EJ, Cines DB, Gernsheimer T, et al. Thrombocytopenia following Pfizer and Moderna SARS-CoV-2 vaccination. Am J Hematol. 2021;96(5):534-537. doi:10.1002/ajh.26132 doi:10.1016/J.VACCINE.2021.04.054 Reference #2: Welsh KJ, Baumblatt J, Chege W, Goud R, Nair N. Thrombocytopenia including immune thrombocytopenia after receipt of mRNA COVID-19 vaccines reported to the Vaccine Adverse Event Reporting System (VAERS). Vaccine. 2021;39(25):3329-3332. Reference #3: Tarawneh O, Tarawneh H. Immune thrombocytopenia in a 22-year-old post Covid-19 vaccine. Am J Hematol. 2021;96(5):E133-E134. doi:10.1002/ajh.26106 DISCLOSURES: No relevant relationships by Timothy Barreiro No relevant relationships by Tiewei Cheng No relevant relationships by Zeina El Amil No relevant relationships by Jin Huang No relevant relationships by Sanaullah Khalid

14.
Chest ; 162(4):A604, 2022.
Article in English | EMBASE | ID: covidwho-2060645

ABSTRACT

SESSION TITLE: COVID-19 Co-Infections SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/19/2022 12:45 pm - 1:45 pm INTRODUCTION: SARS-CoV-2 has been associated with co-infecting pathogens, such as bacteria, viruses, and fungi. Little has been reported about community acquired atypical bacterial co-infections with SARS-CoV-2. We present a case of a patient with recent COVID-19 pneumonia and diagnosis of Legionella and Mycoplasma pneumonia, in addition of E. coli and C. perfringens bacteremia, that emphasizes SARS-CoV-2 impact in human immunity and the need to consider community acquired infections. CASE PRESENTATION: A 64-year-old male with history of hypertension, alcohol use disorder, iron deficiency anemia, and recent COVID-19 pneumonia presented to the ED with shortness of breath, dark urine, and increased confusion. The patient was admitted to the hospital a week prior with COVID-19 pneumonia and acute kidney injury. He received dexamethasone, remdesivir, and IV fluids. After 8 days, he was discharged home. Upon evaluation, he was afebrile and normotensive, but tachycardic, 129/min, on 4 L of nasal cannula sating 100%. On exam, the patient was oriented only to person and had decreased breath sounds bilaterally. Labs revealed an elevated WBC, 15.3 K/mcL, with left shift, low Hgb, 7.8 g/dL, with low MCV, 61 fL, increased BUN/Cr, 56 mg/dL and 2.8 mg/dL, and an abnormal hepatic panel, AST 121 U/L, ALT 45 U/L, alkaline phosphatase 153 U/L. Ammonia, GGT, CPK and lactic acid were within normal range;but the D-dimer and procalcitonin were elevated, 4618 ng/mL and 25.12 ng/mL, respectively. A urinalysis showed gross pyuria, positive leukocyte esterase and mild proteinuria. CT head showed no acute abnormalities, but the chest X-Ray revealed a hazy opacity in the left mid and lower lung, followed by a CT chest that demonstrated peripheral and lower lobe ground glass opacities and a CT abdomen that showed right sided perinephric and periureteral stranding. Given increased risk for thromboembolism, a VQ scan was done being negative for pulmonary embolism. The patient was admitted with acute metabolic encephalopathy, acute kidney injury, transaminitis, pyelonephritis and concern for hospital acquired pneumonia. Vancomycin, cefepime and metronidazole were ordered. HIV screen was negative. COVID-19 PCR, Legionella urine antigen and Mycoplasma IgG and IgM serologies were positive. Blood cultures grew E. coli and C. perfringens. Infectious Disease and Gastroenterology were consulted. The patient was started on azithromycin and a colonoscopy was done showing only diverticulosis. After an extended hospital course, the patient was cleared for discharge, without oxygen needs, to a nursing home with appropriate follow up. DISCUSSION: Co-infection with bacteria causing atypical pneumonia and bacteremia should be considered in patients with recent or current SARS-CoV-2. CONCLUSIONS: Prompt identification of co-existing pathogens can promote a safe and evidence-based approach to the treatment of patients with SARS-CoV-2. Reference #1: Alhuofie S. (2021). An Elderly COVID-19 Patient with Community-Acquired Legionella and Mycoplasma Coinfections: A Rare Case Report. Healthcare (Basel, Switzerland), 9(11), 1598. https://doi.org/10.3390/healthcare9111598 Reference #2: Hoque, M. N., Akter, S., Mishu, I. D., Islam, M. R., Rahman, M. S., Akhter, M., Islam, I., Hasan, M. M., Rahaman, M. M., Sultana, M., Islam, T., & Hossain, M. A. (2021). Microbial co-infections in COVID-19: Associated microbiota and underlying mechanisms of pathogenesis. Microbial pathogenesis, 156, 104941. https://doi.org/10.1016/j.micpath.2021.104941 Reference #3: Zhu, X., Ge, Y., Wu, T., Zhao, K., Chen, Y., Wu, B., Zhu, F., Zhu, B., & Cui, L. (2020). Co-infection with respiratory pathogens among COVID-2019 cases. Virus research, 285, 198005. https://doi.org/10.1016/j.virusres.2020.198005 DISCLOSURES: No relevant relationships by Albert Chang No relevant relationships by Eric Chang No relevant relationships by KOMAL KAUR No relevant relationships by Katiria Pintor Jime ez

15.
Chest ; 162(4):A560, 2022.
Article in English | EMBASE | ID: covidwho-2060631

ABSTRACT

SESSION TITLE: Disseminated Bacterial Infections SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 10:15 am - 11:10 am INTRODUCTION: Tularemia is a rare infectious disease caused by Francisella Tularensis that typically affects the skin, eyes, lymph nodes, and lungs. There are a variety of forms of tularemia with varying rates of contagiousness and mortality. Respiratory tularemia has a high mortality rate if left untreated and presents with non-specific viral like symptoms occurring in conjunction with respiratory symptoms: cough, hemoptysis, and pleuritic chest pain. In this COVID ARDS era, it is important to evaluate a broad differential diagnosis. Therefore, the authors describe a patient presenting with flu-like respiratory symptoms whom was ultimately was diagnosed with acute respiratory distress syndrome (ARDS) due to F. Tulerensis. CASE PRESENTATION: A 44-year-old male presented with a four-day history of night sweats, shortness of breath, a productive cough which progressed to hemoptysis, and oliguria. Prior to admission, his initial symptoms were treated as chronic sinusitis with varied antibiotics. Social history including tobacco abuse and deer hunting 1 month prior to presentation. Vitals were stable except for tachycardia, hypoxia, and tachypnea. Laboratory findings were significant for AKI, lactic acidosis, mild transaminitis, hyperbilirubinemia, and leukocytosis with predominant neutrophilia. Thoracic CTA showed bilateral diffused pulmonary edema without evidence of pulmonary embolism. Due to the patient's worsening respiratory status, he was intubated for support. The patient progressed to Severe ARDS per Berlin Criteria eventually requiring pronation and continuous paralyzing. Bronchoscopy was performed with bronchial lavage. Bacterial, viral, and fungal cultures did not show growth while vasculitic work-up was negative. Empiric antibiotic treatment did not show improvement until the patient was diagnosed with F. Taularensis via serological testing with an IgM of 20 U/mL, and patient was transitioned to gentamycin. Ultimately, the patient was extubated, transitioned to oral doxycycline, and discharged home. DISCUSSION: Approximately 250 cases of tularemia are reported to CDC each year. Respiratory tularemia has a mortality rate up to 30% if not treated. For this reason, F. tularensis is a potential biological weapon and is categorized as a Group A pathogenic agent. Serological testing may be negative early in disease progression;therefore, early inflammatory markers with clinical suspicion are essential to diagnose the disease early in its course. DNA microarray has high specificity and sensitivity for rapid diagnosis of tularemia while being cost effective. After prompt diagnosis, intravenous aminoglycosides;such as gentamycin or streptomycin;must be started. CONCLUSIONS: In the above case, we illustrate the gradual onset and rapid patient deterioration when treatment is delayed;yet, there is rapid recovery once appropriate treatment is used. Reference #1: 1. Ranjbar, Reza, Payam Behzadi, and Caterina Mammina. "Respiratory tularemia: Francisella tularensis and microarray probe designing.” The open microbiology journal 10 (2016): 176. Reference #2: 2. Akhvlediani, N., I. Burjanadze, D. Baliashvili, T. Tushishvili, M. Broladze, A. Navdarashvili, S. Dolbadze et al. "Tularemia transmission to humans: a multifaceted surveillance approach.” Epidemiology & Infection 146, no. 16 (2018): 2139-2145. Reference #3: 3. Tularemia in British Columbia: A case report and review. Issue: BCMJ, vol. 52, No. 6, July August 2010 (Pages 303- 307). Megan Isaac-Renton, BSc, Muhammad Morshed, PhD, SCCM Eleni Galanis, MD, MPH, FRCPC Sunny Mak, MSc Vicente Loyola, MD, FRCPC, Linda M.N. Hoang, MD, MHSc, FRCPC DISCLOSURES: No relevant relationships by Munish Adhikari No relevant relationships by Ashma Ul Husna No relevant relationships by Yan Jiang No relevant relationships by Divya Kharel No relevant relationships by Gregory Polcha

16.
Chest ; 162(4):A480, 2022.
Article in English | EMBASE | ID: covidwho-2060605

ABSTRACT

SESSION TITLE: COVID-19 Case Report Posters 3 SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Exposure to anti-CD20 treatment affects B cell functions involved in anti-COVID immunity and impacts the clinical course of infection. We present two patients with persistent respiratory symptoms and persistent SARS-COv-2 PCR positivity months after initial infection. The aim of presenting these cases is to highlight how exposure to Rituximab can result in patients having significantly prolonged SARS-CoV-2 infections that may require special treatment compared to immunocompetent patients. CASE PRESENTATION: Patient A is a 46-year-old man with a history of marginal zone lymphoma, who was treated with six cycles of bendamustine with rituximab and monthly maintenance rituximab. He has been hypoxic for 7 months after COVID infection with ground glass opacities on imaging, elevated CRP of 58.4, positive PCR, undetectable CD3/CD4 and low cycle threshold of 28, suggesting rapid active viral replication. COVID IGG was negative. T cell subsets counts were undetectable. IgG 351, IgA 59, IgM less than 10. He was treated with a 10-day course of Remdesevir and steroids. Given lack of humoral immunity, he was given convalescent plasma. At discharge he developed positive COVID IgG and remained COVID positive by PCR. He had complete resolution of hypoxia. Patient B is a 68-year-old man with a history of chronic lymphocytic leukemia, who was treated with six years of rituximab maintenance therapy, last rituximab was three years ago. He was diagnosed with SARS-CoV-2 three months prior to admission with worsening hypoxia. He remained PCR positive with persistent respiratory symptoms. At readmission his imaging showed ground glass opacities, CRP 6.6 and cycle threshold was 27.8. The follow studies were abnormally low:IgG 541, IgA 25, IgM 14, absolute CD3 171, absolute CD4 68. He was treated with remdesivir, steroids, granulocyte colony stimulating factor and sotrovimab. Despite these therapies, his hypoxia worsened, and he pursued comfort care. DISCUSSION: There are reports of patients receiving B cell depleting therapy who have persistent shedding of viable SARS-CoV. Persistent viral infection may be suspected in patients with relapsing symptoms, elevated CRP, D-dimer and active ground glass changes imaging. Low T cell subsets and low immunoglobulin levels indicate a CD20 related impairment of adaptive immunity. Time to viral clearance appears to be prolonged compared to general population in immunocompromised patients. There is some published experience using convalescent plasma in this setting. SARS-CoV-2 viremia has been demonstrated to predict adverse outcomes. Median cycle threshold has been shown to be lower, reflecting a high viral load comparable with acute infectious phase of COVID. CONCLUSIONS: To achieve stable clinical responses this subset of patients may benefit from early administration of combination regimens, including both passive immunotherapy and prolonged antiviral treatment. Reference #1: Furlan A, Forner G, Cipriani L, Vian E, Rigoli R, Gherlinzoni F, Scotton P. COVID-19 in B Cell-Depleted Patients After Rituximab: A Diagnostic and Therapeutic Challenge. Front Immunol. 2021 Nov 3;12:763412. doi: 10.3389/fimmu.2021.763412. PMID: 34804051;PMCID: PMC8595333. DISCLOSURES: No relevant relationships by Cheryl Augenstein Primary Investigator relationship with Boehringer Ingelheim Please note: 2/2022-2/2024 Added 04/01/2022 by A. Thanushi Wynn, value=Grant/Research Support

17.
Swiss Medical Weekly ; 152(Supplement 261):6S, 2022.
Article in English | EMBASE | ID: covidwho-2058056

ABSTRACT

Objectives: Routine monitoring of vaccine-induced anti-S responses following mRNA based SARS-CoV-2 vaccination is not recommended routinely as uncertainties exist about the critical threshold of antibody levels that correlate to protection and the optimal timepoint for determination. In our study, anti-S antibody were analysed over 24 weeks following a standard two-dose regimen of mRNA based anti-SARS-CoV-2 vaccines and correlated to the development and persistence of neutralizing activity against SARSCoV- 2 in patients with rheumatoid arthritis (RA) on DMARD therapy compared to healthy controls (HC). Method(s): The RECOVER study was a prospective, controlled, monocentric study. Assessments were performed before vaccination, and at three, six, 12 and 24 weeks after the first vaccine dose. Result(s): In RA patients, anti-S responses developed slower and resulted in lower peak titers compared to HC. A potent neutralizing activity (NT50) as assessed by a SARS-CoV-2 pseudoneutralization assay was observed in 60.3 % of all 73 RA patients and in all 21 HC after 12 weeks. A significant correlation between peak anti-S levels two weeks after the second vaccine dose and the development of a persistent neutralizing activity against SARS-CoV-2 was observed at week 12 and week 24. The analysis of IgG, IgA, and IgM isotype responses to RBD, S1, S2, and N proteins revealed a delayed IgG response, while IgA and IgM responses were maintained, suggesting a delayed isotype switch in RA patients. Conclusion(s): Peak anti-S IgG levels two weeks after the second vaccine dose significantly predicted the development and persistence of a potent neutralizing activity against SARS-CoV-2 after 12 and 24 weeks. Our data suggest that the early determination of anti- S levels allows the timely identification of non- or poor-responding patients.

18.
Pulmonologiya ; 31(6):792-798, 2021.
Article in Russian | EMBASE | ID: covidwho-2033501

ABSTRACT

The main focus in the course of COVID-19 goes on assessing the overall immune response. The role of mucosal immunity in this disease has not been studied sufficiently. The study aimed to analyze published data about secretory IgA as a significant indicator of the mucosal immune response of the respiratory tract in the context of the COVID-19 pandemic. Methods. Articles were identified via PubMed bibliographic database. The time-span of research was two years (2020, 2021). Results. The search identified 54 articles. There is evidence that secretory IgA (sIgA) is the main antibody isotype of the mucosal immunity. It is produced in quantities significantly higher than those of all other isotypes of immunoglobulins combined. sIgA antibodies are effective against various pathogens, including the SARS-CoV-2 virus, due to mechanisms such as neutralization, suppression of adhesion to the mucosal surface and invasion of epithelial cells, agglutination and facilitating the removal of pathogenic microorganisms with the mucosal secretions. Virus-specific IgA antibodies in the blood serum are detected in patients with COVID-19 as early as two days after the first symptoms, while IgM or IgG class antibodies appear only after 5 days. We accessed the efficacy of intranasal immunization as to induction of predominant production of sIgA in the upper and lower respiratory tract. Conclusion. The current information on the local immune response of the respiratory mucosa is important for understanding the pathophysiological mechanisms of the disease, diagnosis, and development of new methods of treatment and prevention of COVID-19.

19.
Medical News of North Caucasus ; 17(2):202-204, 2022.
Article in English | EMBASE | ID: covidwho-2033430

ABSTRACT

The study determined the etiological structure and sensitivity to antibacterial agents of pathogens of uncomplicated and complicated forms of pneumonia in children treated in a multidisciplinary hospital. According to the study, that timely bacteriological diagnosis in the treatment of pneumonia in childhood with an adequate selection of effective antibacterial agents helps reduce hospitalizations and the development of complicated forms of pneumonia.

20.
HemaSphere ; 6:1096-1097, 2022.
Article in English | EMBASE | ID: covidwho-2032152

ABSTRACT

Background: Infectious complications are a major cause of morbidity and mortality in Chronic Lymphocytic Leukaemia (CLL). Therapeutic approaches that deplete CLL cells also affect normal B-cells. Optimal treatment would result in eradication of CLL cells and recovery of normal immune function. FLAIR (ISRCTN01844152) is a phase III trial for previously untreated CLL comparing ibrutinib plus rituximab (IR) with fludarabine, cyclophosphamide and rituximab (FCR) and subsequently amended to also compare ibrutinib plus venetoclax (I+V) and ibrutinib alone (I) with FCR. Measurable residual disease (MRD) and normal B-cell levels were assessed at multiple timepoints. Aims: To assess the depletion of normal B-cells during treatment and recovery after end of treatment. Methods: Participants aged under 75 years with <20% TP53-deleted cells were initially randomised to FCR or IR and subsequently to FCR, IR, I+V or I with the IR arm closed after randomisation of 771 participants to FCR/IR. FCR was given for 6 cycles, while treatment in the IR, I and I+V arms continued for up to 6 years except in participants attaining <0.01% MRD who continued treatment for the time taken to achieved MRD <0.01% and then stopped if MRD remained <0.01%. Month (M) 24 was earliest permitted stopping point. MRD flow cytometry was performed according to ERIC guidelines (panel: CD19/5/20/43/79/81+ROR1, acquisition of 0.5-2.2 million cells, BD Biosciences Lyric). Additional analysis of normal B-cell subsets was performed in a cohort of >500 patients (panel: CD19 to identify B-cells, CD20/5/79b+ROR1 and CD3 to exclude CLL & contaminating cells, with CD27/ 38/IgD/IgM to characterise normal B-cell subsets using a Coulter Cytoflex LX). Results: Normal B-cells were undetectable during FCR treatment and only rarely detectable until 12 months after last FCR cycle. Circulating normal B-cells were reduced in number or undetectable in participants receiving ibrutinibcontaining regimens with greater depletion in the I+V and IR arms relative to I monotherapy. B-progenitors persist through FCR treatment but were depleted during I, I+R or I+V treatment. Normal B-cell levels at 24 and 36 months after randomisation, with time off-treatment if applicable, are shown in Figure 1. In the ibrutinib-containing arms (IR, I, and I+V), there was a trend towards fewer COVID-associated SAE at any time point for participants with detectable B-cells at 24M (4/181, 2.2%) compared to those with no detectable B-cells (14/344, 4.1%) and COVID-associated SAEs were not observed in FCR-treated participants who had recovered any level of normal B-cells by 24M (0/215). However, the data on COVID infections are limited and there was no apparent association between normal B-cell levels at 24M with the proportion of participants experiencing an infectious SAE overall. Assessment of normal B-cell subsets during ibrutinib-based treatment demonstrated a mix of naïve and memory B-cells. Serological response to COVID infection/vaccination in this cohort is currently being performed. Participants stopping I+V treatment at 24-30 months post-randomisation due to MRD eradication showed rapid recovery of normal naive B-cells within 6-12 months after end of treatment in the vast majority (>95%) of evaluable cases. Summary/Conclusion: Normal circulating B-cells are depleted during treatment with rituximab but can persist at a low level during I, IR or I+V treatment. Most patients in remission after treatment with FCR or I+V show recovery of normal B-cells at 12 months of stopping treatment.

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