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Low-grade endotoxemia by lipopolysaccharide (LPS) has been detected in COVID-19 and could favor thrombosis via eliciting a pro-inflammatory and pro-coagulant state. The aim of this study was to analyze the mechanism accounting for low-grade endotoxemia and its relationship with oxidative stress and clotting activation thrombosis in COVID-19. We measured serum levels of sNOX2-dp, zonulin, LPS, D-dimer, and albumin in 175 patients with COVID-19, classified as having or not acute respiratory distress syndrome (ARDS), and 50 healthy subjects. Baseline levels of sNOX2-dp, LPS, zonulin, D-dimer, albumin, and hs-CRP were significantly higher in COVID-19 compared to controls. In COVID-19 patients with ARDS, sNOX2-dp, LPS, zonulin, D-dimer, and hs-CRP were significantly higher compared to COVID-19 patients without ARDS. Conversely, concentration of albumin was lower in patients with ARDS compared with those without ARDS and inversely associated with LPS. In the COVID-19 cohort, the number of patients with ARDS progressively increased according to sNOX2-dp and LPS quartiles; a significant correlation between LPS and sNOX2-dp and LPS and D-dimer was detected in COVID-19. In a multivariable logistic regression model, LPS/albumin levels and D-dimer predicted thrombotic events. In COVID-19 patients, LPS is significantly associated with a hypercoagulation state and disease severity. In vitro, LPS can increase endothelial oxidative stress and coagulation biomarkers that were reduced by the treatment with albumin. In conclusion, impaired gut barrier permeability, increased NOX2 activation, and low serum albumin may account for low-grade endotoxemia and may be implicated in thrombotic events in COVID-19., Competing Interests: The authors declare no conflicts of interest.

Coronavirus disease 2019 (COVID-19) is an infection characterized by the dysregulation of systemic cytokine levels. The measurement of serum levels of inflammatory cyto-/chemokines has been suggested as a tool in the management of COVID-19. The aim of this study is to highlight the significance of measured levels of interleukin (IL)-1α, IL-1β, IL-6, IL-8, IL-10, IL-12(p70), IL-27, interferon (IFN)γ, interferon gamma-induced protein (IP)-10, monocyte chemoattractant protein (MCP)-1, and tumor necrosis factor (TNF)-α in serum samples from infected and recovered subjects, possibly predictive of severity and/or duration of the disease. Serum samples from healthy (HD), positive at hospital admittance (T0), and recovered subjects (T1, 31-60, or 70-200 days post-negativization) were collected and tested through a bead-based cytometric assay and confirmed through ELISA. IL-10 levels were increased in the T0 group compared to both HD and T1. IL-27 significantly decreased in the 31-60 group. IL-1β significantly increased in the 70-200 day group. TNF-α significantly decreased in T0 compared to HD and in the 31-60 group versus HD. IP-10 significantly increased in T0 compared to HD. These results suggest that IP-10 could represent an early marker of clinical worsening, whereas IL-10 might be indicative of the possible onset of post-COVID-19 long syndrome.

Introduction: Casirivimab and imdevimab (CAS/IMV) are two non-competing, high-affinity human IgG1 anti-SARS-CoV-2 monoclonal antibodies, that showed a survival benefit in seronegative hospitalized patients with COVID-19. This study aimed to estimate the day-28 risk of mechanical ventilation (MV) and death in individuals hospitalized for severe COVID-19 pneumonia and receiving CAS/IMV. Additionally, it aimed to identify variables measured at the time of hospital admission that could predict these outcomes and derive a prediction algorithm., Methods: This is a retrospective, observational cohort study conducted in 12 hospitals in Italy. Adult patients who were consecutively hospitalized from November 2021 to February 2022 receiving CAS/IMV were included. A multivariable logistic regression model was used to identify predictors of MV or death by day 28 from treatment initiation, and β-coefficients from the model were used to develop a risk score that was derived by means of leave-one-out internal cross-validation (CV), external CV, and calibration. Secondary outcome was mortality., Results: A total of 480 hospitalized patients in the training set and 157 patients in the test set were included. By day 28, 36 participants (8%) underwent MV and 28 died (6%) for a total of 58 participants (12%) experiencing the composite primary endpoint. In multivariable analysis, four factors [age, PaO 2 /FiO 2 ratio, lactate dehydrogenase (LDH), and platelets] were independently associated with the risk of MV/death and were used to generate the proposed risk score. The accuracy of the score in the area under the curve (AUC) was 0.80 and 0.77 in internal validation and test for the composite endpoint and 0.87 and 0.86 for death, respectively. The model also appeared to be well calibrated with the raw data., Conclusion: The mortality risk reported in our study was lower than that previously reported. Although CAS/IMV is no longer used, our score might help in identifying which patients are not likely to benefit from monoclonal antibodies and may require alternative interventions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Cozzi-Lepri, Borghi, Rotundo, Mariani, Ferrari, Del Borgo, Bai, Colletti, Miraglia, Torti, Cattelan, Cenderello, Berruti, Tascini, Parruti, Coladonato, Gori, Marchetti, Lichtner, Coppola, Sorace, D'Abramo, Mazzotta, Guaraldi, Franceschini, Meschiari, Sarmati, Antinori, Nicastri and Mussini.)

Introduction: Skeletal tuberculosis (TB) accounts for about 10 to 35% of extrapulmonary cases and the knee is the most frequent site after the spine and hip. The diagnosis is difficult and largely clinical., Case Presentation: This is a case of a young Pakistani man with a history of joint pain for about 4 years, who was diagnosed with chronic arthritis of the right knee. Microscopy of synovial fluid and conventional diagnostic tests to identify Mycobacterium tuberculosis were negative, while a non-classical method based on intracellular cytokine flow cytometry response of CD4 T-cells in synovial fluid helped us to address the diagnosis, which was subsequently confirmed by Polymerase Chain Reaction (PCR)., Conclusions: Thanks to an innovative immunological approach, supported by PCR for detection of M. tuberculosis DNA, we were able to diagnose tuberculous arthritis of the knee, which allowed prompt initiation of treatment to reduce morbidity and mortality., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2023 Serena Vita, Claudia Mascia, Blerta Kertusha, Raffaella Marocco, Ilaria Sauzullo, Fabio Mengoni, Irene Pozzetto, Alessandro Scalzi, Parni Nijhawan, Stefano Savinelli, Laura Fondaco, Anna Carraro, Cosmo Del Borgo, Claudio Maria Mastroianni, Miriam Lichtner.)

Background: Monoclonal antibodies are designed to target specific proteins of COVID-19 and can be used as a treatment for people with mild to moderate infection and at a high risk of severe disease. Casirivimab/imdevimab, sotrovimab, and Bamlanivimab/etesevimab have been authorized for emergency use in the treatment of COVID-19. However, during pregnancy, these drugs have not been extensively studied., Methods: A total of 22 pregnant women with mild to moderate infection were treated with three different monoclonal antibodies, and efficacy and safety were evaluated in the first period and until six months of follow-up., Results: No infusion/allergic reactions occurred. No fatal or adverse events were observed in the pregnant women or fetus. The time of negativization with sotrovimab was shorter in comparison to Imdevimav/casirivimab ( p = 0.0187) and Bamlanivimab/etesevimab ( p < 0.00001). The time of negativization with sotrovimab was earlier in comparison to Imdevimav/casirivimab (t-value: 2.92; p = 0.0052) in vaccinated patients and similar in comparison to Imdevimav/casirivimab (t-value: 1.48; p = 0.08). In unvaccinated patients, sotrovimab was faster to achieve negativization in comparison to Bamlanivimab/etesevimab (t-value: 10.75; p < 0.0005)., Conclusions: Pregnant COVID-19 patients receiving sotrovimab obtained better clinical outcomes. Pregnancy or neonatal complications were not observed after monoclonal treatment, confirming the safety and tolerability of these drugs in pregnant women.

Background: The aim of the study was to longitudinally evaluate the association between MMP-2, MMP-9, TIMP-1 and chest radiological findings in COVID-19 patients. Methods: COVID-19 patients were evaluated based on their hospital admission (baseline) and three months after hospital discharge (T post) and were stratified into ARDS and non-ARDS groups. As a control group, healthy donors (HD) were enrolled. Results: At the baseline, compared to HD (n = 53), COVID-19 patients (n = 129) showed higher plasma levels of MMP-9 ( p < 0.0001) and TIMP-1 ( p < 0.0001) and the higher plasma activity of MMP-2 ( p < 0.0001) and MMP-9 ( p < 0.0001). In the ARDS group, higher plasma levels of MMP-9 ( p = 0.0339) and TIMP-1 ( p = 0.0044) and the plasma activity of MMP-2 ( p = 0.0258) and MMP-9 ( p = 0.0021) compared to non-ARDS was observed. A positive correlation between the plasma levels of TIMP-1 and chest computed tomography (CT) score (ρ = 0.2302, p = 0.0160) was observed. At the T post, a reduction in plasma levels of TIMP-1 ( p < 0.0001), whereas an increase in the plasma levels of MMP-9 was observed ( p = 0.0088). Conclusions: The positive correlation between TIMP-1 with chest CT scores highlights its potential use as a marker of fibrotic burden. At T post, the increase in plasma levels of MMP-9 and the reduction in plasma levels of TIMP-1 suggested that inflammation and fibrosis resolution were still ongoing.

In 2022, three antiviral drugs-molnupiravir, remdesivir and nirmatrelvir/ritonavir-were introduced for treatment of mild-to-moderate COVID-19 in high-risk patients. The aim of this study is the evaluation of their effectiveness and tolerability in a real-life setting. A single-center observational study was set up, with the involvement of 1118 patients, with complete follow-up data, treated between the 5th of January and the 3rd of October 2022 at Santa Maria Goretti's hospital in Latina, Central Italy. A univariable and a multivariable analysis were performed on clinical and demographic data and composite outcome, the persistence of symptoms at 30 days and time to negativization, respectively. The three antivirals showed a similar effectiveness in containing the progression of the infection to severe COVID-19 and a good tolerability in the absence of serious adverse effects. Persistence of symptoms after 30 days was more common in females than males and less common in patients treated with molnupiravir and nirmatrelvir/r. The availability of different antiviral molecules is a strong tool and, if correctly prescribed, they can have a significant role in changing the natural history of infection for frail persons, in which vaccination could be not sufficient for the prevention of severe COVID-19.

Gender medicine is now an approach that can no longer be neglected and must be considered in scientific research. We investigated the systemic and mucosal immune response in a population of women living with HIV (WLWH) who were receiving successful ART and the sexual and psychological repercussions of HIV infection on the women's health. As control group, healthy women (HW) matched for age and sex distribution, without any therapy, were included. In summary, our study highlighted the persistence of immune-inflammatory activation in our population, despite virological suppression and a normal CD4 cell count. We found a hyperactivation of the systemic monocyte and an increase in inflammatory cytokine concentrations at the systemic level. The analysis carried out showed a significantly higher risk of HPV coinfection in WLWH compared to HW. Furthermore, our data revealed that WLWH have a profile compatible with sexual dysfunction and generalized anxiety disorders. Our study underlines that patients living with HIV should be evaluated by multidisciplinary teams. These findings also support the idea that more and different immunological markers, in addition to those already used in clinical practice, are needed. Further studies should be carried out to clarify which of these could represent future therapy targets.

Background: The anti-CD20 monoclonal antibody ocrelizumab has been widely employed in the treatment of people with multiple sclerosis (pwMS). However, its B-cell-depleting effect may induce a higher risk of infectious events and alterations in the secretion of B-cell-activating factors, such as BAFF, APRIL and CD40L., Methods: The aim of this study was to investigate plasma BAFF, APRIL and CD40L levels and their relationship with infectious risk in ocrelizumab-treated pwMS at baseline (T0), at 6 months (T6) and at 12 months (T12) after starting the treatment. As a control group, healthy donors (HD) were enrolled too., Results: A total of 38 pwMS and 26 HD were enrolled. At baseline, pwMS showed higher plasma BAFF ( p < 0.0001), APRIL ( p = 0.0223) and CD40L ( p < 0.0001) levels compared to HD. Compared to T0, plasma BAFF levels were significantly increased at both T6 and T12 ( p < 0.0001 and p < 0.0001, respectively). Whereas plasma APRIL and CD40L levels were decreased at T12 ( p = 0.0003 and p < 0.0001, respectively). When stratifying pwMS according to the development of an infectious event during the 12-month follow-up period in two groups-with (14) and without an infectious event (24)-higher plasma BAFF levels were observed at all time-points; significantly, in the group with an infectious event compared to the group without an infectious event (T0: p < 0.0001, T6: p = 0.0056 and T12: p = 0.0400). Conclusions: BAFF may have a role as a marker of immune dysfunction and of infectious risk.

In this retrospective comparative study, we evaluated the effectiveness of remdesivir (RDSV) in patients with SARS-CoV-2 pneumonia. Individuals hospitalized between March 2020 and August 2022 at S.M. Goretti Hospital, Latina, with a positive test for SARS-CoV-2 and, concomitantly, pneumonia, were included. The overall survival was the primary endpoint. The composite secondary endpoint included death or progression in severe ARDS at 40 days. The study population was stratified according to treatment into two groups: the RDSV group (patients treated with RDSV-based regimens) and the no-RDSV group (patients treated with any other, not RDSV-based, regimens). Factors associated with death and progression to severe ARDS or death were assessed by multivariable analysis. A total of 1153 patients (632 belonging to the RDSV group and 521 to the no-RDSV group) were studied. The groups were comparable in terms of sex, PaO2/FiO2 at admission, and duration of symptoms before hospitalization. Further, 54 patients (8.5%) in the RDSV group and 113 (21.7%) in the no-RDSV group ( p < 0.001) died. RDSV was associated with a significantly reduced hazard ratio (HR) of death (HR, 0.69 [95% CI, 0.49-0.97]; p = 0.03), compared to the no-RDSV group, as well as a significantly reduced OR of progression in severe ARDS or death (OR, 0.70 [95% CI 0.49-0.98]; p = 0.04). An overall significantly higher survival rate was observed in the RDSV group ( p < 0.001, by log-rank test). These findings reinforce the survival benefit of RDSV and support its routine clinical use for the treatment of COVID-19 patients.

We investigated specific humoral and T-cell responses in people living with HIV (PLWH) before (T0), after two (T1) and after six months (T2) from the third dose of the BNT162b2 vaccine. Healthy donors (HD) were enrolled. The specific humoral response was present in most PLWH already after the second dose, but the third dose increased both the rate of response and its magnitude. Collectively, no significant differences were found in the percentage of responding T-cells between PLWH and HD. At T0, stratifying PLWH according to CD4 cell count, a lower percentage of responding T-cells in <200 cells/µL subgroup compared to >200 cells/µL one was observed. At T1, this parameter was comparable between the two subgroups, and the same result was found at T2. However, the pattern of co-expression of IFNγ, IL2 and TNFα in PLWH was characterized by a higher expression of TNFα, independently of CD4 cell count, indicating a persistent immunological signature despite successful ART. mRNA vaccination elicited a specific response in most PLWH, although the cellular one seems qualitatively inferior compared to HD. Therefore, an understanding of the T-cell quality dynamic is needed to determine the best vaccination strategy and, in general, the capability of immune response in ART-treated PLWH.

In a male with severe proctitis, monkeypox virus DNA was detected in skin lesions, blood, the nasopharynx, and the rectum, underlying generalized viral spreading. Rectal involvement was still found when skin lesions disappeared. At this early stage, an increase of cytotoxic and activated T cells was observed, while a reduction in CD56dimCD57+ NK cells compared with recovery time point was observed., Competing Interests: Potential conflicts of interest. All authors: no reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The aim of the study was to explore the humoral and T-cell response in lung transplant (LuT) patients. Two-time points were considered, before (T0) and after (Tpost) the third dose of the BNT162b2 mRNA vaccine, comparing LuT with healthy donors (HD). LuT patients showed a lower serologic response against SARS-CoV-2 compared with HD at both time-points (p = 0.0001 and p = 0.0011, respectively). A lower percentage of IFNγ+orIL2+orTNFα+CD4+ and CD8+ T-cells LuT patients was observed in LuT patients compared with HD at T0 (CD4+: p = 0.0001; CD8+: p = 0.0005) and Tpost (CD4+: p = 0.0028; CD8+: p = 0.0114), as well as in the percentage of IFNγ+IL2+TNFα+CD4+ T-cells (T0: p = 0.0247; Tpost: p = 0.0367). Finally, at Tpost, a lower percentage of IFNγ+IL2+TNFα+ CD8+ T-cells in LuT patients compared with HD was found (p = 0.0147). LuT patients were stratified according to the lowest cut-off value for the detection of a humoral response (4.81 BAU/mL) at T0, into responder (R) and non-responder (NR) groups. In the R group, no differences in the percentage of IFNγ+or IL2+orTNFα+ and IFNγ+IL2+TNFα+CD4+ and CD8+ T-cells compared with HD at both time-points were observed. Otherwise, in the NR group, lower percentages of IFNγ+IL2+TNFα+CD4+ T-cells compared with the R group (T0: p = 0.0159; Tpost: p = 0.0159), as well as compared with the HD, at both time-points, were observed (T0: p = 0.0064; Tpost: p = 0.0064). These data seem to confirm that some LuT patients can mount cellular responses even in the absence of a positive humoral response (>33.8 BAU/mL), although this cellular response is dysfunctional and partially detrimental.

Background: CD163, a haptoglobin-hemoglobin scavenger receptor mostly expressed by monocytes and macrophages, is involved in the regulation of inflammatory processes. Following proteolytic cleavage after pro-inflammatory stimulation, CD163 is shed from the cell surface and its soluble form in plasma, sCD163, is a biomarker of monocyte/macrophage lineage activation.The assessment of sCD163 plasmatic levels in an early stage of the disease could have clinical utility in predicting the severity of COVID-19 pneumonia. The use of tocilizumab (monoclonal antibody anti-IL-6 receptor) in COVID-19 patients reduces lethality rate at 30 days. The aim of the study was to investigate the effect of tocilizumab on sCD163 plasmatic levels in a cohort of COVID-19 patients., Methods: In COVID-19 patients, on hospital admission (T0), after 7 days from hospitalization (T7) and after 45 days from discharge (T45) sCD163 plasmatic levels were evaluated, along with other laboratory parameters. COVID-19 patients were stratified into tocilizumab (TCZ) and non-tocilizumab (non-TCZ) groups. TCZ group was further divided into responder (R) and non-responder (NR) groups. Patients who died or required mechanical ventilation were defined as NR. As control group, healthy donors (HD) were enrolled., Results: Seventy COVID-19 patients and 47 HD were enrolled. At T0, sCD163 plasmatic levels were higher in COVID-19 patients compared to HD (p<0.0001) and the longitudinal evaluation showed a reduction in sCD163 plasmatic levels at T7 compared to T0 (p=0.0211). At T0, both TCZ and non-TCZ groups showed higher sCD163 plasmatic levels compared to HD (p<0.0001 and p=0.0147, respectively). At T7, the longitudinal evaluation showed a significant reduction in sCD163 plasmatic levels (p=0.0030) only in the TCZ group, reaching levels comparable to those of HD. Conversely, not statistically significance in non-TCZ group was observed and, at T7, a statistically significance was found comparing non-TCZ group to HD (p=0.0019). At T0, R and NR groups showed not statistically significance in sCD163 plasmatic levels and both groups showed higher levels compared to HD (p=0.0001 and p=0.0340, respectively). The longitudinal evaluation showed significant reductions in both groups (R: p=0.0356; NR: p=0.0273) independently of the outcome. After 45 days of follow-up sCD163 plasmatic levels remain stable., Conclusion: sCD163 plasmatic levels are increased in COVID-19 pneumonia and is efficiently down-regulated by tocilizumab treatment regardless of the clinical outcome., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Marocco, Carraro, Zingaropoli, Nijhawan, Tortellini, Guardiani, Mengoni, Zuccalà, Belvisi, Kertusha, Parente, Del Borgo, Vullo, Ciardi, Mastroianni and Lichtner.)

Objective: To evaluate the effectiveness of Tocilizumab (with or without corticosteroids) in a real-life context among moderate-to-severe COVID-19 patients hospitalized at the Infectious Diseases ward of two hospitals in Lazio region, Italy, during the first wave of SARS-CoV-2 pandemic., Method: We conducted a retrospective cohort study among moderate-to-severe COVID-19 pneumonia to assess the influence of tocilizumab (with or without corticosteroids) on: 1) primary composite outcome: risk for death/invasive mechanical ventilation/ICU-transfer at 14 days from hospital admission; 2) secondary outcome: COVID-related death only. Both outcomes were also assessed at 28 days and restricted to baseline more severe cases. We also evaluated the safety of tocilizumab., Results: Overall, 412 patients were recruited, being affected by mild (6.8%), moderate (66.3%) or severe (26.9%) COVID-19 at baseline. The median participant' age was 63 years, 56.5% were men, the sum of comorbidities was 1.34 (±1.44), and the median time from symptom onset to hospital admission was 7 [3-10] days. Patients were subdivided in 4 treatment groups: standard of care (SoC) only (n = 172), SoC plus corticosteroid (n = 65), SoC plus tocilizumab (n = 50), SoC plus tocilizumab and corticosteroid (n = 125). Twenty-six (6.3%) patients underwent intubation, and 37 (9%) COVID-related deaths were recorded. After adjusting for several factors, multivariate analysis showed that tocilizumab (with or without corticosteroids) was associated to improved primary and secondary outcomes at 14 days, and at 28-days only when tocilizumab administered without corticosteroid. Among more severe cases the protective effect of tocilizumab (± corticosteroids) was observed at both time-points. No safety concerns were recorded., Conclusion: Although contrasting results from randomized clinical trials to date, in our experience tocilizumab was a safe and efficacious therapeutic option for patients with moderate-to-severe COVID-19 pneumonia. Its efficacy was improved by the concomitant administration of corticosteroids in patients affected by severe-COVID-19 pneumonia at baseline., Competing Interests: No competing interests to declare.

Background: Emerging evidence argues that monocytes, circulating innate immune cells, are principal players in COVID-19 pneumonia. The study aimed to investigate the role of soluble (s)CD163 and sCD14 plasmatic levels in predicting disease severity and characterize peripheral blood monocytes and dendritic cells (DCs), in patients with COVID-19 pneumonia (COVID-19 subjects)., Methods: On admission, in COVID-19 subjects sCD163 and sCD14 plasmatic levels, and peripheral blood monocyte and DC subsets were compared to healthy donors (HDs). According to clinical outcome, COVID-19 subjects were divided into ARDS and non-ARDS groups., Results: Compared to HDs, COVID-19 subjects showed higher sCD163 (p<0.0001) and sCD14 (p<0.0001) plasmatic levels. We observed higher sCD163 plasmatic levels in the ARDS group compared to the non-ARDS one (p=0.002). The cut-off for sCD163 plasmatic level greater than 2032 ng/ml was predictive of disease severity (AUC: 0.6786, p=0.0022; sensitivity 56.7% [CI: 44.1-68.4] specificity 73.8% [CI: 58.9-84.7]). Positive correlation between plasmatic levels of sCD163, LDH and IL-6 and between plasmatic levels of sCD14, D-dimer and ferritin were found. Compared to HDs, COVID-19 subjects showed lower percentages of non-classical (p=0.0012) and intermediate monocytes (p=0.0447), slanDCs (p<0.0001), myeloid DCs (mDCs, p<0.0001), and plasmacytoid DCs (pDCs, p=0.0014). Compared to the non-ARDS group, the ARDS group showed lower percentages of non-classical monocytes (p=0.0006), mDCs (p=0.0346), and pDCs (p=0.0492)., Conclusions: The increase in sCD163 and sCD14 plasmatic levels, observed on hospital admission in COVID-19 subjects, especially in those who developed ARDS, and the correlations of these monocyte/macrophage activation markers with typical inflammatory markers of COVID-19 pneumonia, underline their potential use to assess the risk of progression of the disease. In an early stage of the disease, the assessment of sCD163 plasmatic levels could have clinical utility in predicting the severity of COVID-19 pneumonia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zingaropoli, Nijhawan, Carraro, Pasculli, Zuccalà, Perri, Marocco, Kertusha, Siccardi, Del Borgo, Curtolo, Ajassa, Iannetta, Ciardi, Mastroianni and Lichtner.)

Background and Aims: Measles is an infectious disease that represents a serious public health problem worldwide, being associated with increased susceptibility to secondary infections, especially in the respiratory and gastrointestinal tracts. The aim of this study was to evaluate sCD163 and sCD14 levels in measles virus (MV) infected patients, as markers of immune activation, in order to better understand their role in the pathogenesis of the disease. TNF-α plasma levels were also evaluated., Methods: sCD163, sCD14 and TNF-α were measured by ELISA in plasma samples of 27 MV infected patients and 27 healthy donors (HD) included as controls., Results: At the time of hospital admission, sCD163 and sCD14 levels were significantly higher in MV infected patients than in HD, while a decrease in TNF-α levels were found even if without statistical significance. sCD163 and sCD14 levels were significantly decreased after two months from acute infection compared to hospital admission although they remained significantly higher compared to HD. TNF-α levels increased significantly during the follow-up period. Considering clinical parameters, sCD163 levels positively correlated with aspartate aminotransferase, white blood cell count and neutrophils rate, while negatively correlated with the lymphocyte percentage. sCD14 levels positively correlated with the neutrophil and lymphocyte percentages., Conclusions: These results indicate that, despite the resolution of symptoms, an important macrophage/monocyte activation persists in measles patients, even after two months from infection., Competing Interests: The authors have declared that no competing interests exist.

Here, we report a patient who developed diplopia secondary to a right cranial nerve III and IV palsy, as well as fever and headache. Cerebrospinal fluid analysis (CSF) showed high varicella-zoster virus (VZV)-DNA viral load (>300,000,000 copies/ml). VZV antibodies in CSF was ≥1:16. Diagnosis of neurological reactivation of VZV infection was made without the presence of characteristic vesicular rash. Quantitative real-time PCR for VZV and intrathecal dosage of VZV IgM and IgG should be performed in cases suspected for viral encephalitis and also in all patients with not otherwise attributable cranial nerve lesions.

Background: Pyomyoma is a life-threatening complication of uterine leiomyoma. It may occur in post- menopausal women, during pregnancy and in the postpartum period. Fever may be the only manifestation during the early stages of the disease. We detail the first reported case of postpartum pyomyoma-related sepsis due to Sphingomonas paucimobilis, a Gram-negative bacillus that is gaining recognition as an important human pathogen., Case Presentation: A woman presented with an asymptomatic uterine fibroid and a two-week history of fever during the postpartum period. Suppurative uterine leiomyoma was diagnosed, and blood cultures grew Sphingomonas paucimobilis. The myoma was surgically removed from the uterus without hysterectomy. Intravenous antimicrobial therapy was given for fifteen days, and the patient was discharged from hospital in good condition., Conclusion: Pyomyoma should be considered in broad differential diagnosis of postpartum fever. This case highlights a unique disease manifestation of S. paucimobilis, an emerging opportunistic pathogen with increasing significance in the nosocomial setting.

Hepatitis B virus (HBV) reactivation represents an emerging cause of liver disease in patients undergoing treatment with biologic agents. In particular, the risk of HBV reactivation is heightened by the use monoclonal antibodies, such as rituximab (anti-CD20) and alemtuzumab (anti-CD52) that cause profound and long-lasting immunosuppression. Emerging data indicate that HBV reactivation could also develop following the use of other biologic agents, such as tumor necrosis factor (TNF)-α inhibitors. When HBV reactivation is diagnosed, it is mandatory to suspend biologic treatment and start antiviral agents immediately. However, pre-emptive antiviral therapy prior to monoclonal antibody administration is crucial in preventing HBV reactivation and its clinical consequences. Several lines of evidence have shown that risk of HBV reactivation is greatly reduced by the identification of high-risk patients and the use of prophylactic antiviral therapy. In this article, we discuss current trends in the management of HBV reactivation in immunosuppressed patients receiving biologic therapy, such as rituximab, alemtuzumab and TNF-α antagonists.

Background: Dysregulation of host immune responses plays a critical role in the pathogenesis of severe 2009 pandemic H1N1 infection. Whether H1N1 virus could escape innate immune defense in vivo remains to be investigated. The aim of this study was to evaluate the pattern of innate immune response during human 2009 H1N1 infection. We performed the enumeration of circulating myeloid dendritic cells (mDC) and plasmacytoid DC (pDC) in blood from patients with H1N1 pneumonia shortly after the onset of symptoms and during follow-up at different intervals of time. The analysis of CD4 and CD8 count, CD38 T-cell activation marker and serum cytokine/chemokine plasma levels was also done., Methodology/principal Findings: Blood samples were collected from 13 hospitalized patients with confirmed H1N1-related pneumonia at time of admission and at weeks 1, 4, and 16 of follow-up. 13 healthy donors were enrolled as controls. In the acute phase of the disease, H1N1-infected patients exhibited a significant depletion in both circulating pDC and mDC in conjunction with a decrease of CD4 and CD8 T cell count. In addition, we found plasmatic hyperproduction of IP-10 and RANTES, whereas increase in T-cell immune activation was found at all time points. When we assessed the changes in DC count over time, we observed a progressive normalization of mDC number. On the contrary, H1N1-infected patients did not achieve a complete recovery of pDC count as values remained lower than healthy controls even after 16 weeks of follow-up., Conclusions: H1N1 disease is associated with a profound depletion of DC subsets. The persistence of pDC deficit for several weeks after disease recovery could be due to H1N1 virus itself or to a preexisting impairment of innate immunity.

Here, we report a case of a febrile patient with primary bilateral adrenalitis who was successfully treated with an antituberculous regimen. Primary isolated tubercular adrenalitis is a very rare clinical entity but it should be considered in cases of fever and enlargement of the adrenal glands. Integration of radiological pattern data with epidemiological, clinical and immunological data has high accuracy and specificity, even without histological examination.

A case of an immunocompetent man with acute CMV infection associated with a pulmonary embolism is described. Acute CMV infection could be a risk factor for developing thromboembolism. Pulmonary embolism should be included in differential diagnosis in patients with acute CMV infections and pulmonary opacities.

Background: In recent years, the impact of antituberculous treatment on interferon (IFN)-gamma response to Mycobacterium tuberculosis antigens has been widely investigated, but the results have been controversial. The objective of the present study was: i) to evaluate longitudinal changes of IFN-gamma response to M. tuberculosis-specific antigens in TB patients during antituberculous treatment by using the QuantiFERON-TB Gold (QFT-G) assay; ii) to compare the differences in T-cell response after a short or prolonged period of stimulation with mycobacterial antigens; iii) to assess the CD4+ and CD8+ T cells with effector/memory and central/memory phenotype; iv) to investigate the direct in vitro effects of antituberculous drugs on the secretion of IFN-gamma., Principal Findings: 38 TB patients was evaluated at baseline and at month 2 and 4 of treatment and at month 6 (treatment completion). 27 (71%) patients had a QFT-G reversion (positive to negative) at the end of therapy, while 11 (29%) TB patients remained QFT-G positive at the end of therapy. Among the 11 patients with persistent positive QFT-G results, six had a complete response to the treatment, while the remaining 5 patients did not have a resolution of the disease. All 27 patients who became QFT-G negative had a complete clinical and microbiological recovery of the TB disease. In these patients the release of IFN-gamma is absent even after a prolonged 6-day incubation with both ESAT-6 and CFP-10 antigens and the percentage of effector/memory T-cells phenotype was markedly lower than subjects with persistent positive QFT-G results. The in vitro study showed that antituberculous drugs did not exert any inhibitory effect on IFN-gamma production within the range of therapeutically achievable concentrations., Conclusions: The present study suggests that the decrease in the M. tuberculosis-specific T cells responses following successful anti-TB therapy may have a clinical value as a supplemental tool for the monitoring of the efficacy of pharmacologic intervention for active TB. In addition, the antituberculous drugs do not have any direct down-regulatory effect on the specific IFN-gamma response.

Objective: To design a Health-related Quality of Life (HRQoL) instrument for HIV-infected people in the era of highly active antiretroviral therapy (HAART)., Methods: The self-administered questionnaire was developed by an Italian network including researchers, physicians, people living with HIV, national institutions and community-based organizations (CBO) through several steps: (1) review of existing HRQoL literature and questionnaires for HIV-infected people; (2) selection of relevant domains measuring HRQoL in HIV-infected people, and identification of new domains related to new aspects of HRQoL concerning HAART-treated individuals; (3) conduction of two pre-test analyses in independent groups of Italian HIV-positive people (n approximately =100) distributed throughout the country. The objectives of the first pre-test were to verify the usefulness of the questionnaire, to construct a form easily understandable by everyone, to define the domains and their significance; the second pre-test aimed at evaluating and reshaping the questionnaire based on a statistical analysis of the outcomes of first pre-test; (4) validation analysis. A large cohort of people with HIV infection was recruited for the last step., Results: The internal consistence reliability (Cronbach's alpha) was >or=0.70 for all domains. Most domains had Cronbach's coefficient >0.80. All domains demonstrated convergent and discriminant validity. The final version of ISSQoL includes two sections: HRQoL Core Evaluation Form (9 domains) and Additional Important Areas for HRQoL (6 domains). The ISSQoL was administered together with two additional forms: a Daily Impact of Symptoms Form and a Demographic Information Form. The Additional Important Areas for HRQoL include social support, interaction with medical staff, treatment impact, body changes, life planning, and motherhood/fatherhood., Conclusion: The data reported in the present paper provide preliminary evidence of the reliability and validity of the ISSQoL questionnaire for the measurement of HRQoL in HIV-infected people. The direct involvement of HIV-positive people in all the phases of the project was a key aspect of our work.

Two cases of community-acquired septicemia caused by serotype-O1 Yersinia pseudotuberculosis were diagnosed in middle-aged, HIV-positive, immunodeficient patients during an 8-month period. Bacterial isolates were genetically indistinguishable, but no epidemiologic link between the 2 patients was established. HIV-related immunosuppression should be regarded as a risk factor for Y. pseudotuberculosis septicemia.

Objective: To assess rates of prescriptions of protease inhibitors (PI) and determinants of not being prescribed PIs in a cohort of HIV-infected people eligible (according to published guidelines) for highly active antiretroviral therapy (HAART)., Design: Cross-sectional survey., Methods: A total of 684 patients with CD4+ counts <500 cells/microl were enrolled from seven Italian HIV treatment centers from October 1997 to April 1998. A questionnaire on health-related quality of life (MOS-HIV) and patient ratings of the quality of care was administered. Sociodemographic variables, HIV disease-related factors, and prescribed antiretroviral therapy were also recorded., Results: 61% of those enrolled were prescribed PI (median, 7.5 months). In addition, 75% of patients had previously received antiretroviral therapy. Fewer than 1% were prescribed nonnucleoside reverse transcriptase inhibitors (NNRTIs). Using multivariable logistic regression considering those with CD4+ counts <500 cells/microl, patients reporting the least information received (odds ratio [OR], 1.78; 95% confidence interval [CI], 1.23-2.58), injecting drug users (IDUs; OR, 1.73; 95% CI, 1.18-2.54), people with CD4+ counts >200 cells/microl (OR, 1.76; 95% CI, 1.19-2.61), and patients with early stage disease (OR, 2.24; 95% CI, 1.73-2.90) were less likely to have be prescribed PIs., Conclusions: Of patients eligible for HAART, only 61% were prescribed PIs. People who wanted more information, IDUs, and patients in earlier disease stages are significantly less likely to be prescribed PIs. Access to HAART remains a critical issue in the management of HIV disease.

Objectives: To assess temporal trends of the different disorders causing focal brain lesions (FBL) in HIV-infected patients and to examine the reliability of the U.S. Centers for Disease Control and Prevention (CDC) criteria for presumptive diagnosis of toxoplasmic encephalitis (TE) for the years 1991 to 1996., Design/methods: A prospective, monocenter study. Percentages of occurrence of the different FBL-causing disorders for each year were calculated. Temporal trends were analyzed by chi2 test for linear trend and multivariate polytomous nonordinal logistic regression. The positive predictive value (PPV) of the CDC's presumptive criteria for the diagnosis of TE (recent onset of a focal neurologic abnormality consistent in intracranial disease or a reduced level of consciousness, evidence on brain imaging of a lesion having mass effect or the radiographic appearance of which is enhanced by injection of contrast medium, and serum antibody to toxoplasmosis) was calculated using contingency tables for each calendar year., Results: A highly significant decline of the risk of TE and an increase of the probability of patients to take anti-Toxoplasma prophylaxis were observed. A threefold but statistically not significant augmented risk of diagnosing both primary central nervous system lymphoma (PCNSL) and progressive multifocal leucoencephalopathy (PML) has been registered for 1996 compared with 1991. Among FBL showing contrast enhancement, the increased finding of PCNSL over the years studied was significant. The probability of other FBL-causing disorders, such as focal viral encephalitis sustained by cytomegalovirus or herpes simplex virus, increased significantly over the years studied. Multivariate analysis confirmed that the year of diagnosis of FBL had a significant effect on the risk reduction of TE. The PPV of the CDC's criteria for the presumptive diagnosis of TE dropped from 100% for the year 1991 to 39% in the year 1996. A similar result was obtained in calculating the PPV of presumptive criteria only among patients without previous primary prophylaxis., Conclusions: Because of the significant decrease of TE and the increase of PCNSL empiric anti-Toxoplasma therapy no longer seems appropriate as a first-line approach to all HIV-positive patients with FBL. Especially in the case of a finding of FBL by contrast enhancement, new diagnostic strategies should be employed to identify the underlying disorder rapidly and accurately.