COVID-19, what could sepsis, severe acute pancreatitis, gender differences, and aging teach us?

Gallo, Claudio; Fiorino, Sirio; Posabella, Giovanni; Antonacci, Donato; Tropeano, Anne‐Isabelle; Pausini, Emanuele; Pausini, Carlotta; Guarniero, Tommaso; Hong, Wandong; Giampieri, Enrico; Corazza, Ivan; Lari, Federico; Biase, Dario de; Zippi, Maddalena; Zancanaro, Marco

doi:10.1016/j.cyto.2021.155628

Cited by 14 publications

(23 citation statements)

References 317 publications

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“…Although the peaking inflammatory phase of COVID-19 progression is often imprecisely described as a “cytokine storm” [ 35 ], recent studies have shown that systemic levels of cytokines may not be as high as seen in ‘classical’ sepsis or acute respiratory distress syndrome [ 33 , 36 ]. In this regard, we also detected, even on the day with the most critical medical condition, only moderately elevated concentrations of interleukin-6, serum ferritin and C-reactive protein.…”

Section: Discussionmentioning

confidence: 99%

Intravenous IgM-enriched immunoglobulins in critical COVID-19: a multicentre propensity-weighted cohort study

et al. 2022

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Background A profound inflammation-mediated lung injury with long-term acute respiratory distress and high mortality is one of the major complications of critical COVID-19. Immunoglobulin M (IgM)-enriched immunoglobulins seem especially capable of mitigating the inflicted inflammatory harm. However, the efficacy of intravenous IgM-enriched preparations in critically ill patients with COVID-19 is largely unclear. Methods In this retrospective multicentric cohort study, 316 patients with laboratory-confirmed critical COVID-19 were treated in ten German and Austrian ICUs between May 2020 and April 2021. The primary outcome was 30-day mortality. Analysis was performed by Cox regression models. Covariate adjustment was performed by propensity score weighting using machine learning-based SuperLearner to overcome the selection bias due to missing randomization. In addition, a subgroup analysis focusing on different treatment regimens and patient characteristics was performed. Results Of the 316 ICU patients, 146 received IgM-enriched immunoglobulins and 170 cases did not, which served as controls. There was no survival difference between the two groups in terms of mortality at 30 days in the overall cohort (HRadj: 0.83; 95% CI: 0.55 to 1.25; p = 0.374). An improved 30-day survival in patients without mechanical ventilation at the time of the immunoglobulin treatment did not reach statistical significance (HRadj: 0.23; 95% CI: 0.05 to 1.08; p = 0.063). Also, no statistically significant difference was observed in the subgroup when a daily dose of ≥ 15 g and a duration of ≥ 3 days of IgM-enriched immunoglobulins were applied (HRadj: 0.65; 95% CI: 0.41 to 1.03; p = 0.068). Conclusions Although we cannot prove a statistically reliable effect of intravenous IgM-enriched immunoglobulins, the confidence intervals may suggest a clinically relevant effect in certain subgroups. Here, an early administration (i.e. in critically ill but not yet mechanically ventilated COVID-19 patients) and a dose of ≥ 15 g for at least 3 days may confer beneficial effects without concerning safety issues. However, these findings need to be validated in upcoming randomized clinical trials. Trial registrationDRKS00025794, German Clinical Trials Register, https://www.drks.de. Registered 6 July 2021.

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Section: Discussionmentioning

confidence: 99%

Intravenous IgM-enriched immunoglobulins in critical COVID-19: a multicentre propensity-weighted cohort study

et al. 2022

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“…Classically, activated M1 macrophage populations with pro-inflammatory activities and with pathogen-killing abilities are initially predominant, during the onset of inflammation, but they are later replaced by macrophages with an M2 phenotype. Following their stimulation, these cells play important roles in the resolution of inflammation, by promoting tissue regeneration [ 42 , 43 ]. Pro-resolving M2 macrophages and also apoptotic neutrophils produce SPMs [ 44 ] ( Fig.…”

Section: Introductionmentioning

confidence: 99%

“…This conclusion seems to be confirmed even in individuals, suffering from ARDS associated with COVID-19, requiring mechanical ventilation. Serum median levels of IL-6 and IL-8 in subjects with severe COVID-19 are about 10 until 100 times lower than those of patients with the above-mentioned syndromes [ 42 , 54 ]. The group of cytokines involved in the development of these syndromes includes IL-2, IL-6, IL-8, IL-17, IFN-γ, TNF-α.…”

Section: Introductionmentioning

confidence: 99%

“…Cytokine Release Syndrome. Sepsis, ARDS, and MOF are characterized by an exuberant and excessive systemic inflammation and are also associated with a status of immunosuppression [ 55 ], blood hypercoagulability, and thrombophilia [ 42 , 56 ]. The action of inflammatory mediators, which are released following strong harmful stimuli, is systemic [ 57 ].…”

Section: Introductionmentioning

confidence: 99%

“…A recent review has summarized the potential pathogenetic role of an unbalanced stimulation, concerning the pathway ACE2/Angiotensin and derived (1–7) peptides as well as of the inhibition in the activity of renin and ACE/Ang II/AT1R axis in the development of some severe human pathological conditions, such as sepsis, severe acute pancreatitis, and COVID-19. The researchers have suggested that these distinct and different syndromes may display common pathogenetic mechanisms [ 42 ]. Therefore, the modulation of this cascade activity may contribute to preventing the arising of severe COVID-19 forms.…”

Section: Introductionmentioning

confidence: 99%

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The function of specialized pro-resolving endogenous lipid mediators, vitamins, and other micronutrients in the control of the inflammatory processes: Possible role in patients with SARS-CoV-2 related infection

Gallo¹,

Fiorino

Posabella³

et al. 2022

Prostaglandins & Other Lipid Mediators

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Inflammation is an essential protective response against harmful stimuli, such as invading pathogens, damaged cells, or irritants. Physiological inflammation eliminates pathogens and promotes tissue repair and healing. Effective immune response in humans depends on a tightly regulated balance among inflammatory and anti-inflammatory mechanisms involving both innate and adaptive arms of the immune system. Excessive inflammation can become pathological and induce detrimental effects. If this process is not self-limited, an inappropriate remodeling of the tissues and organs can occur and lead to the onset of chronic degenerative diseases. A wide spectrum of infectious and non-infectious agents may activate the inflammation, via the release of mediators and cytokines by distinct subtypes of lymphocytes and macrophages. Several molecular mechanisms regulate the onset, progression, and resolution of inflammation. All these steps, even the termination of this process, are active and not passive events. In particular, a complex interplay exists between mediators (belonging to the group of Eicosanoids), which induce the beginning of inflammation, such as Prostaglandins (PGE2), Leukotrienes (LT), and thromboxane A2 (TXA2), and molecules which display a key role in counteracting this process and in promoting its proper resolution. The latter group of mediators includes: ω-6 arachidonic acid (AA)-derived metabolites, such as Lipoxins (LXs), ω -3 eicosapentaenoic acid (EPA)-derived mediators, such as E-series Resolvins (RvEs), and ω -3 docosahexaenoic (DHA)-derived mediators, such as D-series Resolvins (RvDs), Protectins (PDs) and Maresins (MaRs). Overall, these mediators are defined as specialized pro-resolving mediators (SPMs). Reduced synthesis of these molecules may lead to uncontrolled inflammation with possible harmful effects. ω-3 fatty acids are widely used in clinical practice as rather inexpensive, safe, readily available supplemental therapy. Taking advantage of this evidence, several researchers are suggesting that SPMs may have beneficial effects in the complementary treatment of patients with severe forms of SARS-CoV-2 related infection, to counteract the “cytokine storm” observed in these individuals. Well-designed and sized trials in patients suffering from COVID-19 with different degrees of severity are needed to investigate the real impact in the clinical practice of this promising therapeutic approach.

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Liver alterations and detection of SARS-CoV-2 RNA and proteins in COVID-19 autopsies

et al. 2022

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The most severe alterations in Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) infection are seen in the lung. However, other organs also are affected. Here, we report histopathologic findings in the liver and detection of viral proteins and RNA in COVID-19 autopsies performed at the Semmelweis University (Budapest, Hungary). Between March 2020 through March 2022, 150 autopsies on patients who died of COVID-19 were analyzed. Cause-of-death categories were formed based on the association with SARS-CoV-2 as strong, contributive, or weak. Samples for histopathologic study were obtained from all organs, fixed in formalin, and embedded in paraffin (FFPE). Immunohistochemical study (IHC) to detect SARS-CoV-2 spike protein and nucleocapsid protein (NP), CD31, claudin-5, factor VIII, macrosialin (CD68), and cytokeratin 7, with reverse transcriptase polymerase chain reaction (RT-PCR), and in situ hybridization (ISH, RNAscope®) for SARS-CoV-2 RNA were conducted using FFPE samples of livers taken from 20 autopsies performed ≤ 2 days postmortem. All glass slides were scanned; the digital images were evaluated by semiquantitative scoring and scores were analyzed statistically. Steatosis, single-cell and focal/zonal hepatocyte necrosis, portal fibrosis, and chronic inflammation were found in varying percentages. Sinusoidal ectasia, endothelial cell disruption, and fibrin-filled sinusoids were seen in all cases; these were assessed semiquantitatively for severity (SEF scored). SEF scores did not correlate with cause-of-death categories (p = 0.92) or with severity of lung alterations (p = 0.96). SARS-CoV-2 RNA was detected in 13/20 cases by PCR and in 9/20 by ISH, with IHC demonstration of spike protein in 4/20 cases and NP in 15/20. Viral RNA and proteins were located in endothelial and Kupffer cells, and in portal macrophages, but not in hepatocytes and cholangiocytes. In conclusion, endothelial damage (SEF scores) was the most common alteration in the liver and was a characteristic, but not specific alteration in COVID-19, suggesting an important role in the pathogenesis of COVID-19-associated liver disease. Detection of SARS-CoV-2 RNA and viral proteins in liver non-parenchymal cells suggests that while the most extended primary viral cytotoxic effect occurs in the lung, viral components are present in other organs too, as in the liver. The necrosis/apoptosis and endothelial damage associated with viral infection in COVID-19 suggest that those patients who survive more severe COVID-19 may face prolonged liver repair and accordingly should be followed regularly in the post-COVID period.

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COVID-19, what could sepsis, severe acute pancreatitis, gender differences, and aging teach us?

Cited by 14 publications

References 317 publications

Intravenous IgM-enriched immunoglobulins in critical COVID-19: a multicentre propensity-weighted cohort study

Intravenous IgM-enriched immunoglobulins in critical COVID-19: a multicentre propensity-weighted cohort study

The function of specialized pro-resolving endogenous lipid mediators, vitamins, and other micronutrients in the control of the inflammatory processes: Possible role in patients with SARS-CoV-2 related infection

Liver alterations and detection of SARS-CoV-2 RNA and proteins in COVID-19 autopsies

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