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JAMA Pediatrics Aug 2022Neonatal early-onset sepsis (EOS) is a severe disease, particularly in preterm infants. Timely diagnosis can be challenging owing to unspecific presentation and... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Neonatal early-onset sepsis (EOS) is a severe disease, particularly in preterm infants. Timely diagnosis can be challenging owing to unspecific presentation and questionable performance of the common markers of infection. Presepsin was recently proven to be a promising biomarker for the diagnosis of EOS.
OBJECTIVE
To assess presepsin accuracy for the diagnosis of EOS.
DATA SOURCES
PubMed Medline, EMBASE, Web of Science, and Google Scholar. No publication date restrictions were applied. The literature search was limited to the English language. Articles were checked for duplication.
STUDY SELECTION
Inclusion criteria were studies that (1) included term or preterm newborns (defined as newborns with gestational age ≥37 weeks or <37 weeks, respectively); (2) included a diagnosis of EOS, defined as culture-proven sepsis for primary analysis and as either clinical or culture-proven sepsis for secondary analysis; and (3) assessed presepsin values during the initial workup for suspected EOS. Exclusion criteria were studies that (1) did not include EOS cases; (2) lacked data on presepsin sensitivity and/or specificity; and (3) were case reports, commentaries, or reviews. Two independent reviewers performed the study selection.
DATA EXTRACTION AND SYNTHESIS
Two independent reviewers performed data extraction and quality assessment. Quality assessment was performed using the Quality Assessment for Studies of Diagnostic Accuracy 2 tool, and data were reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data were pooled using a random-effects model.
MAIN OUTCOMES AND MEASURES
The outcomes of interest for both the primary and secondary analyses were presepsin sensitivity, specificity, and diagnostic odds ratio for the diagnosis of EOS.
RESULTS
A total of 12 studies of 245 (4.9%) met inclusion criteria for the primary analysis. Twenty-three studies of 245 (9.4%) met the inclusion criteria for the secondary analysis. In the primary analysis, among 12 studies and 828 newborns of any gestational age, pooled sensitivity and specificity were 0.93 (95% CI, 0.86-0.95) and 0.91 (95% CI, 0.85-0.95), respectively; pooled diagnostic odds ratio was 131.69 (95% CI, 54.93-310.94). Subgroup analysis showed that presepsin specificity was associated with the inclusion of only EOS or all neonatal sepsis. Presepsin accuracy was not associated with gestational age, measurement with chemiluminescence enzyme immunoassay or enzyme-linked immunosorbent assay testing, country where the study was performed, or risk of bias judgment. In the secondary analysis, among 23 studies and 1866 newborns, accuracy was significantly associated with only test type.
CONCLUSIONS AND RELEVANCE
Results of this systematic review and meta-analysis suggest that presepsin was an accurate biomarker of EOS. Clinical trials are warranted to assess its usefulness and safety to reduce early antibiotic exposure, particularly in preterm newborns.
Topics: Biomarkers; Humans; Infant; Infant, Newborn; Infant, Premature; Lipopolysaccharide Receptors; Neonatal Sepsis; Peptide Fragments; Sepsis
PubMed: 35639395
DOI: 10.1001/jamapediatrics.2022.1647 -
Critical Care (London, England) Nov 2018Sepsis is an important cause of neonatal morbidity and mortality; therefore, the early diagnosis of neonatal sepsis is essential. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Sepsis is an important cause of neonatal morbidity and mortality; therefore, the early diagnosis of neonatal sepsis is essential.
METHOD
Our aim was to compare the diagnostic accuracy of procalcitonin (PCT), C-reactive protein (CRP), procalcitonin combined with C-reactive protein (PCT + CRP) and presepsin in the diagnosis of neonatal sepsis. We searched seven databases to identify studies that met the inclusion criteria. Two independent reviewers performed data extraction. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), area under curve (AUC), and corresponding 95% credible interval (95% CI) were calculated by true positive (TP), false positive (FP), false negative (FN), and true negative (TN) classification using a bivariate regression model in STATA 14.0 software. The pooled sensitivity, specificity, PLR, NLR, DOR, AUC, and corresponding 95% CI were the primary outcomes. Secondary outcomes included the sensitivity and specificity in multiple subgroup analyses.
RESULTS
A total of 28 studies enrolling 2661 patients were included in our meta-analysis. The pooled sensitivity of CRP (0.71 (0.63, 0.78)) was weaker than that of PCT (0.85 (0.79, 0.89)), PCT + CRP (0.91 (0.84, 0.95)) and presepsin (0.94 (0.80, 0.99)) and the pooled NLR of presepsin (0.06 (0.02, 0.23)) and PCT + CRP (0.10 (0.05, 0.19)) were less than CRP (0.33 (0.26, 0.42)), and the AUC for presepsin (0.99 (0.98, 1.00)) was greater than PCT + CRP (0.96 (0.93, 0.97)), CRP (0.85 (0.82, 0.88)) and PCT (0.91 (0.89, 0.94)). The results of the subgroup analysis showed that 0.5-2 ng/mL may be the appropriate cutoff interval for PCT. A cut-off value > 10 mg/L for CRP had high sensitivity and specificity.
CONCLUSIONS
The combination of PCT and CRP or presepsin alone improves the accuracy of diagnosis of neonatal sepsis. However, further studies are required to confirm these findings.
Topics: Area Under Curve; Biomarkers; C-Reactive Protein; Humans; Infant, Newborn; Infant, Newborn, Diseases; Lipopolysaccharide Receptors; Neonatal Sepsis; Odds Ratio; Pediatrics; Peptide Fragments; Procalcitonin; ROC Curve
PubMed: 30463590
DOI: 10.1186/s13054-018-2236-1 -
JAMA Oncology Mar 2020Immune checkpoint inhibitors of programmed cell death 1 (PD-1) and its ligand (PD-L1) have led to a paradigm shift in cancer treatment. Understanding the clinical... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Immune checkpoint inhibitors of programmed cell death 1 (PD-1) and its ligand (PD-L1) have led to a paradigm shift in cancer treatment. Understanding the clinical efficacy and safety profile of these drugs is necessary for treatment strategy in clinical practice.
OBJECTIVE
To assess the differences between anti-PD-1 and anti-PD-L1 regarding efficacy and safety shown in randomized clinical trials across various tumor types.
DATA SOURCES
Systematic searches of PubMed, Cochrane CENTRAL, and Embase were conducted from January 1, 2000, to March 1, 2019. In addition, abstracts and presentations from all major conference proceedings were reviewed.
STUDY SELECTION
All randomized clinical trials that compared anti-PD-1 and anti-PD-L1 with standard treatment in patients with cancer were selected as candidates. Retrospective studies, single-arm phase 1/2 studies, and trials comparing anti-PD-1 and anti-PD-L1 with other immunotherapies were excluded. Studies of anti-PD-1 and anti-PD-L1 therapy were screened and paired by the matching of clinical characteristics as mirror groups.
DATA EXTRACTION AND SYNTHESIS
Three investigators independently extracted data from each study following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guideline. Trial names, first author, year of publication, study design, National Clinical Trial identifier number, blinding status, study phase, pathologic characteristics, number of patients, patients' age and sex distribution, Eastern Cooperative Oncology Group Performance Status, lines of treatment, study drugs, biomarker status, follow-up time, incidence of adverse events, and hazard ratios (HRs) with 95% CIs for overall survival and progression-free survival were extracted. A random-effects model was applied for data analysis.
MAIN OUTCOMES AND MEASURES
Differences in OS between anti-PD-1 and anti-PD-L1 across different cancer types were assessed. An effect size was derived from each mirror group and then pooled across all groups using a random-effects model.
RESULTS
Nineteen randomized clinical trials involving 11 379 patients were included in the meta-analysis. Overall, anti-PD-1 exhibited superior overall survival (HR, 0.75; 95% CI, 0.65-0.86; P < .001) and progression-free survival (HR, 0.73; 95% CI, 0.56-0.96; P = .02) compared with anti-PD-L1. No significant difference was observed in their safety profiles. Sensitivity analysis presented consistency in the overall estimates across these analyses. Consistent results were observed through frequentist and bayesian approaches with the same studies.
CONCLUSIONS AND RELEVANCE
Comprehensive analysis suggests that anti-PD-1 exhibited favorable survival outcomes and a safety profile comparable to that of anti-PD-L1, which may provide a useful guide for clinicians.
Topics: Antineoplastic Agents, Immunological; B7-H1 Antigen; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Neoplasms; Programmed Cell Death 1 Receptor; Randomized Controlled Trials as Topic
PubMed: 31876895
DOI: 10.1001/jamaoncol.2019.5367 -
Blood Advances Jan 2023Relapsed/refractory primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL) are associated with short survival and... (Meta-Analysis)
Meta-Analysis
Relapsed/refractory primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL) are associated with short survival and represent an unmet need, requiring novel effective strategies. Anti-CD19 chimeric antigen receptor (CAR) T cells, effective in systemic large B-cell lymphoma (LBCL), have shown responses in PCNSL and SCNSL in early reports, but with limited sample size. We, therefore, performed a comprehensive systematic review and meta-analysis of all published data describing CAR T-cell use in PCNSL and SCNSL. This identified 128 patients with PCNSL (30) and SCNSL (98). Our primary objectives were to evaluate CAR T-cell specific toxicity (immune effector cell-associated neurotoxicity syndrome [ICANS] and cytokine release syndrome [CRS]) as well as response rates in these 2 populations. Seventy percent of patients with PCNSL had CRS of any grade (13% grade 3-4) and 53% had ICANS of any grade (18% grade 3-4). Comparatively, 72% of the SCNSL cohort experienced CRS of any grade (11% grade 3-4) and 48% had ICANS of any grade (26% grade 3-4). Of the patients with PCNSL, 56% achieved a complete remission (CR) with 37% remaining in remission at 6 months. Similarly, 47% of patients with SCNSL had a CR, with 37% in remission at 6 months. In a large meta-analysis of central nervous system (CNS) lymphomas, toxicity of anti-CD19-CAR T-cell therapy was similar to that of registrational studies in systemic LBCL with no increased signal of neurotoxicity observed. Encouraging efficacy was demonstrated in patients with CNS lymphoma with no discernible differences between PCNSL and SCNSL.
Topics: Humans; Antigens, CD19; Central Nervous System Neoplasms; Cytokine Release Syndrome; Immunotherapy, Adoptive; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Neoplasms, Second Primary; Neurotoxicity Syndromes
PubMed: 36260735
DOI: 10.1182/bloodadvances.2022008525 -
Transfusion Medicine Reviews Apr 2019Promising efficacy results of chimeric antigen receptor (CAR) T-cell therapy have been tempered by safety considerations. Our objective was to comprehensively summarize... (Meta-Analysis)
Meta-Analysis
Promising efficacy results of chimeric antigen receptor (CAR) T-cell therapy have been tempered by safety considerations. Our objective was to comprehensively summarize the efficacy and safety of CAR-T cell therapy in patients with relapsed or refractory hematologic or solid malignancies. MEDLINE, Embase, and the Cochrane Register of Controlled Trials (inception - November 21, 2017). Interventional studies investigating CAR-T cell therapy in patients with malignancies were included. Our primary outcome of interest was complete response (defined as the absence of detectable cancer). Two independent reviewers extracted relevant data, assessed risk of bias, and graded the quality of evidence using established methods. A total of 42 hematological malignancy studies and 18 solid tumor studies met were included (913 participants). Of 486 evaluable hematologic patients, 54.4% [95% CI, 42.5%-65.9%] experienced complete response in 27 CD19 CAR-T cell therapy studies. Of 65 evaluable hematologic patients, 24.4% [95% CI, 9.4%-50.3%] experienced complete response in seven non-CD19 CAR-T cell therapy studies. Cytokine release syndrome was experienced by 55.3% [95% CI, 40.3%-69.4%] of patients and neurotoxicity 37.2% [95% CI, 28.6%-46.8%] of patients with hematologic malignancies. Of 86 evaluable solid tumor patients, 4.1% [95% CI, 1.6%-10.6%] experienced complete response in eight CAR-T cell therapy studies. Limitations include heterogeneity of study populations, as well as high risk of bias of included studies. There was a strong signal for efficacy of CAR-T cell therapy in patients with CD19+ hematologic malignancies and no overall signal in solid tumor trials published to date. These results will help inform patients, physicians, and other stakeholders of the benefits and risks associated with CAR-T cell therapy.
Topics: Antigens, CD19; Hematologic Neoplasms; Humans; Immunotherapy; Immunotherapy, Adoptive; Lymphoma, Large B-Cell, Diffuse; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; Risk Assessment; T-Lymphocytes; Treatment Outcome
PubMed: 30948292
DOI: 10.1016/j.tmrv.2019.01.005 -
Cells Aug 2023Immunotherapy has recently been incorporated into the spectrum of biliary tract cancer (BTC) treatment. The identification of predictive response biomarkers is essential... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Immunotherapy has recently been incorporated into the spectrum of biliary tract cancer (BTC) treatment. The identification of predictive response biomarkers is essential in order to identify those patients who may benefit most from this novel treatment option. Here, we propose a systematic literature review and a meta-analysis of PD-1, PD-L1, and other immune-related biomarker expression levels in patients with BTC.
METHODS
Prisma guidelines were followed for this systematic review and meta-analysis. Eligible studies were searched on PubMed. Studies published between 2017 and 2022, reporting data on PD-1/PD-L1 expression and other immune-related biomarkers in patients with BTC, were considered eligible.
RESULTS
A total of 61 eligible studies were identified. Despite the great heterogeneity between 39 studies reporting data on PD-L1 expression, we found a mean PD-L1 expression percentage (by choosing the lowest cut-off per study) of 25.6% (95% CI 21.0 to 30.3) in BTCs. The mean expression percentages of PD-L1 were 27.3%, 21.3%, and 27.4% in intrahepatic cholangiocarcinomas (iCCAs-15 studies), perihilar-distal CCAs (p/dCCAs-7 studies), and gallbladder cancer (GBC-5 studies), respectively. Furthermore, 4.6% (95% CI 2.38 to 6.97) and 2.5% (95% CI 1.75 to 3.34) of BTCs could be classified as TMB-H and MSI/MMRd tumors, respectively.
CONCLUSION
From our analysis, PD-L1 expression was found to occur approximately in 26% of BTC patients, with minimal differences based on anatomical location. TMB-H and MSI molecular phenotypes occurred less frequently. We still lack a reliable biomarker, especially in patients with mismatch-proficient tumors, and we must need to make an effort to conceive new prospective biomarker discovery studies.
Topics: Humans; B7-H1 Antigen; Programmed Cell Death 1 Receptor; Biliary Tract Neoplasms; Immunotherapy; Biomarkers; Bile Duct Neoplasms; Bile Ducts, Intrahepatic
PubMed: 37626908
DOI: 10.3390/cells12162098 -
Clinical and Experimental Medicine Aug 2023Plasmatic presepsin (PSP) is a novel biomarker reported to be useful for sepsis diagnosis and prognosis. During the pandemic, only few studies highlighted a possible... (Meta-Analysis)
Meta-Analysis Review
Plasmatic presepsin (PSP) is a novel biomarker reported to be useful for sepsis diagnosis and prognosis. During the pandemic, only few studies highlighted a possible correlation between PSP and COVID-19 severity, but results remain inconsistent. The present study aims to establish the correlation between PSP and COVID-19 severity. English-language papers assessing a correlation between COVID-19 and PSP from MEDLINE, PubMed, Google Scholar, Cochrane Library, MeSH, LitCovid NLM, EMBASE, CINAHL Plus and the World Health Organization (WHO) website, published from January 2020 were considered with no publication date limitations. Two independent reviewers performed data abstraction and quality assessment, and one reviewer resolved inconsistencies. The protocol was registered on PROSPERO (CRD42022325971).Fifteen articles met our eligibility criteria. The aggregate study population included 1373 COVID-19 patients who had undergone a PSP assessment. The random-effect meta-analysis was performed in 7 out of 15 selected studies, considering only those reporting the mean PSP levels in low- and high-severity cases (n = 707).The results showed that the pooled mean difference of PSP levels between high- and low-severity COVID-19 patients was 441.70 pg/ml (95%CI: 150.40-732.99 pg/ml).Our data show that presepsin is a promising biomarker that can express COVID-19 severity.
Topics: Humans; COVID-19; Prognosis; Biomarkers; Pandemics; Sepsis; Peptide Fragments; Lipopolysaccharide Receptors
PubMed: 36380007
DOI: 10.1007/s10238-022-00936-8 -
Autoimmunity Reviews Jun 2023Giant cell arteritis is the most common form of large vessel vasculitis and preferentially involves large and medium-sized arteries in patients over the age of 50.... (Review)
Review
Giant cell arteritis is the most common form of large vessel vasculitis and preferentially involves large and medium-sized arteries in patients over the age of 50. Aggressive wall inflammation, neoangiogenesis and consecutive remodeling processes are the hallmark of the disease. Though etiology is unknown, cellular and humoral immunopathological processes are well understood. Matrix metalloproteinase-9 mediated tissue infiltration occurs through lysis of basal membranes in adventitial vessels. CD4+ cells attain residency in immunoprotected niches, differentiate into vasculitogenic effector cells and enforce further leukotaxis. Signaling pathways involve the NOTCH1-Jagged1 pathway opening vessel infiltration, CD28 mediated T-cell overstimulation, lost PD-1/PD-L1 co-inhibition and JAK/STAT signaling in interferon dependent responses. From a humoral perspective, IL-6 represents a classical cytokine and potential Th-cell differentiator whereas interferon-γ (IFN- γ) has been shown to induce chemokine ligands. Current therapies involve glucocorticoids, tocilizumab and methotrexate application. However, new agents, most notably JAK/STAT inhibitors, PD-1 agonists and MMP-9 blocking substances, are being evaluated in ongoing clinical trials.
Topics: Humans; Giant Cell Arteritis; Autoimmunity; Programmed Cell Death 1 Receptor; CD4-Positive T-Lymphocytes; Cytokines; Takayasu Arteritis
PubMed: 36990133
DOI: 10.1016/j.autrev.2023.103328 -
Clinical and Experimental Immunology Jul 2021Cytotoxic T lymphocyte antigen 4 (CTLA-4) haploinsufficiency (CHAI) and lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency (LATAIE) are newly identified... (Review)
Review
Cytotoxic T lymphocyte antigen 4 (CTLA-4) haploinsufficiency (CHAI) and lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency (LATAIE) are newly identified inborn errors of immunity with shared molecular pathomechanisms and clinical manifestations. In this review, we aimed to provide differential comparisons regarding demographic, clinical, immunological and molecular characteristics between these two similar conditions. A literature search was conducted in PubMed, Web of Science and Scopus databases and included studies were systematically evaluated. Overall, 434 (222 CHAI and 212 LATAIE) patients were found in 101 eligible studies. The CHAI patients were mainly reported from North America and western Europe, while LATAIE patients were predominantly from Asian countries. In CHAI, positive familial history (P < 0·001) and in LATAIE, consanguineous parents (P < 0·001) were more common. In CHAI patients the rates of granulomas (P < 0·001), malignancies (P = 0·001), atopy (P = 0·001), cutaneous disorders (P < 0·001) and neurological (P = 0·002) disorders were higher, while LATAIE patients were more commonly complicated with life-threatening infections (P = 0·002), pneumonia (P = 0·006), ear, nose and throat disorders (P < 0·001), organomegaly (P = 0·023), autoimmune enteropathy (P = 0·038) and growth failure (P < 0·001). Normal lymphocyte subsets and immunoglobulins except low serum levels of CD9 B cells (14·0 versus 38·4%, P < 0·001), natural killer (NK) cells (21 versus 41·1%, P < 0·001), immunoglobulin (Ig)G (46·9 versus 41·1%, P = 0·291) and IgA (54·5 versus 44·7%, P = 0·076) were found in the majority of CHAI and LATAIE patients, respectively. The most frequent biological immunosuppressive agents prescribed for CHAI and LATAIE patients were rituximab and abatacept, respectively. Further investigations into the best conditioning and treatment regimens pre- and post-transplantation are required to improve the survival rate of transplanted CHAI and LATAIE patients.
Topics: Adaptor Proteins, Signal Transducing; CTLA-4 Antigen; Haploinsufficiency; Humans; Immunoglobulins; Immunosuppressive Agents; Lymphocytes
PubMed: 33788257
DOI: 10.1111/cei.13600 -
Viruses May 2023Patients with chronic hepatitis B (CHB) gradually develop T cell exhaustion, and the inhibitory receptor molecule, cytotoxic T-lymphocyte antigen-4 (CTLA-4), may play a... (Review)
Review
Patients with chronic hepatitis B (CHB) gradually develop T cell exhaustion, and the inhibitory receptor molecule, cytotoxic T-lymphocyte antigen-4 (CTLA-4), may play a role in this phenomenon. This systematic review investigates the role of CTLA-4 in the development of T cell exhaustion in CHB. A systematic literature search was conducted on PubMed and Embase on 31 March 2023 to identify relevant studies. Fifteen studies were included in this review. A majority of the studies investigating CD8 T cells demonstrated increased expression of CTLA-4 in CHB patients, though one study found this only in HBeAg-positive patients. Three out of four studies investigating the expression of CTLA-4 on CD4 T cells found upregulation of CTLA-4. Several studies showed constitutive expression of CLTA-4 on CD4 regulatory T cells. CTLA-4 blockade resulted in heterogeneous responses for all T cell types, as it resulted in increased T cell proliferation and/or cytokine production in some studies, while other studies found this only when combining blockade of CTLA-4 with other inhibitory receptors. Although mounting evidence supports a role of CTLA-4 in T cell exhaustion, there is still insufficient documentation to describe the expression and exact role of CTLA-4 in T cell exhaustion in CHB.
Topics: Humans; CTLA-4 Antigen; Hepatitis B, Chronic; CD8-Positive T-Lymphocytes; T-Cell Exhaustion; T-Lymphocytes, Regulatory; Hepatitis B virus
PubMed: 37243227
DOI: 10.3390/v15051141