Frontiers in Medicine
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Frontiers in Medicine, Volume 10; https://doi.org/10.3389/fmed.2023.1122529
Post-acute sequelae of COVID (PASC), or long COVID, is a multisystem complication of SARS-CoV-2 infection that continues to debilitate millions worldwide thus highlighting the public health importance of identifying effective therapeutics to alleviate this illness. One explanation behind PASC may be attributed to the recent discovery of persistent S1 protein subunit of SARS-CoV-2 in CD16+ monocytes up to 15 months after infection. CD16+ monocytes, which express both CCR5 and fractalkine receptors (CX3CR1), play a role in vascular homeostasis and endothelial immune surveillance. We propose targeting these receptors using the CCR5 antagonist, maraviroc, along with pravastatin, a fractalkine inhibitor, could disrupt the monocytic-endothelial-platelet axis that may be central to the etiology of PASC. Using five validated clinical scales (NYHA, MRC Dyspnea, COMPASS-31, modified Rankin, and Fatigue Severity Score) to measure 18 participants’ response to treatment, we observed significant clinical improvement in 6 to 12 weeks on a combination of maraviroc 300 mg per oral twice a day and pravastatin 10 mg per oral daily. Subjective neurological, autonomic, respiratory, cardiac and fatigue symptoms scores all decreased which correlated with statistically significant decreases in vascular markers sCD40L and VEGF. These findings suggest that by interrupting the monocytic-endothelial-platelet axis, maraviroc and pravastatin may restore the immune dysregulation observed in PASC and could be potential therapeutic options. This sets the framework for a future double-blinded, placebo-controlled randomized trial to further investigate the drug efficacy of maraviroc and pravastatin in treating PASC.
Frontiers in Medicine, Volume 10; https://doi.org/10.3389/fmed.2023.1100211
Background: MOTS-c and Romo1 are mitochondrial peptides that are modulated by oxidative stress. No previous studies have explored circulating levels of MOTS-c in patients with chronic obstructive pulmonary disease (COPD).Methods: We enrolled 142 patients with stable COPD and 47 smokers with normal lung function in an observational cross-sectional study. We assessed serum levels of both MOTS-c and Romo1 and associated these findings with clinical characteristics of COPD.Results: Compared with smokers with normal lung function, patients with COPD had lower levels of MOTS-c (p = 0.02) and higher levels of Romo1 (p = 0.01). A multivariate logistic regression analysis revealed that above-median MOTS-c levels were positively associated with Romo1 levels (OR 1.075, 95% CI 1.005–1.150, p = 0.036), but no association was found with other COPD characteristics. Below-median levels of circulating MOTS-c were associated with oxygen desaturation (OR 3.25 95% CI 1.456–8.522, p = 0.005) and walking <350 meters (OR 3.246 95% CI 1.229–8.577, p = 0.018) in six-minute walk test. Above-median levels of Romo1 were positively associated with current smoking (OR 2.756, 95% CI 1.133–6.704, p = 0.025) and negatively associated with baseline oxygen saturation (OR 0.776 95% CI 0.641–0.939, p = 0.009).Conclusions: Reduced levels of circulating MOTS-c and increased levels of Romo1 were detected in patients diagnosed with COPD. Low levels of MOTS-c were associated with oxygen desaturation and poorer exercise capacity using 6 min walk test. Romo1 was associated with current smoking and baseline oxygen saturation.Trial registration: www.clinicaltrials.gov; No.: NCT04449419; URL: www.clinicaltrials.gov. Date of registration: June 26, 2020.
Frontiers in Medicine, Volume 10; https://doi.org/10.3389/fmed.2023.1058914
Aim: Two ongoing phase I studies are investigating the use of radium-224 adsorbed to calcium carbonate micro particles (224Ra-CaCO3-MP) to treat peritoneal metastasis originating from colorectal or ovarian cancer. The aim of this work was to study the level of radiation exposure from the patients to workers at the hospital, carers and members of the public.Method: Six patients from the phase 1 trial in patients with colorectal cancer were included in this study. Two days after cytoreductive surgery, they were injected with 7 MBq of 224Ra-CaCO3-MP. At approximately 3, 24 and 120 h after injection, the patients underwent measurements with an ionization chamber and a scintillator-based iodide detector, and whole body gamma camera imaging. The patient was modelled as a planar source to calculate dose rate as a function of distance. Scenarios varying in duration and distance from the patient were created to estimate the potential effective doses from external exposure. Urine and blood samples were collected at approximately 3, 6, 24, 48 and 120 h after injection of 224Ra-CaCO3-MP, to estimate the activity concentration of 224Ra and 212Pb.Results: The patients’ median effective whole-body half-life of 224Ra-CaCO3-MP ranged from 2.6 to 3.5 days, with a mean value of 3.0 days. In the scenarios with exposure at the hospital (first 8 days), sporadic patient contact resulted in a range of 3.9–6.8 μSv per patient, and daily contact resulted in 4.3–31.3 μSv depending on the scenario. After discharge from the hospital, at day 8, the highest effective dose was received by those with close daily contact; 18.7–83.0 μSv. The highest activity concentrations of 224Ra and 212Pb in urine and blood were found within 6 h, with maximum values of 70 Bq/g for 224Ra and 628 Bq/g for 212Pb.Conclusion: The number of patients treated with 224Ra-CaCO3-MP that a single hospital worker - involved in extensive care - can receive per year, before effective doses of 6 mSv from external exposure is exceeded, is in the order of 200–400. Members of the public and family members are expected to receive well below 0.25 mSv, and therefore, no restrictions to reduce external exposure should be required.
Frontiers in Medicine, Volume 10; https://doi.org/10.3389/fmed.2023.1124863
A 50-year-old male presented to the emergency department of a hospital with an acute myocardial infarction who underwent cardiopulmonary resuscitation (CPR) followed by extracorporeal membrane oxygenation (ECMO). The patient developed persistent jaundice during the course of the disease, which was later found to be gangrenous cholecystitis. We believe this case report will alert clinicians to the possibility of this complication and encourage early detection and intervention to improve the prognosis. Traditionally, the gallbladder has received secondary attention in patients receiving ECMO support, as vital organs tend to be prioritized. However, this case report illustrates the importance of preserving gallbladder function in patients receiving ECMO support.
Frontiers in Medicine, Volume 10; https://doi.org/10.3389/fmed.2023.1078666
Background and aims: Although COVID-19 vaccination is recommended for the patients with chronic liver disease, the clinical outcomes of COVID-19 vaccinated in patients with chronic hepatitis B (CHB) has not been well characterized. The study aimed to explore the safety and specific antibody responses following COVID-19 vaccination among CHB patients.Methods: Patients with CHB were included. All patients were vaccinated with two doses of inactivated vaccine (CoronaVac) or three doses of adjuvanted protein subunit vaccine (ZF2001). The adverse events were recorded and neutralizing antibody (NAb) were determined 14 days following the whole-course vaccination.Results: A total of 200 patients with CHB were included. Specific NAb against SARS-CoV-2 were positive in 170 (84.6%) patients. The median (IQR) concentrations of NAb were 16.32 (8.44–34.10) AU/ml. Comparison of immune responses between CoronaVac and ZF2001 vaccines showed no significant differences in neither the concentrations of NAb nor the seropositive rates (84.4 vs. 85.7%). Moreover, we observed lower immunogenicity in older patients and in patients with cirrhosis or underlying comorbidities. The incidences of adverse events were 37 (18.5%) with the most common adverse event as injection side pain [25 (12.5%)], followed by fatigue [15 (7.5%)]. There were no differences in the frequencies of adverse between CoronaVac and ZF2001 (19.3% vs. 17.6%). Almost all of the adverse reactions were mild and self-resolved within a few days after vaccination. Severe adverse events were not observed.Conclusions: COVID-19 vaccines, CoronaVac and ZF2001 had a favorable safety profile and induced efficient immune response in patients with CHB.
Frontiers in Medicine, Volume 10; https://doi.org/10.3389/fmed.2023.1096869
Introduction: Romani people have a high prevalence of kidney failure. This study examined a Romani cohort for pathogenic variants in the COL4A3, COL4A4, and COL4A5 genes that are affected in Alport syndrome (AS), a common cause of genetic kidney disease, characterized by hematuria, proteinuria, end-stage kidney failure, hearing loss, and eye anomalies.Materials and methods: The study included 57 Romani from different families with clinical features that suggested AS who underwent next-generation sequencing (NGS) of the COL4A3, COL4A4, and COL4A5 genes, and 83 family members.Results: In total, 27 Romani (19%) had autosomal recessive AS caused by a homozygous pathogenic c.1598G>A, p.Gly533Asp variant in COL4A4 (n = 20) or a homozygous c.415G>C, p.Gly139Arg variant in COL4A3 (n = 7). For p.Gly533Asp, 12 (80%) had macroscopic hematuria, 12 (63%) developed end-stage kidney failure at a median age of 22 years, and 13 (67%) had hearing loss. For p.Gly139Arg, none had macroscopic hematuria (p = 0.023), three (50%) had end-stage kidney failure by a median age of 42 years (p = 0.653), and five (83%) had hearing loss (p = 0.367). The p.Gly533Asp variant was associated with a more severe phenotype than p.Gly139Arg, with an earlier age at end-stage kidney failure and more macroscopic hematuria. Microscopic hematuria was very common in heterozygotes with both p.Gly533Asp (91%) and p.Gly139Arg (92%).Conclusion: These two founder variants contribute to the high prevalence of kidney failure in Czech Romani. The estimated population frequency of autosomal recessive AS from these variants and consanguinity by descent is at least 1:11,000 in Czech Romani. This corresponds to a population frequency of autosomal dominant AS from these two variants alone of 1%. Romani with persistent hematuria should be offered genetic testing.
Frontiers in Medicine, Volume 10; https://doi.org/10.3389/fmed.2023.1079165
Objectives: To evaluate COVID-19 vaccines in primary prevention against infections and lessen the severity of illness following the most recent outbreak of the SARS-CoV-2 Omicron variant in Shanghai.Data sources: Data from 153,544 COVID-19 patients admitted to the Shanghai “Four-Leaf Clover” Fangcang makeshift shelter hospital were collected using a structured electronic questionnaire, which was then merged with electronic medical records of the hospital. For healthy controls, data on vaccination status and other information were obtained from 228 community-based residents, using the same structured electronic questionnaire.Methods: To investigate whether inactivated vaccines were effective in protecting against SARS-CoV-2 virus, we estimated the odds ratio (OR) of the vaccination by comparing cases and matched community-based healthy controls. To evaluate the potential benefits of vaccination in lowering the risk of symptomatic infection (vs. asymptomatic), we estimated the relative risk (RR) of symptomatic infections among diagnosed patients. We also applied multivariate stepwise logistic regression analyses to measure the risk of disease severity (symptomatic vs. asymptomatic and moderate/severe vs. mild) in the COVID-19 patient cohort with vaccination status as an independent variable while controlling for potential confounding factors.Results: Of the 153,544 COVID-19 patients included in the analysis, the mean age was 41.59 years and 90,830 were males (59.2%). Of the study cohort, 118,124 patients had been vaccinated (76.9%) and 143,225 were asymptomatic patients (93.3%). Of the 10,319 symptomatic patients, 10,031 (97.2%), 281 (2.7%), and 7 (0.1%) experienced mild, moderate, and severe infections, respectively. Hypertension (8.7%) and diabetes (3.0%) accounted for the majority of comorbidities. There is no evidence that the vaccination helped protect from infections (OR = 0.82, p = 0.613). Vaccination, however, offered a small but significant protection against symptomatic infections (RR = 0.92, p < 0.001) and halved the risk of moderate/severe infections (OR = 0.48, 95% CI: 0.37–0.61). Older age (≥60 years) and malignant tumors were significantly associated with moderate/severe infections.Conclusion: Inactivated COVID-19 vaccines helped provide small but significant protection against symptomatic infections and halved the risk of moderate/severe illness among symptomatic patients. The vaccination was not effective in blocking the SARS-CoV-2 Omicron Variant community spread.
Frontiers in Medicine, Volume 9; https://doi.org/10.3389/fmed.2022.1010001
Objective: We conducted a scoping review with the aim of comprehensively investigating what tools or methods have been examined in general practice research that capture a wide range of psychosocial problems (PSPs) and serve to identify patients and highlight their characteristics.Methods: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews and the Joanna Briggs Institute Reviewer’s Manual on scoping reviews. A systematic search was conducted in four electronic databases (Medline [Ovid], Web of Science Core Collection, PsycInfo, Cochrane Library) for quantitative and qualitative studies in English, Spanish, French, and German with no time limit. The protocol was registered with Open Science Framework and published in BMJ Open.Results: Of the 839 articles identified, 66 met the criteria for study eligibility, from which 61 instruments were identified. The publications were from 18 different countries, with most studies employing an observational design and including mostly adult patients. Among all instruments, 22 were reported as validated, which we present in this paper. Overall, quality criteria were reported differently, with studies generally providing little detail. Most of the instruments were used as paper and pencil questionnaires. We found considerable heterogeneity in the theoretical conceptualisation, definition, and measurement of PSPs, ranging from psychiatric case findings to specific social problems.Discussion and conclusion: This review presents a number of tools and methods that have been studied and used in general practice research. Adapted and tailored to local circumstances, practice populations, and needs, they could be useful for identifying patients with PSPs in daily GP practice; however, this requires further research. Given the heterogeneity of studies and instruments, future research efforts should include both a more structured evaluation of instruments and the incorporation of consensus methods to move forward from instrument research to actual use in daily practice.
Frontiers in Medicine, Volume 10; https://doi.org/10.3389/fmed.2023.1138464
Drug reaction with eosinophilia and systemic symptoms (DReSS), also known as drug-induced hypersensitivity syndrome (DIHS), carries considerable short- and long-term morbidity, along with a mortality rate of up to 10% (1). Prompt diagnosis, withdrawal of the implicated drug and optimal treatment are crucial to optimize patient outcomes. Clinicians should maintain a high index of suspicion for DReSS/DIHS in patients who present with a new-onset exanthem and fever within 2 to 6 weeks after starting a new medication (1). This is especially true when clinical features progress or when they are accompanied by facial edema, lymphadenopathy, hematological abnormalities (such as lymphopenia, atypical lymphocytosis or eosinophilia), hepatitis or acute kidney injury, although any organ can be involved. Importantly, eosinophilia is an inconsistent or late finding in DReSS/DIHS, and its absence does not exclude the diagnosis. The drugs most strongly associated with DReSS/DIHS have not changed over the last 15 years and include antibiotics (particularly vancomycin, trimethoprim-sulfamethoxazole and minocycline), anticonvulsants (principally lamotrigine, carbamazepine and phenytoin), allopurinol, and non-steroidal anti-inflammatory drugs (2). The management of DReSS/DIHS consists of prompt discontinuation of all potential culprit drugs, meticulous supportive care, and immunosuppressive therapy in all but the mildest cases (1). For decades, systemic corticosteroids have been advocated as first-line agents in patients with moderate to severe DReSS/DIHS, despite a lack of rigorous evidence demonstrating their superiority to other options (3). This recommendation stems at least in part from the familiarity most physicians have in using systemic corticosteroids for other immune-mediated diseases. A variety of dosing strategies are used, ranging from initial intravenous methylprednisolone pulse treatment (10–30 mg/kg/dose) to oral treatment with prednisone (0.5–2 mg/kg/day), tapered over a period of at least 2–3-months, although sometimes considerably longer (1, 3). While the collective medical experience with corticosteroids is extensive, in our view, there are several concerns related to the routine use of corticosteroids in the management of DReSS/DIHS that warrant reassessment of the prevailing “steroids first” treatment paradigm, and consideration of targeted therapies that better address the mechanistic basis of the disease. DReSS/DIHS appears fundamentally different from other inflammatory conditions (e.g., asthma, arthritis, systemic lupus erythematosus) for which short-term corticosteroids are typically prescribed and effective. For instance, while most inflammatory conditions show rapid improvement upon the initiation of steroids, it is not unusual for symptoms related to DReSS/DIHS to improve slowly or even worsen—regardless of corticosteroid dosing or route of administration. Second, DReSS/DIHS is prone to relapse and is notoriously sensitive to relatively small dose changes. For example, when parenteral steroid therapy is transitioned to oral treatment, or when the daily prednisone dose is tapered by 5 mg, it is not uncommon to observe intensification of symptoms and worsening laboratory markers. More importantly, increased disease activity in DReSS/DIHS may be accompanied by the development of features not initially present at diagnosis, such as involvement of a single new organ (e.g., hepatitis or myocarditis). This is in significant contrast with patients with other inflammatory conditions, who normally tolerate such dosing changes well, and in whom disease flares associated with small dose changes are generally mild. Finally, DReSS/DIHS typically necessitates a protracted course of corticosteroids, often over a period of 2 to 3 months, and often longer, to avoid flares in disease activity. This is significantly longer than schedules used for most other inflammatory conditions. While we recognize that corticosteroids are often able to prevent disease progression and its immediate use may be necessary to manage specific complications of DReSS/DIHS (e.g., hemophagocytic syndrome), corticosteroids are a “blunt instrument” that do not target the pathogenesis of DReSS/DIHS directly. The disease process of DReSS/DIHS is primarily characterized by the development and activation of drug-specific T cells, along with dysregulation of regulatory T cells (1). In addition, it remains unclear if latent viral reactivation contributes to the clinical phenotype or is a consequence of T-cell activation or immunosuppressive treatment itself. The severity of DReSS/DIHS predicts cytomegalovirus (CMV) reactivation, which subsequently is a marker of DReSS/DIHS severity and mortality (4). Cyclosporine is a calcineurin inhibitor that primarily inhibits the activation and proliferation of T cells by blocking T-cell receptor (TCR)-induced interleukin-2 (IL-2) synthesis and inhibition of TCR signaling. Given this, along with decades of experience in the use of cyclosporine in other T-cell mediated inflammatory diseases, cyclosporine has been increasingly used in the management of recalcitrant DReSS/DIHS (1, 5, 6). A growing number of case reports describe the use of cyclosporine in DReSS/DIHS. For example, Nguyen et al. described five adults with DReSS/DIHS who were treated with cyclosporine, comparing them to 21 patients who received corticosteroids (5). In this small series, symptom resolution occured quicker in those receiving cyclosporine, resulting in a reduced hospital stay (8.1 vs. 16.2 days) and treatment duration (12.5 vs. 48.5 days). Although it is not possible to draw strong conclusions from these data, in part because there may have been differences in disease severity, their observations align with increasing clinical experience in this area (5, 6). Setting aside the strong mechanistic rationale and anecdotes of favorable outcomes, a short course of...
Frontiers in Medicine, Volume 10; https://doi.org/10.3389/fmed.2023.1083215
Background: Immunocompromised patients are susceptible to high-risk opportunistic infections and malignant diseases. Most antiviral and antifungal drugs are quite toxic, relatively ineffective, and induce resistance in the long term. The transfer of pathogen-specific Cytotoxic T-Lymphocytes has shown a minimal toxicity profile and effectiveness in treating Cytomegalovirus, Adenovirus, Epstein - Barr virus, BK Virus and Aspergillus infections, but this therapy have the main limitations of regulatory issues, high cost, and absence of public cell banks. However, CD45RA– cells containing pathogen-specific memory T-cells involve a less complex manufacturing and regulatory process and are cheaper, feasible, safe, and potentially effective.Methods: We present preliminary data from six immunocompromised patients: four who had severe infectious diseases and two who had EBV lymphoproliferative disease. All of them underwent multiple safe familial CD45RA– T-cell infusions as adoptive passive cell therapy, containing Cytomegalovirus, Epstein - Barr virus, BK virus, and Aspergillus-specific memory T-cells. We also present the method for selecting the best donors for CD45RA– cells in each case and the procedure to isolate and store these cells.Results: The infusions were safe, there was no case of graft-versus host disease, and they showed a clear clinical benefit. The patients treated for BK virus nephritis, Cytomegalovirus encephalitis, Cytomegalovirus reactivation, and disseminated invasive aspergillosis experienced pathogen clearance, complete resolution of symptoms in 4-6 weeks and a lymphocyte increase in 3 of 4 cases after 3–4 months. Donor T cell transient microchimerism was detected in one patient. The two patients treated for EBV lymphoproliferative disease underwent chemotherapy and several infusions of CD45RA– memory T-cells containing EBV cytotoxic lymphocytes. Donor T-cell microchimerism was observed in both patients. The viremia cleared in one of the patients, and in the other, despite the viremia not clearing, hepatic lymphoproliferative disease remained stable and was ultimately cured with EBV-specific Cytotoxic T-Lymphocytes.Conclusion: The use of familial CD45RA– T-cells containing specific Cytotoxic T-lymphocytes is a feasible, safe and potential effective approach for treating severe pathogen infections in immunocompromised patients through a third party donor. Furthermore, this approach might be of universal use with fewer institutional and regulatory barriers.