Casirivimab/imdevimab + remdesivir in hospitalized patients with severe Covid-19: A single centre experience.

Since 2020, COVID-19 pandemic has spread worldwide causing a huge number of cases and casualties. Among direct anti SARS-CoV-2 agents available for the treatment of COVID-19, only remdesivir and casirivimab/imdevimab have been approved for severe disease. As they act at different levels in blocking viral replication, it is theoretically possible to combine them. In this case series we describe tolerability, safety and effectiveness in a small group of 14 patients of the combination of casirivimab/imdevimab monoclonal antibodies with the polymerase inhibitor remdesivir for the treatment of severe COVID-19. We conducted a retrospective study among consecutive patients admitted to the Infectious Disease ward of the University of Naples (Italy) Hospital for COVID-19 that received the combination of casirivimab/imdevimab and remdesivir for the treatment of severe COVID-19 from the August 1, 2021 to the November 30, 2021. During the study period, 78 patients were admitted for severe COVID-19. Fourteen patients (18%) received the combination casirivimab/imdevimab and remdesivir. They were five males and nine females with a median age of 54 years. Eight patients had significant comorbidities; three patients were in the immediate post-partum period. No adverse drug reaction was observed. All patients except one improved clinical condition and respiratory parameters within seven days following the therapy. All patients were discharged in good conditions.

Casirivimab and Imdevimab for Pregnant Women Hospitalized for Severe Coronavirus Disease 2019 (COVID-19).

OBJECTIVE: To evaluate safety and efficacy of casirivimab/imdevimab therapy in pregnant women with severe COVID-19 requiring oxygen therapy. METHODS: This was a prospective case series study aimed to evaluate safety and efficacy of casirivimab/imdevimab therapy in unvaccinated pregnant women with severe COVID-19. Inclusion criteria were: SARS CoV-2 infection documented with PCR, pregnancy, severe COVID-19 requiring oxygen therapy, duration of symptoms of 10 days or less, able to provide informed consent. Vaccinated women, and those with mild-to-moderate disease were excluded from the study. Included patients received casirivimab and imdevimab as single intravenous dose of 4000/4000 mg. Women were also treated with low molecular weight heparin, steroids and antibiotics, if necessary. The primary outcome was maternal death. Secondary outcomes were: rate of adverse events during infusion or within 72 hours, and rate of abortion. RESULTS: Thirteen hospitalized unvaccinated pregnant women with severe COVID-19 requiring oxygen and treated with casirivimab/imdevimab were included in the study. We observed no maternal death, and no patients required intubation or admission to intensive care unit. No abortion or fetal loss were recorded. Nine pregnancies were still ongoing, and there were three cesarean deliveries and one vaginal delivery. Two were preterm deliveries (at 31 and 34 weeks), and two were term deliveries. CONCLUSION: Casirivimab/imdevimab therapy may be considered as therapy in unvaccinated pregnant women with severe COVID-19.

Remdesivir Alone or in Combination with Monoclonal Antibodies as an Early Treatment to Prevent Severe COVID-19 in Patients with Mild/Moderate Disease at High Risk of Progression: A Single Centre, Real-Life Study.

Early treatment with antivirals against SARS-CoV-2 infection can prevent the onset of severe COVID-19 in fragile and immunocompromised patients. In this real-life, prospective, observational study, we evaluated efficacy and safety of a 3-day early treatment with remdesivir in adult and fragile patients with a diagnosis of SARS-CoV-2 infection who referred to the COVID-19 early treatment service of Infectious Diseases Unit of University of Naples Federico from 10 January 2022 to 31 March 2022. The included patients could be treated with either remdesivir alone or with remdesivir plus a monoclonal antibody with activity against SARS-CoV-2. Among the 62 included patients, we showed low rates of hospitalization (8%), increase in oxygen supplementation (3.2%), ICU admission (1.6%) and death (1.6%). The rate of disease progression was 8% and it was similar in patients treated with remdesivir alone or in combination with monoclonal antibodies (6.7% and 9.4%, respectively; p = 0.531). The rate of adverse drug reaction was low and similar in the two groups (13.3% in patients treated with remdesivir, 15.6% in patients treated with the combination; p = 0.543). Most common adverse events were headache and fever. In conclusion, in our cohort of patients at a high risk of worse COVID-19 outcomes, an early course of remdesivir showed low rates of disease progression and adverse drug reactions.

Invasive Fungal Infections in Hospitalized Patients with COVID-19: A Non-Intensive Care Single-Centre Experience during the First Pandemic Waves.

Invasive fungal infections (IFIs) represent a severe complication of COVID-19, yet they are under-estimated. We conducted a retrospective analysis including all the COVID-19 patients admitted to the Infectious Diseases Unit of the Federico II University Hospital of Naples until the 1 July 2021. Among 409 patients, we reported seven cases of IFIs by Candida spp., seven of Pneumocystis jirovecii pneumonia, three of invasive pulmonary aspergillosis, and one of Trichosporon asahii. None of the cases presented underlying predisposing conditions, excluding one oncohematological patient treated with rituximab. Ten cases showed lymphopenia with high rates of CD4+ < 200/µL. All cases received high-dose steroid therapy (mean duration 33 days, mean cumulative dosage 1015 mg of prednisone equivalent), and seven cases had severe COVID-19 disease (OSCI ≥ 5) prior to IFI diagnosis. The cases showed a higher overall duration of hospitalization (63 vs 24 days) and higher mortality rate (23% vs. 7%) compared with the COVID-19 patients who did not developed IFIs. Cases showed a higher prevalence of high-dose steroid therapy and lymphopenia with CD4+ < 200/µL, primarily due to SARS-CoV-2 infection and not related to underlying comorbidities. IFIs strongly impact the overall length of hospitalization and mortality. Therefore, clinicians should maintain a high degree of suspicion of IFIs, especially in severe COVID-19 patients.

COVID-19 chest CT and laboratory features of B.1.617.2 (Delta variant) vs B.1.1.7 (Alpha variant) surge: a single center case-control study.

Purpose: To assess clinical, laboratory and radiological differences between Delta and Alpha SARS-CoV-2 variants. Materials and Methods: Twenty SARS-CoV-2 patients admitted from 30th of August to 30th of October 2021 (period with estimated highest prevalence of Delta variant circulation in Italy) were enrolled. Patients were matched in a 1:1 ratio with same gender and same age +/- 2 years controls admitted from 1st of September 2020 to 30th of January 2021 (predominant circulation of Alpha variant). Chest computed tomography (CT) were retrospectively evaluated. Main clinical parameters, radiological and laboratory findings were compared between two groups. Results: Patients with probable Delta variant had significantly higher CT severity scores, lower PaO2/FiO2 ratio and higher C-reactive protein and lactate dehydrogenase levels at admission. On multivariate analysis, probable Delta variant infection was associated with higher CT severity score. Ground glass opacities and crazy paving patterns were more frequently noticed than consolidation, with the latter being more frequent in Delta cohort, even though not significantly. According to prevalent imaging pattern, the consolidation one was significantly associated with pregnancy (p=0.008). Conclusions: Patients admitted during predominance of Delta variant circulation had a more severe lung involvement compared to patients in infected when Alpha variant was predominant. Despite imaging pattern seems to be not influenced by viral variant and other clinical variables, the consolidative pattern was observed more frequently in pregnancy.

A Simple Non-Invasive Score Based on Baseline Parameters Can Predict Outcome in Patients with COVID-19.

We evaluated the role of CRP and other laboratory parameters in predicting the worsening of clinical conditions during hospitalization, ICU admission, and fatal outcome among patients with COVID-19. Consecutive adult inpatients with SARS-CoV-2 infection and respiratory symptoms treated in three different COVID centres were enrolled, and they were tested for laboratory parameters within 48 h from admission. Three-hundred ninety patients were enrolled. Age, baseline CRP, and LDH were associated with a P/F ratio < 200 during hospitalization. Male gender and CRP > 60 mg/L were shown to be independently associated with ICU admission. Lymphocytes < 1000 cell/µL were associated with the worst P/F ratio. CRP > 60 mg/L predicted exitus. We subsequently devised an 11-points numeric ordinary scoring system based on age, sex, CRP, and LDH at admission (ASCL score). Patients with an ASCL score of 0 or 2 were shown to be protected against a P/F ratio < 200, while patients with an ASCL score of 6 to 8 were shown to be at risk for P/F ratio < 200. Patients with an ASCL score ≥ 7 had a significantly increased probability of death during hospitalization. In conclusion, patients with elevated CRP and LDH and an ASCL score > 6 at admission should be prioritized for careful respiratory function monitoring and early treatment to prevent a progression of the disease.

Monoclonal Antibodies against SARS-CoV-2 Infection: Results from a Real-Life Study before the Omicron Surge.

Despite the lightning-fast advances in the management of SARS-CoV after 2 years of pandemic, COVID-19 continues to pose a challenge for fragile patients, who could benefit from early administration of monoclonal antibodies (mAbs) to reduce the risk of severe disease progression. We conducted a prospective study to evaluate the effectiveness of mAbs against SARS-CoV-2 among patients at risk for severe disease progression, namely elderly and those with comorbidities, before the omicron variant surge. Patients were treated with either casirivimab/imdevimab, sotrovimab, or bamlanivimab/etesevimab. The rates and risk factors for clinical worsening, hospitalization, ICU admission and death (unfavorable outcomes) were evaluated. A stratified analysis according to the presence of SARS-CoV-2 IgG was also performed. Among 185 included patients, we showed low rates of unfavorable outcomes (9.2%), which were more frequent in patients with chronic kidney disease (aOR: 10.44, 95% CI: 1.73-63.03; p < 0.05) and basal D-dimer serum concentrations > 600 ng/mL (aOR 21.74, 95% CI: 1.18-397.70; p < 0.05). Patients with negative SARS-CoV-2 serology at baseline showed higher C-reactive protein values compared with patients with positive serology (p < 0.05) and a trend toward a higher admission rate to SICU and ICU compared with patients with positive serology. Our results thus showed, in a real-life setting, the efficacy of mAbs against SARS-CoV-2 before an Omicron surge when the available mabs become not effective.

Nirmatrelvir/Ritonavir and Molnupiravir in the Treatment of Mild/Moderate COVID-19: Results of a Real-Life Study.

Molnupiravir and nirmatrelvir were the first available oral antivirals (OAs) active against SARS-CoV-2. Trials evaluating the efficacy of OAs involved patients unvaccinated and infected with variants different from those currently circulating. We conducted a retrospective study on patients with confirmed SARS-CoV-2 infection treated with OAs during the omicron surge in Italy in order to provide real-life data on the efficacy and safety of OAs during the omicron surge of the COVID-19 pandemic. Among 257 patients, 56.8% received molnupiravir, while 43.2% received nirmatrelvir/ritonavir. Patients in the molnupiravir group were older, had a lower body mass index, and had a higher rate of chronic heart disease than those treated with nirmatrelvir/ritonavir. Three hospitalizations were recorded in the molnupiravir (2.1%) group and one in the nirmatrelvir/ritonavir (0.9%) group. One patient treated with molnupiravir died. The median time to negativity was 8 days in the nirmatrelvir/ritonavir group vs. 10 days in the molnupiravir group, p < 0.01. We recorded 37 ADRs (mainly dysgeusia, diarrhea, and nausea) in 31 individuals (12.1%). Only two patients (0.8%) treated with molnupiravir terminated treatment due to ADRs. In conclusion, in a population of mostly vaccinated patients treated with OAs, we observed a low rate of hospitalization, death, and adverse drug reactions. These rates were lower than those reported in pivotal trials.

COVID-19 Post-Exposure Evaluation (COPE) Study: Assessing the Role of Socio-Economic Factors in Household SARS-CoV-2 Transmission within Campania Region (Southern Italy).

Campania is the sixth poorest region of Italy, and it is the region with the highest income inequality. The secondary attack rates of SARS-CoV-2 among households are found to be substantially heterogeneous among published studies and are influenced by socio-economic factors. We conducted a retrospective study to describe the role of socio-economic factors in the household transmission of SARS-CoV-2 among patients living in Campania Region and referring to "Federico II" Hospital. We interviewed 413 subjects followed-up for COVID-19 between the 8 March 2020 and the 24 May 2021 with the aim to collect demographic, clinical, economic, and social data regarding their household and the index cases. The variables associated with SARS-CoV-2 attack rate higher than 50% among households were higher age (p = 0.023) and higher Charlson Comorbidity Index of the index case (p = 0.023) and, for household characteristics, higher number of families per house (p = 0.02), location of the houses in Naples' suburbs (Chi2 = 5.3, p = 0.02) and in Caserta City area (Chi2 = 4, p = 0.04), and renting the house compared to owning it (Chi2 = 5.83, p = 0.01). This study confirms the finding described by other authors that household transmission of SARS-CoV-2 is correlated with the income inequality of the analyzed geographical area as well as with the indicators of health and economic wealth of the families, and this correlation also applies to the Campania Region.

Lymphocyte Population Changes at Two Time Points during the Acute Period of COVID-19 Infection.

We previously observed an increase of serum interleukins (IL) and a reduction of most lymphocyte subpopulations in hospitalized COVID-19 patients. Herein, we aimed to evaluate the changes in serum IL-6, IL-10, and IL-17A levels and cytometric lymphocyte profiles in 144 COVID-19 patients at admission and after one week, also in relation to steroid treatment before hospitalization. After one week of hospitalization, we found that: (i) total lymphocytes were increased in all patients; (ii) neutrophils and IL-6 were reduced in mild/moderate patients; (iii) B lymphocytes were increased in severe patients; (iv) T lymphocyte populations increased in mild/moderate patients. In the eight patients that died during hospitalization, total leukocytes increased while T, T helper, T cytotoxic, T regulatory, and NK lymphocytes showed a reducing trend in five of the eight patients. Even if seven days are too few to evaluate the adaptive immunity of patients, we found that the steroid therapy was associated with a reduced COVID-19 inflammation and cytokine activation only in patients with severe disease, while in patients with less severe disease, the steroid therapy seems to have immunosuppressive effects on lymphocyte populations, and this could hamper the antiviral response. A better knowledge of cytokine and lymphocyte alterations in each COVID-19 patient could be useful to plan better treatment with steroids or cytokine targeting.

SARS-CoV-2 in Kidney Transplant Patients: A Real-Life Experience.

Background: The COVID-19 pandemic has significantly impacted the management of solid organ transplant recipients and on clinical evolution in post-transplantation. Little is known on the impact of SARS-CoV-2 infection in these patients. The severity and lethality of this disease in solid organ transplant patients are higher thanin the general population. This study aims to describe clinical characteristics of SARS-CoV-2 infection in solid organ transplant recipients followed in our center. Methods: In this observational study, we enrolled all kidney transplant recipientsattending the A.O.U. Federico II of Naples from March 2020 to January 2021. For each patient we evaluated the epidemiological and clinical characteristics as well as outcome. Results: We enrolled 369 kidney transplant patients (229, male, 62%). Of these, 51 (13.8%) acquired SARS-CoV-2 infection and 29 showed symptomatic disease. Of the 51 patients with the infection, 48 (94.11%) had at least one comorbidity and such comorbidities did not constitute a risk factor for a more severe disease. Hospitalization was necessary for 7 (13.7%) patients. Of these, 2 required low-flow oxygen supplementation, 3 non-invasive/high flow ventilation and 2 invasive ventilation. Finally, 2 patients died. Conclusions: Our study shows a lower mortality and hospitalization rate compared to figures available in the literature (4% vs. 13-30% and 14% vs. 32-100%, respectively). Furthermore, the comorbidities examined (hypertension, dyslipidemia, and diabetes) did not constitute a risk factor for a more severe disease condition in this patient category. Further studies with larger sample size are necessary to confirm these data.

Monoclonal antibodies for mild-to-moderate COVID-19 in multiple sclerosis: A case series.

We reported on five people with MS, using immunodepleting disease modifying treatments (anti-CD20 monoclonal antibodies and sphingosine-one-phosphate modulators) and with reduced COVID-19 vaccine response, who had mild-to-moderate symptomatic COVID-19, and were treated with anti-SARS-CoV-2 monoclonal antibodies. In particular, we showed the possibility to use monoclonal antibodies to speed-up recovery from COVID-19 in MS, in the absence of any COVID-19 residuals or MS changes (e.g., relapses or disability).

Pneumocystis jirovecii Pneumonia in Non-HIV Patients Recovering from COVID-19: A Single-Center Experience.

OBJECTIVE: to describe a single-center experience of Pneumocystis jirovecii pneumonia (PJP) in non-HIV patients recovering from COVID-19. METHODS: We report the cases of five non-HIV patients with COVID-19 who also developed PJP at a University Hospital. RESULTS: With the exception of one subject, who experienced an atypical and prolonged course of COVID-19, all the patients developed PJP after the clinical resolution of COVID-19 pneumonia. All but one patient had no pre-existing immunosuppressive conditions or other risk factors for PJP development at COVID-19 diagnosis. Nonetheless, following the course of COVID-19 infection, all the patients fulfilled at least one host factor for PJP; indeed, all the patients had received at least 2 weeks of high-dose steroids and three out of five had a CD4+ cell count <200/mm3. CONCLUSIONS: The use of corticosteroids for COVID-19 respiratory impairment seems to be the most common risk factor for PJP, together with viral-induced and iatrogenic lymphopenia. The worsening in respiratory function and the characteristic radiological picture during or after COVID-19 pneumonia should raise the suspicion of PJP, even in immunocompetent patients. PJP primary chemoprophylaxis can be considered in selected high-risk COVID-19 patients, but further studies are needed.

Cytometric analysis of patients with COVID-19: what is changed in the second wave?

BACKGROUND: Coronavirus disease 2019 (COVID-19) pandemic had a 1st wave in Europe from March to May 2020 and a 2nd wave since September 2020. We previously studied 35 hospitalized COVID-19 patients of the 1st wave demonstrating a cytokine storm and the exhaustion of most lymphocyte subpopulations. Herein, we describe the results obtained from COVID-19 patients of the 2nd wave. METHODS: We analyzed interleukin (IL)-6 by human-specific enzyme-linked immunosorbent assay and a large set of lymphocyte subpopulations by flow cytometry in 274 COVID-19 patients hospitalized from September 2020 to May 2021. RESULTS: Patients of 2nd wave compared with those of 1st wave showed lower serum IL-6 levels and a higher number of B and most T lymphocyte subpopulations in advanced stages, in relation with the age and the gender. On the other hand, we observed in 2nd wave patients: (i) a reduction of most lymphocyte subpopulations at mild and moderate stages; (ii) a reduction of natural killer cells and T regulatory cells together with a higher number of activated T helper (TH) 17 lymphocytes in all stages, which were mainly related to steroid and azithromycin therapies before hospitalization. CONCLUSIONS: COVID-19 had a less severe impact in patients of the 2nd wave in advanced stages, while the impact appeared more severe in patients of mild and moderate stages, as compared with 1st wave patients. This finding suggests that in COVID-19 patients with milder expression at diagnosis, steroid and azithromycin therapies appear to worsen the immune response against the virus. Furthermore, the cytometric profile may help to drive targeted therapies by monoclonal antibodies to modulate specific IL/lymphocyte inhibition or activation in COVID-19 patients.

Nasopharyngeal Microbiome Signature in COVID-19 Positive Patients: Can We Definitively Get a Role to Fusobacterium periodonticum?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the pandemic Coronavirus Disease 2019 (COVID-19). This virus is highly transmissible among individuals through both droplets and aerosol leading to determine severe pneumonia. Among the various factors that can influence both the onset of disease and the severity of its complications, the microbiome composition has also been investigated. Recent evidence showed the possible relationship between gut, lung, nasopharyngeal, or oral microbiome and COVID-19, but very little is known about it. Therefore, we aimed to verify the relationships between nasopharyngeal microbiome and the development of either COVID-19 or the severity of symptoms. To this purpose, we analyzed, by next generation sequencing, the hypervariable V1-V2-V3 regions of the bacterial 16S rRNA in nasopharyngeal swabs from SARS-CoV-2 infected patients (n=18) and control (CO) individuals (n=12) using Microbiota solution A (Arrow Diagnostics). We found a significant lower abundance of Proteobacteria and Fusobacteria in COVID-19 patients in respect to CO (p=0.003 and p<0.0001, respectively) from the phylum up to the genus (p<0.001). The Fusobacterium periodonticum (FP) resulted as the most significantly reduced species in COVID-19 patients respect to CO. FP is reported as being able to perform the surface sialylation. Noteworthy, some sialic acids residues on the cell surface could work as additional S protein of SARS-CoV-2 receptors. Consequently, SARS-CoV-2 could use sialic acids as receptors to bind to the epithelium of the respiratory tract, promoting its clustering and the disease development. We can therefore speculate that the significant reduction of FP in COVID-19 patients could be directly or indirectly linked to the modulation of sialic acid metabolism. Finally, viral or environmental factors capable of interfering with sialic metabolism could determine a fall in the individual protection from SARS-CoV-2. Further studies are necessary to clarify the precise role of FP in COVID-19.

Pneumocystis jirovecii pneumonia in an immunocompetent patient recovered from COVID-19.

BACKGROUND: Several cases of invasive fungal diseases in patients with COVID-19 have been reported, mostly due to Aspergillus spp., with anecdotic reports of Pneumocystis jirovecii pneumonia (PJP) as co-infections in immunocompromised patients. We describe the first case of PJP in an immunocompetent patient who recovered from COVID-19 pneumonia. CASE DESCRIPTION: Our patient was hospitalized for 18 d for respiratory failure due to Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) pneumonia and successfully treated with continuous positive airway pressure (CPAP) respiratory support, enoxaparin, ceftaroline and intravenous 6 mg of dexamethasone for 10 d, then with oral prednisone tapering. Despite his improved radiological and clinical conditions at discharge, he was admitted again after 18 d for worsening of respiratory conditions. Upon the second admission, a high-resolution CT-scan of the chest showed the development of new ground-glass opacities and P. jirovecii was detected on bronchoalveolar lavage fluid. A therapy with trimethoprim-sulphamethoxazole 20 mg/kg and methylprednisolone 40 mg i.v. bis in die (BID) was started, with improvement of clinical, biochemical and radiological conditions. CONCLUSIONS: COVID-19 patients may have multiple risk factors for development of PJP, in particular lymphopaenia and use of steroids. PJP must be ruled out with direct microbiological methods in patients presenting with radiologic and clinical features of possible or probable PJP, even in immunocompetent hosts.

Chest CT in COVID-19 patients: Structured vs conventional reporting.

PURPOSE: To assess clinician satisfaction with structured (SR) and conventional (CR) radiological reports for chest CT exams in coronavirus disease 2019 (COVID-19) patients, objectively comparing both reporting strategies. METHOD: We retrospectively included 68 CTs (61 patients) with COVID-19. CRs were collected from the digital database while corresponding SRs were written by an expert radiologist, including a sign checklist, severity score index and final impressions. New CRs were prepared for a random subset (n = 10) of cases, to allow comparisons in reporting time and word count. CRs were analyzed to record severity score and final impressions inclusion. A random subset of 40 paired CRs and SRs was evaluated by two clinicians to assess, using a Likert scale, readability, comprehensiveness, comprehensibility, conciseness, clinical impact, and overall quality. RESULTS: Overall, 19/68 (28 %) and 9/68 (13 %) of CRs included final impressions and severity score, respectively. SR writing required significantly (p < 0.001) less time (mean = 308 s; SD ± 60 s) compared to CRs (mean = 458 s; SD ± 72 s). On the other hand, word count was not significantly different (p = 0.059, median = 100 and 106, range = 106-139 and 88-131 for SRs and CRs, respectively). Both clinicians expressed significantly (all p < 0.01) higher scores for SRs compared to CRs in all categories. CONCLUSIONS: Our study supports the use of chest CT SRs in COVID-19 patients to improve referring physician satisfaction, optimizing reporting time and provide a greater amount and quality of information within the report.