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Introduction: Diagnosis of ventilator-associated pneumonia (VAP) in COVID-19 patients remains challenging. Also, the lack of gold standard for microbiological sampling undermines clinical judgement and management. We studied incidences of microbiologically-confirmed VAP comparing endotracheal aspirate (ETA) and bronchoalveolar lavage (BAL) in COVID-19 patients. Etiological agreement between ETA and BAL was then assessed. Method(s): Single-center prospective cohort study (NCT04766983). Patients were enrolled within 48 h from intubation;surveillance ETA ( ETASURV) was performed twice weekly. ETA ( ETACX) and BAL ( BALCX) samples were collected upon VAP suspicion (Johanson's criteria). CDC definitions were used for microbiological confirmation. ETA-BAL agreement (interrater reliability and Cohen's kappa) and clinical/microbiological data were assessed for the first episodes of suspected VAP per patients. Result(s): Ninety intensive care (ICU) patients enrolled from 01/2021 to 05 06/2022, of which 26 females (28.9%);median age was 60 [52-66] years. In-ICU mortality was 30/90 (33.3%), median length of stay in survivors 19 (10-32) days. Fifty-three patients (58.9%) had >= 1 episode of suspected VAP after 6 [5;10] days from ICU admission. ETASURV were available in 52 cases, 2 [1;3] days before VAP suspect, and tested positive in 28 (53.8%). ETACX and BALCX resulted positive in 35 (66.0%) and 29 (54.7%) of episodes. Main microbiological results are displayed in Fig. 1, panel A. Etiological agreement between techniques is shown in Fig. 1, panel B. Incidence rate of VAP suspicions per 1000 ventilator-days was 60.2 (95% CI 43.9-76.4), while incidence rates of microbiologically-confirmed VAP were 27.4 (18.3-36.5) with ETACXand 18.9 (95% CI 12.0-25.8) with BALCX, respectively. Conclusion(s): We observed different incidence of VAP in COVID-19 ICU patients depending on sampling method. Etiological agreement between techniques yielded limited interrater reliability. The potential clinical impact needs further studies.
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Passive immunization with mAbs has been employed in COVID-19. We performed a systematic review of the literature assessing the endogenous humoral immune response against SARS-CoV-2 in patients treated with mAbs. Administration of mAbs in seronegative patients led to a reduction in both antibody titres and neutralizing activity against the virus.Copyright © 2022
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The SARS-CoV-2 is the betacoronavirus responsible for the coronavirus disease 2019 (COVID-19) pandemic. Severe COVID-19 affects approximately 10-15% of patients and results in prolonged morbidity and mortality. Little is known about the immunophenotypic changes of the lung parenchyma driven by the viral infection in patients who die of severe COVID-19. Ultrasound-guided lung biopsies (LB) were collected (IRB approval#1561/21) within few hours from death in 15 severe COVID-19 patients between November 2020 and January 2021, in two patients who underwent lung transplantation after COVID-19 and in one patient who had surgery for bacterial superinfection during COVID-19 disease. All samples underwent histologic and immunohistochemistry evaluation and molecular profiling using the nCounter Host Response and Coronavirus Panel plus. As controls, lungs from end-stage usual interstitial pneumonia (UIP;n=9) and from lobectomy for lung cancer (Norm;n=5) were used. Eleven lungs (61%) were positive for SARS-CoV-2 RNA. Signs of diffuse alveolar damage (DAD) were observed in 6 patients (30%). COVID-19 lungs showed a marked macrophage infiltration with M2 polarization compared with controls. Globally, COVID-19 lungs showed distinct molecular profiles from UIP or Norm lungs. Specifically, a marked upregulation of interferon-genes that was directly correlated with SARS-CoV-2 genes was seen in COVID-19 lungs. COVID-19-specific genes signatures (Log2FC >1.5;adj p<0.05) obtained using VENN diagram showed impairment of the STAT3-pathway accompanied by the upregulation of the NFkB signaling. Results herein provide new insights into lung alterations induced by severe COVID-19 and suggest novel potential targets for therapeutic intervention.
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Background: From January 2022 the Omicron SARS-CoV-2 variant became the dominant circulating variant worldwide, showing increased transmissibility and the ability to evade immunity. Booster vaccinations improved the protective effects of neutralizing antibodies and might have lowered the risk of hospitalization and mortality, as recently observed. Aim: to evaluate the prevalence and outcome of Omicron-related infection in a cohort of liver transplant (LT) recipients. Material and Methods: From January to September 2022, we enrolled in a longitudinal study all LT recipients who became SARS-CoV-2 infected (95% vaccinated;88% receiving a 1st booster dose and 25% a 2nd booster). All patients were included in a protocol of testing anti-spike (a-S) and anti-nucleocapsid (a-N) antibodies titres before/after each dose (Elecsys Anti-SARS-CoV-2, Roche Diagnostic). Diagnostic criteria for SARS-CoV-2 infection were 1) presence of a positive nasopharyngeal swab (NFS) by PCR or antigenic assays or 2) presence of a-N seroconversion (if previously a-N negative). Reinfection was defined by a new NFS positivity or an increased value of a-N titre. Results: Overall, 201 LT-recipients have been infected by SARS-CoV-2 (62% males, median age=61yr, 50% viral-etiology, 35% with HCC, all received a CNI-based regimen, plus MMF=63%). Most of infections were diagnosed by NFS (72%);mild flu-like symptoms were observed in 59% of our LT recipients;72% of them remained untreated, while 28% received antivirals (11%) or monoclonal antibodies (17%). Fifteen LT recipients were hospitalized, 6 of them for interstitial pneumonia and 2 (both with previous lung diseases) died for COVID-19. Conclusions: A mild or asymptomatic infection occurred frequently in our LT recipients with a less severe outcome than the past waves. A possible explanation could be the high prevalence of vaccinated patients in our cohort. Interestingly, the overall prevalence of SARS Cov2 infection might be underestimated without a careful monitoring of SARS-CoV-2 serology against nucleocapsid.
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The gut is of importance in the pathology of COVID-19 both as a route of infection, and gut dysfunction influencing the severity of disease. Systemic changes caused by SARS-CoV-2 gut infection include alterations in circulating levels of metabolites, nutrients and microbial products which alter immune and inflammatory responses. Circulating plasma markers for gut inflammation and damage such as zonulin, lipopolysaccharide and ß-glycan increase in plasma along with severity of disease. However, Intestinal Fatty Acid Binding Protein / Fatty Acid Binding Protein 2 (I-FABP/FABP2), a widely used biomarker for gut cell death, has paradoxically been shown to be reduced in moderate to severe COVID-19. We also found this pattern in a pilot cohort of mild (n = 18) and moderately severe (n = 19) COVID-19 patients in Milan from March to June 2020. These patients were part of the first phase of COVID-19 in Europe and were therefore all unvaccinated. After exclusion of outliers, patients with more severe vs milder disease showed reduced FABP2 levels (median [IQR]) (124 [368] vs. 274 [558] pg/mL, P < 0.01). A reduction in NMR measured plasma relative lipid-CH3 levels approached significance (median [IQR]) (0.081 [0.011] vs. 0.073 [0.024], P = 0.06). Changes in circulating lipid levels are another feature commonly observed in severe COVID-19 and a weak positive correlation was observed in the more severe group between reduced FABP2 and reduced relative lipid-CH3 and lipid-CH2 levels. FABP2 is a key regulator of enterocyte lipid import, a process which is inhibited by gut SARS-CoV-2 infection. We propose that the reduced circulating FABP2 in moderate to severe COVID-19 is a marker of infected enterocyte functional change rather than gut damage, which could also contribute to the development of hypolipidemia in patients with more severe disease.
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COVID-19 , Humans , Enterocytes/metabolism , SARS-CoV-2 , Fatty Acid-Binding Proteins/metabolism , Biomarkers , Cell Death , LipidsABSTRACT
Background: Rheumatic musculoskeletal diseases (RMD) are pathological conditions characterized by an impaired immunological system that is determinant both in the pathogenesis and in the inadequate response to infections. The use of disease-modifying anti-rheumatic drugs (DMARDs), which include conventional synthetic (cs) or biologic and targeted synthetic (b/ts) DMARDs, contribute to compromise immunological reactivity. Objectives: To analyze the immune response to SARS-CoV-2 in patients with rheumatoid arthritis (RA) or spondyloarthritis (SpA) receiving treatment with DMARDs and to investigate the effect of the different classes of drugs on humoral and cellular response. Methods: Patients were tested for anti-SARS-CoV-2 IgG, IgM and IgA antibodies to nucleoprotein (N) and receptor-binding domain (RBD) through ELISA and neutralization assays. Then, we performed a fow cytometry analysis of monocytes, NK cells, B and T lymphocytes from PBMCs of serologically positive patients. We also included a cohort of non-RMD individuals recovered from COVID-19 as a reference group of non-immunosuppressed subjects. A frst recruitment occurred in May-June 2020 (T1) and a second recruitment, 3-4 months after (T2), allowed to evaluate the persistence of the antibody response over time and to investigate the cellular immune response to SARS-CoV-2 in RMD patients having resolved the infection. Results: During T1, 358 patients with RA (n=200) or SpA (n=158) were recruited. Mean age was 52.8, 64% were female. All patients were treated with DMARDs, 299 with b/tsDMARDs and 59 received csDMARDs alone. One third was also receiving corticosteroids (CS). At T2, 36 subjects were recruited. We found a seroprevalence rate of 18.4%, which did not signifcantly differ between RA and SpA groups, and between patients treated with b/ts-DMARD or csDMARDs, either alone or in combination with CS (Table 1). Antibody levels of RMD patients were lower than non-RMD individuals (Figure 1), with CTLA4-Ig-treated patients having the lowest IgG levels. This difference was less marked in symptomatic RMD patients. 72% of seropositive patients elicited neutralizing sera. Despite an overall decrease in anti-RBD and anti-N titers, more than two-third of patients maintained antibodies titers above positivity threshold at T2. Concerning cellular response, we found that CD8+ T-cells frequency was overall comparable between RMD and non-RMD convalescents, and did not differ in b-or cs-DMARD treated ones. Conversely, CD4+ T-cell frequencies were signifcantly lower in RMD patients, especially those treated with anti-IL6R and CTLA4-Ig. B-cell subpopulations (class-switched, memory, and IgG+ memory B-cells) had sustained frequencies in anti-TNFα treated patients, while they had a trend of reduction in patients treated with anti-IL6R and CTLA4-Ig. Conclusion: Our data provide a comprehensive picture of the humoral and cellular immune responses to SARS-CoV-2 infection in RMD patients. We showed that DMARDs treatments did not alter a successful antibody response to the virus and did not hamper the antibody neutralizing ability. However, the magnitude of antibody response was slightly reduced compared to non-RMD individuals, especially in patients receiving CTLA4-Ig. We did not observe marked differences in the B-and T-cell populations between RMD patients compared to non-RMD individuals. However, in patients receiving anti-TNFα we found a higher relative abundance of effector adaptive population compared to other bDMARDs.
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Background and Aims: SARS-CoV-2 mRNA vaccines have been approved to prevent COVID-19. We assessed immunogenicity, effectiveness and safety of vaccines in patients with compensated and decompesated cirrhosis. Method: This is a prospective single center study assessing humoral and cellular responses in cirrhotics compared to healthy controls, incidence post-vaccination SARS-CoV-2 infections and adverse events (AEs). Antibodies against the spike- and nucleocapside-protein (anti-S and anti-N) were tested at baseline, 21 days after the first and second doses and during follow-up. Spike-specific T-cells quantity assessment was longitudinally conducted by the stimulation of whole blood with peptides covering the SARS-CoV-2 spike protein, followed by IFN-γ and IL-2 measurement. Results: 182 cirrhotics (61 years, 75% males, 45% viral-related, 74% Child-Pugh A, 31% HCC, 85% COVID-19 naïve) and 38 healthy subjects were enrolled. Previous SARS-CoV-2 infection predicted higher anti-S titres at all time points after vaccination, in both groups. COVID-19 naïve cirrhotics showed significantly lower anti-S titres compared to controls [998.5 (0.4-12,500) vs 1,520 (259-12,500) U/mL, p=0.048], anti-S titres significantly decreased after a median of 133 (70-182) days [536 (0.4-8,777) U/mL, p<0.0001] and were lower in decompensated vs compensated cirrhosis [632 (0.4-12,500) vs 1,377 (0.4-12,500) U/mL, p=0.028]. By multivariable analysis in COVID-19 naïve cirrhotics, independent predictors of lower anti-S were active HCC, immunocompromised conditions, BNT162b2 and lower anti-S after first dose. The spike-specific T-cell response was evaluated in 14 cirrhotics, showing a heterogeneous magnitude of response, but on average the quantity and kinetics of decline of the spike-specific cellular responses diverged in cirrhotics compared to controls, with lower concentrations of both IFN-γ and IL-2. During follow-up, 4/133 (3%) COVID-19 naïve cirrhotics tested positive for anti-N, all asymptomatic. Neither unexpected nor severe AEs emerged. Conclusion: Humoral and cellular responses to SARS-CoV-2 mRNA vaccines appeared suboptimal in patients with cirrhosis, however the rate of post-vaccination infection seems low.
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Introduction: Registration studies have shown high efficacy of BNT162b2 mRNA COVID-19 vaccine. We evaluated vaccine effectiveness (VE) of BNT162b2 mRNA COVID-19 vaccine in a cohort of healthcare workers (HCWs) of a large hospital in Milan, Lombardy, Italy. Material and Methods: Follow-up started on 27 December 2020 (beginning of the vaccination campaign). HCWs without history of SARS-CoV-2 infection before the start date and with at least a nasopharyngeal test afterwards were included. Vaccination was treated as a time-dependent variable. For selected periods after vaccination we calculated incidence rate ratios (IRR) and 95% confidence intervals (CI) of infection with a Poisson regression model adjusted for gender, age, occupation, and 30-day periods, and then VE as (1 – IRR)x100 using unvaccinated person-time as reference. Databases were closed on 27 September 2021. The study was approved by the hospital’s ethics committee (Milano Area 2, Prot. No. 828_2021bis). Results and Conclusions: We included 3,809 HCWs, 131 still unvaccinated and 3,678 vaccinated (3,576 with two doses). We identified 134 infections (62% symptomatic). Adjusted VE was 77% (CI: 43-91) from day 14 after the first vaccine dose and 87% (CI: 79-92) at least 7 days after the second dose. After full vaccination schedule VE was 89% (CI: 82-94) for symptomatic and 77% (CI: 45-90) for asymptomatic infections. In conclusion, we found high effectiveness of BNT162b2 vaccine in reducing incidence of both symptomatic and asymptomatic infections. The follow-up is continuing to assess long-term effectiveness, also considering emerging SARS-CoV-2 variants.
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Introduction Randomized controlled trials showed efficacy of vaccines against coronavirus disease 19 (COVID-19). There is the need to quantify vaccine effectiveness in real-word contexts, including people at high risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), such as health care workers (HCWs). Objectives To evaluate vaccine effectiveness among hospital HCWs. Methods We performed a cohort study among HCWs of a large University hospital in Milan, Lombardy, Italy by merging routinely collected data on demographics, COVID-19 vaccination, and polymerase chain-reaction (PCR) tests performed on nasopharyngeal swabs. Follow-up started on December 27, 2020 (start of vaccination campaign). We included HCWs never PCR-positive before the start date and with at least a PCR test afterwards. Vaccination was treated as a time-dependent variable by calculating person-years (PY) at risk before and after vaccine doses. Subjects contributed PY until first positive PCR test (cases) or last test for never positive HCWs (to avoid immortal time bias). We calculated infection rates (cases per 1000 PY), rate ratios (RR, with a Poisson regression model adjusted for gender, age, occupation and 30-day periods), vaccine effectiveness (VE = (1-RR)x100) and 95% confidence intervals (CI) taking never vaccinated HCWs as reference. Results As of May 10, there were 3,152 vaccinated (97% with BNT162b2, 140 with one dose, 2,679 with two doses) and 333 non-vaccinated. We counted 29 infected cases (rate 385) among non-vaccinated, 6 (rate 65) from day 14 after the first dose (VE 79%, CI 49-92%), and 24 (rate 65) from day 7 after the second dose (VE 89%, CI 80-94%). Most cases after vaccination were asymptomatic or mildly symptomatic. Conclusion In these preliminary analysis we found high effectiveness of COVID-19 vaccine in HCWs in our hospital. Further work is needed to assess long-term effectiveness and to better plan future preventive strategies among this high-risk occupational group.
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Background and aim: Gastrointestinal infections represent a risk factor for functional gastrointestinal and somatoform extraintesti-nal disorders. We investigated the prevalence and relative risk (RR) of gastrointestinal and somatoform symptoms five months after SARS-CoV-2 infection compared with a control cohort. Materials and methods: 378 subjects, age range 18-60 years, were stu-died. 177 SARS-CoV-2 infected patients and 201 controls responded to an online questionnaire about symptoms and signs during the acute phase of the infection and after 4.8±0.3 months. 13 and 18 patients were respectively excluded because of a previous gastrointestinal dise-ase. Presence and severity of gastrointestinal symptoms, somatization, anxiety and depression were recorded with a structured standardized questionnaire, including the Structured Assessment of Gastrointestinal Symptoms (SAGIS) questionnaire, the Symptom Check List (SCL)-12 for somatization and the Hospital Anxiety and Depression Scale (HADS). Stool form through Bristol Stool scale and a yes/no question summari-zing the Rome IV criteria for Irritable Bowel Syndrome (IBS) were also recorded. Any association between exposure to infection and symp-toms was evaluated by calculating crude and adjusted RR values and score differences with 95% confidence intervals (CI). Results: Fever, dyspnea, loss of smell/taste/weight, diarrhea, myal-gia, arthralgia and asthenia were reported by more than 40% of patients during the acute phase. Abdominal pain/discomfort, diar-rhea/incontinence and gastroesophageal reflux disease/regurgita-tion symptoms persisted after SARS-CoV-2 infection, but with very low severity;the relative increase on the mean score of each domain was minimal (score difference up to +0.16). Compared with con-trols, adjusted RRs for loose stools, chronic fatigue and somatization were increased after infection: 1.88 (95% CI 0.99–3.54), 2.24 (95% CI 1.48–3.37), 3.62 (95% CI 1.01–6.23) respectively. The prevalence of IBS and HADS scores tended to be greater in patients than in con-trols. Gastrointestinal sequelae were greater in patients with diar-rhea during the acute phase. Conclusions: Mild gastroenterological symptoms persist five months after SARS-CoV-2 infection, in particular in patients report-ing diarrhea in the acute phase. Infected patients are at increased risk of chronic fatigue and somatoform disorders, thus supporting the hypothesis that both functional gastrointestinal and somato-form disorders may have a common biological orig
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Patients with Covid-19 frequently develop atypical thyroiditis coexisting with non-thyroidal illness syndrome (Muller et al LancetD& E 2020). We analysed thyroid dysfunction: 1) in relation to Covid-19 disease severity;2) observing its evolution over time. Baseline assessment of 179 patients hospitalised in sub-intensive care units for Covid-19 disease, without known history of thyroid dysfunction or amiodarone therapy, with thyroid function and inflammatory markers measured at hospital admission. Thyroidultrasound (thyroid-US) and thyroid autoantibodies measurement were performed in 65 patients after they became SARS-CoV-2 negative, of whom 14 were also studied with radioisotope thyroiduptake (99mTc or I123) since showing focal-hypoechoic-areas. 46 patients were re-evaluated at 6 months of follow-up. Patients on steroid treatment started before hospitalization (N = 62) were excluded due to its lowering effect on TSH. At baseline 11/117 patients (9.4%) had thyrotoxicosis (low TSH and/or high FT4);23/117 (19.7%) had low TSH and required a more intensive oxygen support during hospitalization (P = 0.02). TSH positively correlated with lymphocyte count (P < 0.01). FT3 correlated negatively with length of hospitalization (P = 0.04) and death rate (P = 0.03). Only 7.7% patients had detectable TgAb/TPOAb and none TRAb. Thyroid-US showed focal-hypoechoic-areas in 28% patients, of whom thyroid-uptake was focally-reduced in 57%, diffusely-reduced in 14% and normal in 28%. Importantly, focalhypoechoic-areas were more frequent among patients with baseline low TSH compared with normal TSH (P = 0.03). Furthermore, patients with focal-hypoechoic-areas had higher baseline FT4 (P = 0.02) and IL-6 (P = 0.02) than those without. Thyroid function and inflammatory markers had normalized at 3 months and remained normal thereafter. At 6 months focalhypoechoic-areas persisted in the majority of patients, often reduced in size;thyroid-uptake was repeated in 8 patients and resulted increased in 7 (87.5%). Thyroid dysfunction during moderate-to-severe Covid-19 disease was mild and transient and correlated with increased death rate and length of hospitalization;low TSH correlated with lymphopenia and was associated with increased need of oxygen support during hospitalization. Focal-hypoechoic-areas at thyroid-US persisted up to 6 months in nearly 1/3 of patients and correlated with thyroid and inflammatory parameters at hospital admission, confirming a key role of thyroiditis in Covid-19 related thyroid dysfunction;long-term effects are unknown.
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Background and aims: Although COVID-19 infection predominantly manifests with respiratory symptoms, recent studies have also reported the occurrence of neurological involvement in the acute phase as well as in the follow-up of recovered subjects Methods: Our study focuses on assessing the prevalence of neurological sequelae in COVID-19 patients hospitalized at Ospedale Maggiore Policlinico in Milan. Seventy-five COVID-19 recovered subjects followed a general follow-up protocol including pneumological, infectious and cardiovascular assessment 5-10 months after the onset of SARS-CoV2 infection;among them, a subset of 53 patients was evaluated through a self-administered 18-item questionnaire developed ad-hoc addressing sensory, motor and cognitive neurological symptoms. Results: Collected data has shown that 77.4% patients developed at least one neurological sequela, and 46.3% presented with more than three symptoms. Among symptomatic patients, the most prevalent manifestations were insomnia (65.9%) and daytime sleepiness (46.3%), followed by walking difficulties (31.7%). Other less frequent symptoms were headache (15.1%), hyposmia and hypogeusia (15.1%), and tremor (9.4%). Prevalence of symptoms 18-item questionnare showing the distribution of neurological manifestations Conclusion: Post-COVID-19 manifestations are reported in about 90% of recovered patients. This preliminary study suggests that neurological findings represent a significant part of such manifestations. We are currently expanding the questionnaire to a larger cohort of patients and correlating our findings with patients' demographical and clinical features, as well as with the severity of the previous SARSCoV2 infection. Currently, the same questionnaire is also being validated and administered to age-and sex-matched healthy controls who have not developed symptoms suggestive of Covid-19, and a cohort of non-COVID-19 hospitalized patients.