Severe Immunodeficiency Research Articles

Cytarabine and EIP co-administration synergistically reduces viability of acute lymphoblastic leukemia cells with high ERG expression

The E26 transformation sequence-related gene ERG encodes a transcription factor involved in normal hematopoiesis, and its expression is abnormal in leukemia. Especially in a type of acute lymphoblastic leukemia (ALL) that is refractory and easy to relapse, the expression of ERG protein is abnormally increased. Chemotherapy can alleviate the condition of ALL, but the location and survival mechanism of the remaining ALL cells after chemotherapy are still not fully understood. It is becoming increasingly clear that the interaction between leukemia cells and their microenvironment plays an important role in the acquisition of drug resistance mutations and disease recurrence. We selected an acute lymphocytic leukemia cell line with high ERG expression, and studied the synergistic effect of chemotherapeutics and small molecule peptides through cell proliferation, apoptosis, and cell cycle experiments; At the same time, we inoculated acute lymphocytic leukemia cells with high ERG expression into mice with severe immunodeficiency to simulate human ALL and investigated (i) the effects of co-administration on the nesting and invasion of leukemia cells and (ii) the effects of the small molecule peptide drug EIP, which targets ERG, on the sensitivity of ALL chemotherapy and the underlying mechanisms.Ara-c and EIP synergistically reduces viability of ALL cells with high ERG expression may be achieved by promoting their apoptosis and inhibiting their nesting.

Clinical, Laboratory Features and Clinical Courses of Patients with Wiskott Aldrich Syndrome and X–linked Thrombocytopenia–A single center study

ABSTRACT Objective: Wiskott Aldrich Syndrome is an X-linked primary immunodeficiency disorder characterized by microthrombocytopenia, severe immunodeficiency, and eczema. To define clinical-laboratory features, genetic defects (known/novel) of 23 patients of Wiskott Aldrich Syndrome/X-linked Thrombocytopenia (WAS/XLT) cohort, establish relationships between molecular defects and clinical features if present, evaluate patients who underwent hematopoietic stem cell transplantation (HSCT) and did not. Methods: Qualitative analysis from patients’ hospital files and Sanger sequencing for molecular diagnosis was performed. Twenty-two WAS patients and one XLT patient were included in the study. Results: The median age of diagnosis was 15 months (2.5–172 months). The most common symptom was otitis media and all patients had microthrombocytopenia. Autoimmune findings were detected in 34.7% (8 patients) of the patients; three patients (13%) had positive anti-nuclear antibody (ANA), three patients (13%) hemolytic anemia, one patient autoimmune neutropenia, two patients vasculitis, and one patient demyelinating polyneuropathy. Nine of the 23 (39,1%) patients had HSCT with nearly 90% success. We identified 13 different mutations in our cohort; seven were novel. Conclusions: HSCT is the only curative treatment for WAS. The study confirms that early diagnosis is very important for the success of therapy, so we must increase awareness in society and physicians to keep an eye out for clues. Our study cohort and follow-up period are not sufficient to establish phenotype-genotype correlation, so a larger cohort from various centers with longer follow-up will be more decisive.

ED2 Elements of Value for Gene Therapy: A Systematic Review

ISPOR recommends that value assessments include elements beyond traditional quality-adjusted life years (QALYs) and costs. We aimed to identify non-traditional value elements relevant to gene therapies as it is unclear to what extent they have been included in gene therapy value assessments. We searched PubMed and Embase for full-text articles discussing non-traditional value elements defined by the 2018 ISPOR framework in the context of gene therapy that were published in English between 2015-2020. Health technology assessment (HTA) reports published by the Institute of Clinical and Economic Review and National Institute for Health and Care Excellence were collected. Articles and reports were included if they proposed methods for incorporation or accounted for specified value elements in economic evaluations or real-world decision making. Twenty-four of 644 articles identified met inclusion criteria; 17 were peer-reviewed journal articles and 8 HTA reports. Disease areas for which specific gene therapies were discussed included cancer, beta thalassemia, inherited eye disease, hemophilia, spinal muscular atrophy, and severe immunodeficiency. The most common non-traditional value elements were productivity (n=12), severity of disease (n=10), equity (n=4), and scientific spillover (n=4). Productivity was captured as an indirect cost in cost-effectiveness analyses (CEAs). Although severity of disease, equity, and scientific spillover were not explicitly quantified, they were incorporated into HTA body decisions: severity through conditional market access, QALY weighting, higher CEA thresholds, and lower discount rates; equity through higher CEA thresholds and QALY weighting; and scientific spillover through accelerated market access. Multi-criteria decision analysis was also proposed. Use of novel value elements for gene therapies appears to be sparse in health economic studies to date. Methods of QALY weighting, varying CEA thresholds, discount rates, and specialized access pathways accounted for novel elements in value assessments. Future research on the feasibility, quantification, and incorporation of novel value elements for gene therapies is warranted.

Evaluating the Potential of Harnessing Anti-Leukemia T cells for Treating T-ALL

Abstract T cell Acute Lymphoblastic Leukemia (T-ALL) is a devastating malignancy found primarily in pediatric populations. Although patient outcome has improved, standard of care for T-ALL has not progressed from intensive regimens of chemotherapy. Immunotherapy may offer an alternative approach for treating T-ALL with lower toxicity profiles. In the case of B-ALL, adoptive transfer of engineered cells (e.g. CAR cells) has had resounding success. Unfortunately this may not translate to T-ALL due to severe immunodeficiency from ablating the T cell compartment. These studies therefore sought to determine the therapeutic potential of harnessing anti-leukemia T cells that spontaneously arise in tumor-bearing hosts in response to T-ALL. As very little is known about the interplay between T-ALL and T cells, we initially examined changes to the T cell compartment in response to T-ALL during disease progression by transplanting primary leukemia cells into immune-competent, congenic mice. This model revealed an increase in effector memory CD8 T cells with increased levels of PD1 and OX40 that largely correlated with tumor burden. Importantly, co-targeting PD1 with OX40 resulted in drastic reduction in tumor burden while expanding actively proliferating CD8+GrzB+ T cells. To gain a better understanding of T cell interactions with T-ALL in situ, we have begun utilizing NanoString Technologies’ Digital Spatial Profiling platform. This platform has already shown distinct functional states of T cells between those interacting with leukemia compared with those at distal sights. Ongoing studies aim to identify therapeutic targets in multiple organs which can activate T cell populations of interest to maximize their anti-leukemia effector responses.

Modern possibilities of diagnostics of tuberculosis in patients with HIV infection

The problem of the steady growth of HIV-associated tuberculosis has become increasingly urgent in recent years in Russia. Diagnosis of tuberculosis is particularly difficult at the stage of severe immunodeficiency. Objective. to evaluate the effectiveness of the T-SPOT ® method.TB in the diagnosis of tuberculosis infection in patients with HIV infection. Materials and methods. in the period for 2019-2020, the T-SPOT®.TB results were analyzed in 396 patients. The criteria for inclusion in this study were the age of 18 years and older, the diagnosis of HIV infection, follow-up at the AIDS center. Results. in the group with a positive T-SPOT®.TB and changes on the computed tomogram, the verified diagnosis of tuberculosis was 90.7% of the group with both signs and 75.5% of those with a positive result T-SPOT®.TB. The group with a positive result T-SPOT®.TB and no changes on the CT scan is 16.8% of those with a positive result T-SPOT®.TB,such patients were diagnosed with „latent tuberculosis infection”. Conclusion. T-SPOT®.TB can be used in the diagnostic complex of monitoring patients with HIV infections — as a screening method that allows not only to verify the diagnosis, but also to detect latent tuberculosis.

A case of new coronavirus infection course in a child with severe secondary immunodeficiency associated with hematopoietic stem cell transplantation

Numerous articles have been published on COVID-19 cases in the child population now. Children become infected and get sick with a new infection much less often and more easily than adults. The supposed relative resistance of children to SARS-CoV-2 can be explained by a number of reasons, one of which is the immaturity of the ACE2 receptor, or by the fact that children have certain features of innate immunity that disappear in ontogenesis. On the contrary, the maturity of the immune system may explain the unfavorable type of triggered immune response associated with the development of acute respiratory distress syndrome in adult patients.
 The article describes a case of a new coronavirus infection in a 5-year-old child with a severe secondary immunodeficiency condition associated with hematopoietic stem cell transplantation. By describing this clinical case, we wanted to draw attention to a mild course of COVID-19 infection in a child with a burdened premorbid history in the form of severe secondary immunodeficiency associated with hematopoietic stem cell transplantation in the treatment of acute promyelocytic leukemia.

The Role of IgM-Enriched Immunoglobulin (Pentaglobin) in Septic Patients with Hematological Disease

Background: Patients with hematological disease are 15 times more likely to develop sepsis than the general population. The patient with hematological disease and, mainly, those undergoing hematopoietic stem cell transplantation (HSCT), develop a severe secondary humoral immunodeficiency, with low serum levels of IgM, which may take more than a year to be restored. Materials andMethods: This is a retrospective, controlled and observational study that analyzed 51 patients with underlying hematological disease, who were diagnosed with sepsis or septic shock during the study period, to evaluate whether IgM-rich Ig replacement decreases the 30-day mortality.Results: Of the 51 patients, 35 patients received IgM-rich immunoglobulin (group A) and 16 (31%) received conventional therapy. Eleven (69%) patients in the control group were alive after 30 days compared to 11 (34%) patients in the intervention group, p= 0.013. Conclusion: There are no apparent benefits in the use of IgM-rich immunoglobulin in septic patients with hematological disease.

Virologic and immunologic status of children with HIV-TB co-infections

Background Studies about virologic and immunologic status of HIV children are lacking. Tuberculosis (TB) is the most common opportunistic infection in HIV patients and co-infection is associated with much worse prognosis.
 Objective To describe the virologic and immunologic status of patients with HIV and TB co-infection, before and after HIV and TB treatment.
 Methods A prospective study was conducted in HIV co-infected with TB patients in an Indonesian tertiary hospital between November 2016—December 2018. Viral load and CD4 levels were performed at diagnosis and after 6 months of HIV and TB treatment.
 Results Of 44 children hospitalized due to HIV, 15 newly diagnosed HIV cases had TB co-infection. Thirteen were included as subjects. Most patients (10/13) were under 5 years of age, with similar female and male proportions (7/13 vs. 6/13, respectively). All were diagnosed with stage 4 HIV. Six patients had respiratory problems at admission. First examinations revealed severe immunodeficiency (CD4+ <20%) in all patients, and high viral loads (>105 copies/mL) in most (9/13) patients. Despite good compliance to medications, 8/13 patients died before the sixth month follow-up. Deterioration of virologic and immunologic status was seen in 3/4 of the followed-up patients.
 Conclusion Children with HIV-TB coinfections have severe immunodeficiency and high viral loads. Most such patients die before 6 months, while survivors experience virologic and immunologic status deterioration. Future study must take into account for HIV drug resistance investigation.

An Analysis of Omenn Syndrome– A Rare Combined Immunodeficiency Syndrome

Omenn Syndrome is a rare combined immunodeficiency syndrome manifested mainly by generalisederythroderma, alopecia, loss of eyebrow and eye lashes, generalised oedema and metabolic disturbances.Poor prognosis is reported as it mimics the appearance of severe eczema and immunodeficiency and is undernoticed as there is presence of circulating lymphocytes. Understanding the guidelines of prompt diagnosiswill facilitate early treatment and improve prognosis.

The Presence of Secondary Evans Syndrome in AIDS Patients with Talaromyces marneffei Infection.

ObjectiveTalaromyces marneffei (T.M) is a common opportunistic fungus in human immunodeficiency virus (HIV) infection individual. Secondary Evans syndrome in AIDS patients with Talaromyces marneffei infection has not been reported before. Here, we described cases related to this comorbidity.MethodsAIDS patients diagnosed with Talaromyces marneffei infection from 2016 to 2020 at Xixi Hospital of Hangzhou were included in this retrospective study.ResultsTotal 76 AIDS patients with T.M infection were enrolled. The most common symptoms were fever and cough (70/76; 55/76, respectively). 53/76 (69.74%) patients got positive results of direct antiglobulin test. 14/76 AIDS-T.M patients combined with secondary Hemophagocytic lymphohistiocytosis (HLH). Five patients were diagnosed with AIDS-T.M associated Evans syndrome. There were severe inflammatory reaction, liver dysfunction, coagulation dysfunction and immunodeficiency status in AIDS-T.M patients with secondary Evans syndrome. All patients received antifungal therapy and three patients received corticosteroids for Evans syndrome treatment. One patient died due to sepsis.ConclusionAIDS-T.M patients with secondary Evans syndrome is extremely rare and we need to be alert to the occurrence of secondary Evans syndrome in AIDS-T.M patients. Clinicians should timely start effective antifungal treatments with suspicious T.M infection in AIDS patients.

A Novel Homozygous Mutation Destabilizes IKKβ and Leads to Human Combined Immunodeficiency.

Mutations in the IKBKB gene cause severe immunodeficiency, characterized clinically by persistent respiratory or gastrointestinal infections. Targeted gene panel sequencing revealed a novel homozygous missense mutation in the IKBKB gene of a patient with immune dysregulation and combined T and B cell functional defects. PBMCs from the patient, Ikbkb Y397H mice, and transfected cells were used to elucidate how the Y395H mutation triggers IKKβ deficiency and impairs immune function. Here, we found that cells from both the patient and Ikbkb Y397H mice lacked or showed decreased levels of IKKβ protein, along with impaired lymphocyte function. IKKα and IKKγ protein expression by human PBMCs harboring the Y395H mutation was normal, but degradation of IKKβ protein was accelerated. Binding of human NF-κB to DNA in patient PBMCs fell upon stimulation with TNF-α or LPS. Additionally, a structural model of Y395H revealed loss of the hydrogen bond with D389. These data suggest that IKBKB deficiency induces abnormal IKKβ protein degradation, leading to impaired NF-κB signaling and immune function. We postulate that the Y395H variant in the IKKβ protein lost the hydrogen bond with D389, thereby affecting interaction between Y395 and D389 and increasing protein instability.

Serum vitamin D receptor and High Mobility Group Box-1 (HMGB1) levels in HIV-infected patients with different immunodeficiency status: A cross-sectional study

BackgroundHIV-AIDS patients typically have hypovitaminosis D. Vitamin D is a key mediator in inflammatory and infectious diseases, which VDR mediates its biological effect. High-mobility group box 1 protein (HMGB1) modulates HIV-1 replication in vitro. Vitamin D played a role in inhibiting HMGB1 secretion in the animal study. ObjectivesThis study aimed to examine differences and correlation of vitamin D receptor and HMGB1 protein levels in HIV patients with mild and severe immunodeficiency and healthy control participants. MethodsThis study using a cross-sectional design conducted at Volunteer Counseling and Testing (VCT) Clinic in Mataram, West Nusa Tenggara, Indonesia, from January to June 2020. Three groups of study participants were classified as HIV patients with severe immune deficiency (SID), HIV patients with mild immune deficiency (MID), and healthy controls (HC). ResultsMean level of vitamin D receptor in SID HIV group was 25.89 ± 3.95 ng/ml, lower than those in MID-HIV group; 33.72 ± 1.69 ng/ml and in HC group; 50.65 ± 3.64 ng/ml. Mean levels of HMGB1 protein in the SID HIV group were 3119.81 ± 292.38 pg/ml higher than those in the MID HIV group 1553.55 ± 231.08 pg/ml and HC 680.82 ± 365.51 pg/ml. There was a significant and strong negative correlation (r = −0.932) between vitamin D receptor and HMGB1 levels (p < 0.01). ConclusionsStrong negative correlation between VDR and HMGB1 in different immunodeficiency statuses suggesting an important role of vitamin D in inflammation control in HIV infection. However, it needs to be confirmed in a further prospective study.

Impact of Advanced HIV Disease on Quality of Life and Mortality in the Era of Combined Antiretroviral Treatment.

Currently, AIDS or severe immunodeficiency remains as a challenge for people with HIV (PWHIV) and healthcare providers. Our purpose was to analyze the impact of advanced HIV disease (AHD) on mortality, life expectancy and health-related quality of life (HRQoL). We reviewed cohort studies and meta-analyses conducted in middle- and high-income countries. To analyze HRQoL, we selected studies that reported overall health and/or physical/mental health scores on a validated HRQoL instrument. AIDS diagnosis supposes a higher risk of mortality during the first six months, remaining higher for 48 months. It has been reported that cancer and cardiovascular disease persist as frequent causes of mortality in PWHIV, especially those with previous or current AHD. PWHIV who initiate combination antiretroviral therapy (cART) with CD4 < 200 cells/µL have significantly lower estimated life expectancy than those with higher counts. AHD is associated with lower HRQoL, and a worse physical health or mental health status. AIDS and non-AIDS defining events are significant predictors of a lower HRQoL, especially physical health status. AHD survivors are in risk of mortality and serious comorbidities, needing special clinical attention and preventive programs for associated comorbidities. Their specific needs should be reflected in HIV guidelines.

T Cell Repertoire During Ontogeny and Characteristics in Inflammatory Disorders in Adults and Childhood.

Since the first day of life, a newborn has to deal with various pathogens from the environment. While passive immune protection is provided by diaplacental maternal antibodies, the development of cellular immunity is ongoing. A mature immune system should be able not only to defend against pathogens, but should also be able to differentiate between self- and non-self-antigens. Dysregulation in the development of cellular immunity can lead to severe disorders like immunodeficiency, autoimmunity and chronic inflammation. In this review, we explain the role of T cell immunity in antigen detection and summarize the characteristics of a mature TCR repertoire as well as the current state of knowledge about the development of the TCR repertoire in ontogenesis. In addition, methods of assessments are outlined, with a focus on the advantages and disadvantages of advanced methods such as next generation sequencing. Subsequently, we provide an overview of various disorders occuring in early childhood like immunodeficiencies, autoimmunity, allergic diseases and chronic infections and outline known changes in the TCR repertoire. Finally, we summarize the latest findings and discuss current research gaps as well as potential future developments.

Development of a humanized mouse model to analyze antibodies specific for human leukocyte antigen (HLA).

In organ transplantation, human leukocyte antigen (HLA)-mismatch grafts not only induce the activation of cellular mediated immune response but also the development of chronic antibody-mediated rejection due to the donor-specific anti-HLA antibody (DSA) produced by B cells and plasma cells interacting with the graft endothelium. Significant improvement in long-term survival after transplantation can be expected if antibody-mediated rejection due to the DSA can be overcome. However, the mechanism of producing or controlling the DSA remains to be elucidated. In recent decades, “humanized” mouse models have been widely used for the basic research of human immune systems, but a humanized mouse model to analyze the mechanism of DSA production has not been established yet. Thus, we aimed to create a humanized mouse using a severe immunodeficiency mouse (NSG mouse) administered with human peripheral blood mononuclear cells (PBMCs). Initially, we detected a very low level of human total-IgG and no anti-HLA antibodies (Abs) in these mice. In our next attempt, we mixed PBMCs of various HLA antigenic combinations with or without regulatory T cells and preconditioned them by culturing on feeder cells stably transfected with human CD40 ligand (h-CD40L) alone or with h-CD40L and human B cell activating factor (h-BAFF). They were subsequently co-cultured with the corresponding irradiated stimulator PBMCs, and all cells were administered into naïve NSG mice. Although all three humanized models had sufficient human total-IgG and anti-HLA antibody production, allospecific anti-HLA Ab production was prominently suppressed whereas non-specific anti-HLA Abs were sufficiently detected. Therefore, this novel humanized mouse model might be useful for analyzing the mechanism of anti-allogeneic human B cell tolerance induction.

Torque Teno Virus plasma level as novel biomarker of retained immunocompetence in HIV-infected patients

PurposeTo predict the course of immune recovery (IR) in HIV-1-infected patients after initiation of combined antiretroviral therapy (cART) by determination of the plasma concentration of Torque Teno Virus (TTV).TTV has been identified as marker for risk assessment in immunosuppressed patients after transplantation procedures. Here, TTV was analyzed in HIV-1-infected therapy-naïve patients to evaluate its use as predictor of the course of IR for guidance of individualized treatment.MethodsTTV DNA was quantified in plasma samples of 301 therapy-naïve HIV-1-infected patients and correlated to CD4+ cell count, HIV viral load, presence of the herpes viruses CMV, EBV and HHV-8, age and sex. Patients were classified according to their initial CD4+ cell count and to the extent of CD4+ T-cell increase within the first year of cART.ResultsTTV DNA was detectable in 96% of the patients’ plasma samples with a median TTV plasma concentration of 5.37 log10 cop/ml. The baseline CD4+ cell count was negatively correlated with TTV plasma concentration (p = 0.003). In patients with a CD4+ cell recovery < 50 cells/µl, the median TTV plasma concentration was significantly higher compared to patients with a CD4+ cell recovery of > 200 CD4+ cells/µl (5.68 log10 cop/ml versus 4.99 log10 cop/ml; p = 0.011). TTV plasma concentration in combination with baseline CD4+ cell count were significantly correlated to CD4+ cell recovery (p = 0.004). For all other parameters considered, no significant correlation for CD4+ cell recovery was found.ConclusionWithin the cohort, the significantly elevated TTV plasma concentration in patients with diminished CD4+ cell recovery indicates a more profound immune defect. Baseline TTV plasma concentrations and CD4+ cell count are predictive for the course of immune recovery in HIV-1-infected patients with severe immunodeficiency.

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

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). 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. 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). 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.

Fibrotischer Lungenparenchymumbau nach Lungen- und Stammzelltransplantation

Transplantation of solid organs and hematopoietic stem cells represents an important therapeutic option for avariety of end-stage pulmonary diseases, aggressive hematopoietic neoplasms, or severe immunodeficiencies. Although the overall survival following transplantation has generally improved over recent decades, long-time survival of lung and stem-cell transplant recipients is still alarmingly low with an average 5‑year survival rate of only 50-60%. Chronic allo-immunoreactions in general and pulmonary allo-immunoreactions with subsequent fibrosis in particular are major reasons for this poor outcome. Comparable patterns of fibrotic lung remodeling are observed following both lung and hematopoietic stem-cell transplantation. Besides the meanwhile well-established obliterative and functionally obstructive remodeling of the small airways - obliterative bronchiolitis - aspecific restrictive subform of fibrosis, namely alveolar fibroelastosis, has been identified. Despite their crucial impact on patient outcome, both entities can be very challenging to detect by conventional histopathological analysis. Their underlying mechanisms are considered overreaching aberrant repair attempts to acute lung injuries with overactivation of (myo-) fibroblasts and excessive and irreversible deposition of extracellular matrix. Of note, the underlying molecular mechanisms are widely divergent between these two morphological entities and are independent of the underlying clinical setting.Further comprehensive investigations of these fibrotic alterations are key to the development of much-needed predictive diagnostics and curative concepts, considering the high mortality of pulmonary fibrosis following transplantation.

Humoral and Cellular Immune Response Elicited by mRNA Vaccination Against SARS-CoV-2 in People Living with HIV (PLWH) Receiving Antiretroviral Therapy (ART) According with Current CD4 T-Lymphocyte Count

Background: Data on SARS-CoV-2 vaccine immunogenicity in PLWH are currently limited. Aim of the study was to investigate immunogenicity according to current CD4 T-cell count and predictive role on immune response to vaccination in PLWH.Methods: PLWH attending a single-center SARS-CoV-2 vaccination program in Italy, were included in a prospective evaluation for immunogenicity after receiving BNT162b2 or mRNA-1273. PLWH were stratified according to current CD4 T-cell count (severe immunodeficiency, SID: 500/mm 3 ). RBD-binding IgG, SARS-CoV-2 neutralizing antibodies (nAbs) and cell-mediated (IFN-γ/IL-2) immune response were measured. As control group, not-matched HIV-negative healthcare workers (HCWs) were used.Findings: Participants were 166 PLWH (SID=32; MID=56; NID=78) on ART. After 1 month from the booster dose, detectable RBD-binding IgG in 86.7% of SID, in 100% of MID, in 98.7% of NID (SID vs NID, p=0.021) and nAbs (titre ≥1:10) in 70.0%, 88.2% and 93.1%, respectively (SID vs NID, p=0.002), were elicited. Compared to NID, magnitude of anti-RBD, nAbs and IFN-γ production was significantly lower in SID and comparable in MID. After adjusting for confounders, current CD4 T-cell Interpretation: Neutralizing and cell-mediated immune response against SARS-CoV-2 were elicited in most of PLWH receiving ART, albeit significantly poorer in those with current CD4 T-cell 500/mm 3 and HIV-negative controls. A marginal decreased immunogenicity than HCWs was also observed in PLWH with CD4 T-cell 200-500/mm 3 , whereas immune response elicited in PLWH with a CD4 T-cell >500/mm 3 was comparable to HIV-negative population.Funding: Italian Ministry of Health; European Commission, European Virus Archive – GLOBAL.Declaration of Interest: None to declare. Ethical Approval: The study was approved by the Scientific Committee of the Italian Drug Agency (AIFA) and by the Ethical Committee of the Lazzaro Spallanzani Institute, as National Review Board for COVID-19 pandemic in Italy (approval number 323/2021).

Potential use of in vitro tests in the diagnosis of tuberculosis (literature review)

SummaryThe search for methods to improve early diagnosis of tuberculosis has been particularly active in the last two decades. Diagnostics of latent tuberculosis infection will increase the efficacy of anti-tuberculosis measures. Tu-berculosis in HIV patients, which is increasingly common in the incident population, has specific clinical, immuno-logical, and pathomorphological characteristics posing challenges to diagnosis confirmation. HIV-infected indi-viduals have a 30-fold risk of tuberculosis compared with the general population. Diagnostic challenges are par-ticularly high at the stage of severe immunodeficiency. In the last two decades, IGRAs, which have a higher specifi-city versus tuberculin skin tests, have been increasingly used. We present a literature review of studies comparing the diagnostic efficacy of T-SPOT.TB and QuantiFERON-TB Gold in-Tube assays in patients with suspected active tuberculosis. According to literature data, QuantiFERON assay more frequently yields false negative results in HIV patients with markedly decreased CD4+ cell counts. T-SPOT.TB sensitivity is essentially independent of age, whereby the sensitivity of QuantiFERON-TB reduces after the age of 30 years. T-SPOT.TB assay was not found to be affected by drug therapy. Based on this literature review, we assume that the use of T-SPOT.TB assay is most ap-propriate in the following cases: in patients taking drugs that inhibit gamma interferon production (glucocorti-coids); in patients taking drugs that reduce leukocyte lev-els (NSAIDs: aspirin, paracetamol, Ketorol; also cytostatic agents etc.); in children under 5 years and in elderly sub-jects. T-SPOT.TB appears to be a promising test within the assessment of HIV-infected patients.