Synergistic Activity of Remdesivir-Nirmatrelvir Combination on a SARS-CoV-2 In Vitro Model and a Case Report.

BACKGROUND: This study aims to investigate the activity of the remdesivir-nirmatrelvir combination against Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and to report a case of Coronavirus Disease 2019 (COVID-19) cured with this combination. METHODS: A Vero E6 cell-based infection assay was used to investigate the in vitro activity of the remdesivir-nirmatrelvir combination. The SARS-CoV-2 strains tested were 20A.EU1, BA.1 and BA.5. After incubation, a viability assay was performed. The supernatants were collected and used for viral titration. The Highest Single Agent (HSA) reference model was calculated. An HSA score >10 is considered synergic. RESULTS: Remdesivir and nirmatrelvir showed synergistic activity at 48 and 72 h, with an HSA score of 52.8 and 28.6, respectively (p < 0.0001). These data were confirmed by performing supernatant titration and against the omicron variants: the combination reduced the viral titer better than the more active compound alone. An immunocompromised patient with prolonged and critical COVID-19 was successfully treated with remdesivir, nirmatrelvir/ritonavir, tixagevimab/cilgavimab and dexamethasone, with an excellent clinical-radiological response. However, she required further off-label prolonged therapy with nirmatrelvir/ritonavir until she tested negative. CONCLUSIONS: Remdesivir-nirmatrelvir combination has synergic activity in vitro. This combination may have a role in immunosuppressed patients with severe COVID-19 and prolonged viral shedding.

When Does the Cytokine Storm Begin in COVID-19 Patients? A Quick Score to Recognize It.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that is responsible for coronavirus disease 2019 (COVID-19), which has rapidly spread across the world, becoming a pandemic. The "cytokine storm" (CS) in COVID-19 leads to the worst stage of illness, and its timely control through immunomodulators, corticosteroids, and cytokine antagonists may be the key to reducing mortality. After reviewing published studies, we proposed a Cytokine Storm Score (CSs) to identify patients who were in this hyperinflammation state, and at risk of progression and poorer outcomes. We retrospectively analyzed 31 patients admitted to Infectious Disease Department in "St. Maria" Hospital in Terni with confirmed SARS-CoV-2 infections, and analyzed the "CS score" (CSs) and the severity of COVID-19. Then we conducted a prospective study of COVID-19 patients admitted after the definition of the CSscore. This is the first study that proposes and applies a new score to quickly identify COVID-19 patients who are in a hyperinflammation stage, to rapidly treat them in order to reduce the risk of intubation. CSs can accurately identify COVID-19 patients in the early stages of a CS, to conduct timely, safe, and effect administration of immunomodulators, corticosteroids, and cytokine antagonists, to prevent progression and reduce mortality.

Tuberculosis-Related Hospitalizations in a Low-Incidence Country: A Retrospective Analysis in Two Italian Infectious Diseases Wards.

In recent years, a decrease in the incidence of tuberculosis (TB) has been recorded worldwide. However, an increase in TB cases has been reported in foreign people living in low-incidence countries, with an increase in extrapulmonary TB (EPTB) in the western region of the world. In the present work, a retrospective study was conducted in two Italian infectious diseases wards to evaluate the clinical characteristics of TB admission in the time period 2013-2017. A significant increase in TB was shown in the study period: 166 (71% males) patients with TB were enrolled, with ~70% coming from outside Italy (30% from Africa, 25% from Europe, and 13% from Asia and South America). Compared to foreign people, Italians were significantly older (71.5 (interquartile range, IQR: 44.5-80.0) vs. 30 (IQR: 24-40) years; p < 0.0001) more immunocompromised (48% vs. 17%; p < 0.0001), and affected by comorbidities (44% vs. 14%; p < 0.0001). EPTB represented 37% of all forms of the disease, and it was more incident in subjects coming from Africa than in those coming from Europe (39.3% vs. 20%, respectively). In logistic regression analysis, being European was protective (odd ratio, OR (95% CI): 0.2 (0.1-0.6); p = 0.004) against the development of EPTB forms. In conclusion, an increase in the rate of TB diagnosis was documented in two Italian reference centers in the period 2013-2017, with 39% of EPTB diagnosed in patients from outside Europe.

Listeria monocytogenes Brain Abscess: Controversial Issues for the Treatment-Two Cases and Literature Review.

Listeria monocytogenes (LM) is an opportunistic pathogen, and the most common central nervous system manifestation is meningitis while listerial brain abscesses are rare. We describe 2 cases of brain abscess due to LM and a literature review. Only 73 cases were reported in the literature from 1968 to 2017. The mean age was 51.9, and the mortality rate was 27.3%. In 19% of cases, no risk factors for neurolisteriosis were identified. Blood cultures were positive in 79.5% while CSF or brain abscess biopsy material was positive in 50.8%. In 40% was started a monotherapy regimen while in 60% a combination therapy without substantial differences in mortality. Fifty-two percent underwent neurosurgery while 45.3% has been treated only with medical therapy. The mortality rates were, respectively, 13% and 38.2%. Only 25% of patients who were treated for ≤6 weeks underwent neurosurgery, while 80% of those who were treated for ≥8 weeks were operated. The mortality rates were, respectively, 12.5% and 0%, suggesting that a combined approach of surgery and prolonged medical therapy would have an impact on mortality. We believe that it is essential to carry out this review as brain abscesses are rare, and there are no definitive indications on the optimal management, type, and duration of therapy.

Cytomegalovirus myocarditis in a patient with systemic lupus erythematosus (SLE) successfully treated with ganciclovir.

Myocarditis is an inflammatory disease of the myocardium. Viruses, such as enterovirus, adenovirus, parvovirus B19, HHV6 or cytomegalovirus (CMV) and autoimmune diseases are recognized causes of myocarditis. We describe the clinical case of a young Indian woman with SLE and a concomitant acute CMV related myocarditis with favourable outcome after ganciclovir therapy. CMV myocarditis may range from being a subclinical infection with incidental findings on ECG to a life threating presentation. There are no trials demonstrating the efficacy of antiviral therapy in myocarditis. Case series of patients with CMV myocarditis have reported an excellent clinical outcome after antiviral agents. Lupus Myocarditis (LM) is more prevalent in young females. There are no specific ECG or echocardiographic signs. Treatment strategies of LM are based on corticosteroids, immunosuppressive agents and cardiovascular support, usually with a favorable prognosis, but LM often lead to a severe clinical picture, with mortality of 10.3%. Endomyocardial biopsy (EBM) is recommended as the gold standard but it is very underused in clinical practice, It should be performed in a specialized center but there are concerns on lack of specificity, low negative predictive value, risk of complication, and sampling errors due to the focal nature of myocarditis. Both SLE and CMV are potentially responsible of acute myocarditis. In our knowledge, CMV myocarditis with SLE was described in only one other patient. The initiation of antiviral therapy improved the clinical picture and, in our opinion, it is mandatory when CMV related life threating conditions develop.