Pancytopenia due to proguanil toxicity in a returning traveller with fever

A patient known to have renal insufficiency was admitted to the hospital with fever and pancytopenia after returning from a trip to Mali. Pancytopenia was not caused by a tropical infection but was a side effect of atovaquone/proguanil used as malaria chemoprophylaxis. High and prolonged detectable proguanil serum levels can result in bone marrow suppression in patients with renal insufficiency. This should be taken into account in a returning traveller with fever and pancytopenia

Influence of Polymorphisms in Innate Immunity Genes on Susceptibility to Invasive Aspergillosis after Stem Cell Transplantation

The innate immune system plays a pivotal role in the primary defence against invasive fungal infection. Genetic variation in genes that regulate this response, initiated by pulmonary macrophages, may influence susceptibility to invasive aspergillosis in patients at risk. We investigated in a clinical setting whether common polymorphisms in Toll-like receptor (TLR) and cytokine genes involved in macrophage regulation are associated with susceptibility to invasive aspergillosis. Forty-four allogeneic stem cell transplantation recipients diagnosed with probable or proven IA according to the criteria of the European Organization for Research and Treatment of Cancer/Mycoses Study Group, were enrolled. The control group consisted of 64 allogeneic stem cell transplantation recipients without invasive aspergillosis. The TLR4 1063A>G single nucleotide polymorphism was associated with invasive aspergillosis when present in donors of allogeneic stem cell transplantation recipients (unadjusted OR 3.77 95%CI 1.08–13.2, p = 0.03). In a multivariate analysis, adjusted for occurrence of graft-versus-host-disease, Cytomegalovirus serostatus and duration of neutropenia, paired presence of the TLR4 1063A>G and IFNG 874T>A single nucleotide polymorphisms showed a trend towards increased susceptibility to invasive aspergillosis (p = 0.04). These findings point to the relevant immunological pathway involved in resistance to invasive aspergillosis and warrant further study of the effects of TLR and cytokine polymorphisms and their interaction, which may occur on different levels of the complex biological interplay between the immunocompromised host and Aspergillus sp

Immune Responses 6 Months After mRNA-1273 COVID-19 Vaccination and the Effect of a Third Vaccination in Patients with Inborn Errors of Immunity

Purpose: Patients with inborn errors of immunity (IEI) are at increased risk of severe coronavirus disease-2019 (COVID-19). Effective long-term protection against COVID-19 is therefore of great importance in these patients, but little is known about the decay of the immune response after primary vaccination. We studied the immune responses 6 months after two mRNA-1273 COVID-19 vaccines in 473 IEI patients and subsequently the response to a third mRNA COVID-19 vaccine in 50 patients with common variable immunodeficiency (CVID).Methods: In a prospective multicenter study, 473 IEI patients (including X-linked agammaglobulinemia (XLA) (N = 18), combined immunodeficiency (CID) (N = 22), CVID (N = 203), isolated or undefined antibody deficiencies (N = 204), and phagocyte defects (N = 16)), and 179 controls were included and followed up to 6 months after two doses of the mRNA-1273 COVID-19 vaccine. Additionally, samples were collected from 50 CVID patients who received a third vaccine 6 months after primary vaccination through the national vaccination program. SARS-CoV-2-specific IgG titers, neutralizing antibodies, and T cell responses were assessed.Results: At 6 months after vaccination, the geometric mean antibody titers (GMT) declined in both IEI patients and healthy controls, when compared to GMT 28 days after vaccination. The trajectory of this decline did not differ between controls and most IEI cohorts; however, antibody titers in CID, CVID, and isolated antibody deficiency patients more often dropped to below the responder cut-off compared to controls. Specific T cell responses were still detectable in 77% of controls and 68% of IEI patients at 6 months post vaccination. A third mRNA vaccine resulted in an antibody response in only two out of 30 CVID patients that did not seroconvert after two mRNA vaccines.Conclusion: A similar decline in IgG titers and T cell responses was observed in patients with IEI when compared to healthy controls 6 months after mRNA-1273 COVID-19 vaccination. The limited beneficial benefit of a third mRNA COVID-19 vaccine in previous non-responder CVID patients implicates that other protective strategies are needed for these vulnerable patients.</p

Immune Responses 6 Months After mRNA-1273 COVID-19 Vaccination and the Effect of a Third Vaccination in Patients with Inborn Errors of Immunity

Purpose: Patients with inborn errors of immunity (IEI) are at increased risk of severe coronavirus disease-2019 (COVID-19). Effective long-term protection against COVID-19 is therefore of great importance in these patients, but little is known about the decay of the immune response after primary vaccination. We studied the immune responses 6 months after two mRNA-1273 COVID-19 vaccines in 473 IEI patients and subsequently the response to a third mRNA COVID-19 vaccine in 50 patients with common variable immunodeficiency (CVID).Methods: In a prospective multicenter study, 473 IEI patients (including X-linked agammaglobulinemia (XLA) (N = 18), combined immunodeficiency (CID) (N = 22), CVID (N = 203), isolated or undefined antibody deficiencies (N = 204), and phagocyte defects (N = 16)), and 179 controls were included and followed up to 6 months after two doses of the mRNA-1273 COVID-19 vaccine. Additionally, samples were collected from 50 CVID patients who received a third vaccine 6 months after primary vaccination through the national vaccination program. SARS-CoV-2-specific IgG titers, neutralizing antibodies, and T cell responses were assessed.Results: At 6 months after vaccination, the geometric mean antibody titers (GMT) declined in both IEI patients and healthy controls, when compared to GMT 28 days after vaccination. The trajectory of this decline did not differ between controls and most IEI cohorts; however, antibody titers in CID, CVID, and isolated antibody deficiency patients more often dropped to below the responder cut-off compared to controls. Specific T cell responses were still detectable in 77% of controls and 68% of IEI patients at 6 months post vaccination. A third mRNA vaccine resulted in an antibody response in only two out of 30 CVID patients that did not seroconvert after two mRNA vaccines.Conclusion: A similar decline in IgG titers and T cell responses was observed in patients with IEI when compared to healthy controls 6 months after mRNA-1273 COVID-19 vaccination. The limited beneficial benefit of a third mRNA COVID-19 vaccine in previous non-responder CVID patients implicates that other protective strategies are needed for these vulnerable patients.</p

B-Cell Immunophenotyping to Predict Vaccination Outcome in the Immunocompromised-A Systematic Review

Vaccination is the most effective measure to prevent infections in the general population.Its efficiency strongly depends on the function and composition of the immune system. Ifthe immune system lacks critical components, patients will not be fully protected despite acompleted vaccination schedule. Antigen-specific serum immunoglobulin levels arebroadly used correlates of protection. These are the products of terminally differentiatedB cells – plasma cells. Here we reviewed the literature on how aberrancies in B-cellcomposition and function influence immune responses to vaccinations. In a searchthrough five major literature databases, 6,537 unique articles published from 2000 andonwards were identified. 75 articles were included along three major research lines:extremities of life, immunodeficiency and immunosuppression. Details of the protocol canbe found in the International Prospective Register of Systematic Reviews [PROSPERO(registration number CRD42021226683)]. The majority of articles investigated immuneresponses in adults, in which vaccinations against pneumococci and influenza werestrongly represented. Lack of baseline information was the most common reason ofexclusion. Irrespective of study group, three parameters measured at baseline seemed tohave a predictive value in assessing vaccine efficacy: (1) distribution of B-cell subsets(mostly a reduction in memory B cells), (2) presence of exhausted/activated B cells, or Bcells with an aberrant phenotype, and (3) pre-existing immunological memory. In thisreview we showed how pre-immunization (baseline) knowledge of circulating B cells canbe used to predict vaccination efficacy. We hope that this overview will contribute tooptimizing vaccination strategies, especially in immunocompromised patients

Genotype and allele frequencies of SNPs in <i>TLR</i>, <i>IL10, IL12</i> and <i>IFNG</i> genes in the donor DNA of patients who developed invasive aspergillosis after allogeneic stem cell transplantation.

<p><b>Legenda:</b> IL denotes interleukin; TLR: toll-like receptor; IFN: interferon; ASCT: allogeneic stem cell transplantation; IA: invasive aspergillosis; <i>X</i><b><i>²</i></b>: chi-square test value; OR: odds ratio; 95%CI: 95% confidence interval. ∑: distribution of this genotype was not in Hardy-Weinberg equilibrium (p = 0.045).</p><p>*:Due to incidental failing of genotyping the No. of cases and controls are not equal for each SNP; m: minor allele; M:major allele.</p

Final results of contingency table analysis for the association between the paired presence of TLR and cytokine polymorphisms in donors of ASCT recipients and development of invasive aspergillosis using all 10 polymorphisms.

<p><b>Legenda:</b><i>∫</i>: p-value calculated with Fisher's exact test. IL: interleukin; TLR: toll-like receptor; IFN: interferon.</p><p>*: Adjusted for presence of GVHD, CMV serostatus of donor and acceptor (either one or both CMV IgG+), and prolonged neutropenia (>14 days) by binary logistic regression. OR: odds ratio; 95%CI: 95% confidence interval.</p

Genetic polymorphisms in the innate immune system considered of potential influence on susceptibility to invasive aspergillosis.

<p><b>Legenda:</b> IL denotes interleukin; TLR: toll-like receptor; IFN: interferon; ASCT: allogeneic stem cell transplantation; IA: invasive aspergillosis; SNPdb id: Single Nucleotide Polymorphism database identification number.</p