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Background: Krebs von den Lungen-6 (KL-6) is a mucin glycoprotein mainly produced on the surface of alveolar type 2 epithelial cells. Some case-control studies comparing healty subjects to COVID-19 patients in different stages of severity have documented that serum KL-6 levels predict COVID-19 severity and poor clinical outcomes. However, the relevance of KL-6 in patients with severe and critical COVID-19 have not fully elucidated. Method(s): Retrospective data from consecutive severe to critical COVID-19 patients were collected at UOC Clinical Pnuemologica "Vanvitelli", A.O. dei Colli, Naples, Italy. Study included patients with a positive rhinopharyngeal swab for SARS-COV-2 RNA with severe or critical COVID-19. Result(s): Study population characteristics are reported in Table 1. Among 87 patients 24 had poor outcomes (IOT or death). Median KL-6 value in survivors was significantly lower when compared with patients dead or intubated (530 U/mL versus 1069 U/mL p<0.001). KL-6 was correlated with BMI (r: 0.279, p:0.009), LUS Score (r: 0.429, p<0.001), Chung Score (r: 0.390, p<0.001). KL-6 was associated with risk of death or IOT after adjusting for gender, BMI, Charlson Index, Chung Score, and P/F (OR 1.003 95%IC 1.001-1.004, p <0.001). Serum KL-6 value of 968 has a sensivity of 79.2%, specificity of 87.1%, PPV 70.4%, NPV 91.5%, AUC: O.85 for risk of death or IOT (Figure 1). Conclusion(s): The presented research highlights the relevance of serum KL-6 in severe to critical COVID-19 patients in predicting the risk of death or IOT.
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Aim: The aim of this study was to determine severity in patients who have had SARS-CoV2 pneumonia. Method(s): A cohort of 802 patients from our post-COVID multidisciplinary unit treated at least 30 days after being discharged from hospital was analyzed. Patients were divided into three groups: group 1 (admission to the Intensive Care Unit or Intermediate Respiratory Care Unit), group 2 (admission to conventional hospitalization), and group 3 (outpatient management without hospitalization). Symptoms, quality of life, daily physical activity, emotional state, biomarkers of systemic inflammation and KL-6 levels were evaluated. Result(s): A total of 802 patients with a median (interquartile range) age 59 (48-70 years) at diagnosis were reviewed, of whom 439 (54.8%) were women. Dyspnea was reported by 351 (66.%) patients and 142 (36.4%) had a grade more than 2 on the mMRC scale. Likewise, 106 (20.1%) presented dry cough and 233 (44.5%) asthenia. There were significant differences between groups 2 and 3 in: dyspnea (p=0.04), myalgia (p=0.04) and asthenia (p=0.01). Group 1 had a higher score in the TTO and VAS rates of the EuroQuoL scale compared to group 2. Finally, the KL6 levels in groups 1, 2 and 3 were: 381.50 (304 - 511.75) U/ml, 372 (249 - 483) U/ml and 298 (231.5 - 398) U/ml, respectively. Statistically significant differences were observed between the 3 groups (p=0.001) and in the post-hoc analysis, lower levels of KL-6 were observed in group 3 compared to the other two groups. Conclusion(s): There is evidence to affirm that KL6 levels in post-COVID patients are related to the severity of the acute episode.
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Introduction: Krebs von den Lungen-6(KL-6) is useful in the diagnosis and severity assessment of diffuse interstitial lung disease. The objective of our study was to determine the prognostic value of the initial KL-6 plasma level in COVID-19 pneumonia Methods: All patients hospitalized between March 2020 and May 2020 for a suspected COVID-19 pneumonia in our Chest department of university hospital (Paris, France) were included. Initial referred as within 72 h of diagnostic suspicion, KL-6 plasma concentration in U/mL was measured by a ChemiLuminescent Enzyme Immunoassay (LUMIPULSE, Japan). Survival analyses were performed using a Cox regression and modeled by a Kaplan-Meier curve Results: 66 COVID-19 patients with initial KL-6 plasma measurement were analyzed, among whom 47 were men and average age was 64+/-14 yrs. Median KL-6 plasma concentration was 409+/-312 U/mL. KL-6 was significantly higher in men (p=0.003), elders (p=0.0001) and for higher Charlson's score (p=0.002). Higher KL-6 concentration was significantly associated with in-hospital mortality (HR: 8.66;95% CI:1.1-69.2), radiological extension of lesions on chest CT-scan (p=0.0040), higher WHO severity score (p=0.042), but not with admission in intensive care unit. In the 9 (14%) non surviving COVID-19 patients, KL-6 plasma concentration increased while it remained stable or decreased in survivors. At 3 months (n=48), DLCO was negatively correlated with the initial KL-6 value (r = -0.47, p=0.001) Conclusion(s): Initial KL-6 plasma concentration is associated with in-hospital mortality, unfavorable outcome, and persistent impairment of DLCO at 3 months. Initial KL-6 plasma determination appears as a prognostic biomarker in COVID-19 pneumonia.
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On March 23, 2022, the U.S. Food and Drug Administration (FDA) approved Pluvicto (lutetium Lu 177 vipivotide tetraxetan), also known as 177Lu-PSMA-617, for the treatment of adult patients with metastatic castration-resistant prostate cancer (mCRPC) who have highly expressed prostate-specific membrane antigen (PSMA) and have at least one metastatic lesion. It is the first FDA-approved targeted radioligand therapy for eligible men with PSMA-positive mCRPC. Lutetium Lu 177 vipivotide tetraxetan is a radioligand that strongly binds to PSMA, making it ideal for treating cancers of the prostate by targeted radiation, resulting in DNA damage and cell death. PSMA is overexpressed in cancer cells while being lowly expressed in normal tissues, which makes it an ideal theranostic target. As precision medicine advances, this is a thrilling turning point for highly individualized treatments. This review aims to summarize the pharmacology and clinical studies of the novel drug lutetium Lu 177 vipivotide tetraxetan for the treatment of mCRPC, emphasizing its mechanism of action, pharmacokinetics and safety.
Subject(s)
Lutetium , Prostatic Neoplasms, Castration-Resistant , Male , Humans , Lutetium/adverse effects , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostate-Specific Antigen/therapeutic use , Treatment OutcomeABSTRACT
There is an unmet need to unearth alternative treatment options for malaria, wherein this quest is more pressing in recent times due to high morbidity and mortality data arising mostly from the endemic countries coupled with partial diversion of attention from the disease in view of the SARS-Cov-2 pandemic. Available therapeutic options for malaria have been severely threatened with the emergence of resistance to almost all the antimalarial drugs by the Plasmodium falciparum parasite in humans, which is a worrying situation. Artemisinin combination therapies (ACT) that have so far been the mainstay of malaria have encountered resistance by malaria parasite in South East Asia, which is regarded as a notorious ground zero for the emergence of resistance to antimalarial drugs. This review analyzes a few key druggable targets for the parasite and the potential of specific inhibitors to mitigate the emerging antimalarial drug resistance problem by providing a concise assessment of the essential proteins of the malaria parasite that could serve as targets. Moreover, this work provides a summary of the advances made in malaria parasite biology and the potential to leverage these findings for antimalarial drug production.
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Background and aims: Small fiber neuropathy (SFN) is a polymorphous disease affecting thin nervous fibers conducting temperature and pain sensations and involved in autonomic transmission. Etiology is diverse and remains elusive in 70% of cases. Methods: We describe a case series of 6 patients who developed symptoms of SFN following SARS-COV-19 vaccination. Neurologic examination was normal whilst paraclinical results were consistent with SFN. Confirmation by skin biopsy was obtained in 4 cases. Results: Six patients, 5 female and 1 male, ages 31, 34, 39, 42, 44 and 62 years, consulted our department with intense pain and numbness involving the arms and legs 2 to 15 days following SARS-COV-19 vaccination. Neurologic examination was normal. A preliminary diagnostic protocol comprising autoimmune, metabolic, infectious and inflammatory panel, cerebral and spinal cord magnetic resonance imaging and electromyography was normal. Functional neurophysiologic testing showed reduced activation of fibers involved in sweat gland control indicating SFN. Skin biopsy of distal calf and thigh in 4 patients, three female and one male, showed rarefaction of thin intraepidermic nerve fibers in a non length dependent manner, allowing for a diagnosis of SFN. Conclusion: Whereas autoimmune, infectious, metabolic, toxic and genetic causes are well described in SFN, evidence of possible association with vaccination is confounding. Given their small caliber and richness of surface antigens, small nervous fibers are vulnerable to a wide spectrum of disease. Immunologic factors intervening on a predisposing substrate could be a hypothesis for the mechanism involved in development of SFN following SARS-COV-19 and possibly other vaccination.
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Background and aims: Georgia introduced routine infant hepatitis B (HepB) vaccination in 2001 with >90% coverage over the last decade. In 2015, a nationwide serosurvey demonstrated an anti-hepatitis B core antibody (anti-HBc) prevalence of 25.9% and hepatitis B surface antigen (HBsAg) prevalence of 2.9% among adults ≥18 years. No prevalence data were available for children. In 2021, we assessed hepatitis B virus (HBV) infection prevalence among children and updated estimates for adults in a combined COVID-19, hepatitis C and hepatitis B serosurvey of persons aged ≥5 years. Method: We used a stratified, multi-stage cluster design. We collected data on demographics, medical and exposure history;we tested blood samples for anti-HBc and, if positive, for HBsAg. Nationally representative weighted proportions and 95% confidence intervals (CI) for anti-HBc and HBsAg were calculated. Participants aged 5–20 years had been eligible for routine HepB vaccination as infants. Results: Among children aged 5–17 years, 0.7% were anti-HBc+ and 0.03%were HBsAg+ (Table). Among adults ≥18 years, 21.7%were anti- HBc+ and 2.7%were HBsAg+. Anti-HBc prevalence increased with age from 1.3% among 18–23-year-olds to 28.6% among ≥60 years. HBsAg prevalence was lowest (0.2%) among 18–23-year-olds and highest (8.6%) among 35–39-year-olds. Males had higher HBsAg prevalence than females (3.6% versus 2.0%;p = 0.003). Anti-HBc prevalence was highest in Samegrelo-Zemo Svaneti, Adjara, and Imereti regions. Higher education and income were associated with lower anti-HBc, and unemployment-with higher HBsAg prevalence. (Table Presented) Conclusion: The impact of HepB vaccination in Georgia is demonstrated by a low HBsAg prevalence among children that is below the 0.5% European regional hepatitis B control target and meets the ≤0 .1% seroprevalence target for elimination of mother-to-child transmission of HBV. Chronic HBV infection remains a problem among adults born before routine infant HepB vaccination. Focusing efforts on screening, treatment, and preventive interventions among adults, along with sustaining high immunization coverage among children, can help Georgia achieve elimination of hepatitis B as public health threat by 2030.
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Background and Aims: In Spain, HIV, HBV, and HCV prevalence are lower in females. A 2017–2018 Ministry of Health serosurvey in 7, 675 primary care patients found 0.35% and 0.08% chronic HCV infection in men and women. A previous opportunistic, population-based screening program in 11, 449 primary care patients seen in our health department found 0.18% and 0.06% HIV infection prevalence, 1.11% and 0.56% chronic HBV infection prevalence, and 0.73% and 0.25% chronic HCV infection prevalence in men and women from February to December 2019. We aimed to assess HIV, HBV, and HCV prevalence among women seeking care in our health department’s 5 Sexual and Reproductive Health Units (SRHU), in the Human Reproduction Unit (HRU), and the Obstetrics and Gynecology Service (OGS). Method: We implemented opportunistic HIV, HBV, and HCV screening from March to October 2021, despite challenges related to a fifth wave of the SARS-CoV-2 pandemic. We used existing infrastructure and staff, aided by electronic health record system modifications, to identify screening eligibility and request serologies. Patients were eligible for testing upon verbal consent if they were between 18 and 80, and had no record of testing in the previous year, and required blood tests in their current health care visit. Follow-up or discharge was given, regardless of test results. A case manager contacted positive patients to ensure and monitor linkage to specialist medical care. Herein we analyze data from patients aged 18 to 45 — the maximum age of patients seen in the HRU. Results: We screened 934 women, of whom 48.1% (449) in SRHUs, 26.0% (243) in the HRU, and 25.9% (242) in the OGS (26%). Regarding age and nationality,14.6.% (136)were aged 18 to 25, 45.5% (425)were 26 to 35, 39.9% (373) were 36 to 45, and 20.6% (192) were foreigners. We found 1 (0.1%) HIV antibody positive patient (a 45-year-old from the Dominican Republic), 1 (0.1%) HBV surface antigen positive patient (a 36-year-old from China), 1 (0.1%) HCV antibody positive patient, and no HCV RNA positive patients. Conclusion: HIV prevalence among Valencian women in reproductive and sexual health serviceswas similar to the general population in primary health care in the area. In contrast, chronic HBV infection prevalence was low, and chronic HCV infection was not found. Our data suggest that opportunistic HBV and HCV screening of women aged 18 to 45 out of populations at increased risk is an inefficient public health strategy in our area
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Background: As there are comparative studies between 68Ga-PSMA and 99mTc-PSMA and spectrum of PSMA expression, this is the first case report that notifies distribution of 99mTc-PSMA on COVID-19 pneumonia era on the literature. Case presentation An asymptomatic 70-Y-old male who is known case of prostate adenocarcinoma underwent initial staging. SPECT/CT of the chest region reveals bilateral peripheral multifocal ground glass opacities which shows 99mTc-PSMA uptake. Diagnosis of corona virus was confirmed by positive RT-PCR. Discussion: Unexclusive role of radiotracers in nuclear medicine has an importance for wide range of applications. Comparison between 68Ga-PSMA and 99mTc-PSMA in detection of metastatic disease in prostate cancer is also under evaluation. Conclusions: This case implicates possible role of PSMA imaging in inflammation/infection process as well as necessity for lung review in hybrid imaging especially during this recent pandemic.
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Background: COVID-19 pandemic has caused more than 4.7 million deaths worldwide to date and still continues globally unabated. Numerous studies have linked the mortality in COVID-19 to aggressive immune response and cytokine storm. However, little is known about the cytokine profiles of individual immune cells that are directly involved in tissue damage. Here we investigate intracellular cytokines in individual T and NK cells of COVID-19 patients. Design: We studied 50 blood samples from 22 COVID-19 patients, 4 with mild, 6 moderate and 12 severe disease. There were 6 healthy controls. We performed high-dimensional 30-color spectral flow cytometry to characterize the immune cell subsets. For cytokine study, cells were stimulated for 6 hours, and stained for surface antigens and intracellular cytokines (IL1b, IL2, IL4, IL6, IL8, IL10, IL12, IL17a, IL21, INFg, GnzB, TNFa, and GMCSF). Data ware acquired on FACSymphony 50-parameter analyzer and analysis performed using FlowJo. Results: Our studies revealed significant differences in lymphocyte cytokine profiles between COVID+ and healthy controls (Fig 1). CD4+ and CD8+ T-cells exhibited increased percentages of IL2+ and IFNg+ cells, indicating a shift towards Th1 reaction. Granzyme B is highly upregulated in all T and NK cell subsets, demonstrating highly armed cytotoxic cells in COVID patients. The most prominent changes were noted in NK cells, 7 cytokines were highly expressed, most are proinflammatory cytokines. Of particular interest are IL-21 and GMCSF, both are known to play important roles in inflammatory cell recruitment, activation and renewal, which can lead to augmented tissue inflammation and injury. These changes were already evident in patients with mild disease, but there is heightened cytokine production in severe cases. Conclusions: Using high-dimensional flow cytometry we demonstrated for the first time significantly increased production of multiple proinflammatory cytokines and cytotoxic molecules in individual T and NK cells of COVID-19 patients. NK cells are most drastically activated. It is conceivable that when recruited to the target tissue such as lung, these highly primed cells will play a major role in tissue injury and ultimately organ failure via their direct cytotoxicity and cytokine secretion. This is consistent with previous reports of increased NK cells in the COVID lungs. Analysis of NK cell cytokine profiles may serve to predict disease progression, and reveal new targets for immune-therapy for severe COVID patients. (Table Presented).
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To investigate the class-dependent properties of anti-viral IgM antibodies, we use membrane antigen capture activated cell sorting to isolate spike-protein-specific B cells from donors recently infected with SARS-CoV-2, allowing production of recombinant antibodies. We isolate 20, spike-protein-specific antibodies of classes IgM, IgG, and IgA, none of which shows any antigen-independent binding to human cells. Two antibodies of class IgM mediate virus neutralization at picomolar concentrations, but this potency is lost following artificial switch to IgG. Although, as expected, the IgG versions of the antibodies appear to have lower avidity than their IgM parents, this is not sufficient to explain the loss of potency.
Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Monoclonal , Antibodies, Viral , Humans , Immunoglobulin G , Immunoglobulin MABSTRACT
Introduction: Virus-specific humoral and cellular immune responses act synergistically to protect from viral infection. In our recent observational monocentric study of 117 hematopoietic stem cell adult recipients, we found that 54% and 83 % patients achieved a humoral response after two doses of BNT162b2 anti-SARS-CoV-2 messenger RNA vaccine (Pfizer BioNTech), respectively. Here, we evaluated the T-cell response against the SARS-Cov-2 spike protein after two doses of BNT162b2 vaccine in some allografted patients from the same cohort and compared these results to those from healthy controls. Methods: To quantify SARS-CoV-2 specific T-cells, we used an INFg ELISpot assay that detects these cells after activation of peripheral blood mononuclear cells (PBMC) with 3 peptide pools covering the whole protein sequence of the spike glycoprotein (Prot _S1;_S+ and _S PepTivator peptide pools, Miltenyi Biotec, Bergisch Gladbach, Germany). EBV and CMV specific T-cells were also quantified as controls. The immunophenotype of PBMC was determined by flow cytometry, after dead cell exclusion, with monoclonal antibodies identifying the following surface antigens: CD45, CD3, CD14, CD19 and HLA-DR. The frequencies of spot-forming units (SFU) were reported as per 10 6 CD3+ T-cells. Results: Samples from 46 allografted patients (acute myeloblastic leukemia, N=27, myelodysplastic syndrome, N=19) and 16 healthy controls were available. Characteristics of the population are given in Table 1. All fully vaccinated healthy donors became seropositive and developed a positive T-cell response to spike peptide pools even though variable frequencies were observed. The median response was 195 SFU/10 6 T-cells. By comparison, the frequency of EBV-specific T-cells was 774 SFU/10 6 T-cells (Figure 1). In the group of patients, 78% (n=36/46) had achieved a humoral response after the second dose of vaccine. Among these humoral responders (HR), 89% (n=32/36) also had a positive anti-spike T-cell response with variable frequencies (median =119 SFU/10 6 T-cells. For 8 patients, this T cell response was higher than that of controls (>800 SFU/10 6 T-cells) (Figure 1), which is equivalent to more than 1 specific T-cell per microliter of blood (Figure 2). The humoral responders (HR) who did not develop a T-cell response (11%, n=4/36) had a median time from transplant to vaccination of 523 days compared to 1032 days for cellular responder patients. Among the 10 patients who were non humoral responders (NHR) (22%, n=10/46), 4 (40%) developed a cellular immunity, including one with a very high T cell response (1333 SFU/10 6 T-cells). As expected, the absence of humoral response was observed in patients who were within one year of the transplant. Of note, somehow unexpectedly, patients often presented a high frequency of EBV- and CMV-specific T cells (Figures 1 & 2). As expected, PBMC immunophenotypic analysis revealed that CD3+ frequencies were lower in patients compared to those of controls but were similar between HR and NHR. NHR had very low frequencies of B cells and interestingly, they had an elevated frequency of CD14+ monocytes with low/neg HLA-DR expression potentially corresponding to myeloid-derived suppressor cells (MDSCs) (Figure 3). Conclusion: In this series, 89% of allografted patients who developed an anti-spike humoral response also presented an anti-SARS-Cov-2 cellular immunity. Interestingly, anti-SARS-Cov-2 specific T-cells could be detected in 40% of NHR patients. Although a larger group of patients is required to confirm these results, it remains to be determined whether this T-cell response is protective against SARS-Cov-2 infection as previously demonstrated for CMV (Litjens et al, 2017). Finally, the role of potential immunosuppressive MDSCs must be explored in patients who develop no sign of T-cell response after vaccination. [Formula presented] Disclosures: Moreau: Oncopeptides: Honoraria;Celgene BMS: Honoraria;Sanofi: Honoraria;Abbvie: Honoraria;Janssen: Honoraria;Amgen: Honoraria.
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The COVID-19 pandemic has now reached most countries. However, the referred patients to a nuclear medicine department will be primarily the asymptomatic ones. We report the case of a patient (84-year-old male) who was sent for18F-prostate-specific membrane antigen positron emission tomography computed tomography (PSMA PET-CT) with suspicion of recurrent disease after prostate cancer and total prostatectomy 2 years prior to the examination. He suffered from COVID-19 pneumonia 4 weeks prior to PET-CT examination. The18F-PSMA PET-CT revealed moderate elevated uptake in the area of previous pneumonia in the right lung. The radiological findings showed ground glass changes in this area indicating possible residual inflammatory disease even weeks after infection.