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1.
The Mutual Relationship among Cardiovascular Diseases and COVID-19: Focus on Micronutrients Imbalance.
Severino, P, D'Amato, A, Prosperi, S, Myftari, V, Labbro Francia, A, Önkaya, M, Notari, C, Papisca, I, Canuti, ES, Yarden Revivo, M, et al
Nutrients. 2022;(16)
Abstract
Micronutrients are ions and vitamins humbly required by the human body. They play a main role in several physiological mechanisms and their imbalance is strongly associated with potentially-fatal complications. Micronutrient imbalance is associated with many cardiovascular diseases, such as arrythmias, heart failure, and ischemic heart disease. It has been also observed in coronavirus disease 2019 (COVID-19), particularly in most severe patients. The relationship between cardiovascular diseases and COVID-19 is mutual: the latter triggers cardiovascular disease onset and worsening while patients with previous cardiovascular disease may develop a more severe form of COVID-19. In addition to the well-known pathophysiological mechanisms binding COVID-19 and cardiovascular diseases together, increasing importance is being given to the impact of micronutrient alterations, often present during COVID-19 and able to affect the balance responsible for a good functioning of the cardiovascular system. In particular, hypokalemia, hypomagnesemia, hyponatremia, and hypocalcemia are strongly associated with worse outcome, while vitamin A and D deficiency are associated with thromboembolic events in COVID-19. Thus, considering how frequent the cardiovascular involvement is in patients with COVID-19, and how it majorly affects their prognosis, this manuscript provides a comprehensive review on the role of micronutrient imbalance in the interconnection between COVID-19 and cardiovascular diseases.
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Ozone as adjuvant support in the treatment of COVID-19: A preliminary report of probiozovid trial.
Araimo, F, Imperiale, C, Tordiglione, P, Ceccarelli, G, Borrazzo, C, Alessandri, F, Santinelli, L, Innocenti, GP, Pinacchio, C, Mauro, V, et al
Journal of medical virology. 2021;(4):2210-2220
Abstract
The evaluation of new therapeutic resources against coronavirus disease 2019 (COVID-19) represents a priority in clinical research considering the minimal options currently available. To evaluate the adjuvant use of systemic oxygen-ozone administration in the early control of disease progression in patients with COVID-19 pneumonia. PROBIOZOVID is an ongoing, interventional, randomized, prospective, and double-arm trial enrolling patient with COVID-19 pneumonia. From a total of 85 patients screened, 28 were recruited. Patients were randomly divided into ozone-autohemotherapy group (14) and control group (14). The procedure consisted in a daily double-treatment with systemic Oxygen-ozone administration for 7 days. All patients were treated with ad interim best available therapy. The primary outcome was delta in the number of patients requiring orotracheal-intubation despite treatment. Secondary outcome was the difference of mortality between the two groups. Moreover, hematological parameters were compared before and after treatment. No differences in the characteristics between groups were observed at baseline. As a preliminary report we have observed that one patient for each group needed intubation and was transferred to ITU. No deaths were observed at 7-14 days of follow up. Thirty-day mortality was 8.3% for ozone group and 10% for controls. Ozone therapy did not significantly influence inflammation markers, hematology profile, and lymphocyte subpopulations of patients treated. Ozone therapy had an impact on the need for the ventilatory support, although did not reach statistical significance. Finally, no adverse events related to the use of ozone-autohemotherapy were reported. Preliminary results, although not showing statistically significant benefits of ozone on COVID-19, did not report any toxicity.
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Targeting Microbiome: An Alternative Strategy for Fighting SARS-CoV-2 Infection.
Spagnolello, O, Pinacchio, C, Santinelli, L, Vassalini, P, Innocenti, GP, De Girolamo, G, Fabris, S, Giovanetti, M, Angeletti, S, Russo, A, et al
Chemotherapy. 2021;(1-2):24-32
Abstract
Respiratory and gastrointestinal symptoms are the predominant clinical manifestations of the coronavirus disease 2019 (COVID-19). Infecting intestinal epithelial cells, the severe acute respiratory syndrome coronavirus-2 may impact on host's microbiota and gut inflammation. It is well established that an imbalanced intestinal microbiome can affect pulmonary function, modulating the host immune response ("gut-lung axis"). While effective vaccines and targeted drugs are being tested, alternative pathophysiology-based options to prevent and treat COVID-19 infection must be considered on top of the limited evidence-based therapy currently available. Addressing intestinal dysbiosis with a probiotic supplement may, therefore, be a sensible option to be evaluated, in addition to current best available medical treatments. Herein, we summed up pathophysiologic assumptions and current evidence regarding bacteriotherapy administration in preventing and treating COVID-19 pneumonia.
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Cognitive impairment and CSF proteome modification after oral bacteriotherapy in HIV patients.
Landi, C, Santinelli, L, Bianchi, L, Shaba, E, Ceccarelli, G, Cavallari, EN, Borrazzo, C, Pinacchio, C, Scagnolari, C, Vullo, V, et al
Journal of neurovirology. 2020;(1):95-106
Abstract
OBJECTIVE To investigate whether a probiotic supplementation to cART patients modifies the cerebrospinal fluid (CSF) proteome and improves neurocognitive impairment. METHODS 26 CSF samples from 13 HIV-positive patients [six patients living with HIV (PLHIV) and seven patients with a history of AIDS (PHAIDS)] were analyzed. All patients underwent to neurocognitive evaluation and blood sampling at baseline and after 6 months of oral bacteriotherapy. Immune phenotyping and activation markers (CD38 and HLA-DR) were evaluated on peripheral blood mononuclear cells (PBMC). Plasma levels of IL-6, sCD14, and MIP-1β were detected, by enzyme-linked immunosorbent assay (ELISA). Functional proteomic analysis of CSF sample was conducted by two-dimensional electrophoresis; a multivariate analysis was performed by principal component analysis (PCA) and data were enriched by STRING software. RESULTS Oral bacteriotherapy leads to an improvement on several cognitive test and neurocognitive performance in both groups of HIV-positive subjects. A reduction in the percentage of CD4+CD38+HLA-DR+ T cells was also observed at peripheral level after the probiotic intake (p = 0.008). In addition, the probiotic supplementation to cART significantly modifies protein species composition and abundance at the CSF level, especially those related to inflammation (β2-microglobulin p = 0.03; haptoglobin p = 0.06; albumin p = 0.003; hemoglobin p = 0.003; immunoglobulin heavy chains constant region p = 0.02, transthyretin p = 0.02) in PLHIV and PHAIDS. CONCLUSIONS Our results suggest that oral bacteriotherapy as a supplement to cART could exert a role in the amelioration of inflammation state at peripheral and CNS level.
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5.
Diet Supplementation, Probiotics, and Nutraceuticals in SARS-CoV-2 Infection: A Scoping Review.
Infusino, F, Marazzato, M, Mancone, M, Fedele, F, Mastroianni, CM, Severino, P, Ceccarelli, G, Santinelli, L, Cavarretta, E, Marullo, AGM, et al
Nutrients. 2020;(6)
Abstract
The severe acute respiratory syndrome coronavirus 2 (Sars-CoV-2) global pandemic is a devastating event that is causing thousands of victims every day around the world. One of the main reasons of the great impact of coronavirus disease 2019 (COVID-19) on society is its unexpected spread, which has not allowed an adequate preparation. The scientific community is fighting against time for the production of a vaccine, but it is difficult to place a safe and effective product on the market as fast as the virus is spreading. Similarly, for drugs that can directly interfere with viral pathways, their production times are long, despite the great efforts made. For these reasons, we analyzed the possible role of non-pharmacological substances such as supplements, probiotics, and nutraceuticals in reducing the risk of Sars-CoV-2 infection or mitigating the symptoms of COVID-19. These substances could have numerous advantages in the current circumstances, are generally easily available, and have negligible side effects if administered at the already used and tested dosages. Large scientific evidence supports the benefits that some bacterial and molecular products may exert on the immune response to respiratory viruses. These could also have a regulatory role in systemic inflammation or endothelial damage, which are two crucial aspects of COVID-19. However, there are no specific data available, and rigorous clinical trials should be conducted to confirm the putative benefits of diet supplementation, probiotics, and nutraceuticals in the current pandemic.
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6.
Real word outcomes associated with use of raltegravir in older people living with HIV: results from the 60 months follow-up of the RAL-age cohort.
Santinelli, L, Ceccarelli, G, Borrazzo, C, Celani, L, Pavone, P, Innocenti, GP, Spagnolello, O, Fimiani, C, Ceci, F, Di Sora, F, et al
Expert review of anti-infective therapy. 2020;(5):485-492
Abstract
Objective: In people living with HIV (PLWH), antiretroviral treatments have increased the median life expectancy. Raltegravir (RAL) represents a long-term safe regimen used both in the first-line antiretroviral treatments and in the optimization strategies. Aim of the study was to evaluate the real-life efficacy, tolerability, and safety of the long-term RAL use in a multicenter cohort of elderly PLWH.Methods: A 60-month follow-up observational study was carried out in the RAL-AGE Cohort including aged PLWH (≥60 years old) treated with RAL-based regimens (n = 96). The control group was a cohort of PLWH aged less than 60 years (n = 50).Results: RAL treated aged HIV population experiences an increase of CD4+ cells and a stable control of viral load at 60 months of follow-up. A significant improvement in lipid metabolism profile, a decrease of platelet count and a reduction in cardiovascular risk levels were observed in the older population. Immune activation markers expressed on CD4+ T cells decreased compared to baseline, but this difference was greater in the control group.Conclusion: A 60-month treatment with RAL-containing regimens is safe and highly effective in the older PLWH and these data give new insights on the elderly population.Clinical trial registration: NCT02765776 and NCT03579485.
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Short-Term Probiotic Administration Increases Fecal-Anti Candida Activity in Healthy Subjects.
De Angelis, M, Scagnolari, C, Oliva, A, Cavallari, EN, Celani, L, Santinelli, L, Innocenti, GP, Borrazzo, C, Ceccarelli, G, Vullo, V, et al
Microorganisms. 2019;(6)
Abstract
BACKGROUND Candida albicans' ability to evade host immune responses represents a serious threat for vulnerable patients. OBJECTIVES To investigate if (1) feces from healthy subjects exert anti-Candida activity; (2) fecal anti-Candida activity is modified by probiotic administration and (3) different probiotic differently modulate anti-Candida activity. PATIENTS AND METHODS Feces from healthy donors were analyzed before and after seven days of dietary supplementation with two different probiotic formulations (VSL#3®; Vivomixx®). Candida albicans was cultured with decreasing concentrations of diluted feces, obtained before and after the treatment period. The relationship between anti-Candida activity of feces, interferon-α, anti-interferon-α antibodies and the expression of MxA, ISG15 and IFNAR1 was also evaluated. RESULTS Feces obtained prior to probiotic intake and feces collected after supplementation with VSL#3® did not affect Candida albicans growth. On the contrary, a 3log10 inhibition of Candida development was observed after Vivomixx® intake. Interferon-α played a role in the inhibition of Candida growth. CONCLUSION Fecal anti-Candida activity was not observed prior to probiotic supplementation. Seven days of administration of Vivomixx® increased fecal anti-Candida activity, the same effect was not observed after intake of VSL#3®. The probiotic-induced anti-Candida activity seems to be related to an increased local production and release of interferon-α. Clinical trials are needed to determine if a short pretreatment with specific probiotic formulations may increase anti-Candida defenses in patients at risk.
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8.
Long-term data on the efficacy and tolerability of lamivudine plus dolutegravir as a switch strategy in a multi-centre cohort of HIV-1-infected, virologically suppressed patients.
Baldin, G, Ciccullo, A, Rusconi, S, Capetti, A, Sterrantino, G, Colafigli, M, d'Ettorre, G, Giacometti, A, Cossu, MV, Borghetti, A, et al
International journal of antimicrobial agents. 2019;(6):728-734
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Abstract
BACKGROUND Results from clinical trials and observational studies suggest that lamivudine plus dolutegravir (3TC+DTG) could be an effective and tolerated option for simplification in human immunodeficiency virus (HIV)-1-positive patients. MATERIALS AND METHODS This observational study enrolled HIV-1-infected, virologically suppressed patients switching to 3TC+DTG. Kaplan-Meyer survival analysis was performed to evaluate time to virological failure (VF; defined by a single HIV-RNA determination ≥1000 copies/mL or by two consecutive HIV-RNA determinations ≥50 copies/mL) and time to treatment discontinuation (TD; defined as interruption of either 3TC or DTG), Cox regression was performed to assess predictors, and linear mixed model was performed for repeated measures to measure changes in immunological and metabolic parameters. RESULTS Five hundred and fifty-six patients were eligible for analysis. Their median CD4+ count at baseline was 668 cells/mm3 and median time of virological suppression was 88 months. Estimated probabilities of maintaining virological suppression at 96 and 144 weeks of follow-up were 97.5% [standard deviation (SD) 0.8] and 96.5% (SD 1.0), respectively. Years since HIV diagnosis was the only predictor of VF. In patients with time of virological suppression <88 months, the rate of VF was higher in the presence of the M184V mutation. Estimated probabilities of remaining on 3TC+DTG at 96 and 144 weeks of follow-up were 79.2% (SD 1.9) and 75.2% (SD 2.2), respectively. A significant increase in CD4 cell count (+44 cells/mm3, P=0.015), CD4/CD8 ratio (+0.10, P=0.002) and high-density lipoprotein cholesterol (+5.4 mg/dL, P=0.036) was found at 144 weeks of follow-up; meanwhile, total cholesterol (-9.1 mg/dL, P=0.007) and triglycerides (-2.7, P=0.009) decreased significantly. CONCLUSIONS These findings confirm the efficacy and tolerability of 3TC+DTG in virologically suppressed patients.
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A pilot study on the effects of probiotic supplementation on neuropsychological performance and microRNA-29a-c levels in antiretroviral-treated HIV-1-infected patients.
Ceccarelli, G, Fratino, M, Selvaggi, C, Giustini, N, Serafino, S, Schietroma, I, Corano Scheri, G, Pavone, P, Passavanti, G, Alunni Fegatelli, D, et al
Brain and behavior. 2017;(8):e00756
Abstract
INTRODUCTION The gut microbiota is involved in the regulation of cognition, mood, anxiety, and pain, and can impact cognitive functions by producing neuroactive substances or releasing bacterial by-products and metabolites. No information is available on the effects of a probiotic supplementation on brain function of HIV+ subjects. In light of the above considerations, we performed a pilot study in cART-treated HIV-1-positive patients with long-term virologic suppression. The aims were to analyze the effect of high-concentration multistrain probiotic supplementation (Vivomixx®; Visbiome®) on several neurocognitive abilities and to evaluate the safety of this supplementation. METHODS To address those issues, neurocognitive performances were explored by administering neuropsychological tests; moreover, miRNA-29a-c levels were measured in cerebrospinal fluid (CSF) to confirm the persistent undetectable levels of HIV-RNA in the central nervous system after probiotic supplementation. RESULTS Our results show that the Rey auditory verbal learning test (RAVLT) (immediate and delayed recall), Rey-Osterrieth complex figure test (ROCF) (copy immediate and delayed recall), phonological verbal fluency (PVF) test, Toronto alexithymia scale-20 (Tas-20), State-trait anxiety inventory Y-2 (STAY Y-2), and time and weight estimation test (STEP) scores improved significantly during the study. Moreover, we found unchanged levels, associated to high degree of individual variability, in miRNA-29 levels in CSF collected before and after probiotic supplementation. CONCLUSIONS In conclusion, we observed that HIV patients treated with 6 months of this probiotic supplementation appear to have an improvement in some neurocognitive functions; moreover, this approach is safe and did not modify significantly the levels of miRNA in CSF. Further studies are needed to better understand the contribution of the probiotics in modulating gut-brain-axis in HIV patients.
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Cardiovascular risk and dyslipidemia among persons living with HIV: a review.
Maggi, P, Di Biagio, A, Rusconi, S, Cicalini, S, D'Abbraccio, M, d'Ettorre, G, Martinelli, C, Nunnari, G, Sighinolfi, L, Spagnuolo, V, et al
BMC infectious diseases. 2017;(1):551
Abstract
BACKGROUND Aim of this review is to focus the attention on people living with HIV infection at risk of developing a cardiovascular event. What is or what would be the most suitable antiretroviral therapy? Which statin or fibrate to reduce the risk? How to influence behavior and lifestyles? DISCUSSION Prevention of cardiovascular disease (CVD) risk remains the first and essential step in a medical intervention on these patients. The lifestyle modification, including smoking cessation, increased physical activity, weight reduction, and the education on healthy dietary practices are the main instruments. Statins are the cornerstone for the treatment of hypercholesterolemia. They have been shown to slow the progression or promote regression of coronary plaque, and could also exert an anti-inflammatory and immunomodulatory effect. However the current guidelines for the use of these drugs in general population are dissimilar, with important differences between American and European ones. The debate between American and European guidelines is still open and, also considering the independent risk factor represented by HIV, specific guidelines are warranted. Ezetimibe reduces the intestinal absorption of cholesterol. It is effective alone or in combination with rosuvastatin. It does not modify plasmatic concentrations of antiretrovirals. A number of experimental new classes of drugs for the treatment of hypercholesterolemia are being studied. Fibrates represent the first choice for treatment of hypertriglyceridemia, however, the renal toxicity of fibrates and statins should be considered. Omega 3 fatty acids have a good safety profile, but their efficacy is limited. Another concern is the high dose needed. Other drugs are acipimox and tesamorelin. Current antiretroviral therapies are less toxic and more effective than regimens used in the early years. Lipodistrophy and dyslipidemia are the main causes of long-term toxicities. Not all antiretrovirals have similar toxicities. Protease Inhibitors may cause dyslipidemia and lipodystrophy, while integrase inhibitors have a minimal impact on lipids profile, and no evidence of lipodystrophy. There is still much to be written with the introduction of new drugs in clinical practice. CONCLUSIONS Cardiovascular risk among HIV infected patients, interventions on behavior and lifestyles, use of drugs to reduce the risk, and switch in antiretroviral therapy, remain nowadays major issues in the management of HIV-infected patients.