Publications by authors named "Stephen Jolles"

105 Publications

COVID-19 vaccine response in people with multiple sclerosis.

Ann Neurol 2021 Oct 22. Epub 2021 Oct 22.

Preventive Neurology Unit, Wolfson Institute of Population Health, Queen Mary University London.

Objective: To investigate the effect of disease modifying therapies on immune response to SARS-CoV2 vaccines in people with multiple sclerosis.

Methods: 473 people with multiple sclerosis provided one or more dried blood spot samples. Information about COVID-19 and vaccine history, medical and drug history were extracted from questionnaires and medical records. Dried blood spots were eluted and tested for antibodies to SARS-CoV2. Antibody titres were partitioned into tertiles with people on no disease modifying therapy as a reference. We calculated the odds ratio of seroconversion (univariate logistic regression) and compared quantitative vaccine response (Kruskal Wallis) following SARS-CoV2 vaccine according to disease modifying therapy. We used regression modelling to explore the effect of vaccine timing, treatment duration, age, vaccine type and lymphocyte count on vaccine response.

Results: Compared to no disease modifying therapy, the use of anti-CD20 monoclonal antibodies (odds ratio 0.03; 95% confidence interval 0.01-0.06, p<0.001) and fingolimod (odds ratio 0.04; 95% confidence interval 0.01-0.12) were associated with lower seroconversion following SARS-CoV2 vaccine. All other drugs did not differ significantly from the untreated cohort. Both time since last anti-CD20 treatment and total time on treatment were significantly associated with response to vaccination. Vaccine type significantly predicted seroconversion, but not in those on anti-CD20 medications. Preliminary data on cellular T-cell immunity showed 40% of seronegative subjects had measurable anti-SARS-CoV2 T cell responses.

Interpretation: Some disease modifying therapies convey risk of attenuated serological response to SARS-CoV2 vaccination in people with MS. We provide recommendations for the practical management of this patient group. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/ana.26251DOI Listing
October 2021

Fatigue Symptoms Associated With COVID-19 in Convalescent or Recovered COVID-19 Patients; a Systematic Review and Meta-Analysis.

Ann Behav Med 2021 Oct 19. Epub 2021 Oct 19.

Department of Psychiatry, University of Queensland, Brisbane, Australia.

Background: The prevalence and prognosis of post-acute stage SARS-CoV-2 infection fatigue symptoms remain largely unknown.

Aims: We performed a systematic review to evaluate the prevalence of fatigue in post-recovery from SARS-CoV-2 infection.

Method: Medline, Embase, PsycINFO, CINAHL, Web of Science, Scopus, trial registries, Cochrane Central Register of Controlled Trials, and Google Scholar were searched for studies on fatigue in samples that recovered from polymerase chain reaction (PCR) diagnosed COVID-19. English, French, and Spanish studies were included. Meta-analyses were conducted separately for each recruitment setting.

Results: We identified 41 studies with 9,362 patients that recovered from COVID-19. Post-COVID-19 patients self-report of fatigue was higher compared to healthy controls (risk ratio (RR) = 3.688, 95%CI [2.502, 5.436], p < .001). Over 50% of patients discharged from inpatient care reported symptoms of fatigue during the first (event rate [ER] = 0.517, 95%CI [0.278, 0.749]) and second month following recovery (ER = 0.527, 95%CI [0.337, 0.709]). Ten percent of the community patients reported fatigue in the first-month post-recovery. Patient setting moderated the association between COVID-19 recovery and fatigue symptoms (R2 = 0.11, p < .001). Female patients recovering from COVID-19 had a greater self-report of fatigue (odds ratio [OR] = 1.782, 95%CI [1.531, 2.870]). Patients recruited through social media had fatigue above 90% across multiple time points. Fatigue was highest in studies from Europe.

Conclusion: Fatigue is a symptom associated with functional challenges which could have economic and social impacts. Developing long-term planning for fatigue management amongst patients beyond the acute stages of SARS-CoV-2 infection is essential to optimizing patient care and public health outcomes. Further studies should examine the impact of sociodemographic, pandemic-related restrictions and pre-existing conditions on fatigue.
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http://dx.doi.org/10.1093/abm/kaab081DOI Listing
October 2021

COVID-19 and X-linked agammaglobulinemia (XLA) - insights from a monogenic antibody deficiency.

Curr Opin Allergy Clin Immunol 2021 Sep 29. Epub 2021 Sep 29.

Immunodeficiency Centre for Wales, University Hospital for Wales Henry Wellcome Building, Division of Infection & Immunity, School of Medicine, Cardiff University, Cardiff Paediatric Immunology, Great North Children's Hospital, Newcastle upon Tyne Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.

Purpose Of Review: The clinical outcomes from COVID-19 in monogenic causes of predominant antibody deficiency have pivotal implications for our understanding of the antiviral contribution of humoral immunity. This review summarizes the lessons learned from COVID-19 infection in X-linked agammaglobulinemia (XLA) due to genetic defects in Bruton's tyrosine kinase (BTK).

Recent Findings: Key molecular pathways underlying the development of severe COVID-19 are emerging, highlighting the possible contribution of BTK to hyperinflammation. SARS-CoV-2 specific T-cell responses and complement activation appear insufficient to achieve viral clearance in some B-cell deficient individuals. Whilst appearing efficacious in this group, use of convalescent plasma has been recently associated with the evolution of viral escape variants. Early data suggests individuals with XLA can mount a viral-specific T-cell vaccine response, however, the clinical significance of this is still emerging.

Summary: In contrast to reports made early in the pandemic, we show XLA patients remain susceptible to severe disease. Persistent infection was common and is likely to carry a significant symptom burden and risk of novel variant evolution. COVID-19 infection in this vulnerable, antibody deficient group due to genetic, therapeutic or disease causes may require prompt and specific intervention for both patient and societal benefit.
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http://dx.doi.org/10.1097/ACI.0000000000000792DOI Listing
September 2021

Antibody deficiency, Chronic Lung Disease, and Comorbid Conditions: A Case Based Approach.

J Allergy Clin Immunol Pract 2021 Sep 27. Epub 2021 Sep 27.

Division of Allergy & Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL; Massachusetts General Hospital for Children, Boston, MA, USA.

New emerging pulmonary phenotypes associated with antibody deficiency, such as neutrophilic asthma, frequent exacerbations of chronic obstructive pulmonary disease, and unexplained interstitial lung disease, particularly in younger adults, are discussed in this review through a case-based approach. Also discussed in similar fashion are antibody deficiency syndromes that lead to end-stage lung disease and the indications for lung transplantation in primary immunodeficiency disease. These challenging cases require timely and individualized strategies for genetic and immunologic diagnosis, decisions about therapeutic approaches, and long-term monitoring.
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http://dx.doi.org/10.1016/j.jaip.2021.09.031DOI Listing
September 2021

Infections in secondary immunodeficiency patients treated with Privigen or Hizentra: a retrospective US administrative claims study in patients with hematological malignancies.

Leuk Lymphoma 2021 Sep 27:1-11. Epub 2021 Sep 27.

McGill University Health Centre, Montreal, Canada.

B cell-derived lymphoproliferative disorders are associated with secondary immunodeficiency (SID); some patients require immunoglobulin replacement therapy (IgRT) to mitigate infections. Using IQVIA's PharMetrics Plus database, patients with SID who received IgPro10/IgPro20 in the 12 months post-diagnosis (IgRT users) were matched to patients with SID not receiving IgRT (non-IgRT users). The risk of severe infection was compared using within-patient change from baseline to follow-up as well as between cohorts. Overall, 277 IgRT users were matched to 1019 non-IgRT users. Before IgRT, more IgRT users experienced any bacterial infection (88.4% vs. 72.9%; <.0001) or ≥1 severe bacterial infection (SBI) (42.2% vs. 31.8%; =.0011) vs. non-IgRT users. During follow-up, risk of SBI among IgRT users (21.7%) reached parity with non-IgRT users (21.2%). IgRT was associated with a reduction in SBIs to levels comparable with the lower 'baseline infection risk' of non-IgRT users. These criteria help define SID patients who may benefit from IgRT.
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http://dx.doi.org/10.1080/10428194.2021.1961233DOI Listing
September 2021

Heterozygous variants in ZBTB7A cause a neurodevelopmental disorder associated with symptomatic overgrowth of pharyngeal lymphoid tissue, macrocephaly, and elevated fetal hemoglobin.

Am J Med Genet A 2021 Sep 13. Epub 2021 Sep 13.

Department of Medical Genetics, St. Olavs University Hospital, Trondheim, Norway.

By clinical whole exome sequencing, we identified 12 individuals with ages 3 to 37 years, including three individuals from the same family, with a consistent phenotype of intellectual disability (ID), macrocephaly, and overgrowth of adenoid tissue. All 12 individuals harbored a rare heterozygous variant in ZBTB7A which encodes the transcription factor Zinc finger and BTB-domain containing protein 7A, known to play a role in lympho- and hematopoiesis. ID was generally mild. Fetal hemoglobin (HbF) fraction was elevated 2.2%-11.2% (reference value <2% in individuals > 6 months) in four of the five individuals for whom results were available. Ten of twelve individuals had undergone surgery at least once for lymphoid hypertrophy limited to the pharynx. In the most severely affected individual (individual 1), airway obstruction resulted in 17 surgical procedures before the age of 13 years. Sleep apnea was present in 8 of 10 individuals. In the nine unrelated individuals, ZBTB7A variants were novel and de novo. The six frameshift/nonsense and four missense variants were spread throughout the gene. This is the first report of a cohort of individuals with this novel syndromic neurodevelopmental disorder.
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http://dx.doi.org/10.1002/ajmg.a.62492DOI Listing
September 2021

Serum Protein Electrophoresis May Be Used as a Screening Tool for Antibody Deficiency in Children and Adolescents.

Front Immunol 2021 23;12:712637. Epub 2021 Aug 23.

Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.

Background: Patients with antibody deficiency may experience exceptionally long diagnostic delays, increasing the risk of life-threatening infections, end-organ damage, mortality, and health costs.

Objective: This study aimed to analyze serum protein electrophoresis and verify the correlation between calculated globulin (CG, total protein minus albumin levels) or electrophoretically determined serum gamma globulin fraction (Gamma) with IgG levels in children and adolescents under 18 years old (yo).

Methods: We analyzed serum protein electrophoresis (GC or Gamma) and IgG levels from 1215 children and adolescents under 18 yo, classified into 5 age groups. We verified the correlation between CG or Gamma with serum IgG levels.

Results: Serum IgG levels varied according to age groups (from 4.3 ± 2.3 g/l in children under 6 months old to 11.4 ± 3.2 g/l in adolescents in the 10-<18 yo group). CG sensitivity and specificity to detect IgG below the reference range for all patients were 93.1% and 81.8%, respectively, and varied according to age group. Gamma sensitivity and specificity for all patients were 100% and 87.8%, respectively, and varied according to age group as well. We found serum IgG levels below the age reference level in 29 patients (2.4% of the cases) using CG or Gamma levels.

Conclusion: Both CG and Gamma levels may be of utility as a screening tool for earlier diagnosis of antibody deficiency in children and adolescents under 18 yo.
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http://dx.doi.org/10.3389/fimmu.2021.712637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419225PMC
August 2021

Persistent SARS-CoV-2 infection: the urgent need for access to treatment and trials.

Lancet Infect Dis 2021 10 16;21(10):1345-1347. Epub 2021 Aug 16.

Department of Immunology, Royal Free London NHS Foundation Trust, London, UK; Institute of Immunity and Transplantation, University College London, London, UK.

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http://dx.doi.org/10.1016/S1473-3099(21)00464-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8367192PMC
October 2021

Genetic errors of immunity distinguish pediatric nonmalignant lymphoproliferative disorders.

J Allergy Clin Immunol 2021 Jul 28. Epub 2021 Jul 28.

Department of Pediatrics, Baylor College of Medicine, Houston, Tex; Texas Children's Hospital, Houston, Tex; Division of Pediatric Hematology/Oncology, Texas Children's Hospital Cancer Center, Houston, Tex. Electronic address:

Background: Pediatric nonmalignant lymphoproliferative disorders (PLPDs) are clinically and genetically heterogeneous. Long-standing immune dysregulation and lymphoproliferation in children may be life-threatening, and a paucity of data exists to guide evaluation and treatment of children with PLPD.

Objective: The primary objective of this study was to ascertain the spectrum of genomic immunologic defects in PLPD. Secondary objectives included characterization of clinical outcomes and associations between genetic diagnoses and those outcomes.

Methods: PLPD was defined by persistent lymphadenopathy, lymph organ involvement, or lymphocytic infiltration for more than 3 months, with or without chronic or significant Epstein-Barr virus (EBV) infection. Fifty-one subjects from 47 different families with PLPD were analyzed using whole exome sequencing.

Results: Whole exome sequencing identified likely genetic errors of immunity in 51% to 62% of families (53% to 65% of affected children). Presence of a genetic etiology was associated with younger age and hemophagocytic lymphohistiocytosis. Ten-year survival for the cohort was 72.4%, and patients with viable genetic diagnoses had a higher survival rate (82%) compared to children without a genetic explanation (48%, P = .03). Survival outcomes for individuals with EBV-associated disease and no genetic explanation were particularly worse than outcomes for subjects with EBV-associated disease and a genetic explanation (17% vs 90%; P = .002). Ascertainment of a molecular diagnosis provided targetable treatment options for up to 18 individuals and led to active management changes for 12 patients.

Conclusions: PLPD defines children at high risk for mortality, and whole exome sequencing informs clinical risks and therapeutic opportunities for this diagnosis.
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http://dx.doi.org/10.1016/j.jaci.2021.07.015DOI Listing
July 2021

Hematopoietic Cell Transplantation Cures Adenosine Deaminase 2 Deficiency: Report on 30 Patients.

J Clin Immunol 2021 Oct 29;41(7):1633-1647. Epub 2021 Jul 29.

Pediatric Immunology, Hematology and Rheumatology Unit, Hôpital Necker-Enfants Malades, APHP, Paris, France.

Purpose: Deficiency of adenosine deaminase 2 (DADA2) is an inherited inborn error of immunity, characterized by autoinflammation (recurrent fever), vasculopathy (livedo racemosa, polyarteritis nodosa, lacunar ischemic strokes, and intracranial hemorrhages), immunodeficiency, lymphoproliferation, immune cytopenias, and bone marrow failure (BMF). Tumor necrosis factor (TNF-α) blockade is the treatment of choice for the vasculopathy, but often fails to reverse refractory cytopenia. We aimed to study the outcome of hematopoietic cell transplantation (HCT) in patients with DADA2.

Methods: We conducted a retrospective study on the outcome of HCT in patients with DADA2. The primary outcome was overall survival (OS).

Results: Thirty DADA2 patients from 12 countries received a total of 38 HCTs. The indications for HCT were BMF, immune cytopenia, malignancy, or immunodeficiency. Median age at HCT was 9 years (range: 2-28 years). The conditioning regimens for the final transplants were myeloablative (n = 20), reduced intensity (n = 8), or non-myeloablative (n = 2). Donors were HLA-matched related (n = 4), HLA-matched unrelated (n = 16), HLA-haploidentical (n = 2), or HLA-mismatched unrelated (n = 8). After a median follow-up of 2 years (range: 0.5-16 years), 2-year OS was 97%, and 2-year GvHD-free relapse-free survival was 73%. The hematological and immunological phenotypes resolved, and there were no new vascular events. Plasma ADA2 enzyme activity normalized in 16/17 patients tested. Six patients required more than one HCT.

Conclusion: HCT was an effective treatment for DADA2, successfully reversing the refractory cytopenia, as well as the vasculopathy and immunodeficiency.

Clinical Implications: HCT is a definitive cure for DADA2 with > 95% survival.
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http://dx.doi.org/10.1007/s10875-021-01098-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8452581PMC
October 2021

Burden of nosocomial COVID-19 in Wales: results from a multicentre retrospective observational study of 2508 hospitalised adults.

Thorax 2021 Jul 22. Epub 2021 Jul 22.

Department of Respiratory Medicine, Cardiff and Vale University Health Board, Cardiff, UK.

The burden of nosocomial SARS-CoV-2 infection remains poorly defined. We report on the outcomes of 2508 adults with molecularly-confirmed SARS-CoV-2 admitted across 18 major hospitals, representing over 60% of those hospitalised across Wales between 1 March and 1 July 2020. Inpatient mortality for nosocomial infection ranged from 38% to 42%, consistently higher than participants with community-acquired infection (31%-35%) across a range of case definitions. Those with hospital-acquired infection were older and frailer than those infected within the community. Nosocomial diagnosis occurred a median of 30 days following admission (IQR 21-63), suggesting a window for prophylactic or postexposure interventions, alongside enhanced infection control measures.
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http://dx.doi.org/10.1136/thoraxjnl-2021-216964DOI Listing
July 2021

Haematopoietic Stem Cell Transplant for Norovirus-Induced Intestinal Failure in X-linked Agammaglobulinemia.

J Clin Immunol 2021 Oct 23;41(7):1574-1581. Epub 2021 Jun 23.

Paediatric Immunology, Newcastle Upon Tyne Hospital Trusts, Great North Children's Hospital, Clinical Resource Building, Floor 4, Block 2, Queen Victoria Road, Newcastle upon Tyne, NE1 4LP, UK.

Since the first clinical description in 1952, immunoglobulin replacement therapy remains the mainstay of treatment of patients with X-linked agammaglobulinemia (XLA). However, this therapy only replaces IgG isotype and does not compensate for the loss of Bruton tyrosine kinase in non-B-lymphocytes. Patients may still therefore develop complications despite current standard of care. Here, we describe an XLA patient with persistent chronic norovirus infection, refractory to treatment and causing intestinal failure. The patient underwent haematopoietic stem cell transplantation, curing XLA and allowed clearance of norovirus prior to humoral immunoreconstitution, suggesting non-humoral immunodeficiency in these patients.
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http://dx.doi.org/10.1007/s10875-021-01088-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221090PMC
October 2021

Medical algorithm: Diagnosis and management of antibody immunodeficiencies.

Allergy 2021 May 26. Epub 2021 May 26.

Immunodeficiency Centre for Wales, University Hospital of Wales, Cardiff, UK.

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http://dx.doi.org/10.1111/all.14961DOI Listing
May 2021

International retrospective study of allogeneic hematopoietic cell transplantation for activated PI3K-delta syndrome.

J Allergy Clin Immunol 2021 May 24. Epub 2021 May 24.

Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.

Background: Activated phosphoinositide 3-kinase delta syndrome (APDS) is a combined immunodeficiency with a heterogeneous phenotype considered reversible by allogeneic hematopoietic cell transplantation (HCT).

Objectives: This study sought to characterize HCT outcomes in APDS.

Methods: Retrospective data were collected on 57 patients with APDS1/2 (median age, 13 years; range, 2-66 years) who underwent HCT.

Results: Pre-HCT comorbidities such as lung, gastrointestinal, and liver pathology were common, with hematologic malignancy in 26%. With median follow-up of 2.3 years, 2-year overall and graft failure-free survival probabilities were 86% and 68%, respectively, and did not differ significantly by APDS1 versus APDS2, donor type, or conditioning intensity. The 2-year cumulative incidence of graft failure following first HCT was 17% overall but 42% if mammalian target of rapamycin inhibitor(s) (mTORi) were used in the first year post-HCT, compared with 9% without mTORi. Similarly, 2-year cumulative incidence of unplanned donor cell infusion was overall 28%, but 65% in the context of mTORi receipt and 23% without. Phenotype reversal occurred in 96% of evaluable patients, of whom 17% had mixed chimerism. Vulnerability to renal complications continued post-HCT, adding new insights into potential nonimmunologic roles of phosphoinositide 3-kinase not correctable through HCT.

Conclusions: Graft failure, graft instability, and poor graft function requiring unplanned donor cell infusion were major barriers to successful HCT. Post-HCT mTORi use may confer an advantage to residual host cells, promoting graft instability. Longer-term post-HCT follow-up of more patients is needed to elucidate the kinetics of immune reconstitution and donor chimerism, establish approaches that reduce graft instability, and assess the completeness of phenotype reversal over time.
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http://dx.doi.org/10.1016/j.jaci.2021.04.036DOI Listing
May 2021

Editorial: The Complexity of Primary Antibody Deficiencies.

Front Immunol 2021 21;12:635482. Epub 2021 Apr 21.

Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.

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http://dx.doi.org/10.3389/fimmu.2021.635482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097173PMC
September 2021

Development of a high-sensitivity ELISA detecting IgG, IgA and IgM antibodies to the SARS-CoV-2 spike glycoprotein in serum and saliva.

Immunology 2021 09 24;164(1):135-147. Epub 2021 May 24.

Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.

Detecting antibody responses during and after SARS-CoV-2 infection is essential in determining the seroepidemiology of the virus and the potential role of antibody in disease. Scalable, sensitive and specific serological assays are essential to this process. The detection of antibody in hospitalized patients with severe disease has proven relatively straightforward; detecting responses in subjects with mild disease and asymptomatic infections has proven less reliable. We hypothesized that the suboptimal sensitivity of antibody assays and the compartmentalization of the antibody response may contribute to this effect. We systematically developed an ELISA, optimizing different antigens and amplification steps, in serum and saliva from non-hospitalized SARS-CoV-2-infected subjects. Using trimeric spike glycoprotein, rather than nucleocapsid, enabled detection of responses in individuals with low antibody responses. IgG1 and IgG3 predominate to both antigens, but more anti-spike IgG1 than IgG3 was detectable. All antigens were effective for detecting responses in hospitalized patients. Anti-spike IgG, IgA and IgM antibody responses were readily detectable in saliva from a minority of RT-PCR confirmed, non-hospitalized symptomatic individuals, and these were mostly subjects who had the highest levels of anti-spike serum antibodies. Therefore, detecting antibody responses in both saliva and serum can contribute to determining virus exposure and understanding immune responses after SARS-CoV-2 infection.
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http://dx.doi.org/10.1111/imm.13349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242512PMC
September 2021

Examining the utility of extended laboratory panel testing in the emergency department for risk stratification of patients with COVID-19: a single-centre retrospective service evaluation.

J Clin Pathol 2021 Feb 19. Epub 2021 Feb 19.

Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK.

Background: The role of specific blood tests to predict poor prognosis in patients admitted with infection from SARS-CoV-2 remains uncertain. During the first wave of the global pandemic, an extended laboratory testing panel was integrated into the local pathway to guide triage and healthcare resource utilisation for emergency admissions. We conducted a retrospective service evaluation to determine the utility of extended tests (D-dimer, ferritin, high-sensitivity troponin I, lactate dehydrogenase and procalcitonin) compared with the core panel (full blood count, urea and electrolytes, liver function tests and C reactive protein).

Methods: Clinical outcomes for adult patients with laboratory-confirmed COVID-19 admitted between 17 March and 30 June 2020 were extracted, alongside costs estimates for individual tests. Prognostic performance was assessed using multivariable logistic regression analysis with 28-day mortality used as the primary endpoint and a composite of 28-day intensive care escalation or mortality for secondary analysis.

Results: From 13 500 emergency attendances, we identified 391 unique adults admitted with COVID-19. Of these, 113 died (29%) and 151 (39%) reached the composite endpoint. 'Core' test variables adjusted for age, gender and index of deprivation had a prognostic area under the curve of 0.79 (95% CI 0.67 to 0.91) for mortality and 0.70 (95% CI 0.56 to 0.84) for the composite endpoint. Addition of 'extended' test components did not improve on this.

Conclusion: Our findings suggest use of the extended laboratory testing panel to risk stratify community-acquired COVID-19 positive patients on admission adds limited prognostic value. We suggest laboratory requesting should be targeted to patients with specific clinical indications.
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http://dx.doi.org/10.1136/jclinpath-2020-207157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898230PMC
February 2021

Hematopoietic Stem Cell Transplantation Resolves the Immune Deficit Associated with STAT3-Dominant-Negative Hyper-IgE Syndrome.

J Clin Immunol 2021 07 1;41(5):934-943. Epub 2021 Feb 1.

Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.

Autosomal dominant hyper-IgE syndrome caused by dominant-negative loss-of-function mutations in signal transducer and activator of transcription factor 3 (STAT3) (STAT3-HIES) is a rare primary immunodeficiency with multisystem pathology. The quality of life in patients with STAT3-HIES is determined by not only the progressive, life-limiting pulmonary disease, but also significant skin disease including recurrent infections and abscesses requiring surgery. Our early report indicated that hematopoietic stem cell transplantation might not be effective in patients with STAT3-HIES, although a few subsequent reports have reported successful outcomes. We update on progress of our patient now with over 18 years of follow-up and report on an additional seven cases, all of whom have survived despite demonstrating significant disease-related pathology prior to transplant. We conclude that effective cure of the immunological aspects of the disease and stabilization of even severe lung involvement may be achieved by allogeneic hematopoietic stem cell transplantation. Recurrent skin infections and abscesses may be abolished. Donor T17 cells may produce comparable levels of IL17A to healthy controls. The future challenge will be to determine which patients should best be offered this treatment and at what point in their disease history.
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http://dx.doi.org/10.1007/s10875-021-00971-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249289PMC
July 2021

Treating secondary antibody deficiency in patients with haematological malignancy: European expert consensus.

Eur J Haematol 2021 Apr 2;106(4):439-449. Epub 2021 Feb 2.

Département de Recherche Clinique, Avicenne Hospital, Sorbonne Paris Nord University, Bobigny, France.

Objectives: Secondary antibody deficiency (SAD), associated with severe, recurrent or persistent infections, is common in patients with haematological malignancies (HM), but unifying guidance on immunoglobulin replacement therapy (IgRT) in these patients is lacking. We aimed to develop consensus statements for the use of IgRT in patients with HM.

Methods: A Delphi exercise was employed to test the level of agreement on statements developed by a Task Force based on available data and their clinical experience. In Round 1, an Expert Panel, comprising specialist EU physicians caring for patients with HM, helped to refine the statements. In Round 2, experts rated their agreement with the statements. In Round 3, experts who had scored their agreement as ≤4 were invited to review their agreement based on the overall feedback.

Results: Three definitions and 20 statements were formulated and tested for consensus, covering measurement of IgG levels, initiation and discontinuation of IgRT, dosing, and the use of subcutaneous IgG. Consensus (agreement ≥70% on Likert-type scale) was reached for all three definitions and 18 statements.

Conclusions: Recommendations have been developed with the aim of providing guidance for the use of IgRT to prevent severe, recurrent or persistent infections in patients with HM and SAD.
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http://dx.doi.org/10.1111/ejh.13580DOI Listing
April 2021

Anti-tumour necrosis factor treatment for the prevention of ischaemic events in patients with deficiency of adenosine deaminase 2 (DADA2).

Rheumatology (Oxford) 2021 09;60(9):4373-4378

Infection, Inflammation and Rheumatology Section, University College London Great Ormond Street Institute of Child Health, London.

Objective: To evaluate the impact of anti-Tumour Necrosis Factor-α (anti-TNF) treatment on the occurrence of vasculitic ischaemic events in patients with deficiency of adenosine deaminase 2 (DADA2).

Methods: A retrospective analysis of DADA2 patients referred from six centres to Great Ormond Street Hospital for Children was conducted. Ischaemic events, vasculitic disease activity, biochemical, immunological, and radiological features were compared, before and after anti-TNF treatment.

Results: A total of 31 patients with genetically confirmed DADA2 were included in the study. The median duration of active disease activity prior to anti-TNF treatment was 73 months (inter-quartile range [IQR] 27.5-133.5 months). Twenty seven/31 patients received anti-TNF treatment for a median of 32 months (IQR 12.0-71.5 months). The median event rate of central nervous system (CNS) and non-CNS ischemic events before anti-TNF treatment was 2.37 per 100 patient-months (IQR 1.25-3.63); compared with 0.00 per 100 patient-months (IQR 0.0-0.0) post-treatment (p< 0.0001). Paediatric vasculitis activity score (PVAS) was also significantly reduced: median score of 20/63 (IQR 13.0-25.8/63) pre-treatment vs. 2/63 (IQR 0.0-3.8/63) following anti-TNF treatment (p< 0.0001), with mild livedoid rash being the main persisting feature. Anti-TNF treatment was not effective for severe immunodeficiency or bone marrow failure, which required haematopoietic stem cell transplantation (HSCT).

Conclusion: Anti-TNF treatment significantly reduced the incidence of ischaemic events and other vasculitic manifestations of DADA2, but was not effective for immunodeficiency or bone marrow failure.
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http://dx.doi.org/10.1093/rheumatology/keaa837DOI Listing
September 2021

Managing Granulomatous-Lymphocytic Interstitial Lung Disease in Common Variable Immunodeficiency Disorders: e-GLILDnet International Clinicians Survey.

Front Immunol 2020 26;11:606333. Epub 2020 Nov 26.

UCL Respiratory, University College London, London, United Kingdom.

Background: Granulomatous-lymphocytic interstitial lung disease (GLILD) is a rare, potentially severe pulmonary complication of common variable immunodeficiency disorders (CVID). Informative clinical trials and consensus on management are lacking.

Aims: The European GLILD network (e-GLILDnet) aims to describe how GLILD is currently managed in clinical practice and to determine the main uncertainties and unmet needs regarding diagnosis, treatment and follow-up.

Methods: The e-GLILDnet collaborators developed and conducted an online survey facilitated by the European Society for Immunodeficiencies (ESID) and the European Respiratory Society (ERS) between February-April 2020. Results were analyzed using SPSS.

Results: One hundred and sixty-one responses from adult and pediatric pulmonologists and immunologists from 47 countries were analyzed. Respondents treated a median of 27 (interquartile range, IQR 82-maximum 500) CVID patients, of which a median of 5 (IQR 8-max 200) had GLILD. Most respondents experienced difficulties in establishing the diagnosis of GLILD and only 31 (19%) had access to a standardized protocol. There was little uniformity in diagnostic or therapeutic interventions. Fewer than 40% of respondents saw a definite need for biopsy in all cases or performed bronchoalveolar lavage for diagnostics. Sixty-six percent used glucocorticosteroids for remission-induction and 47% for maintenance therapy; azathioprine, rituximab and mycophenolate mofetil were the most frequently prescribed steroid-sparing agents. Pulmonary function tests were the preferred modality for monitoring patients during follow-up.

Conclusions: These data demonstrate an urgent need for clinical studies to provide more evidence for an international consensus regarding management of GLILD. These studies will need to address optimal procedures for definite diagnosis and a better understanding of the pathogenesis of GLILD in order to provide individualized treatment options. Non-availability of well-established standardized protocols risks endangering patients.
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http://dx.doi.org/10.3389/fimmu.2020.606333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726128PMC
June 2021

Development of a high-throughput SARS-CoV-2 antibody testing pathway using dried blood spot specimens.

Ann Clin Biochem 2021 03 26;58(2):123-131. Epub 2020 Dec 26.

Immunodeficiency Centre for Wales, University Hospital of Wales, Cardiff, UK.

Background: Serological assays for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) have roles in seroepidemiology, convalescent plasma-testing, antibody durability and vaccine studies. Currently, SARS-CoV-2 serology is performed using serum/plasma collected by venepuncture. Dried blood spot (DBS) testing offers significant advantages as it is minimally invasive, avoids venepuncture with specimens being mailed to the laboratory.

Methods: A pathway utilizing a newborn screening laboratory infrastructure was developed using an enzyme-linked immunosorbent assay to detect IgG antibodies against the receptor-binding domain of the SARS-CoV-2 spike protein in DBS specimens. Paired plasma and DBS specimens from SARS-CoV-2 antibody-positive and -negative subjects and polymerase chain reaction positive subjects were tested. DBS specimen stability, effect of blood volume and punch location were also evaluated.

Results: DBS specimens from antibody-negative ( = 85) and -positive ( = 35) subjects and polymerase chain reaction positive subjects ( = 11) had a mean (SD; range) optical density (OD) of 0.14 (0.046; 0.03-0.27), 0.98 (0.41; 0.31-1.64) and 1.12 (0.37; 0.49-1.54), respectively. An action value OD >0.28 correctly assigned all cases. The weighted Deming regression for comparison of the DBS and the plasma assay yielded:  = 0.004041 + 1.005,  = 0.991, Sy/ 0.171,  = 82. Extraction efficiency of antibodies from DBS specimens was >99%. DBS specimens were stable for at least 28 days at ambient room temperature and humidity.

Conclusions: SARS-CoV-2 IgG receptor-binding domain antibodies can be reliably detected in DBS specimens. DBS serological testing offers lower costs than either point of care or serum/plasma assays that require patient travel, phlebotomy and hospital/clinic resources; the development of a DBS assay may be particularly important for resource poor settings.
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http://dx.doi.org/10.1177/0004563220981106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844389PMC
March 2021

Global immunoglobulin supply: steaming towards the iceberg?

Curr Opin Allergy Clin Immunol 2020 12;20(6):557-564

Immunodeficiency Centre for Wales, University Hospital for Wales, Cardiff, UK.

Purpose Of Review: This review describes how plasma is sourced for fractionation into plasma-derived medicinal products (PDMPs), such as immunoglobulin (Ig) together with differences between plasma from whole blood (recovered plasma) and from plasmapheresis (source plasma) in terms of global plasma supply. Specific areas of growth in immunoglobulin use are identified alongside novel therapies, which may reduce demand for some immunoglobulin indications.

Recent Findings: There has been a 6--8% annual growth in immunoglobulin use. Secondary immunodeficiency alongside improved recognition and diagnosis primary immunodeficiency disorders are drivers whereas the novel neonatal Fc receptor inhibitors (FcRni) may reduce demand for some immunomodulatory indications.

Summary: There is a significant geographical imbalance in global supply of plasma with 65% collected in the United States. This results in a dependency of other countries on United States supply and argues for both more plasma supply and greater regionally balanced plasma collection. In addition, progress towards a transparent, regulated and well tolerated framework for the coexistence of unpaid and compensated plasma donations is needed as unpaid donation will not be sufficient. These discussions should be informed by the needs of patients for this life-saving therapy, the care of donors and the safety of plasma and PDMPs.
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http://dx.doi.org/10.1097/ACI.0000000000000696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752222PMC
December 2020

Hematopoietic Stem Cell Transplantation and Vasculopathy Associated With STAT3-Dominant-Negative Hyper-IgE Syndrome.

Front Pediatr 2020 10;8:575. Epub 2020 Sep 10.

Immunodeficiency Centre for Wales, University Hospital for Wales, Cardiff, United Kingdom.

Dominant negative mutations in the transcription-factor underlie the rare primary immunodeficiency Job's syndrome. Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) has shown promise in correction of the underlying immunological defect, with one report suggesting HSCT can prevent development of wider connective tissue complications. Here, we report the case of a 26 year old male who developed an acute ST-elevation myocardial infarction due to coronary artery ectasia and thrombosis, occurring despite pediatric allogeneic HSCT for STAT3-HIES and a predicted 10-year conventional cardiovascular risk of 0.1%. Vasculopathy associated with STAT3-HIES may persist or arise following HSCT and can precipitate life-threatening complications. This has implications for counseling and vascular surveillance, and highlights the need for further studies to determine the risk, pathogenesis, and optimal management of the vasculopathy associated with STAT3-HIES.
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http://dx.doi.org/10.3389/fped.2020.00575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511721PMC
September 2020

Coronavirus disease 2019 in patients with inborn errors of immunity: An international study.

J Allergy Clin Immunol 2021 Feb 24;147(2):520-531. Epub 2020 Sep 24.

Istituto Molecolare "A Nocivelli," Department of Experimental and Clinical Sciences, University of Brescia & Asst Spedali civili, Brescia, Italy.

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.
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http://dx.doi.org/10.1016/j.jaci.2020.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832563PMC
February 2021

Long-term outcomes for adults with chronic granulomatous disease in the United Kingdom.

J Allergy Clin Immunol 2021 03 21;147(3):1104-1107. Epub 2020 Sep 21.

Department of Immunology, Royal Free London NHS Foundation Trust, London, United Kingdom; University College London Institute of Immunity and Transplantation, London, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2020.08.034DOI Listing
March 2021

Targeting FcRn for immunomodulation: Benefits, risks, and practical considerations.

J Allergy Clin Immunol 2020 09;146(3):479-491.e5

Immunodeficiency Centre for Wales, University Hospital of Wales, Cardiff, United Kingdom. Electronic address:

The neonatal fragment crystallizable (Fc) receptor (FcRn) functions as a recycling mechanism to prevent degradation and extend the half-life of IgG and albumin in the circulation. Several FcRn inhibitors selectively targeting IgG recycling are now moving rapidly toward clinical practice in neurology and hematology. These molecules accelerate the destruction of IgG, reducing pathogenic IgG and IgG immune complexes, with no anticipated effects on IgA, IgM, IgE, complement, plasma cells, B cells, or other cells of the innate or adaptive immune systems. FcRn inhibitors have potential for future use in a much wider variety of antibody-mediated autoimmune diseases. Given the imminent clinical use, potential for broader utility, and novel mechanism of action of FcRn inhibitors, here we review data from 4 main sources: (a) currently available activity, safety, and mechanism-of-action data from clinical trials of FcRn inhibitors; (b) other procedures and treatments that also remove IgG (plasma donation, plasma exchange, immunoadsorption); (c) diseases resulting in loss of IgG; and (d) primary immunodeficiencies with potential mechanistic similarities to those induced by FcRn inhibitors. These data have been evaluated to provide practical considerations for the assessment, monitoring, and reduction of any potential infection risk associated with FcRn inhibition, in addition to highlighting areas for future research.
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http://dx.doi.org/10.1016/j.jaci.2020.07.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471860PMC
September 2020

Phase 2 multiple-dose study of an FcRn inhibitor, rozanolixizumab, in patients with primary immune thrombocytopenia.

Blood Adv 2020 09;4(17):4136-4146

Immunodeficiency Centre for Wales, University Hospital of Wales, Cardiff, United Kingdom.

Primary immune thrombocytopenia (ITP) is a predominantly immunoglobulin G (IgG)-autoantibody-mediated disease characterized by isolated thrombocytopenia. Rozanolixizumab, a subcutaneously infused humanized monoclonal anti-neonatal Fc receptor (FcRn) antibody, reduced serum IgG in healthy volunteers. In this phase 2, multicenter, open-label study, patients with persistent/chronic primary ITP received 1 to 5 once-weekly subcutaneous infusions of rozanolixizumab (cumulative doses, 15-21 mg/kg). Primary objectives were safety and tolerability, and secondary objectives were clinical efficacy (change in platelet count) and pharmacodynamic effect (change in IgG). In all, 51 (77.3%) of 66 patients reported 1 or more adverse events (AEs), all mild-to-moderate, most commonly headaches (26 [39.4%] of 66), of which 15 were treatment related. Four patients had serious AEs, but none were treatment related. No AEs resulted in discontinuation of the study drug. No serious infections occurred. Platelet counts of ≥50 × 109/L were achieved at least once at any time after multiple infusions (5 × 4, 3 × 7, or 2 × 10 mg/kg: 35.7%, 35.7%, and 45.5% of patients, respectively) or single infusions (15 or 20 mg/kg: 66.7% and 54.5% patients, respectively). Minimum mean IgG levels and maximum mean platelet counts both occurred by day 8 in the higher (15 and 20 mg/kg) single-dose cohorts and maximum platelet count occurred by day 11 onward in the multiple-dose cohorts. No clinically meaningful changes occurred in IgA, IgM, IgE, or albumin levels. In patients with persistent/chronic primary ITP, rozanolixizumab demonstrated a favorable safety profile and rapid, substantial platelet increases concordant with substantial IgG reductions, especially with single doses. By day 8, in the 15 and 20 mg/kg single-dose cohorts, >50% patients achieved clinically relevant platelet responses (≥50 × 109/L), coinciding with the lowest mean IgG levels. These data support phase 3 development of rozanolixizumab in persistent/chronic primary ITP. This trial was registered at www.clinicaltrials.gov as #NCT02718716.
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http://dx.doi.org/10.1182/bloodadvances.2020002003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479959PMC
September 2020
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