Long-standing COVID-19 disease in immunedeficient patients; case reports and literature review

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We describe here the effect of rituximab therapy in 5 patients with humoral and cellular immune deficiencies (1 patient with thymoma or Good`syndrome, 1 HIV/AIDS positive patient, 2 patients with Multiple Sclerosis (MS) and 1 patient with chronic lymphocytic leukemia (CLL). T cell responses were evaluated using the QuantiFERON SARS-CoV-2 assay following incubation with the SARS-CoV-2 Ag1, Ag2 and Ag3 viral antigens. Immunephenotyping of T cells (TCD4+, TCD8+) and B cells (CD19+ and CD20+) was determined by flow cytometry. Results: All studied immunocompromised patients showed reduced cellular immune responses (release of interferon (IFN)-g) to SARS-CoV-2 antigens than healthy controls [patients; Ag1, Ag2 and Ag3 and Nil (Median 5-95% percentile) (12 (1-95), 12 (1.5-78), 13.5 (12-95) and 3 (1-98) U/ml)], ]controls; Ag1,Ag2 and Ag3 and Nil (Median 5-95% percentile) 24.5 (7-89), 65 (31-173), 53.5 (13-71.5) and 3 (1-14) U/ml)]. The frequency of peripheral blood B cells was also reduced in these patients compared to healthy control subjects (p=0.0282). Conclusion : T-cell dependent antibody responses require the activation of B cells by helper T cells. Reduced B cell numbers in immunocompromised patients infected with SARS-CoV-2 indicates the need for these patients to take additional precautions to prevent COVID-19 infection Immunodeficiency COVID-19 vaccine SARS-COV-2 Introduction In December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV‐2) was identified in Wuhan (China) as a novel human pathogen causing coronavirus disease 2019 (COVID‐19) which rapidly became a pandemic ( 1 , 2 ). In the immune response against SARS-CoV-2 infection, the innate immune system acts as the first line of defense, recognizing the virus through pattern recognition receptors and activating inflammatory pathways that promote viral removal ( 3 ). The adaptive immune response is a major determinant of the clinical outcome after SARS-CoV-2 infection and underpins vaccine efficacy ( 1 , 4 ). Adaptive immune responses are necessary to control and redirect SARS-CoV-2 infection but its relative importance is unclear. Observations from patients infected with SARS-CoV-1 and Middle East respiratory syndrome )MERS( shows that T cells may be the major mediators of disease control ( 5 ) and high antibody levels have been associated with increased inflammation and impaired clinical outcome in SARS-CoV-1 ( 6 ). T cell responses develop early and correlate with protection but are relatively impaired in severe disease and are associated with intense activation and lymphopenia ( 5 , 7 ). Both genetic and acquired factors play a role in effective interferon signaling during acute infection by SARS-CoV-2 ( 8 , 9 ). In patients with COVID-19, severe clinical outcomes corresponds with a slow decline in viral load and early and continuous inflammation with increasing levels of cytokines such as (IFN)-α, IFN-γ and tumor necrosis factor) TNF( ( 10 – 12 ). In first steps of the adaptive immune response, cytotoxic CD8 + T cell appear within 7 days of symptoms and they reach their peak at 14 days correlating with effective viral clearance ( 13 , 14 ). Humoral response kinetics against SARS-CoV-2 is similar to that for cellular responses ( 15 ). In patients with SARS-CoV-2 infection, B cell responses typically arise first against the nucleocapsid (N) protein followed by antibody responses to the S protein after 4–8 days ( 16 , 17 ). The importance of the adaptive immune system suggests that immunocompromised patients may be at higher risk for development of severe COVID-19 disease. Indeed, the risk of COVID-19 disease severity depends on comorbidities and underlying disorders such as diabetes, hypertension and obesity ( 15 ). In comparison to the general population, adult patients with primary immune deficiency (PID) and symptomatic acquired immune deficiency (AID) show a greater morbidity and mortality from COVID-19 disease ( 18 ). People with multiple sclerosis (MS) treated with B cell depleting antibodies, have a higher risk of infection and related mortality than healthy controls ( 19 – 21 ). Human immunodeficiency virus (HIV) is responsible for an acquired immune deficiency and people living with HIV/AIDS (PLWH) are in the high-risk group for the SARS-COV-2 infection. In addition to T cell defects, antibody responses following immune system challenge are also impaired in PLWH these patients have a high risk for severe SARS-CoV-2 infection ( 22 ). Here we reported unusual long standing SARS-COV-2 infection in patients with various underlying immunosuppressed disease. Material And Methods Patient sample collection 5 confirmed COVID-19 patients with predominant Omicron (B.1.1.529) SARS-CoV-2 variant infection, including 3 patients vaccinated with two doses of Sinopharm [Vero], 1 patient vaccinated with a single dose of Oxford/AstraZeneca (ChAdOx1-S [recombinant] vaccine) COVID-19 vaccine, 1 patient who had not received any vaccine were enrolled into the study upon admission to the Masih Daneshvari Hospital of the Shahid Beheshti Medical University, Tehran-Iran between May 8th - July 5th 2022. COVID-19 disease was confirmed by polymerase chain reaction (PCR) from nasopharyngeal samples using specific primers for SARS-CoV-2. All patients were diagnosed according to World Health Organization (WHO) interim guidelines ( 23 , 24 ). 5 ml peripheral blood samples were collected in heparin anticoagulant tubes for detection of IFN-γ release assays and T cell and B cell immunephenotyping as described previously ( 25 ). Evaluation of cell response by QuantiFERON (Q-FN) SARS-CoV-2 test T cell responses were evaluated using the Q-FN SARS-CoV-2 assay as described previously ( 25 ). This assay consists of three antigens (Ag) tubes, including SARS-CoV-2 Ag1, Ag2 and Ag3. The Q-FN SARS CoV-2 Ag1 tube contains CD4 + epitopes derived from the S1 subunit, Ag2 tube contains CD4 + and CD8 + epitopes from the S1 and S2 subunits, and the Ag3 tube consists of CD4 + and CD8 + epitopes from S1 and S2, plus immunodominant CD8 + epitopes derived from whole genome. 5 ml whole fresh blood was added to each tube and after 24h, the plasma was harvested and the release of IFN-γ was evaluated by ELISA. Elevated IFN-γ was defined as a value at least 0.20 IU/ml greater than the background as indicated as described earlier ( 25 ). Flow Cytometry To determine CD4 + and CD8 + T, NK and B cell immunophenotyping, surface staining of CD4, CD8, CD19, CD20 and CD16/56 markers was undertaken using specific antibodies (Table 1 ). 10000 events were evaluated with BD FACSCalibur (BD Biosciences, CA, USA) and analyzed using FlowJo Software version 10 (BD Bioscience). Cases Presentation Data Case 1 A 47-year old man with Good's syndrome (GS, thymoma with immunodeficiency; a rare cause of combined B and T cell immunodeficiency in adults) was referred to the Masih Daneshvari Hospital on June 19th 2022 complaining of cough and progressive shortness of breath at admission. The patient had been PCR positive for SARS-CoV-2 RNA for one year. Upon admission, he had a PCR positive nasopharyngeal swab. This patient had received 2 doses of SINO vaccine. Chest x-ray image revealed bilateral infiltrates in lungs indicative of COVID-19 pneumonia. Sequence analysis showed the presence of the Delta variant (B.1.617.2). Shortly after admission, the patient deteriorated, and laboratory analysis of blood tests showed a white blood cell count of 4.3 × 10 9 /l (4–11.0) with a profound lymphopenia (0.5 x 10 9 /l) and elevated systemic levels of IL-6 (76 pg/ml, normal levels < 8pg/ml), lactate dehydrogenase (LDH, 813 U/L), creatine phosphokinase (CPK, 24 mg/l) and erythrocyte sedimentation rate (ESR, 24 mm/hr). Immunophenotyping of surface markers indicated 77.4% CD3 + T cells, 29.9% CD4 + T cells, 62.9% CD8 + T cells, 2.2% CD19 + B cells and 1.3% CD20 + B cells (Tables 2 and 3 ). The levels of IFN-γ shows responses to Nil, Ag1, Ag2, Ag3 and mitogen tubes as 98, 95, 78, 95 and 866 IU/ml, respectively. The patient developed acute respiratory distress syndrome (ARDS) after 2 days and was admitted to the intensive care unit (ICU). Oxygenation was maintained with continuous positive airway pressure therapy (CPAP) before the patient was eventually intubated. He was treated with antiviral drugs, broad spectrum antibiotics and steroids as well as the IL-6 inhibitor, Tocilizumab (8–12 mg/kg) according to the hospital policy resulting in a marked drop in the levels of inflammatory markers. The patient developed a pulmonary embolism and cardiac arrest and died. Case 2 A 53-year old man with known chronic lymphocytic leukemia (CLL) and diabetes mellitus in history was referred to the Hospital on 17th May 2022. CLL was treated with chemotherapy and anti-CD20 monoclonal antibody (Rituximab 375 mg/m 2 IV infusion, given on Day 1 of each cycle of chemotherapy, for up to 8 doses). He had a prolonged COVID-19 disease with a positive SARS-CoV-2 PCR for the previous 6 months. He was hospitalized with fever, cough and sputum and had a previous history of hospitalization for an embolus. The patient had received 1 dose of AZD vaccine. He had a PCR positive nasopharyngeal swab which was predominantly of the Omicron (B.1.1.529) variant. Laboratory tests showed elevated ESR (75 mm/hr), LDH (492 U/L) and IL-6 (149 pg/ml) levels. The white blood cell count was 5.515 x 10 9 /l with a lymphopenia of 0.4 x 10 9 /l. Immunophenotyping gave 16% CD4 + T cells, 64% CD8 + T cells, 4.04% CD19 + B cells and 0% CD20 + B cells. The release of IFN-γ in response to Nil, Ag1, Ag2, Ag3 and mitogen tubes was 3, 1, 2.5, 13.5 and 664 IU/ml, respectively ( Tables 2 and 3 ) . The patient was treated with antiviral drugs (Remdesivir 100 mg once daily), Dexamethasone 8mg/Day, tocilizumab 8 mg/kg/dose for 5 days and gradually recovered and had a negative SARS-CoV-2 PCR after 30 days of treatment. Case 3 A 31-year old man with signs of COVID-19 was referred to the Hospital on 11th May 2022. He had a cough and progressive shortness of breath for the previous 4 months. He was HIV/AIDS antibody positive and positive for HIV by PCR. The patient had received their 2nd dose of SINO vaccine two months previously. Chest x-ray revealed bilateral lung infiltrates and was diagnosed as having COVID-19 pneumonia. He had a positive SARS-CoV-2 PCR test with a predominance of the Omicron (B.1.1.529) variant. Laboratory evaluation of blood samples revealed LDH (425 U/l), ESR (54 mm/hr), CPK (44 mg/l) and a WBC of 6.6 x 10 9 /l with a lymphopenia of 0.9 x 10 9 /l. Immunophenotyping of blood cells indicated 49.6% CD3 + cells, 0.78 CD4 + T cells, 91% CD8 + T cells, 14.5% CD19 + B cells and 13% CD20 + B cells frequencies. The concentration of IFN-γ in response to Nil, Ag1, Ag2, Ag3 and mitogen tubes was 1, 1, 1.5, 13 and 397 IU/ml respectively ( Tables 2 and 3 ). Upon hospitalization, he had been PCR positive for SARS-CoV-2 for the previous 5 months. He was treated with anti-HIV viral therapy according to standard protocols ( https://www.cdc.gov/hiv/basics/livingwithhiv/treatment.html ). He also had a high cytomegalovirus (CMV) load which was negative after treatment. Five months after admission, the patient gave a negative nasopharyngeal SARS-CoV-2 PCR test. The patient was discharged home in good condition on the 21st June 2022 Case 4 A 27-year old woman was referred to the Hospital in 8th May 2022 with signs of COVID-19 disease. In her past medical history included Multiple Sclerosis (MS). She had a history of hospitalization and was under treatment with rituximab (500 mg). She had prolonged COVID-19 disease for the previous 6 months as defined by positive PCR tests. At admission, she complained of fever (up to 39.5 C), chills, cough and progressive shortness of breath and gave two positive nasopharyngeal SARS-CoV-2 tests. The patient had not received a COVID-19 vaccine. Upon hospitalization, the patient deteriorated and laboratory tests showed high serum LDH (315 U/l), IL-6 (1 pg/ml) and specific IgG and IgA against S1 subunit of SARS-CoV-2 (0.3 and 3 mg/dl) respectively. The total IgG was 678 mg/dl, IgA 38 mg/dl and IgM 58 mg/dl. Moreover, the patient had a WBC of 5.1 x 10 9 /L with a lymphocyte count of 1.32 x 10 9 /l. She was blood test negative for mycobacterium tuberculosis (MTB) culture and PCR, CMV, Toxoplasma and respiratory syncytial virus (RSV). Immunophenotyping of blood cells showed frequencies of 62% CD3 + cells, 45% CD4 + T cells, 20% CD8 + T cells, 1.1% CD19 + B cells and 1% CD20 + B cells. The concentration of IFN-γ in response to Nil, Ag1, Ag2, Ag3 and mitogen tubes was 1, 12, 12, 12 and 988 IU/ml, respectively ( Tables 2 and 3 ) . She was treated with Rituximab every six months for her underlying disease. The patient was treated with Remdesivir (200 mg), Dexamethasone (8 mg) and intravenous immunoglobulin (IVIG, 2 g/kg) and subsequently discharged. Case 5 A 31-year old woman with a history of MS was referred to the Masih Daneshvari Hospital on 9th May 2022. She had been treated with rituximab (500 mg, every 6–12 months) for the past 13 years for her MS. One month before admission, she had developed a fever, sore throat and cough. At admission, she complained about the cough and progressive shortness of breath. She had received her 2nd dose of SINO vaccine 3 months previously. A chest x-ray revealed bilateral lung infiltrates and the diagnosis of severe COVID-19 pneumonia was made following a positive nasopharyngeal SARS-CoV-2 PCR test. She had a history of a low blood B-cell frequency in blood. Laboratory analysis gave high serum LDH (315 U/L), total serum IgG (292 mg/dl), IgA (38 mg/dl) and IgM (28 mg/dl). The WBC was 6.1 x 10 9 /l with a normal lymphocyte count range (1.23 x 10 9 /l). Immunophenotyping of blood immune cells gave frequencies of 55% CD3 + cells, 41% CD4 + T cells, 12% CD8 + T cells, 2.5% CD19 + B cells and 0% CD20 + B cells 0%. The concentration of IFN-γ in responding to Nil, Ag1, Ag2, Ag3 and mitogen tubes was 7, 25, 13.5, 59 and 999 IU/ml, respectively ( Tables 2 and 3 ) . The patient was treated with Remdesivir (200 mg on day one followed by 100 mg on days two and three), hydrocortisone (50 mg of hydrocortisone intravenously every 8 hours) for 7 to 10 days), meropenem (1 gm), ciprofloxacin (500 mg two times a day) and IVIG (20 g/kg) and then discharged from hospital. Discussion Innate and adaptive immunity provide pathogen-specific immunity by stimulating humoral and cellular immune responses. By producing antibodies, B cells play a critical role in anti-viral humoral immunity. Specific cellular immunity to SARS-CoV-2 is mediated by T cells. Interestingly, previous studies have reported cooperation between T cell immunity and humoral responses in eliminating the SARS-CoV-2 virus ( 2 ). High-affinity interactions between self MHC presented SARS-CoV-2 peptides and T cell receptors (TCR) on T cells induces proliferation and differentiation of T cells which participates in the eradication of virus-infected cells and induces activation of B cells for antibody production. In this study, we presented 5 cases with long standing, more than 6 months PCR-positive COVID-19, patients admitted to hospital. All of these five patients had an underlying immunodeficiency. Lab analysis of blood of patients revealed defects in immune systems compartments mainly humoral responses. Most of these patients had defects in systemic B cell numbers and in their humoral responses which may account for their long standing SARS-CoV-2 infection. For example, in patients with GS infection with SARS-CoV-2 virus is generally fatal ( 26 ). In the GS patient investigated in the current study, the cellular immune response to SARS-CoV-2 antigens (Ag1, Ag2 and Ag3) was defective as indicated by the Q-FN SARS-CoV-2 assays. A low frequency of peripheral blood B and CD4 + T cells were also detected in this patient. CD4 + T cells are essential for sustaining germinal center (GC) formation and B cell differentiation leading to isotype switch and immunoglobulin maturation, two features of T cell-dependent humoral ( 27 ). In addition, CD4 + T cell depletion is associated with GC formation in the lymph nodes of severe COVID-19 patients ( 28 ). Persistent SARS-CoV-2 infection has previously been reported in CLL patients ( 29 ) which was the underlying disease in the second of the 5 patients studied here. The patient had a very weak cell mediated response against SARS-CoV-2 antigens as detected by the Q-FN test. Patients with CLL have a reduced adaptive immune and T-cell response indicated by hypogammaglobulinemia. In these patients, T cells are usually increased at early stages of the disease with increasing exhaustion of T cells as the disease progresses ( 30 ). Thus, the persistence of the SARS-CoV-2 viral infection in patient 2 may result from a long-term defect in both B and T cells. Many studies have shown that patients with HIV infection are susceptible to SARS-CoV-2 infection due to their defect in T cell function ( 33 , 34 ). In the current study, evaluation of the cell-mediated response in the HIV patient indicates a very low release of IFN-γ following exposure to SARS-CoV2 antigens. Thus, we conclude that defects in CD4 + cells in HIV patients impacts upon the B cell humoral response. Patients 4 and 5 both suffered from MS and were treated with an anti-CD20 monoclonal antibody and had been PCR positive for SARS-CoV-2 infection for 6 months. The rate of hospitalization in MS patients was generally higher than in other groups although mortality was rare in these patients following SARS-CoV-2 infection ( 35 – 37 ). Due to their anti-CD20 treatment, the frequency of CD19+/20 + cells in these patients was low. Evaluation of their cell mediated responses indicated that one MS patient had low IFN-γ release in response to SARS-CoV2 antigens especially to Ag 1 and 2 suggesting a B cell impact on T cell function ( 38 , 39 ) In conclusion, T-cell dependent antibody responses require the activation of B cells byT helper cells responding to the same antigen ( 40 , 41 ). In all our cases, the B cell frequency and in the absence of B cells, the body critically suffers from an inability to generate specific antibodies against SARS-CoV-2 antigens. Thus, it is very important for health workers to be aware of the high risk of infection in immunocompromised patients during pandemics. Early recognition of these patients and their access to adequate protection and health care is essential. Patients with a weak immune system are thereby able to sustain the virus for the long time enabling the virus to mutate and generate new variants. Declarations Ethical Approval The study was approved by the institutional ethics board of the Masih Daneshvari Hospital (Ethics number SBMU.NRITLD.REC.1399.226). Competing interests: There is no confidential interest in this work. Authors' contributions: EM did experiments and wrote first draft of analysis. NDR and SH helped in experiments and analysis, HRJ, ZA, BA and MR approved the patients and provided samples. Ian M Adcock extensively revised manuscript and PT approved final version of manuscript. Acknowledgement The authors appreciated from all participants in this study. Funding: IMA supported by the EPSRC (EP/T003189/1 and EP/V052462/1), the UK MRC (MR/T010371/1 and MR/M016579/1), Wellcome Trust (208340/Z/17/Z) and the Imperial College Jameel Trust for work on COVID-19. Availability of data and materials: All provided data available in this paper. References Mortaz E, Tabarsi P, Varahram M, Folkerts G, Adcock IM. The immune response and immunopathology of COVID-19. Front Immunol. 2020;11:2037. Melenotte C, Silvin A, Goubet A-G, Lahmar I, Dubuisson A, Zumla A, et al. Immune responses during COVID-19 infection. Oncoimmunology. 2020;9(1):1807836. Rezaei M, Mahmoudi S, Mortaz E, Marjani M. Immune cell profiling and antibody responses in patients with COVID-19. BMC Infect Dis. 2021;21(1):646. Ahmadpoor P, Rostaing L. Why the immune system fails to mount an adaptive immune response to a Covid-19 infection. Transpl Int. 2020;33(7):824–5. Chen Z, John Wherry E. T cell responses in patients with COVID-19. Nat Rev Immunol. 2020;20(9):529–36. 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Tables Table 1 Antibodies used for immunophenotyping Clone Company Mouse anti-human CD4-FITC S 3.5 Life technologies Mouse anti-human CD8-PE Cyt-8PE9 Cytogenos Mouse anti human CD3-PerCP-Cyanine 5.5 Cyt-3C9 Cytogenos Mouse anti-human CD19-FITC LT19 eBioscience Mouse anti-human CD20-PE 2H7 Biolegend Mouse anti-human CD16/56-PE-Cy5 RPA-T4 eBioscience Table 2 Patient characteristics and biochemical information Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Mean ± SEM Healthy subjects (n = 4) Gender M F M F F Age, years 46 54 31 27 31 37 ± 5.19 32.5 ± 3.279 WBC count (cell × 10 3 /µl) 4.3 5.515 6.6 5.1 6.1 Lymphocyte (cell × 10 3 /mm 3 ) 0.5 0.4 0.9 1.32 1.28 0.88 ± 0.1909 - LDH (U/L) 813 492 425 486 315 506 ± 83.03 - CPK (mg/l) 24 - 44 - - 34 ± 10 - ESR (mm/hr) 52 75 54 70 - 62.75 ± 5.735 - IL-6 (pg/ml) 76 149 1 - 1 56.75 ± 35.47 - IgM (mg/dl) 28 - - 58 - 43 ± 15 - IgG (mg/dl) 392 - - 678 - 535 ± 143 - Ig A (mg/dl) 38 - - 38 - 38 ± 0.0 - Vaccines received 2 doses Sinopharm 1 dose AZD 2 doses Sinopharm No vaccine 2 doses Sinopharm Table 3 The frequency of T and B cells and IFN-γ response to SARS-CoV2 Antigens Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Mean ± SEM Control 1 Control 2 Control 3 Control 4 Mean ± SEM *P value CD3 + cells (%) 77.4 - 49.6 62 55 61 ± 6.027 57.2 62.4 54.2 47.2 55.25 ± 3.17 0.6557 CD4 + cells (%) 29.9 16 0.78 45 41 26.54 ± 8.17 37.8 67.1 36.7 24.3 41.48 ± 9.07 0.5556 CD8 + cells (%) 62.9 64 91 20 12 49.98 ± 14.81 30.6 29.4 28.8 43.1 32.98 ± 3.39 0.3520 CD19 + cells (%) 10 4.04 14.5 1.1 2.5 6.43 ± 2.52 12.1 21.5 11.9 23.4 17.23 ± 3.04 0.0282 CD20 + cells (%) 1.3 0 13 1 0 3.06 ± 2.49 12 20 11.6 22.4 16.5 ± 2.76 0.0087 CD16 + CD56+ 2.2 13 15 2.2 12 8.88 ± 2.77 14.1 10.5 14.9 3.41 10.73 ± 2.62 0.6496 Median (5–95 percentile) Median (5–95 percentile) IFN-γ IU/mL (Nil) 98 1 1 7 3 3 (1–98) 14 4 1 2 3 (1–14) - IFN-γ IU/mL (Ag1) 95 1 12 25 1 12 (1–95) 89.5 14 7 35 24.5 (7–89) - IFN-γ IU/mL (Ag2) 78 1.5 12 13.5 2.5 12 (1.5–78) 173 31 41 89 65 (31–173) - IFN-γ IU/mL (Ag3) 95 13 12 59 13.5 13.5 (12–95) 71.5 41 13 66 53.5 (13-71.5) - IFN-γ IU/mL (mitogen) 866 397 988 999 664 866 (397–999) 999 845 932 938 935( 845–999) - *Comparisons of data were performed using Mann-Whitney U test. 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case reports and literature review","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIn December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV‐2) was identified in Wuhan (China) as a novel human pathogen causing coronavirus disease 2019 (COVID‐19) which rapidly became a pandemic (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). In the immune response against SARS-CoV-2 infection, the innate immune system acts as the first line of defense, recognizing the virus through pattern recognition receptors and activating inflammatory pathways that promote viral removal (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). The adaptive immune response is a major determinant of the clinical outcome after SARS-CoV-2 infection and underpins vaccine efficacy (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAdaptive immune responses are necessary to control and redirect SARS-CoV-2 infection but its relative importance is unclear. Observations from patients infected with SARS-CoV-1 and Middle East respiratory syndrome )MERS( shows that T cells may be the major mediators of disease control (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) and high antibody levels have been associated with increased inflammation and impaired clinical outcome in SARS-CoV-1 (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). T cell responses develop early and correlate with protection but are relatively impaired in severe disease and are associated with intense activation and lymphopenia (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Both genetic and acquired factors play a role in effective interferon signaling during acute infection by SARS-CoV-2 (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). In patients with COVID-19, severe clinical outcomes corresponds with a slow decline in viral load and early and continuous inflammation with increasing levels of cytokines such as (IFN)-α, IFN-γ and tumor necrosis factor) TNF( (\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn first steps of the adaptive immune response, cytotoxic CD8\u0026thinsp;+\u0026thinsp;T cell appear within 7 days of symptoms and they reach their peak at 14 days correlating with effective viral clearance (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Humoral response kinetics against SARS-CoV-2 is similar to that for cellular responses (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). In patients with SARS-CoV-2 infection, B cell responses typically arise first against the nucleocapsid (N) protein followed by antibody responses to the S protein after 4\u0026ndash;8 days (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). The importance of the adaptive immune system suggests that immunocompromised patients may be at higher risk for development of severe COVID-19 disease. Indeed, the risk of COVID-19 disease severity depends on comorbidities and underlying disorders such as diabetes, hypertension and obesity (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn comparison to the general population, adult patients with primary immune deficiency (PID) and symptomatic acquired immune deficiency (AID) show a greater morbidity and mortality from COVID-19 disease (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). People with multiple sclerosis (MS) treated with B cell depleting antibodies, have a higher risk of infection and related mortality than healthy controls (\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHuman immunodeficiency virus (HIV) is responsible for an acquired immune deficiency and people living with HIV/AIDS (PLWH) are in the high-risk group for the SARS-COV-2 infection. In addition to T cell defects, antibody responses following immune system challenge are also impaired in PLWH these patients have a high risk for severe SARS-CoV-2 infection (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Here we reported unusual long standing SARS-COV-2 infection in patients with various underlying immunosuppressed disease.\u003c/p\u003e"},{"header":"Material And Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient sample collection\u003c/h2\u003e \u003cp\u003e5 confirmed COVID-19 patients with predominant Omicron (B.1.1.529) SARS-CoV-2 variant infection, including 3 patients vaccinated with two doses of Sinopharm [Vero], 1 patient vaccinated with a single dose of Oxford/AstraZeneca (ChAdOx1-S [recombinant] vaccine) COVID-19 vaccine, 1 patient who had not received any vaccine were enrolled into the study upon admission to the Masih Daneshvari Hospital of the Shahid Beheshti Medical University, Tehran-Iran between May 8th - July 5th 2022. COVID-19 disease was confirmed by polymerase chain reaction (PCR) from nasopharyngeal samples using specific primers for SARS-CoV-2. All patients were diagnosed according to World Health Organization (WHO) interim guidelines (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e5 ml peripheral blood samples were collected in heparin anticoagulant tubes for detection of IFN-γ release assays and T cell and B cell immunephenotyping as described previously (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eEvaluation of cell response by QuantiFERON (Q-FN) SARS-CoV-2 test\u003c/h2\u003e \u003cp\u003eT cell responses were evaluated using the Q-FN SARS-CoV-2 assay as described previously (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). This assay consists of three antigens (Ag) tubes, including SARS-CoV-2 Ag1, Ag2 and Ag3. The Q-FN SARS CoV-2 Ag1 tube contains CD4\u0026thinsp;+\u0026thinsp;epitopes derived from the S1 subunit, Ag2 tube contains CD4\u0026thinsp;+\u0026thinsp;and CD8\u0026thinsp;+\u0026thinsp;epitopes from the S1 and S2 subunits, and the Ag3 tube consists of CD4\u0026thinsp;+\u0026thinsp;and CD8\u0026thinsp;+\u0026thinsp;epitopes from S1 and S2, plus immunodominant CD8\u0026thinsp;+\u0026thinsp;epitopes derived from whole genome. 5 ml whole fresh blood was added to each tube and after 24h, the plasma was harvested and the release of IFN-γ was evaluated by ELISA.\u003c/p\u003e \u003cp\u003eElevated IFN-γ was defined as a value at least 0.20 IU/ml greater than the background as indicated as described earlier (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eFlow Cytometry\u003c/h3\u003e\n\u003cp\u003eTo determine CD4\u0026thinsp;+\u0026thinsp;and CD8\u0026thinsp;+\u0026thinsp;T, NK and B cell immunophenotyping, surface staining of CD4, CD8, CD19, CD20 and CD16/56 markers was undertaken using specific antibodies (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). 10000 events were evaluated with BD FACSCalibur (BD Biosciences, CA, USA) and analyzed using FlowJo Software version 10 (BD Bioscience).\u003c/p\u003e"},{"header":"Cases Presentation Data","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eCase 1\u003c/h2\u003e \u003cp\u003eA 47-year old man with Good's syndrome (GS, thymoma with immunodeficiency; a rare cause of combined B and T cell immunodeficiency in adults) was referred to the Masih Daneshvari Hospital on June 19th 2022 complaining of cough and progressive shortness of breath at admission. The patient had been PCR positive for SARS-CoV-2 RNA for one year. Upon admission, he had a PCR positive nasopharyngeal swab. This patient had received 2 doses of SINO vaccine. Chest x-ray image revealed bilateral infiltrates in lungs indicative of COVID-19 pneumonia. Sequence analysis showed the presence of the Delta variant (B.1.617.2). Shortly after admission, the patient deteriorated, and laboratory analysis of blood tests showed a white blood cell count of 4.3 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/l (4\u0026ndash;11.0) with a profound lymphopenia (0.5 x 10\u003csup\u003e9\u003c/sup\u003e/l) and elevated systemic levels of IL-6 (76 pg/ml, normal levels\u0026thinsp;\u0026lt;\u0026thinsp;8pg/ml), lactate dehydrogenase (LDH, 813 U/L), creatine phosphokinase (CPK, 24 mg/l) and erythrocyte sedimentation rate (ESR, 24 mm/hr). Immunophenotyping of surface markers indicated 77.4% CD3\u003csup\u003e+\u003c/sup\u003e T cells, 29.9% CD4\u0026thinsp;+\u0026thinsp;T cells, 62.9% CD8\u0026thinsp;+\u0026thinsp;T cells, 2.2% CD19\u0026thinsp;+\u0026thinsp;B cells and 1.3% CD20\u0026thinsp;+\u0026thinsp;B cells (Tables\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe levels of IFN-γ shows responses to Nil, Ag1, Ag2, Ag3 and mitogen tubes as 98, 95, 78, 95 and 866 IU/ml, respectively. The patient developed acute respiratory distress syndrome (ARDS) after 2 days and was admitted to the intensive care unit (ICU). Oxygenation was maintained with continuous positive airway pressure therapy (CPAP) before the patient was eventually intubated. He was treated with antiviral drugs, broad spectrum antibiotics and steroids as well as the IL-6 inhibitor, Tocilizumab (8\u0026ndash;12 mg/kg) according to the hospital policy resulting in a marked drop in the levels of inflammatory markers. The patient developed a pulmonary embolism and cardiac arrest and died.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eCase 2\u003c/h2\u003e \u003cp\u003eA 53-year old man with known chronic lymphocytic leukemia (CLL) and diabetes mellitus in history was referred to the Hospital on 17th May 2022. CLL was treated with chemotherapy and anti-CD20 monoclonal antibody (Rituximab 375 mg/m\u003csup\u003e2\u003c/sup\u003e IV infusion, given on Day 1 of each cycle of chemotherapy, for up to 8 doses). He had a prolonged COVID-19 disease with a positive SARS-CoV-2 PCR for the previous 6 months. He was hospitalized with fever, cough and sputum and had a previous history of hospitalization for an embolus. The patient had received 1 dose of AZD vaccine. He had a PCR positive nasopharyngeal swab which was predominantly of the Omicron (B.1.1.529) variant. Laboratory tests showed elevated ESR (75 mm/hr), LDH (492 U/L) and IL-6 (149 pg/ml) levels. The white blood cell count was 5.515 x 10\u003csup\u003e9\u003c/sup\u003e/l with a lymphopenia of 0.4 x 10\u003csup\u003e9\u003c/sup\u003e/l. Immunophenotyping gave 16% CD4\u0026thinsp;+\u0026thinsp;T cells, 64% CD8\u0026thinsp;+\u0026thinsp;T cells, 4.04% CD19\u0026thinsp;+\u0026thinsp;B cells and 0% CD20\u0026thinsp;+\u0026thinsp;B cells. The release of IFN-γ in response to Nil, Ag1, Ag2, Ag3 and mitogen tubes was 3, 1, 2.5, 13.5 and 664 IU/ml, respectively \u003cb\u003e(\u003c/b\u003eTables\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003eThe patient was treated with antiviral drugs (Remdesivir 100 mg once daily), Dexamethasone 8mg/Day, tocilizumab 8 mg/kg/dose for 5 days and gradually recovered and had a negative SARS-CoV-2 PCR after 30 days of treatment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eCase 3\u003c/h2\u003e \u003cp\u003eA 31-year old man with signs of COVID-19 was referred to the Hospital on 11th May 2022. He had a cough and progressive shortness of breath for the previous 4 months. He was HIV/AIDS antibody positive and positive for HIV by PCR. The patient had received their 2nd dose of SINO vaccine two months previously. Chest x-ray revealed bilateral lung infiltrates and was diagnosed as having COVID-19 pneumonia. He had a positive SARS-CoV-2 PCR test with a predominance of the Omicron (B.1.1.529) variant.\u003c/p\u003e \u003cp\u003eLaboratory evaluation of blood samples revealed LDH (425 U/l), ESR (54 mm/hr), CPK (44 mg/l) and a WBC of 6.6 x 10\u003csup\u003e9\u003c/sup\u003e/l with a lymphopenia of 0.9 x 10\u003csup\u003e9\u003c/sup\u003e/l. Immunophenotyping of blood cells indicated 49.6% CD3\u0026thinsp;+\u0026thinsp;cells, 0.78 CD4\u0026thinsp;+\u0026thinsp;T cells, 91% CD8\u0026thinsp;+\u0026thinsp;T cells, 14.5% CD19\u0026thinsp;+\u0026thinsp;B cells and 13% CD20\u0026thinsp;+\u0026thinsp;B cells frequencies. The concentration of IFN-γ in response to Nil, Ag1, Ag2, Ag3 and mitogen tubes was 1, 1, 1.5, 13 and 397 IU/ml respectively \u003cb\u003e(\u003c/b\u003eTables\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cb\u003e).\u003c/b\u003e\u003c/p\u003e \u003cp\u003eUpon hospitalization, he had been PCR positive for SARS-CoV-2 for the previous 5 months. He was treated with anti-HIV viral therapy according to standard protocols (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.cdc.gov/hiv/basics/livingwithhiv/treatment.html\u003c/span\u003e\u003cspan address=\"https://www.cdc.gov/hiv/basics/livingwithhiv/treatment.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). He also had a high cytomegalovirus (CMV) load which was negative after treatment. Five months after admission, the patient gave a negative nasopharyngeal SARS-CoV-2 PCR test. The patient was discharged home in good condition on the 21st June 2022\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eCase 4\u003c/h2\u003e \u003cp\u003eA 27-year old woman was referred to the Hospital in 8th May 2022 with signs of COVID-19 disease. In her past medical history included Multiple Sclerosis (MS). She had a history of hospitalization and was under treatment with rituximab (500 mg). She had prolonged COVID-19 disease for the previous 6 months as defined by positive PCR tests. At admission, she complained of fever (up to 39.5 C), chills, cough and progressive shortness of breath and gave two positive nasopharyngeal SARS-CoV-2 tests. The patient had not received a COVID-19 vaccine. Upon hospitalization, the patient deteriorated and laboratory tests showed high serum LDH (315 U/l), IL-6 (1 pg/ml) and specific IgG and IgA against S1 subunit of SARS-CoV-2 (0.3 and 3 mg/dl) respectively. The total IgG was 678 mg/dl, IgA 38 mg/dl and IgM 58 mg/dl. Moreover, the patient had a WBC of 5.1 x 10\u003csup\u003e9\u003c/sup\u003e/L with a lymphocyte count of 1.32 x 10\u003csup\u003e9\u003c/sup\u003e/l. She was blood test negative for mycobacterium tuberculosis (MTB) culture and PCR, CMV, Toxoplasma and respiratory syncytial virus (RSV).\u003c/p\u003e \u003cp\u003eImmunophenotyping of blood cells showed frequencies of 62% CD3\u0026thinsp;+\u0026thinsp;cells, 45% CD4\u0026thinsp;+\u0026thinsp;T cells, 20% CD8\u0026thinsp;+\u0026thinsp;T cells, 1.1% CD19\u0026thinsp;+\u0026thinsp;B cells and 1% CD20\u0026thinsp;+\u0026thinsp;B cells. The concentration of IFN-γ in response to Nil, Ag1, Ag2, Ag3 and mitogen tubes was 1, 12, 12, 12 and 988 IU/ml, respectively \u003cb\u003e(\u003c/b\u003eTables\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. She was treated with Rituximab every six months for her underlying disease. The patient was treated with Remdesivir (200 mg), Dexamethasone (8 mg) and intravenous immunoglobulin (IVIG, 2 g/kg) and subsequently discharged.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eCase 5\u003c/h2\u003e \u003cp\u003eA 31-year old woman with a history of MS was referred to the Masih Daneshvari Hospital on 9th May 2022. She had been treated with rituximab (500 mg, every 6\u0026ndash;12 months) for the past 13 years for her MS. One month before admission, she had developed a fever, sore throat and cough. At admission, she complained about the cough and progressive shortness of breath. She had received her 2nd dose of SINO vaccine 3 months previously. A chest x-ray revealed bilateral lung infiltrates and the diagnosis of severe COVID-19 pneumonia was made following a positive nasopharyngeal SARS-CoV-2 PCR test.\u003c/p\u003e \u003cp\u003eShe had a history of a low blood B-cell frequency in blood. Laboratory analysis gave high serum LDH (315 U/L), total serum IgG (292 mg/dl), IgA (38 mg/dl) and IgM (28 mg/dl). The WBC was 6.1 x 10\u003csup\u003e9\u003c/sup\u003e/l with a normal lymphocyte count range (1.23 x 10\u003csup\u003e9\u003c/sup\u003e/l). Immunophenotyping of blood immune cells gave frequencies of 55% CD3\u0026thinsp;+\u0026thinsp;cells, 41% CD4\u0026thinsp;+\u0026thinsp;T cells, 12% CD8\u0026thinsp;+\u0026thinsp;T cells, 2.5% CD19\u0026thinsp;+\u0026thinsp;B cells and 0% CD20\u0026thinsp;+\u0026thinsp;B cells 0%. The concentration of IFN-γ in responding to Nil, Ag1, Ag2, Ag3 and mitogen tubes was 7, 25, 13.5, 59 and 999 IU/ml, respectively \u003cb\u003e(\u003c/b\u003eTables\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. The patient was treated with Remdesivir (200 mg on day one followed by 100 mg on days two and three), hydrocortisone (50 mg of hydrocortisone intravenously every 8 hours) for 7 to 10 days), meropenem (1 gm), ciprofloxacin (500 mg two times a day) and IVIG (20 g/kg) and then discharged from hospital.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eInnate and adaptive immunity provide pathogen-specific immunity by stimulating humoral and cellular immune responses. By producing antibodies, B cells play a critical role in anti-viral humoral immunity. Specific cellular immunity to SARS-CoV-2 is mediated by T cells. Interestingly, previous studies have reported cooperation between T cell immunity and humoral responses in eliminating the SARS-CoV-2 virus (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). High-affinity interactions between self MHC presented SARS-CoV-2 peptides and T cell receptors (TCR) on T cells induces proliferation and differentiation of T cells which participates in the eradication of virus-infected cells and induces activation of B cells for antibody production.\u003c/p\u003e \u003cp\u003eIn this study, we presented 5 cases with long standing, more than 6 months PCR-positive COVID-19, patients admitted to hospital. All of these five patients had an underlying immunodeficiency. Lab analysis of blood of patients revealed defects in immune systems compartments mainly humoral responses. Most of these patients had defects in systemic B cell numbers and in their humoral responses which may account for their long standing SARS-CoV-2 infection.\u003c/p\u003e \u003cp\u003eFor example, in patients with GS infection with SARS-CoV-2 virus is generally fatal (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). In the GS patient investigated in the current study, the cellular immune response to SARS-CoV-2 antigens (Ag1, Ag2 and Ag3) was defective as indicated by the Q-FN SARS-CoV-2 assays. A low frequency of peripheral blood B and CD4\u0026thinsp;+\u0026thinsp;T cells were also detected in this patient. CD4\u003csup\u003e+\u003c/sup\u003e T cells are essential for sustaining germinal center (GC) formation and B cell differentiation leading to isotype switch and immunoglobulin maturation, two features of T cell-dependent humoral (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). In addition, CD4\u0026thinsp;+\u0026thinsp;T cell depletion is associated with GC formation in the lymph nodes of severe COVID-19 patients (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePersistent SARS-CoV-2 infection has previously been reported in CLL patients (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e) which was the underlying disease in the second of the 5 patients studied here. The patient had a very weak cell mediated response against SARS-CoV-2 antigens as detected by the Q-FN test. Patients with CLL have a reduced adaptive immune and T-cell response indicated by hypogammaglobulinemia. In these patients, T cells are usually increased at early stages of the disease with increasing exhaustion of T cells as the disease progresses (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Thus, the persistence of the SARS-CoV-2 viral infection in patient 2 may result from a long-term defect in both B and T cells.\u003c/p\u003e \u003cp\u003eMany studies have shown that patients with HIV infection are susceptible to SARS-CoV-2 infection due to their defect in T cell function (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). In the current study, evaluation of the cell-mediated response in the HIV patient indicates a very low release of IFN-γ following exposure to SARS-CoV2 antigens. Thus, we conclude that defects in CD4\u0026thinsp;+\u0026thinsp;cells in HIV patients impacts upon the B cell humoral response.\u003c/p\u003e \u003cp\u003ePatients 4 and 5 both suffered from MS and were treated with an anti-CD20 monoclonal antibody and had been PCR positive for SARS-CoV-2 infection for 6 months. The rate of hospitalization in MS patients was generally higher than in other groups although mortality was rare in these patients following SARS-CoV-2 infection (\u003cspan additionalcitationids=\"CR36\" citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e). Due to their anti-CD20 treatment, the frequency of CD19+/20\u0026thinsp;+\u0026thinsp;cells in these patients was low. Evaluation of their cell mediated responses indicated that one MS patient had low IFN-γ release in response to SARS-CoV2 antigens especially to Ag 1 and 2 suggesting a B cell impact on T cell function (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eIn conclusion, T-cell dependent antibody responses require the activation of B cells byT helper cells responding to the same antigen (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e). In all our cases, the B cell frequency and in the absence of B cells, the body critically suffers from an inability to generate specific antibodies against SARS-CoV-2 antigens. Thus, it is very important for health workers to be aware of the high risk of infection in immunocompromised patients during pandemics. Early recognition of these patients and their access to adequate protection and health care is essential. Patients with a weak immune system are thereby able to sustain the virus for the long time enabling the virus to mutate and generate new variants.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical Approval\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the institutional ethics board of the Masih Daneshvari Hospital (Ethics number SBMU.NRITLD.REC.1399.226).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere is no confidential interest in this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEM did experiments and wrote first draft of analysis. NDR and SH helped in experiments and analysis, HRJ, ZA, BA and MR approved the patients and provided samples. Ian M Adcock extensively revised manuscript and PT approved final version of manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors appreciated from all participants in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIMA supported by the EPSRC (EP/T003189/1 and EP/V052462/1), the UK MRC (MR/T010371/1 and MR/M016579/1), Wellcome Trust (208340/Z/17/Z) and the Imperial College Jameel Trust for work on COVID-19.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll provided data available in this paper.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMortaz E, Tabarsi P, Varahram M, Folkerts G, Adcock IM. 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Ann Neurol. 2021;89(4):780\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSahraian MA, Azimi A, Navardi S, Ala S, Moghadasi AN. Evaluation of the rate of COVID-19 infection, hospitalization and death among Iranian patients with multiple sclerosis. Multiple Scler Relat disorders. 2020;46:102472.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLanger-Gould A, Smith JB, Li BH, Group tKMS. Multiple sclerosis, rituximab, and COVID-19. Ann Clin Transl Neurol. 2021;8(4):938\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGrimbacher B, Hutloff A, Schlesier M, Glocker E, Warnatz K, Dr\u0026auml;ger R, et al. Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat Immunol. 2003;4(3):261\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTay C, Kanellakis P, Hosseini H, Cao A, Toh B-H, Bobik A, et al. B Cell and CD4 T Cell Interactions Promote Development of Atherosclerosis. Frontiers in Immunology. 2020;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu Y, Wu Y, Ramarathinam L, Guo Y, Huszar D, Trounstine M, et al. Gene-targeted B-deficient mice reveal a critical role for B cells in the CD4 T cell response. Int Immunol. 1995;7(8):1353\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLund FE, Randall TD. Effector and regulatory B cells: modulators of CD4 + T cell immunity. Nat Rev Immunol. 2010;10(4):236-.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAntibodies used for immunophenotyping\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eClone\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCompany\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMouse anti-human CD4-FITC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eS 3.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLife technologies\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMouse anti-human CD8-PE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCyt-8PE9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCytogenos\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMouse anti human CD3-PerCP-Cyanine 5.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCyt-3C9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCytogenos\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMouse anti-human CD19-FITC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLT19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eeBioscience\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMouse anti-human CD20-PE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2H7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBiolegend\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMouse anti-human CD16/56-PE-Cy5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRPA-T4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eeBioscience\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient characteristics and biochemical information\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePatient 1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePatient 2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePatient 3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePatient 4\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePatient 5\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SEM\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eHealthy subjects (n\u0026thinsp;=\u0026thinsp;4)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e37\u0026thinsp;\u0026plusmn;\u0026thinsp;5.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e32.5\u0026thinsp;\u0026plusmn;\u0026thinsp;3.279\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWBC count (cell \u0026times; 10\u003csup\u003e3\u003c/sup\u003e/\u0026micro;l)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.515\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphocyte (cell \u0026times; 10\u003csup\u003e3\u003c/sup\u003e/mm\u003csup\u003e3\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e0.88\u0026thinsp;\u0026plusmn;\u0026thinsp;0.1909\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLDH (U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e813\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e492\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e425\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e486\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e315\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e506\u0026thinsp;\u0026plusmn;\u0026thinsp;83.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCPK (mg/l)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e34\u0026thinsp;\u0026plusmn;\u0026thinsp;10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eESR (mm/hr)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e62.75\u0026thinsp;\u0026plusmn;\u0026thinsp;5.735\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIL-6 (pg/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e149\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e56.75\u0026thinsp;\u0026plusmn;\u0026thinsp;35.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIgM (mg/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e43\u0026thinsp;\u0026plusmn;\u0026thinsp;15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIgG (mg/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e392\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e678\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e535\u0026thinsp;\u0026plusmn;\u0026thinsp;143\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIg A (mg/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c7\"\u003e \u003cp\u003e38\u0026thinsp;\u0026plusmn;\u0026thinsp;0.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVaccines received\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 doses Sinopharm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 dose AZD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 doses Sinopharm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo vaccine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2 doses Sinopharm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe frequency of T and B cells and IFN-γ response to SARS-CoV2 Antigens\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"13\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePatient 1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePatient 2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePatient 3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePatient 4\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePatient 5\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SEM\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eControl 1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eControl 2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eControl 3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003eControl 4\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c12\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SEM\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c13\"\u003e \u003cp\u003e*P value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD3\u0026thinsp;+\u0026thinsp;cells (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e77.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e49.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e61\u0026thinsp;\u0026plusmn;\u0026thinsp;6.027\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e57.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e62.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e54.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e47.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e55.25\u0026thinsp;\u0026plusmn;\u0026thinsp;3.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.6557\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD4\u0026thinsp;+\u0026thinsp;cells (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e26.54\u0026thinsp;\u0026plusmn;\u0026thinsp;8.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e37.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e67.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e36.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e24.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e41.48\u0026thinsp;\u0026plusmn;\u0026thinsp;9.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.5556\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD8\u0026thinsp;+\u0026thinsp;cells (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e49.98\u0026thinsp;\u0026plusmn;\u0026thinsp;14.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e30.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e29.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e28.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e43.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e32.98\u0026thinsp;\u0026plusmn;\u0026thinsp;3.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.3520\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD19\u0026thinsp;+\u0026thinsp;cells (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6.43\u0026thinsp;\u0026plusmn;\u0026thinsp;2.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e12.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e21.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e11.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e23.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e17.23\u0026thinsp;\u0026plusmn;\u0026thinsp;3.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u003cb\u003e0.0282\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD20\u0026thinsp;+\u0026thinsp;cells (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.06\u0026thinsp;\u0026plusmn;\u0026thinsp;2.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e11.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e22.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e16.5\u0026thinsp;\u0026plusmn;\u0026thinsp;2.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u003cb\u003e0.0087\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD16\u0026thinsp;+\u0026thinsp;CD56+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e8.88\u0026thinsp;\u0026plusmn;\u0026thinsp;2.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e14.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e10.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e14.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e3.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e10.73\u0026thinsp;\u0026plusmn;\u0026thinsp;2.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.6496\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMedian (5\u0026ndash;95 percentile)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c11\" namest=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eMedian (5\u0026ndash;95 percentile)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIFN-γ IU/mL (Nil)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3 (1\u0026ndash;98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e3 (1\u0026ndash;14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIFN-γ IU/mL (Ag1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e12 (1\u0026ndash;95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e89.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e24.5 (7\u0026ndash;89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIFN-γ IU/mL (Ag2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e12 (1.5\u0026ndash;78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e173\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e65 (31\u0026ndash;173)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIFN-γ IU/mL (Ag3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e13.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e13.5 (12\u0026ndash;95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e71.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e53.5 (13-71.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIFN-γ IU/mL (mitogen)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e866\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e397\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e988\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e664\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e866 (397\u0026ndash;999)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e845\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e932\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e938\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e935( 845\u0026ndash;999)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"13\"\u003e*Comparisons of data were performed using Mann-Whitney U test.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Immunodeficiency, COVID-19, vaccine, SARS-COV-2","lastPublishedDoi":"10.21203/rs.3.rs-2225095/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2225095/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction:\u003c/strong\u003e Patients with primary or secondary immunodeficiency are at higher risk of severe disease and death following SARS-CoV-2 infection compared with the general population. We describe here the effect of rituximab therapy in 5 patients with humoral and cellular immune deficiencies (1 patient with thymoma or Good`syndrome, 1 HIV/AIDS positive patient, 2 patients with Multiple Sclerosis (MS) and 1 patient with chronic lymphocytic leukemia (CLL). T cell responses were evaluated using the QuantiFERON SARS-CoV-2 assay following incubation with the SARS-CoV-2 Ag1, Ag2 and Ag3 viral antigens.\u003cstrong\u003e \u003c/strong\u003eImmunephenotyping of T cells (TCD4+, TCD8+) and B cells (CD19+ and CD20+) was determined by flow cytometry.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e All studied immunocompromised patients showed reduced cellular immune responses (release of interferon (IFN)-g) to SARS-CoV-2 antigens than healthy controls [patients; Ag1, Ag2 and Ag3 and Nil (Median 5-95% percentile) (12 (1-95), 12 (1.5-78), 13.5 (12-95) \u0026nbsp;and 3 (1-98) U/ml)], ]controls; Ag1,Ag2 and Ag3 and Nil (Median 5-95% percentile) 24.5 (7-89), 65 (31-173), 53.5 (13-71.5) and 3 (1-14) U/ml)]. The frequency of peripheral blood B cells was also reduced in these patients compared to healthy control subjects (p=0.0282).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: T-cell dependent antibody responses require the activation of B cells by helper T cells. Reduced B cell numbers in immunocompromised patients infected with SARS-CoV-2 indicates the need for these patients to take additional precautions to prevent COVID-19 infection\u003c/p\u003e","manuscriptTitle":"Long-standing COVID-19 disease in immunedeficient patients; case reports and literature review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-11-14 22:02:23","doi":"10.21203/rs.3.rs-2225095/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ef3336ff-396f-4f0f-b4df-206150c0a9e8","owner":[],"postedDate":"November 14th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-03-09T12:59:17+00:00","versionOfRecord":[],"versionCreatedAt":"2022-11-14 22:02:23","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2225095","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2225095","identity":"rs-2225095","version":["v1"]},"buildId":"FbvkV6FR0MCFSLy54lSbu","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}