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1.
Biomedicines ; 10(5)2022 Apr 29.
Article in English | MEDLINE | ID: covidwho-1820168

ABSTRACT

Patients with severely impaired antibody responses represent a group at-risk in the SARS-CoV-2 pandemic due to the lack of Spike-specific neutralizing antibodies. The main objective of this paper was to assess, by a longitudinal prospective study, COVID-19 infection and mortality rates, and disease severity in the first two years of the pandemic in a cohort of 471 Primary Antibody Defects adult patients. As secondary endpoints, we compared SARS-CoV-2 annual mortality rate to that observed over a 10-year follow-up in the same cohort, and we assessed the impact of interventions done in the second year, vaccination and anti-SARS-CoV-2 monoclonal antibodies administration on the disease outcome. Forty-one and 84 patients were infected during the first and the second year, respectively. Despite a higher infection and reinfection rate, and a higher COVID-19-related mortality rate compared to the Italian population, the pandemic did not modify the annual mortality rate for any cause in our cohort compared to that registered over the last ten years in the same cohort. PADs patients who died from COVID-19 had an underlying end-stage lung disease. We showed a beneficial effect of MoAbs administration on the likelihood of hospitalization and development of severe disease. In conclusion, COVID-19 did not cause excess mortality in Severe Antibody Deficiencies.

2.
J Clin Immunol ; 2022 Apr 20.
Article in English | MEDLINE | ID: covidwho-1802997

ABSTRACT

COVID-19 manifestations range from asymptomatic to life-threatening infections. The outcome in different inborn errors of immunity (IEI) is still a matter of debate. In this retrospective study, we describe the experience of the of the Italian Primary Immunodeficiencies Network (IPINet). Sixteen reference centers for adult or pediatric IEI were involved. One hundred fourteen patients were enrolled including 35 pediatric and 79 adult patients. Median age was 32 years, and male-to-female ratio was 1.5:1. The most common IEI were 22q11.2 deletion syndrome in children (26%) and common variable immunodeficiency (CVID) in adults (65%). Ninety-one patients did not require hospital admission, and among these, 33 were asymptomatic. Hospitalization rate was 20.17%. Older age (p 0.004) and chronic lung disease (p 0.0008) represented risk factors for hospitalization. Hospitalized patients mainly included adults suffering from humoral immunodeficiencies requiring immunoglobulin replacement therapy and as expected had lower B cell counts compared to non-hospitalized patients. Infection fatality rate in the whole cohort was 3.5%. Seroconversion was observed is 86.6% of the patients evaluated and in 83.3% of CVID patients. 16.85% of the patients reported long-lasting COVID symptoms. All but one patient with prolonged symptoms were under IgRT. The fatality rate observed in IEI was slightly similar to the general population. The age of the patients who did not survive was lower compared to the general population, and the age stratified mortality in the 50-60 age range considerable exceeded the mortality from 50 to 60 age group of the Italian population (14.3 vs 0.6%; p < 0.0001). We hypothesize that this is due to the fact that comorbidities in IEI patients are very common and usually appear early in life.

3.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-330092

ABSTRACT

The Job Syndrome or Autosomal Dominant Hyper Immunoglobulin E Syndrome (AD-HIES, LOF-STAT3 gene) is a very rare inborn error of immunity disorder with multi-organ involvement and long-life post-infective damages. Longitudinal registries are of main importance to improve knowledge on natural history and management of these rare disorders. This study aims to describe the natural history of 30 Italian patients recorded in the IPINet registry with AD-HIES, with a cumulative observational-time of 721.1 patient-years. Age at disease onset was < 12 months in the 66.7% of patients, but the mean time of diagnostic delay was 13.7 years. At diagnosis skin involvement was present in 93.3% of patients (eczema 80.8%, abscess 66.7%). At the follow up eczema was still present in 63.3% and abscess in 56.7%. Respiratory complications such as bronchiectasis and pneumatoceles were present at diagnosis in the 46.7% and 43.3% respectively. Antimicrobial prophylaxis resulted in decrease of pneumonia from 76.7–46.7%. Antifungal prophylaxis decreased mucocutaneous candidiasis occurrence from 70–56.7%. In the course of SARS-CoV-2 pandemic, seven patients developed COVID-19. Survival analyses showed that 27 out of 30 patients are still alive, while three patients died at age of 28, 39 and 46 as consequence of lungs bleeding, lymphoma and sepsis, respectively. Our study shows that many severe complications can affect AD-HIES patients. Analysis of a cumulative follow-up of 278.7 patient-years has shown that early diagnosis, adequate management at expertise centres for primary immunodeficiency, prophylactic antibiotic and antifungal therapy improve outcome and can positively influence patients’ life expectancy.

4.
J Infect Dis ; 225(5): 820-824, 2022 03 02.
Article in English | MEDLINE | ID: covidwho-1722476

ABSTRACT

BACKGROUND: Previous reports highlighted the efficacy of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific monoclonal antibodies (mAbs) against coronavirus disease 2019. METHODS: We conducted a prospective study on the clinical outcome and antiviral effects of mAbs added to standard of care therapy in SARS-CoV-2-infected patients with primary antibody defects. RESULTS: Median time of SARS-CoV-2 quantitative polymerase chain reaction (qPCR) positivity was shorter in 8 patients treated with mAbs (22 days) than in 10 patients treated with standard of care therapy only (37 days, P=.026). Median time of SARS-CoV-2 qPCR positivity from mAb administration was 10 days. CONCLUSIONS: The SARS-CoV-2 mAbs treatment was effective and well tolerated in patients with primary antibody defects.


Subject(s)
Antibodies, Viral/therapeutic use , COVID-19/drug therapy , Common Variable Immunodeficiency , Primary Immunodeficiency Diseases/drug therapy , SARS-CoV-2/isolation & purification , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , Antibodies, Viral/immunology , Antineoplastic Agents, Immunological , Humans , Prospective Studies , Real-Time Polymerase Chain Reaction , Standard of Care
5.
J Infect Dis ; 225(5): 820-824, 2022 03 02.
Article in English | MEDLINE | ID: covidwho-1506650

ABSTRACT

BACKGROUND: Previous reports highlighted the efficacy of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific monoclonal antibodies (mAbs) against coronavirus disease 2019. METHODS: We conducted a prospective study on the clinical outcome and antiviral effects of mAbs added to standard of care therapy in SARS-CoV-2-infected patients with primary antibody defects. RESULTS: Median time of SARS-CoV-2 quantitative polymerase chain reaction (qPCR) positivity was shorter in 8 patients treated with mAbs (22 days) than in 10 patients treated with standard of care therapy only (37 days, P=.026). Median time of SARS-CoV-2 qPCR positivity from mAb administration was 10 days. CONCLUSIONS: The SARS-CoV-2 mAbs treatment was effective and well tolerated in patients with primary antibody defects.


Subject(s)
Antibodies, Viral/therapeutic use , COVID-19/drug therapy , Common Variable Immunodeficiency , Primary Immunodeficiency Diseases/drug therapy , SARS-CoV-2/isolation & purification , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , Antibodies, Viral/immunology , Antineoplastic Agents, Immunological , Humans , Prospective Studies , Real-Time Polymerase Chain Reaction , Standard of Care
6.
Cells ; 10(11)2021 10 27.
Article in English | MEDLINE | ID: covidwho-1488494

ABSTRACT

BACKGROUND: Patients with primary antibody deficiencies are at risk in the current COVID-19 pandemic due to their impaired response to infection and vaccination. Specifically, patients with common variable immunodeficiency (CVID) generated poor spike-specific antibody and T cell responses after immunization. METHODS: Thirty-four CVID convalescent patients after SARS-CoV-2 infection, 38 CVID patients immunized with two doses of the BNT162b2 vaccine, and 20 SARS-CoV-2 CVID convalescents later and immunized with BNT162b2 were analyzed for the anti-spike IgG production and the generation of spike-specific memory B cells and T cells. RESULTS: Spike-specific IgG was induced more frequently after infection than after vaccination (82% vs. 34%). The antibody response was boosted in convalescents by vaccination. Although immunized patients generated atypical memory B cells possibly by extra-follicular or incomplete germinal center reactions, convalescents responded to infection by generating spike-specific memory B cells that were improved by the subsequent immunization. Poor spike-specific T cell responses were measured independently from the immunological challenge. CONCLUSIONS: SARS-CoV-2 infection primed a more efficient classical memory B cell response, whereas the BNT162b2 vaccine induced non-canonical B cell responses in CVID. Natural infection responses were boosted by subsequent immunization, suggesting the possibility to further stimulate the immune response by additional vaccine doses in CVID.


Subject(s)
/immunology , COVID-19/immunology , Primary Immunodeficiency Diseases/immunology , SARS-CoV-2/immunology , Adult , Antibodies, Viral/immunology , COVID-19/complications , COVID-19/prevention & control , Convalescence , Female , Humans , Immunization , Immunoglobulin G/immunology , Male , Middle Aged , Primary Immunodeficiency Diseases/complications , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes/immunology
7.
J Clin Immunol ; 41(8): 1709-1722, 2021 11.
Article in English | MEDLINE | ID: covidwho-1474048

ABSTRACT

BACKGROUND: Data on immune responses to SARS-CoV-2 in patients with Primary Antibody Deficiencies (PAD) are limited to infected patients and to heterogeneous cohorts after immunization. METHODS: Forty-one patients with Common Variable Immune Deficiencies (CVID), six patients with X-linked Agammaglobulinemia (XLA), and 28 healthy age-matched controls (HD) were analyzed for anti-Spike and anti-receptor binding domain (RBD) antibody production, generation of Spike-specific memory B-cells, and Spike-specific T-cells before vaccination and one week after the second dose of BNT162b2 vaccine. RESULTS: The vaccine induced Spike-specific IgG and IgA antibody responses in all HD and in 20% of SARS-CoV-2 naive CVID patients. Anti-Spike IgG were detectable before vaccination in 4 out 7 CVID previously infected with SARS-CoV-2 and were boosted in six out of seven patients by the subsequent immunization raising higher levels than patients naïve to infection. While HD generated Spike-specific memory B-cells, and RBD-specific B-cells, CVID generated Spike-specific atypical B-cells, while RBD-specific B-cells were undetectable in all patients, indicating the incapability to generate this new specificity. Specific T-cell responses were evident in all HD and defective in 30% of CVID. All but one patient with XLA responded by specific T-cell only. CONCLUSION: In PAD patients, early atypical immune responses after BNT162b2 immunization occurred, possibly by extra-follicular or incomplete germinal center reactions. If these responses to vaccination might result in a partial protection from infection or reinfection is now unknown. Our data suggests that SARS-CoV-2 infection more effectively primes the immune response than the immunization alone, possibly suggesting the need for a third vaccine dose for patients not previously infected.


Subject(s)
Antibodies, Viral/blood , COVID-19 Vaccines/immunology , COVID-19/prevention & control , Immunologic Deficiency Syndromes/immunology , SARS-CoV-2/immunology , Humans , Immunoglobulin G/blood , Immunologic Memory , Lymphocytes/immunology , Spike Glycoprotein, Coronavirus/immunology
9.
Curr Opin Allergy Clin Immunol ; 21(6): 535-544, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1440659

ABSTRACT

PURPOSE OF REVIEW: In the general population, the risk of severe COVID-19 is associated with old age, male sex, hypertension, obesity and chronic diseases. Chronic lung diseases are listed as additional risk factors for hospitalization and ICU admission. The purpose of this review is to define whether chronic lung diseases, such as bronchiectasis and interstitial diseases, represent a risk for a severe SARS-CoV-2 infection in patients affected by common variable immunodeficiency (CVID), the most common symptomatic primary antibody defect. RECENT FINDINGS: CVID patients with SARS-CoV-2 infection have been reported since the beginning of the pandemic with a wide range of clinical presentations ranging from asymptomatic to mild/moderate and severe COVID-19. The meta-analysis of 88 CVID cases described in large cohorts and case reports demonstrated that CVID patients with chronic lung involvement have an increased risk for severe COVID-19 in comparison to CVID without lung diseases (50 vs. 28%, relative risk 1.75, 95% confidence interval 1.04--2.92, P = 0.043). Differently from the general population, age and metabolic comorbidities did not represent a risk factor for severe course in this patient's population. SUMMARY: Underlying chronic lung diseases but not age represent a risk factor for severe COVID-19 in CVID. Prompt therapeutic intervention should be adopted in SARS-CoV-2 positive CVID patients with chronic lung diseases independently of their age.


Subject(s)
Bronchiectasis/epidemiology , COVID-19/diagnosis , Common Variable Immunodeficiency/complications , Lung Diseases, Interstitial/epidemiology , Severity of Illness Index , Age Factors , Bronchiectasis/immunology , COVID-19/immunology , COVID-19/virology , Chronic Disease/epidemiology , Common Variable Immunodeficiency/immunology , Disease Susceptibility , Humans , Lung Diseases, Interstitial/immunology , Risk Factors , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification
11.
Vaccines (Basel) ; 9(6)2021 Jun 09.
Article in English | MEDLINE | ID: covidwho-1282653

ABSTRACT

Primary antibody deficiencies (PADs) are the most common primary immunodeficiencies (PIDs). They can be divided into the following groups, depending on their immunological features: agammaglobulinemia; common variable immunodeficiency (CVID) isotype; hyper IgM isotype; light chain or functional deficiencies with normal B cell count; specific antibody deficiency with normal Ig concentrations and normal numbers of B cells and transient hypogammaglobulinemia of infancy. The role of vaccination in PADs is recognized as therapeutic, diagnostic and prognostic and may be used in patients with residual B-cell function to provide humoral immunity to specific infective agents. According to their content and mechanisms, vaccines are grouped as live attenuated, inactivated (conjugated, polysaccharide), mRNA or replication-deficient vector vaccines. Vaccination may be unsafe or less effective when using certain vaccines and in specific types of immunodeficiency. Inactivated vaccines can be administered in PAD patients even if they could not generate a protective response; live attenuated vaccines are not recommended in major antibody deficiencies. From December 2020, European Medicines Agency (EMA) approved vaccines against COVID-19 infection: according to ESID advises, those vaccinations are recommended in patients with PADs. No specific data are available on safety and efficacy in PAD patients.

12.
Front Cell Infect Microbiol ; 11: 655896, 2021.
Article in English | MEDLINE | ID: covidwho-1200086

ABSTRACT

A large repertoire of IgA is produced by B lymphocytes with T-independent and T-dependent mechanisms useful in defense against pathogenic microorganisms and to reduce immune activation. IgA is active against several pathogens, including rotavirus, poliovirus, influenza virus, and SARS-CoV-2. It protects the epithelial barriers from pathogens and modulates excessive immune responses in inflammatory diseases. An early SARS-CoV-2 specific humoral response is dominated by IgA antibodies responses greatly contributing to virus neutralization. The lack of anti-SARS-Cov-2 IgA and secretory IgA (sIgA) might represent a possible cause of COVID-19 severity, vaccine failure, and possible cause of prolonged viral shedding in patients with Primary Antibody Deficiencies, including patients with Selective IgA Deficiency. Differently from other primary antibody deficiency entities, Selective IgA Deficiency occurs in the vast majority of patients as an asymptomatic condition, and it is often an unrecognized, Studies are needed to clarify the open questions raised by possible consequences of a lack of an IgA response to SARS-CoV-2.


Subject(s)
Antibodies, Viral/blood , COVID-19/immunology , IgA Deficiency , Immunoglobulin A/blood , Antibodies, Neutralizing/blood , Humans , SARS-CoV-2/immunology , Virus Shedding
13.
Expert Rev Clin Immunol ; 17(2): 163-168, 2021 02.
Article in English | MEDLINE | ID: covidwho-1066077

ABSTRACT

Introduction: Patients affected by Inborn Errors of Immunity (IEI) represent a potential group-at-risk in the current COVID-19 pandemic. Studies on large and small cohorts of IEI reported a huge variability clinical manifestations associated to SARS-Cov-2, ranging from asymptomatic, mild, moderate/severe to death. A great impulse to improve remote assistance programs and to switch to home-based treatment to reduce mobility and face to face contacts has been implemented.Areas covered: The authors completed a comprehensive review of the literature by searching the PubMed database for studies on large and small cohorts and case reports of IEI patients with COVID-19, with the aim to provide useful information for their clinical management during the COVID-19 pandemic.Expert opinion: Surprisingly, a low number of IEI patients affected by SARS-Cov-2 were reported with a risk to die for COVID-19 overlapping that of the general population. The low number might be explained by the choice of most physicians to inform early in the pandemic about safety measures, to switch most of the IEI patients to home therapy and to remote assistance. The guidelines issued by the scientific societies and periodically updated, represent the best tool for the clinical management of IEI patients.


Subject(s)
COVID-19/epidemiology , COVID-19/therapy , Primary Immunodeficiency Diseases/epidemiology , Primary Immunodeficiency Diseases/therapy , COVID-19/diagnosis , COVID-19/prevention & control , Humans , Immunization, Passive , Practice Guidelines as Topic , Remote Consultation , SARS-CoV-2/isolation & purification
14.
Front Immunol ; 11: 610300, 2020.
Article in English | MEDLINE | ID: covidwho-1005638

ABSTRACT

SARS-CoV-2 is a novel coronavirus, not encountered before by humans. The wide spectrum of clinical expression of SARS-CoV-2 illness suggests that individual immune responses to SARS-CoV-2 play a crucial role in determining the clinical course after first infection. Immunological studies have focused on patients with moderate to severe disease, demonstrating excessive inflammation in tissues and organ damage. In order to understand the basis of the protective immune response in COVID-19, we performed a longitudinal follow-up, flow-cytometric and serological analysis of innate and adaptive immunity in 64 adults with a spectrum of clinical presentations: 28 healthy SARS-CoV-2-negative contacts of COVID-19 cases; 20 asymptomatic SARS-CoV-2-infected cases; eight patients with Mild COVID-19 disease and eight cases of Severe COVID-19 disease. Our data show that high frequency of NK cells and early and transient increase of specific IgA, IgM and, to a lower extent, IgG are associated with asymptomatic SARS-CoV-2 infection. By contrast, monocyte expansion and high and persistent levels of IgA and IgG, produced relatively late in the course of the infection, characterize severe disease. Modest increase of monocytes and different kinetics of antibodies are detected in mild COVID-19. The importance of innate NK cells and the short-lived antibody response of asymptomatic individuals and patients with mild disease suggest that only severe COVID-19 may result in protective memory established by the adaptive immune response.


Subject(s)
Adaptive Immunity , Antibodies, Viral/immunology , COVID-19/immunology , Immunity, Innate , Immunoglobulin A/immunology , Immunoglobulin M/immunology , Killer Cells, Natural/immunology , SARS-CoV-2/immunology , Adult , COVID-19/pathology , Female , Humans , Killer Cells, Natural/pathology , Male , Severity of Illness Index
15.
J Allergy Clin Immunol ; 147(2): 520-531, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-792893

ABSTRACT

BACKGROUND: There is uncertainty about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in individuals with rare inborn errors of immunity (IEI), a population at risk of developing severe coronavirus disease 2019. This is relevant not only for these patients but also for the general population, because studies of IEIs can unveil key requirements for host defense. OBJECTIVE: We sought to describe the presentation, manifestations, and outcome of SARS-CoV-2 infection in IEI to inform physicians and enhance understanding of host defense against SARS-CoV-2. METHODS: An invitation to participate in a retrospective study was distributed globally to scientific, medical, and patient societies involved in the care and advocacy for patients with IEI. RESULTS: We gathered information on 94 patients with IEI with SARS-CoV-2 infection. Their median age was 25 to 34 years. Fifty-three patients (56%) suffered from primary antibody deficiency, 9 (9.6%) had immune dysregulation syndrome, 6 (6.4%) a phagocyte defect, 7 (7.4%) an autoinflammatory disorder, 14 (15%) a combined immunodeficiency, 3 (3%) an innate immune defect, and 2 (2%) bone marrow failure. Ten were asymptomatic, 25 were treated as outpatients, 28 required admission without intensive care or ventilation, 13 required noninvasive ventilation or oxygen administration, 18 were admitted to intensive care units, 12 required invasive ventilation, and 3 required extracorporeal membrane oxygenation. Nine patients (7 adults and 2 children) died. CONCLUSIONS: This study demonstrates that (1) more than 30% of patients with IEI had mild coronavirus disease 2019 (COVID-19) and (2) risk factors predisposing to severe disease/mortality in the general population also seemed to affect patients with IEI, including more younger patients. Further studies will identify pathways that are associated with increased risk of severe disease and are nonredundant or redundant for protection against SARS-CoV-2.


Subject(s)
COVID-19/epidemiology , Genetic Diseases, Inborn/epidemiology , Immunologic Deficiency Syndromes/epidemiology , SARS-CoV-2 , Adolescent , Adult , Aged , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , Middle Aged , Retrospective Studies , Risk Factors , Severity of Illness Index , Young Adult
17.
J Allergy Clin Immunol Pract ; 8(6): 1894-1899.e2, 2020 06.
Article in English | MEDLINE | ID: covidwho-46747

ABSTRACT

BACKGROUND: A rapidly expanding pandemic of the new coronavirus has become the focus of global scientific attention. Data are lacking on the impact of the pandemic caused by the severe acute respiratory syndrome coronavirus 2 on health-related quality of life among patients affected by primary antibody deficiencies (PADs). OBJECTIVE: To identify factors impacting the health-related-quality of life (HRQOL) among Italian patients affected by PADs switched to remote assistance at the time of the coronavirus disease 2019 pandemic. METHODS: The quality of life was surveyed in 158 patients with PADs by the Common Variable Immune Deficiency Quality of Life questionnaire, a disease-specific tool, and by the 12-item General Health Questionnaire, a generic tool to assess the risk of anxiety/depression. Since the beginning of the coronavirus disease 2019 epidemic, we shifted all patients with PADs to home therapy, and activated remote visits. Questionnaires were sent by email 4 weeks later. Common Variable Immune Deficiency Quality of Life questionnaire and 12-item General Health Questionnaire data scores were compared with the same set of data from a survey done in 2017. RESULTS: Of 210 patients, 158 (75%) agreed to participate. The quality of life was worse in the group of patients who were at risk of anxiety/depression at the study time. HRQOL was similar in patients forced to shift from hospital-based to home-based immunoglobulin treatment and in patients who continued their usual home-based replacement. The risk of anxiety/depression is associated with pandemia caused by the severe acute respiratory syndrome coronavirus 2 and with patients' fragility, and not with related clinical conditions associated with common variable immune deficiencies. Anxiety about running out of medications is a major new issue. CONCLUSIONS: The coronavirus disease 2019 epidemic impacted HRQOL and the risk of anxiety/depression of patients with PADs. The remote assistance program was a useful possibility to limit personal contacts without influencing the HRQOL.


Subject(s)
Anxiety/psychology , Common Variable Immunodeficiency/psychology , Common Variable Immunodeficiency/therapy , Coronavirus Infections/prevention & control , Depression/psychology , Immunoglobulins/administration & dosage , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Quality of Life/psychology , Adolescent , Adult , Aged , COVID-19 , Coronavirus Infections/epidemiology , Female , Home Infusion Therapy/psychology , Humans , Infusions, Subcutaneous , Italy/epidemiology , Male , Middle Aged , Pneumonia, Viral/epidemiology , Surveys and Questionnaires , Telemedicine , Young Adult
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