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1.
International Journal of Molecular Sciences ; 23(9):4830, 2022.
Article in English | MDPI | ID: covidwho-1809944

ABSTRACT

The main aim of this study was to identify the most relevant cytokines which, when assessed in the earliest stages from hospital admission, may help to select COVID-19 patients with worse prognosis. A retrospective observational study was conducted in 415 COVID-19 patients (272 males;mean age 68 ±14 years) hospitalized between May 2020 and March 2021. Within the first 72 h from hospital admission, patients were tested for a large panel of biomarkers, including C-reactive protein (CRP), Mid-regional proadrenomedullin (MR-proADM), Interferon-γ, interleukin 6 (IL-6), IL-1β, IL-8, IL-10, soluble IL2-receptor-α(sIL2Rα), IP10 and TNFα. Extensive statistical analyses were performed (correlations, t-tests, ranking tests and tree modeling). The mortality rate was 65/415 (15.7%) and a negative outcome (death and/or orotracheal intubation) affected 98/415 (23.6%) of cases. Univariate tests showed the majority of biomarkers increased in severe patients, but ranking tests helped to select the best variables to put on decisional tree modeling which identified IL-6 as the first dichotomic marker with a cut-off of 114 pg/mL. Then, a good synergy was found between IL-10, MR-proADM, sIL2Rα, IP10 and CRP in increasing the predictive value in classifying patients at risk or not for a negative outcome. In conclusion, beside IL-6, a panel of other cytokines representing the degree of immunoparalysis and the anti-inflammatory response (IP10, sIL2Rαand IL-10) showed synergic role when combined to biomarkers of systemic inflammation and endothelial dysfunction (CRP, MR-proADM) and may also better explain disease pathogenesis and suggests targeted intervention.

2.
J Autoimmun ; 129: 102827, 2022 Apr 11.
Article in English | MEDLINE | ID: covidwho-1783457

ABSTRACT

OBJECTIVE: To evaluate B-cell- and T-cell-mediated immune response to SARS-CoV-2 mRNA vaccination in patients with complex or rare systemic autoimmune diseases previously been treated with or under continuous treatment with B-cell-targeted therapies including rituximab (RTX) and belimumab (BEL). MATERIALS AND METHODS: Twenty-eight consecutive patients receiving RTX (n = 11) or BEL (n = 17) treatment and 13 age-/sex-matched controls (non-rheumatic healthcare personnel) were recruited. None of the patients had detectable anti-SARS-CoV-2 antibodies caused by prior exposure to the virus. All the patients and controls received mRNA vaccines and were tested three to four weeks after completion of vaccination. In all the RTX patients, vaccination was started within 5 months from the last infusion, and B-cell depletion was confirmed in all but one of them. Total anti-SARS-CoV-2 RBD antibodies were analyzed using a diagnostic assay, while T-cell response was evaluated using the interferon-gamma release assay (IGRA). Further, SARS-CoV-2 pseudoviruses were employed to verify the strain-specific neutralizing capacity of the antibodies. RESULTS: Detectable anti-SARS-CoV-2 antibodies were documented in 1 out of the 11 RTX patients and 16 of the 17 BEL patients. The median concentration in the RTX and BEL patients was significantly lower than that in the controls (39.6 AU/ml vs. 1133 AU/ml, p = 0.002). The result of IGRA was positive in 8 of the 11 (72.7%) RTX patients and 16 of the 17 (94.1%) BEL patients, and interferon release in both the RTX and BEL patients was comparable to that in the control participants. CONCLUSION: B-cell-targeted therapies do not preclude SARS-CoV-2 vaccination, since virus-specific cellular immunity can be induced even in the absence of circulating B cells. An important finding was that lupus patients treated with BEL developed immune responses to SARS-CoV-2; this indicates retention of the immunogenicity of the COVID-19 vaccine.

3.
Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases ; 2022.
Article in English | EuropePMC | ID: covidwho-1755981

ABSTRACT

Objectives To describe the impact of vaccination and the role of humoral responses on post-coronavirus disease 2019 (COVID-19) syndrome one year after the onset of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods A prospective study. Interviews investigated post-COVID-19 syndrome 6 and 12 months after the disease onset of all adult in- and outpatients with COVID-19 attending Udine Hospital (March–May 2020). Vaccination status and two different serological assays to distinguish between response to vaccination (receptor-binding domain –RBD SARS-CoV-2 IgG) and/or natural infection (non-RBD- SARS-CoV-2 IgG) were also assessed. Results 479 individuals (52.6% female, mean age 53 years) were interviewed 13.5 months (0.6 SD) after acute infection. Post-COVID-19 syndrome was observed in 47.2% (226/479) of patients after one year. There were no significant differences in the worsening of post-COVID 19 symptoms (22.7% vs 15.8%, p = 0.209) among vaccinated (n=132) and unvaccinated (n=347) patients. The presence of non-RBD SARS-CoV-2 IgG induced by natural infection showed a significant association with post-COVID-19 syndrome (OR 1.35, 95% CI 1.11–1.64, p = 0.003), and median non-RBD SARS-CoV-2 IgG titres were significantly higher in long-haulers than in patients without symptoms 22 (IQR 9.7–37.2) vs 14.1 (IQR 5.4–31.3) kAU/L, p = 0.009) after one year. In contrast, the presence of RBD SARS-CoV-2 IgG was not associated with the occurrence of post-COVID-19 syndrome (>2500 U/mL vs 0.9–2500 U/mL, OR 1.36, 95% CI 0.62–3.00, p = 0.441) and RBD SARS-CoV-2 IgG titres were similar in long-haulers than in patients without symptoms (50% values > 2500 U/mL vs 55.6% values > 2500 U/mL, p = 0.451) Conclusions The SARS-CoV-2 vaccination is not associated with the emergence of post-COVID-19 symptoms over one year after acute infection. The persistence of high serological titres response induced by natural infection but not by vaccination, may play a role in long-COVID-19. Graphical Image 1

4.
J Clin Microbiol ; 59(11): e0113821, 2021 10 19.
Article in English | MEDLINE | ID: covidwho-1480237

ABSTRACT

The aim of this study was to assess the long-term dynamics and factors associated with the serological response against the severe acute respiratory syndrome coronavirus 2 after primary infection. A prospective longitudinal study was conducted with monthly serological follow-up during the first 4 months, and then at 6, 8, and 10 months after the disease onset of all recovered adult in- and outpatients with coronavirus disease 2019 (COVID-19) attending Udine Hospital (Italy) during the first wave (from March to May 2020). A total of 546 individuals were included (289 female, mean age 53.1 years), mostly with mild COVID-19 (370, 68.3%). Patients were followed for a median of 302 days (interquartile range, 186 to 311). The overall seroconversion rate within 2 months was 32% for IgM and 90% for IgG. Seroreversion was observed in 90% of patients for IgM at 4 months and in 47% for IgG at 10 months. Older age, number of symptoms at acute onset, and severity of acute COVID-19 were all independent predictors of long-term immunity both for IgM (ß, linear regression coefficient, 1.10, P = 0.001; ß 5.15 P = 0.014; ß 43.84 P = 0.021, respectively) and for IgG (ß 1.43 P < 0.001; ß 10.46 P < 0.001; ß 46.79 P < 0.001, respectively), whereas the initial IgG peak was associated only with IgG duration (ß 1.12, P < 0.001). IgM antibodies disappeared at 4 months, and IgG antibodies declined in about half of patients 10 months after acute COVID-19. These effects varied depending on the intensity of the initial antibody response, age, and burden of acute COVID-19.


Subject(s)
COVID-19 , SARS-CoV-2 , Adult , Aged , Antibodies, Viral , Antibody Formation , Critical Illness , Female , Humans , Immunoglobulin M , Longitudinal Studies , Middle Aged , Prospective Studies
5.
Inflammation ; 45(1): 1-5, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1415062

ABSTRACT

Novel Coronavirus Disease in most cases produces mild symptoms which resolve after a few days. Some authors hypothesized that SARS-CoV-2 infection could trigger excessive cytokine production leading to a severe multi-organ disease requiring intensive care admission. Respiratory and neurological symptoms are the most frequently reported manifestation of the disease. Indeed, cardiac involvement is reported mostly as a part of a systemic disease. Few isolated cardiac manifestations of COVID-19 infection have been described. We report herein a case of SARS-CoV-2 related severe isolated pericardial involvement requiring ICU admission due to cardiac tamponade needing urgent drainage. Analysis of pericardial fluid from drainage demonstrated a higher cytokine concentration than blood values. Other causes of pericardial disease, such as autoimmunity, bacterial or other than COVID-19 infection, neoplasms or acute myocardial infarction were also evaluated, but all tests confirmed negative results. The suspicion of isolated involvement of the pericardium was therefore demonstrated by the analysis of cytokines which strongly support our hypothesis.


Subject(s)
COVID-19/pathology , Cardiac Tamponade/pathology , Cytokines/analysis , Pericardial Effusion/surgery , Pericardial Fluid/chemistry , Pericardium/pathology , Aged , Cardiac Tamponade/surgery , Cytokine Release Syndrome/pathology , Humans , Male , Pericardial Effusion/pathology , Pericardium/virology , SARS-CoV-2
7.
J Med Virol ; 93(9): 5432-5437, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1363681

ABSTRACT

This case series describes three patients affected by severe acute respiratory syndrome coronavirus 2, who developed polyradiculoneuritis as a probable neurological complication of coronavirus disease 2019 (COVID-19). A diagnosis of Guillain Barré syndrome was made on the basis of clinical symptoms, cerebrospinal fluid analysis, and electroneurography. In all of them, the therapeutic approach included the administration of intravenous immunoglobulin (0.4 gr/kg for 5 days), which resulted in the improvement of neurological symptoms. Clinical neurophysiology revealed the presence of conduction block, absence of F waves, and in two cases, a significant decrease in amplitude of compound motor action potential cMAP. Due to the potential role of inflammation on symptoms development and prognosis, interleukin-6 (IL-6) and IL-8 levels were measured in serum and cerebrospinal fluid during the acute phase, while only serum was tested after recovery. Both IL-6 and IL-8 were found increased during the acute phase, both in the serum and cerebrospinal fluid, whereas 4 months after admission (at complete recovery), only IL-8 remained elevated in the serum. These results confirm the inflammatory response that might be linked to peripheral nervous system complications and encourage the use of IL-6 and IL-8 as prognostic biomarkers in COVID-19.


Subject(s)
COVID-19/complications , Guillain-Barre Syndrome/complications , Interleukin-6/cerebrospinal fluid , Interleukin-8/cerebrospinal fluid , Respiratory Insufficiency/complications , SARS-CoV-2/pathogenicity , Action Potentials/drug effects , Acute Disease , Aged , Anti-Bacterial Agents/therapeutic use , Biomarkers/blood , Biomarkers/cerebrospinal fluid , COVID-19/cerebrospinal fluid , COVID-19/drug therapy , COVID-19/virology , Convalescence , Darunavir/therapeutic use , Drug Combinations , Guillain-Barre Syndrome/cerebrospinal fluid , Guillain-Barre Syndrome/drug therapy , Guillain-Barre Syndrome/virology , Humans , Hydroxychloroquine/therapeutic use , Immunoglobulins, Intravenous/therapeutic use , Interleukin-6/blood , Interleukin-8/blood , Lopinavir/therapeutic use , Male , Neural Conduction/drug effects , Peripheral Nervous System/drug effects , Peripheral Nervous System/pathology , Peripheral Nervous System/virology , Prognosis , Respiratory Insufficiency/cerebrospinal fluid , Respiratory Insufficiency/drug therapy , Respiratory Insufficiency/virology , Ritonavir/therapeutic use , SARS-CoV-2/drug effects
8.
Eur J Clin Microbiol Infect Dis ; 40(12): 2597-2604, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1351309

ABSTRACT

The aim of the study was to assess reinfection rates in relation to long-term antibody dynamics against SARS-CoV-2 after the first wave. A prospective longitudinal study with monthly serological follow-up during the first 4 months, and then at 6, 8, and 10 months after the disease onset of all recovered adult in- and outpatients with COVID-19 attending Udine Hospital (Italy) from March to May 2020. During the follow-up, reinfections were collected. A total of 546 unselected individuals with COVID-19 acquired from March to May 2020 were included (292 female, mean age 53 years). After a median follow-up of 10 months (IQR 6.2-10.4), reinfection occurred in 6 (1.1%) patients, median age of 44.5 years (IQR 33‒49). All had a previous history of mild COVID-19 (all were healthcare workers) and reinfection occurred a median of 9 months (IQR 8.2‒10.2) after the onset of the first episode. Patients with reinfection were either seronegative (2/56, n = 3.6%), seroreverted (2/137, 1.5%), or seropositive (2/353, 0.6%) (p = 0.085). All reinfections were mild (n = 5) or asymptomatic (n = 1). After reinfection, none of patients developed IgM response and only two had a transitory boosted IgG immunization response. In an unselected population after the first wave of COVID-19, after a prolonged observation period (mean 10 months), reinfection was very uncommon; occurred in patients with a previous history of mild infection, mostly with weak or absent serological response; and manifested with mild or asymptomatic clinical presentation.


Subject(s)
Antibodies, Viral/blood , COVID-19/blood , Reinfection/virology , Adult , COVID-19/virology , Female , Follow-Up Studies , Humans , Immunoglobulin G/blood , Immunoglobulin M/blood , Longitudinal Studies , Male , Middle Aged , Prospective Studies , Reinfection/blood , SARS-CoV-2/genetics , SARS-CoV-2/immunology
9.
Clin Neurol Neurosurg ; 208: 106839, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1322036

ABSTRACT

Several central and peripheral nervous system complications associated with the severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection have been recently described. An effective mass vaccination program is necessary to effectively reduce infection spread and, consequently, limit long-term sequelae, including those affecting the nervous system. Nevertheless, as more patients gain access to coronavirus disease 2019 (COVID-19) vaccines, it is important to report potential adverse events. Herein, we report a patient with previous history of post-infectious rhombencephalitis who developed an acute disseminated encephalomyelitis (ADEM) two weeks after being vaccinated for COVID-19.


Subject(s)
COVID-19 Vaccines/adverse effects , COVID-19/prevention & control , Myelitis, Transverse/etiology , Female , Humans , Middle Aged , SARS-CoV-2
10.
Int Immunopharmacol ; 98: 107874, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1267706

ABSTRACT

BACKGROUND: Following positive experience on the use of blood ozonation in SARS-CoV-2, the CORMOR randomized trial was designed to evaluate the adjuvant role of oxygen/ozone therapy in mild to moderate SARS-CoV-2 pneumonia. METHODS: The trial (ClinicalTrial.gov NCT04388514) was conducted in four different Italian centers (April-October 2020). Patients were treated according to best available standard of care (SoC) therapy, with or without O3-autohemotherapy (O3-AHT). RESULTS: A total of 92 patients were enrolled: SoC + O3-AHT (48 patients) were compared to the SoC treatment (44 patients). The two groups differed in steroids therapy administration (72.7% in SoC arm vs. 50.0% in O3-AHT arm; p = 0.044). Steroid therapy was routinely started when it was subsequently deemed as effective for the treatment of COVID-19 disease. No significant differences in mortality rates, length of hospital stay, mechanical ventilation requirement and ICU admission were observed. Clinical improvement in patients with pneumonia was assessed according to a specifically designed score (decrease in SIMEU class, improvement in radiology imaging, improvement in PaO2/FiO2, reduction in LDH and requirement of oxygen therapy ≤ 5 days). Score assessment was performed on day-3 (T3) and day-7 (TEnd) of O3-AHT treatment. A significant increase in the score was reported at TEnd, in the O3-AHT treatment arm (0 [0-1] in the SoC arm vs. 2 [1-3] the O3-AHT arm; p = 0.018). No adverse events related O3-AHT treatment was observed. CONCLUSION: In mild-to-moderate pneumonia due to SARS-CoV-2, adjuvant oxygen/ozone therapy did not show any effect on mortality, or mechanical intubation but show a clinical improvement a day 7 from randomization in a composite clinical endpoint. Larger Randomized prospective studies alone or in combination with steroids are needed to confirm our results.


Subject(s)
COVID-19/therapy , Lung/physiopathology , Ozone/administration & dosage , Respiratory Insufficiency/therapy , Aged , COVID-19/blood , COVID-19/mortality , COVID-19/physiopathology , Female , Hospital Mortality , Humans , Italy , Length of Stay , Lung/virology , Male , Middle Aged , Ozone/adverse effects , Ozone/blood , Prospective Studies , Respiration, Artificial , Respiratory Insufficiency/blood , Respiratory Insufficiency/mortality , Respiratory Insufficiency/physiopathology , Severity of Illness Index , Time Factors , Treatment Outcome
11.
Clin Microbiol Infect ; 27(10): 1507-1513, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1260693

ABSTRACT

OBJECTIVES: To assess the prevalence of and factors associated with post-coronavirus disease 2019 (COVID-19) syndrome 6 months after the onset. METHODS: A bidirectional prospective study. Interviews investigated symptoms potentially associated with COVID-19 6 months after the disease onset of all consecutive adult inpatients and outpatients with COVID-19 attending Udine Hospital (Italy) from March to May 2020. IgG antibodies against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) were also evaluated 6 months after the onset of symptoms, at the time of the interview. RESULTS: A total of 599 individuals were included (320 female, 53.4%; mean age 53 years, SD 15.8) and interviewed 187 days (22 SD) after onset. The prevalence of post-COVID-19 syndrome was 40.2% (241/599). The presence of IgG antibodies was significantly associated with the occurrence of post-COVID-19 syndrome (OR 2.56, 95% CI 1.48-4.38, p 0.001) and median SARS-CoV-2 IgG titres were significantly higher in patients with post-COVID-19 syndrome than in patients without symptoms (42.1, IQR 17.1-78.4 vs. 29.1, IQR 12.1-54.2 kAU/L, p 0.004). Female gender (OR 1.55, 95% CI 1.05-2.27), a proportional increase in the number of symptoms at the onset of COVID-19 (OR 1.81, 95% CI 1.59-2.05) and ICU admission OR 3.10, 95% CI 1.18-8.11) were all independent risk factors for post-COVID-19 syndrome. The same predictors also emerged in a subgroup of 231 patients with the serological follow-up available at the time of the interview alongside the proportional increase in anti-SARS-CoV-2 IgG (OR 1.01, 95% CI 1.00-1.02, p 0.04). DISCUSSION: Prospective follow-up could be offered to specific subgroups of COVID-10 patients, to identify typical symptoms and persistently high anti-SARS-CoV-2 IgG titres as a means of early detection of post-COVID-19 long-term sequelae.


Subject(s)
COVID-19/complications , Adolescent , Adult , Aged , Antibodies, Viral/blood , COVID-19/blood , COVID-19/diagnosis , COVID-19/epidemiology , Female , Follow-Up Studies , Humans , Immunoglobulin G/blood , Italy/epidemiology , Male , Middle Aged , Prevalence , Prospective Studies , Risk Factors , SARS-CoV-2/immunology , Young Adult
12.
J Med Virol ; 93(9): 5432-5437, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1258081

ABSTRACT

This case series describes three patients affected by severe acute respiratory syndrome coronavirus 2, who developed polyradiculoneuritis as a probable neurological complication of coronavirus disease 2019 (COVID-19). A diagnosis of Guillain Barré syndrome was made on the basis of clinical symptoms, cerebrospinal fluid analysis, and electroneurography. In all of them, the therapeutic approach included the administration of intravenous immunoglobulin (0.4 gr/kg for 5 days), which resulted in the improvement of neurological symptoms. Clinical neurophysiology revealed the presence of conduction block, absence of F waves, and in two cases, a significant decrease in amplitude of compound motor action potential cMAP. Due to the potential role of inflammation on symptoms development and prognosis, interleukin-6 (IL-6) and IL-8 levels were measured in serum and cerebrospinal fluid during the acute phase, while only serum was tested after recovery. Both IL-6 and IL-8 were found increased during the acute phase, both in the serum and cerebrospinal fluid, whereas 4 months after admission (at complete recovery), only IL-8 remained elevated in the serum. These results confirm the inflammatory response that might be linked to peripheral nervous system complications and encourage the use of IL-6 and IL-8 as prognostic biomarkers in COVID-19.


Subject(s)
COVID-19/complications , Guillain-Barre Syndrome/complications , Interleukin-6/cerebrospinal fluid , Interleukin-8/cerebrospinal fluid , Respiratory Insufficiency/complications , SARS-CoV-2/pathogenicity , Action Potentials/drug effects , Acute Disease , Aged , Anti-Bacterial Agents/therapeutic use , Biomarkers/blood , Biomarkers/cerebrospinal fluid , COVID-19/cerebrospinal fluid , COVID-19/drug therapy , COVID-19/virology , Convalescence , Darunavir/therapeutic use , Drug Combinations , Guillain-Barre Syndrome/cerebrospinal fluid , Guillain-Barre Syndrome/drug therapy , Guillain-Barre Syndrome/virology , Humans , Hydroxychloroquine/therapeutic use , Immunoglobulins, Intravenous/therapeutic use , Interleukin-6/blood , Interleukin-8/blood , Lopinavir/therapeutic use , Male , Neural Conduction/drug effects , Peripheral Nervous System/drug effects , Peripheral Nervous System/pathology , Peripheral Nervous System/virology , Prognosis , Respiratory Insufficiency/cerebrospinal fluid , Respiratory Insufficiency/drug therapy , Respiratory Insufficiency/virology , Ritonavir/therapeutic use , SARS-CoV-2/drug effects
14.
J Med Virol ; 93(2): 766-774, 2021 02.
Article in English | MEDLINE | ID: covidwho-1196399

ABSTRACT

We report a case series of five patients affected by SARS-CoV-2 who developed neurological symptoms, mainly expressing as polyradiculoneuritis and cranial polyneuritis in the 2 months of COVID-19 pandemic in a city in the northeast of Italy. A diagnosis of Guillain-Barré syndrome was made on the basis of clinical presentation, cerebrospinal fluid analysis, and electroneurography. In four of them, the therapeutic approach included the administration of intravenous immunoglobulin (0.4 g/kg for 5 days), which resulted in the improvement of neurological symptoms. Clinical neurophysiology revealed the presence of conduction block, absence of F waves, and in two cases a significant decrease in amplitude of compound motor action potential compound muscle action potential (cMAP). Four patients presented a mild facial nerve involvement limited to the muscles of the lower face, with sparing of the forehead muscles associated to ageusia. In one patient, taste assessment showed right-sided ageusia of the tongue, ipsilateral to the mild facial palsy. In three patients we observed albuminocytological dissociation in the cerebrospinal fluid, and notably, we found an increase of inflammatory mediators such as the interleukin-8. Peripheral nervous system involvement after infection with COVID-19 is possible and may include several signs that may be successfully treated with immunoglobulin therapy.


Subject(s)
COVID-19/complications , Guillain-Barre Syndrome/cerebrospinal fluid , Guillain-Barre Syndrome/diagnosis , Nervous System Physiological Phenomena , Neuritis/diagnosis , Aged , Aged, 80 and over , Ageusia/diagnosis , Ageusia/virology , COVID-19/cerebrospinal fluid , COVID-19/therapy , Facial Paralysis/diagnosis , Facial Paralysis/virology , Female , Guillain-Barre Syndrome/therapy , Humans , Immunization, Passive , Interleukin-8/cerebrospinal fluid , Italy , Male , Middle Aged , Neuritis/therapy , Neuritis/virology , Polyradiculoneuropathy/diagnosis , Polyradiculoneuropathy/virology
15.
Sci Rep ; 11(1): 5121, 2021 03 04.
Article in English | MEDLINE | ID: covidwho-1117669

ABSTRACT

Mid Regional pro-ADM (MR-proADM) is a promising novel biomarker in the evaluation of deteriorating patients and an emergent prognosis factor in patients with sepsis, septic shock and organ failure. It can be induced by bacteria, fungi or viruses. We hypothesized that the assessment of MR-proADM, with or without other inflammatory cytokines, as part of a clinical assessment of COVID-19 patients at hospital admission, may assist in identifying those likely to develop severe disease. A pragmatic retrospective analysis was performed on a complete data set from 111 patients admitted to Udine University Hospital, in northern Italy, from 25th March to 15th May 2020, affected by SARS-CoV-2 pneumonia. Clinical scoring systems (SOFA score, WHO disease severity class, SIMEU clinical phenotype), cytokines (IL-6, IL-1b, IL-8, TNF-α), and MR-proADM were measured. Demographic, clinical and outcome data were collected for analysis. At multivariate analysis, high MR-proADM levels were significantly associated with negative outcome (death or orotracheal intubation, IOT), with an odds ratio of 4.284 [1.893-11.413], together with increased neutrophil count (OR = 1.029 [1.011-1.049]) and WHO disease severity class (OR = 7.632 [5.871-19.496]). AUROC analysis showed a good discriminative performance of MR-proADM (AUROC: 0.849 [95% Cl 0.771-0.730]; p < 0.0001). The optimal value of MR-proADM to discriminate combined event of death or IOT is 0.895 nmol/l, with a sensitivity of 0.857 [95% Cl 0.728-0.987] and a specificity of 0.687 [95% Cl 0.587-0.787]. This study shows an association between MR-proADM levels and the severity of COVID-19. The assessment of MR-proADM combined with clinical scoring systems could be of great value in triaging, evaluating possible escalation of therapies, and admission avoidance or inclusion into trials. Larger prospective and controlled studies are needed to confirm these findings.


Subject(s)
Adrenomedullin/blood , COVID-19/blood , Peptide Fragments/blood , Protein Precursors/blood , Aged , Biomarkers/blood , Female , Humans , Male , Middle Aged , Prognosis , Retrospective Studies
16.
Cytokine ; 140: 155438, 2021 04.
Article in English | MEDLINE | ID: covidwho-1032450

ABSTRACT

BACKGROUND: Patients infected by SARS-CoV-2 can develop interstitial pneumonia, requiring hospitalisation or mechanical ventilation. Increased levels of inflammatory biomarkers are associated with development of acute respiratory distress syndrome (ARDS). The aim of the present study was to determine which cytokines are associated with respiratory insufficiency in patients hospitalised for COVID-19. PATIENTS AND METHODS: Data on 67 consecutive patients were collected between March 8 and March 30, 2020. PaO2/FiO2 ratio (P/F) was calculated at hospital admission. The following cytokines were analysed: interleukin (IL)-6, IL-1α, IL-18, tumour necrosis factor (TNF)-ß, macrophage colony-stimulating factor (M-CSF), macrophage migration inhibitory factor (MIF), soluble IL-2 receptor alpha (sIL-2Rα; CD25), IL-12ß, IL-3, interferon (IFN) α2a, monokine induced by gamma interferon (MIG), monocyte-chemotactic protein 3 (MCP3) and hepatocyte growth factor (HGF). RESULTS: P/F lower than 300 was recorded in 22 out of 67 patients (32.8%). P/F strongly correlated with IL-6 (r = -0.62, P < 0.0001), M-CSF (r = -0.63, P < 0.0001), sIL-2Rα (r = -0.54, P < 0.0001), and HGF (r = -0.53, P < 0.0001). ROC curve analyses for IL-6 (AUC 0.83, 95% CI 0.73-0.93, P < 0.0001), M-CSF (AUC 0.87, 95% CI 0.79-0.96, P < 0.0001), HGF (AUC 0.81, 95% CI 0.70-0.93, P < 0.0001), and sIL-2Rα (AUC 0.80, 95% CI, 0.69-0.90, P < 0.0001) showed that these four soluble factors were highly significant. All four soluble factors correlated with LDH, white blood cell count, neutrophil count, lymphocyte count, and CRP. CONCLUSION: IL-6, M-CSF, sIL-2Rα, and HGF are possibly involved in the main biological processes of severe COVID-19, mirroring the level of systemic hyperinflammatory state, the level of lung inflammation, and the severity of organ damage.


Subject(s)
COVID-19/blood , Cytokines/blood , Immunity, Innate/immunology , Inflammation/blood , Interleukin-2 Receptor alpha Subunit/blood , Multiple Organ Failure/blood , Pneumonia/blood , Aged , COVID-19/complications , COVID-19/virology , Female , Hepatocyte Growth Factor/blood , Host-Pathogen Interactions , Humans , Inflammation/complications , Interleukin-6/blood , Macrophage Colony-Stimulating Factor/blood , Male , Middle Aged , Multiple Organ Failure/complications , Pneumonia/complications , Pneumonia/virology , Retrospective Studies , SARS-CoV-2/physiology
18.
J Med Virol ; 92(11): 2852-2856, 2020 11.
Article in English | MEDLINE | ID: covidwho-866098

ABSTRACT

INTRODUCTION: The most serious COVID-19 deriving from severe acute respiratory syndrome coronavirus 2 causes a cytokine release storm and it is associated with worse outcomes. In COVID-19 patients, interleukin-6 (IL-6) levels are significantly elevated. Blocking IL-6 preliminarily resulted in the improvement of this hyperinflammatory state. It is unknown which patients could require higher doses of tocilizumab to get out of the cytokine storm. MATERIALS AND METHODS: Twenty-four patients affected by COVID-19 pneumonia were included. All the patients underwent tocilizumab 8 mg/kg intravenously and were tested for serum IL-6 24 to 48 hours before and 12 to 48 hours after tocilizumab infusion. Comparisons between survivors and nonsurvivors were performed. RESULTS: Eighteen patients were discharged, while six patients died, with no clinical or laboratory differences between the two groups at baseline. IL-6 was not different at baseline (P = .41), while 24 to 48 hours post-tocilizumab IL-6 serum levels were significantly higher in nonsurvivors than in survivors (2398.5 [430.5-9372] vs 290.5 [58.5-1305.5] pg/mL, P = .022). Serum IL-6 post-tocilizumab showed a good predictive ability to discriminate survivors from nonsurvivors (area under the curve, 0.815; 95% confidence interval, 0.63-0.99, P = .02). CONCLUSION: Repeated measurement of the serum level of IL-6 early after tocilizumab may distinguish nonsurvivors from survivors and support the choice of deeper targeting IL-6 in COVID-19 pneumonia.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/drug therapy , Interleukin-6/blood , Survivors/statistics & numerical data , Administration, Intravenous , Aged , Biomarkers/blood , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/virology , Female , Humans , Male , Middle Aged , Retrospective Studies , Severity of Illness Index
19.
Neurol Sci ; 41(12): 3391-3394, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-815976

ABSTRACT

We report the clinical and immunological features in a case of SARS-CoV-2-induced Guillain-Barré syndrome (Si-GBS), suggesting that (1) Si-GBS can develop even after paucisymptomatic COVID-19 infection; (2) a distinctive cytokine repertoire is associated with this autoimmune complication, with increased CSF concentration of IL-8, and moderately increased serum levels of IL-6, IL-8, and TNF-α; (3) a particular genetic predisposition can be relevant, since the patient carried several HLA alleles known to be associated with GBS, including distinctive class I (HLA-A33) and class II alleles (DRB1*03:01 and DQB1*05:01). To the best of our knowledge, this is the first case of GBS in which SARS-CoV-2 antibodies were detected in the CSF, further strengthening the role of the virus as a trigger. In conclusion, our study suggests that SARS-CoV-2 antibodies need to be searched in the serum and CSF in patients with GBS living in endemic areas, even in the absence of a clinically severe COVID-19 infection, and that IL-8 pathway can be relevant in Si-GBS pathogenesis. Further studies are needed to conclude on the relevance of the genetic findings, but it is likely that HLA plays a role in this setting as in other autoimmune neurological syndromes, including those triggered by infections.


Subject(s)
Coronavirus Infections/complications , Guillain-Barre Syndrome/genetics , Guillain-Barre Syndrome/immunology , Guillain-Barre Syndrome/virology , Pneumonia, Viral/complications , Antibodies, Viral/immunology , Autoantibodies/immunology , Autoantigens/immunology , Betacoronavirus , COVID-19 , Cytokines/immunology , Genotype , HLA Antigens/genetics , Humans , Male , Middle Aged , Pandemics , SARS-CoV-2
20.
Clin Pharmacokinet ; 59(10): 1251-1260, 2020 10.
Article in English | MEDLINE | ID: covidwho-734040

ABSTRACT

BACKGROUND: Darunavir is an anti-HIV protease inhibitor repurposed for SARS-CoV-2 treatment. OBJECTIVE: The aim of this study was to assess the population pharmacokinetics of darunavir in SARS-CoV-2 patients compared with HIV patients. METHODS: Two separate models were created by means of a nonlinear mixed-effect approach. The influence of clinical covariates on each basic model was tested and the association of significant covariates with darunavir parameters was assessed at multivariate regression and classification and regression tree (CART) analyses. Monte Carlo simulation assessed the influence of covariates on the darunavir concentration versus time profile. RESULTS: A one-compartment model well-described darunavir concentrations in both groups. In SARS-CoV-2 patients (n = 30), interleukin (IL)-6 and body surface area were covariates associated with darunavir oral clearance (CL/F) and volume of distribution (Vd), respectively; no covariates were identified in HIV patients (n = 25). Darunavir CL/F was significantly lower in SARS-CoV-2 patients compared with HIV patients (4.1 vs. 10.3 L/h; p < 0.001). CART analysis found that an IL-6 level of 18 pg/mL may split the SARS-CoV-2 population in patients with low versus high darunavir CL/F (mean ± standard deviation 3.47 ± 1.90 vs. 8.03 ± 3.24 L/h; proportion of reduction in error = 0.46). Median (interquartile range) darunavir CL/F was significantly lower in SARS-CoV-2 patients with IL-6 levels ≥ 18 pg/mL than in SARS-CoV-2 patients with IL-6 levels < 18 pg/mL or HIV patients (2.78 [2.16-4.47] vs. 7.24 [5.88-10.38] vs. 9.75 [8.45-13.79] L/h, respectively; p < 0.0001). Increasing IL-6 levels affected darunavir concentration versus time simulated profiles. We hypothesized that increases in IL-6 levels associated with severe SARS-CoV-2 disease may downregulate the cytochrome P450 (CYP) 3A4-mediated metabolism of darunavir. CONCLUSIONS: This is a proof-of-concept of SARS-CoV-2 disease-drug interactions, and may support the need for optimal dose selection of sensitive CYP3A4 substrates in severe SARS-CoV-2 patients.


Subject(s)
Coronavirus Infections/drug therapy , Darunavir/pharmacokinetics , HIV Infections/drug therapy , HIV Protease Inhibitors/pharmacokinetics , Interleukin-6/blood , Pneumonia, Viral/drug therapy , Adult , Age Factors , Aged , Betacoronavirus , Body Weights and Measures , COVID-19 , Comorbidity , Cytochrome P-450 CYP3A , Darunavir/therapeutic use , Dose-Response Relationship, Drug , Female , HIV Protease Inhibitors/therapeutic use , Humans , Male , Metabolic Clearance Rate , Middle Aged , Models, Biological , Monte Carlo Method , Pandemics , Retrospective Studies , SARS-CoV-2 , Sex Factors
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