COVID-19 Pneumonia with Migratory Pattern in Agammaglobulinemic Patients: A Report of Two Cases and Review of Literature.

X-linked agammaglobulinemia (XLA) is a primary immunodeficiency characterized by marked reduction in serum immunoglobulins and early-onset infections. Coronavirus Disease-2019 (COVID-19) pneumonia in immunocompromised patients presents clinical and radiological peculiarities which have not yet been completely understood. Very few cases of agammaglobulinemic patients with COVID-19 have been reported since the beginning of the pandemic in February 2020. We report two cases of migrant COVID-19 pneumonia in XLA patients.

Timing and implications for immune response to vaccine in SARS-CoV-2 breakthrough infections

COVID-19 vaccines elicit a strong anti-S antibodies response. We aim to describe antibody titers in peri-vaccination SARS-CoV-2 infections. This is a retrospective longitudinal single-cohort study. Serological tests were performed at the time of the first SARS-CoV-2 vaccine dose (T0) and 60 (T1), 120 (T2) and 240 (T3) days after. The study included 4682 subjects. Group A had the infection without an anti-S Ig response. Group B and C seroconverted for anti-N Ig between T0 and T1 and between T1 and T2, respectively. Group D was persistently anti-N Ig negative. Group B showed an initial suboptimal response, reaching the highest titer at T3. Those who received the second dose 120 days after the infection had higher titers compared to those who received it 21 days after the first dose. The immune response depends on the number and the timing of vaccine doses, highlighting the need for a more personalized approach to vaccination. Graphical

The impact of early therapies for COVID-19 on death, hospitalization and persisting symptoms: a retrospective study.

PURPOSE: Oral antivirals (nirmatrelvir/ritonavir and molnupiravir), intravenous short treatment of remdesivir and anti-SARS-CoV-2 monoclonal antibodies (mAbs) have been used for early COVID-19 treatments in high risk of disease progression patients. The term long COVID has been used to refer to a range of new, returning, or ongoing symptoms after SARS-CoV-2 infection. Little is known about the impact of such therapies on long COVID. METHODS: This is a retrospective observational study, including all outpatients evaluated from April 2021 to March 2022 in Brescia, Lombardy, northern Italy. Patients were stratified in three groups: (a) treated with mAbs, (b) treated with antivirals drugs and (c) controls (patients eligible for a or b who refused treatment). Data were collected at baseline and at month 1 and 3 (data on self-reported symptoms were collected using a telephone-administered questionnaire). We assessed early COVID-19 therapies effectiveness in preventing hospitalization, death at 1 or 3 months and persisting symptoms at 3 months after the onset of SARS-CoV-2 infection. RESULTS: A total of 649 patients were included in the study, of which 242 (37.3%) were treated with mAbs, 197 (30.3%) with antiviral drugs and 210 (32.4%) were not treated. Patients most frequently reported cerebro-cardiovascular diseases (36.7%) followed by obesity (22%). Overall, 29 patients (4.5%) died or were hospitalized at 1 or 3-month follow-up. Death or hospitalization was positively associated with older ages, with a significant linear trend (OR 3.05; 95% CI 1.16-8.06, for patients aged 80 or more years compared to those aged less than 65). Data on long COVID at 3 months were available for 323 (49.8%) patients. A positive association emerged for females compared to men, with an OR of 2.14 (95% CI 1.30-3.53) for any symptoms. Conversely, inverse associations were found for treatment groups as compared to the control one, with significant estimates among patients treated with antiviral drugs for any symptoms (OR 0.43, 95% CI 0.21-0.87) and patients treated with mAbs for any neuro-behavioral symptoms (OR 0.48, 95% CI 0.25-0.92). CONCLUSIONS: We report beneficial effect of early use of anti-SARS-CoV-2 antivirals and mAbs on long COVID.

Developmental safety of nirmatrelvir in zebrafish (Danio rerio) embryos.

BACKGROUND: Nirmatrelvir, in combination with ritonavir, is one of the first orally available antiviral treatment for coronavirus disease 2019 (COVID-19). Symptomatic pregnant women are at increased risk for severe illness and complications that can affect the developing baby. No malformations or lower embryo-fetal survival have been observed when nirmatrelvir were administered to pregnant rats and rabbits. Safety evaluation of drugs used for treating COVID-19 also in pregnancy is urgent for public health, then in this study we further investigated nirmatrelvir developmental toxicity using zebrafish as in vivo model. MATERIAL AND METHODS: Using the standardized Fish Embryo Toxicity (FET) test, we first determined the lethal concentration 50 (LC50), exposing embryos from gastrula stage up to 120 hr post fertilization (hpf) and daily recording lethality. Then, we exposed embryos to five doses comprising the human therapeutic one and up to the LC50 (25 µM). Morphology was evaluated at 72 and 120 hpf. RESULTS: Nirmatrelvir did not affect survival rate and did not induce morphological defects up to the human therapeutic dose. Exposure at higher doses (2.4× and 3× the human Cmax ) however resulted in decreased hatching rate, reduced growth, slower heartbeat with pericardial edema, reduction of eye dimension, absence of the swim bladder and disruption of the anterior-posterior axis, with lack of tail detachment, spinal curvature and straight and smaller head. CONCLUSIONS: Our findings in zebrafish embryos add further information about developmental nirmatrelvir safety. Further studies are needed for pharmacological safety assessment of nirmatrelvir exposure during pregnancy.

From the Global North to the Global South: preparing students for away rotations.

Makerere University College of Health Sciences, Kampala, Uganda, has established partnerships with several other institutions worldwide, including the University of Brescia and "Magna Græcia" University, which have agreed to collaborate for the primary purpose of student exchange. Our aim is to comment on students' preparation for away rotations based on the authors' own experiences and opinions alongside a review of selected papers on the preparation of students for global health and ethical collaboration. Medical electives represent a unique opportunity for all medical students, not merely for those who will work in resource-limited settings due to increasing globalization. The emergence of ethical international collaborations is of paramount importance to stimulate these projects and ensure that they are implemented safely and with adequate preparation even and especially during the COVID-19 pandemic.

Efficacy and safety of early soluble urokinase plasminogen receptor plasma-guided anakinra treatment of COVID-19 pneumonia: A subgroup analysis of the SAVE-MORE randomised trial.

Background: The SAVE-MORE trial demonstrated that anakinra treatment in COVID-19 pneumonia with plasma soluble urokinase plasminogen activator (suPAR) levels of 6 ng/mL or more was associated with 0.36 odds for a worse outcome compared to placebo when expressed by the WHO-Clinical Progression Scale (CPS) at day 28. Herein, we report the results of subgroup analyses and long-term outcomes. Methods: This prospective, double-blind, randomised clinical trial, recruited patients with a confirmed SARS-CoV-2 infection, in need of hospitalisation, lower respiratory tract infection and plasma suPAR ≥6 ng/mL from 37 academic and community hospitals in Greece and Italy. Patients were 1:2 randomised to subcutaneous treatment with placebo or anakinra (100 mg) once daily for 10 days. Pre-defined subgroups of Charlson's comorbidity index (CCI), sex, age, level of suPAR, and time from symptom onset were analysed for the primary endpoint (overall comparison of distribution of frequencies of the scores from the WHO-CPS between treatments on day 28), by multivariable ordinal regression analysis in the intention to treat (ITT) population. This trial is registered with the EU Clinical Trials Register (2020-005828-11) and ClinicalTrials.gov (NCT04680949). Findings: Patients were enrolled between 23 December 2020 and 31 March 2021; 189 patients in the placebo arm and 405 patients in the anakinra arm were the ITT population. Multivariable analysis showed that anakinra treatment was accompanied by significantly lower odds for worse outcome compared to placebo at day 28 for all studied subgroups (CCI ≥ 2, OR: 0.34, 95% confidence intervals [CI] 0.22-0.50; CCI < 2, OR: 0.38, 95% CI 0.21-0.68; suPAR > 9 ng/mL, OR: 0.35, 95% CI 0.19-0.66; suPAR 6-9 ng/mL, OR: 0.35, 95% CI 0.24-0.52; patients ≥65 years, OR: 0.41, 95% CI 0.25-0.66; and patients <65 years, OR: 0.29, 95% CI 0.19-0.45). The benefit was uniform, irrespective of the time from start of symptoms until the start of the study drug. At days 60 and 90, anakinra treatment had odds of 0.40 (95% CI 0.28-0.57) and 0.46 (95% CI 0.32-0.67) respectively, for a worse outcome compared to placebo. The costs of general ward stay, ICU stay, and drugs were lower with anakinra treatment. Interpretation: Anakinra represents an important therapeutic tool in the management of COVID-19 that may be administered in all subgroups of patients; benefits are maintained until day 90. Funding: Hellenic Institute for the Study of Sepsis; Swedish Orphan Biovitrum AB.

Interferon gamma-induced protein 10 (IP-10) for the early prognosis of the risk for severe respiratory failure and death in COVID-19 pneumonia.

OBJECTIVES: Elevated concentrations of soluble urokinase plasminogen activator receptor (suPAR) predict progression to severe respiratory failure (SRF) or death among patients with COVID-19 pneumonia and guide early anakinra treatment. As suPAR testing may not be routinely available in every health-care setting, alternative biomarkers are needed. We investigated the performance of C-reactive protein (CRP), interferon gamma-induced protein-10 (IP-10) and TNF-related apoptosis-inducing ligand (TRAIL) for predicting SRF or death in COVID-19. METHODS: Two cohorts were studied; one discovery cohort with 534 patients from the SAVE-MORE clinical trial; and one validation cohort with 364 patients from the SAVE trial including also 145 comparators. CRP, IP-10 and TRAIL were measured by the MeMed Key® platform in order to select the biomarker with the best prognostic performance for the early prediction of progression into SRF or death. RESULTS: IP-10 had the best prognostic performance: baseline concentrations 2000 pg/ml or higher predicted equally well to suPAR (sensitivity 85.0 %; negative predictive value 96.6 %). Odds ratio for poor outcome among anakinra-treated participants of the SAVE-MORE trial was 0.35 compared to placebo when IP-10 was 2,000 pg/ml or more. IP-10 could divide different strata of severity for SRF/death by day 14 in the validation cohort. Anakinra treatment decreased this risk irrespective the IP-10 concentrations. CONCLUSIONS: IP-10 concentrations of 2,000 pg/ml or higher are a valid alternative to suPAR for the early prediction of progression into SRF or death the first 14 days from hospital admission for COVID-19 and they may guide anakinra treatment. CLINICALTRIALS: gov, NCT04680949 and NCT04357366.

What is the impact of SARS-CoV-2 pandemic on antimicrobial stewardship programs (ASPs)? The results of a survey among a regional network of infectious disease centres.

Discontinuation of antimicrobial stewardship programs (ASPs) and increased antibiotic use were described during SARS-CoV-2 pandemic. In order to measure COVID-19 impact on ASPs in a setting of high multidrug resistance organisms (MDRO) prevalence, a qualitative survey was designed. In July 2021, eighteen ID Units were asked to answer a questionnaire about their hospital characteristics, ASPs implementation status before the pandemic and impact of SARS-CoV-2 pandemic on ASPs after the 1st and 2nd pandemic waves in Italy. Nine ID centres (50%) reported a reduction of ASPs and in 7 cases (38.9%) these were suspended. After the early pandemic waves, the proportion of centres that restarted their ASPs was higher among the ID centres where antimicrobial stewardship was formally identified as a priority objective (9/11, 82%, vs 2/7, 28%). SARS-CoV-2 pandemic had a severe impact in ASPs in a region highly affected by COVID-19 and antimicrobial resistance but weaknesses related to the pre-existent ASPs might have played a role.

New insights on malaria

Malaria is long known as a deadly vector borne infection, caused by five parasite species of the coccidian genus Plasmodia that are present in as many as 85 countries. Despite significant progresses have been achieved to control the infection by early diagnosis and artemisinin combination treatment, insecticide-treated nets and indoor residual spraying, malaria still represents a major public health issue in many endemic low-income countries. New diagnostic tools of higher sensitivity and specificity are now available for use in endemic countries to better guide diagnosis and treatment. In particular, highly sensitive rapid antigenic tests are now available and the loop-mediated isothermal amplification is a very promising and highly sensitive diagnostic tool. After 2015, decreasing morbidity and mortality trends have been stagnating because of limited funding, emergence of parasite and vector resistance to drugs and insecticides respectively and, recently, by the disrupting effect of COVID-19 pandemic. The incomplete knowledge of the complex immunity of malaria infection has slowed the development of an effective vaccine. However, in 2021, the RTS-S vaccine, however of suboptimal protective efficacy, has been made available for routine use in children above 5 months of age. Population movements has increased the chance of observing imported malaria in non-endemic areas, where malaria competent vectors may still exist.

SARS-CoV-2 Infection and Vaccination Coverage among Fragile Populations in a Local Health Area of Northern Italy.

Italy was dramatically hit by the COVID-19 pandemic, and the province of Brescia was one of the epicenters of the outbreak. Furthermore, Brescia has one of the highest incidences of people living with HIV (PLWH) and a substantial presence of migrants. We conducted a retrospective cohort study involving all citizens connected to the Brescia Health Protection Agency, assessing the SARS-CoV-2 burden, COVID-19 prevalence, and vaccination coverage. A total of 1,004,210 persons were included, 3817 PLWH and 134,492 foreigners. SARS-CoV-2 infection, hospitalizations and death were more frequent among Italians than foreigners. SARS-CoV-2 infections and deaths were more frequent in HIV-uninfected people than in PLWH. PLWH and foreigners were less likely to have a SARS-CoV-2 diagnosis compared to HIV-negative patients. Migrants were more likely to be hospitalized but had a lower risk of death compared to HIV-negative patients. Regarding vaccination, 89.1% of the population received at least one dose of vaccine, while 70.4% of the Italian citizens and 36.3% of the foreigner subjects received three doses of vaccine. Foreigners showed a lower risk of being diagnosed with SARS-CoV-2 but a higher risk of complications. HIV infection was not associated with a higher risk of SARS-CoV-2 severe manifestations compared to the general population. COVID-19 vaccine hesitancy was not different between PLWH and HIV uninfected people, but foreigners were more hesitant.

"Immuni" and the National Health System: Lessons Learnt from the COVID-19 Digital Contact Tracing in Italy.

Since the early stage of the current pandemic, digital contact tracing (DCT) through mobile phone apps, called "Immuni", has been introduced to complement manual contact tracing in Italy. Until 31 December 2021, Immuni identified 44,880 COVID-19 cases, which corresponds to less than 1% of total COVID-19 cases reported in Italy in the same period (5,886,411). Overall, Immuni generated 143,956 notifications. Although the initial download of the Immuni app represented an early interest in the new tool, Immuni has had little adoption across the Italian population, and the recent increase in its download is likely to be related to the mandatory Green Pass certification for conducting most daily activities that can be obtained via the application. Therefore, Immuni failed as a support tool for the contact tracing system. Other European experiences seem to show similar limitations in the use of DTC, leaving open questions about its effectiveness, although in theory, contact tracing could allow useful means of "proximity tracking".

Immuni';and the National Health System: Lessons Learnt from the COVID-19 Digital Contact Tracing in Italy

Since the early stage of the current pandemic, digital contact tracing (DCT) through mobile phone apps, called 'Immuni';, has been introduced to complement manual contact tracing in Italy. Until 31 December 2021, Immuni identified 44,880 COVID-19 cases, which corresponds to less than 1% of total COVID-19 cases reported in Italy in the same period (5,886,411). Overall, Immuni generated 143,956 notifications. Although the initial download of the Immuni app represented an early interest in the new tool, Immuni has had little adoption across the Italian population, and the recent increase in its download is likely to be related to the mandatory Green Pass certification for conducting most daily activities that can be obtained via the application. Therefore, Immuni failed as a support tool for the contact tracing system. Other European experiences seem to show similar limitations in the use of DTC, leaving open questions about its effectiveness, although in theory, contact tracing could allow useful means of 'proximity tracking';.

New insights on malaria.

Malaria is long known as a deadly vector borne infection, caused by five parasite species of the coccidian genus Plasmodia that are present in as many as 85 countries. Despite significant progresses have been achieved to control the infection by early diagnosis and artemisinin combination treatment, insecticide-treated nets and indoor residual spraying, malaria still represents a major public health issue in many endemic low-income countries. New diagnostic tools of higher sensitivity and specificity are now available for use in endemic countries to better guide diagnosis and treatment. In particular, highly sensitive rapid antigenic tests are now available and the loop-mediated isothermal amplification is a very promising and highly sensitive diagnostic tool. After 2015, decreasing morbidity and mortality trends have been stagnating because of limited funding, emergence of parasite and vector resistance to drugs and insecticides respectively and, recently, by the disrupting effect of COVID-19 pandemic. The incomplete knowledge of the complex immunity of malaria infection has slowed the development of an effective vaccine. However, in 2021, the RTS-S vaccine, however of suboptimal protective efficacy, has been made available for routine use in children above 5 months of age. Population movements has increased the chance of observing imported malaria in non-endemic areas, where malaria competent vectors may still exist.

Non-neutralizing antibodies: Deleterious or propitious during SARS-CoV-2 infection?

Antibody-dependent enhancement (ADE) is a complex phenomenon mediated by antibodies, frequently pre-existing non-neutralizing or sub-neutralizing antibodies. In the course of infectious diseases, ADE may be responsible for worsening the clinical course of the disease by increasing the virulence of pathogens (ADE of infection) or enhancing disease severity (ADE of disease). Here we reviewed the mechanisms thought to be behind the ADE phenomenon and its potential relationship with COVID-19 severity. Since the early COVID-19 epidemics, ADE has been mentioned as a possible mechanism involved in severe COVID-19 disease and, later, as a potential risk in the case of infection after vaccination. However, current data do not support its role in disease severity, both after infection and reinfection.

The impact of COVID-19 on communicable and non-communicable diseases in Africa: a narrative review.

The global pandemic of coronavirus disease 2019 (COVID-19) has disproportionately impacted global human health, economy, and security. Because of weaker health-care systems, existing comorbidities burden (HIV, malaria, tuberculosis, and non-communicable conditions), and poor socioeconomic determinants, initial predictive models had forecast a disastrous impact of COVID-19 in Africa in terms of transmission, severity, and deaths. Nonetheless, current epidemiological data seem not to have matched expectations, showing lower SARS-CoV-2 infection and fatality rates compared to Europe, the Americas and Asia. However, only few studies were conducted in low- and middle-income African settings where high poverty and limited access to health services worsen underlying health conditions, including endemic chronic infectious diseases such as HIV and tuberculosis. Furthermore, limited, and heterogeneous research was conducted to evaluate the indirect impact of the pandemic on general health services and on major diseases across African countries. International mitigation measures, such as resource reallocation, lockdowns, social restrictions, and fear from the population have had multi-sectoral impacts on various aspects of everyday life, that shaped the general health response. Despite the vast heterogeneity of data across African countries, available evidence suggests that the COVID-19 pandemic has severely impacted the control and prevention programs, the diagnosis capacity and the adherence to treatment of major infectious diseases (HIV, TB, and Malaria) - including neglected diseases - and non-communicable diseases. Future research and efforts are essential to deeply assess the medium- and long-term impact of the pandemic, and to implement tailored interventions to mitigate the standstill on decades of improvement on public health programs.

Explorative study regarding influenza vaccine hesitancy among HIV-infected patients.

There are scarce data regarding influenza vaccination among people with HIV infection (PWHIV). The goal of this explorative study is to assess hesitancy toward influenza vaccination in a group of PWHIV during the COVID-19 pandemic. A questionnaire was administered to 219 patients vaccinated at our clinic during the 2020-2021 campaign. It evaluated subjects' adherence to influenza vaccine over the last three seasonal vaccination campaigns, vaccine confidence, complacency and convenience, and the effect of the pandemic on the choice to become vaccinated. The population was divided into two groups: fully adherent to influenza vaccine (all three campaigns, 117 patients) and non-fully adherent (one or two campaigns, 102 patients). Adherence increased in the non-fully adherent group in 2020-2021, but the pandemic did not affect the choice. Misbeliefs emerged: the influenza vaccine was considered protective against SARS-CoV-2 (22.8% of the total population); almost half of all patients thought the influenza vaccine could improve their CD4 T cell level (57.3% in fully adherent, 40.2% in non-fully adherent, p < .05). In 2020-2021 campaign, three quarters of the non-fully adherent group would not have been vaccinated in a location other than our clinic (75.5% vs. 88.9% in the fully adherent group, p < .05). Conclusively, offering a secure and private space for vaccination against influenza seems to encourage vaccination; healthcare professionals should improve counseling to increase adherence and correct misbeliefs.

Psychological and Emotional Impact of COVID-19 Pandemic on People Living with Chronic Disease: HIV and Cancer.

People living with chronic disease (PLWCD) are the frailest category, both for the risk of severe COVID-19 illness and for the impact on the care continuum. Aim of this study was to analyze coping strategies and resilience in people living with HIV (PLWH) compared to people living with oncological diseases (PLWOD) during COVID-19 pandemic. We administrated an anonymous questionnaire, which explored the emotional experience, the demographic factors linked to a COVID-19-related stress syndrome, the patient's perception about the adequacy of clinical undertaking from the hospital and the resilience. We analyzed 324 questionnaires. There were no significant differences in prevalence of psychological distress among the whole cohort; however, PLWOD were calmer, less troubled, and more serene than PLWH. Moreover, PLWH smoked more, ate more, and gained more weight than PLWOD. Most patients didn't feel lonely and continued to take pleasure from their activities. No differences in resilience were found between the groups. In the whole cohort lower levels of resilience were found in patients that were unemployed, with history of psychological disorders and in those who experienced more feelings of anger, anxiety and concern. In our study, patients seemed to preserve their well-being, and to activate adaptive coping during the pandemic.

Omicron Genetic and Clinical Peculiarities That May Overturn SARS-CoV-2 Pandemic: A Literature Review.

The Coronavirus disease 2019 (COVID-19) pandemic poses a great threat to global public health. The original wild-type strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has genetically evolved, and several variants of concern (VOC) have emerged. On 26 November 2021, a new variant named Omicron (B.1.1.529) was designated as the fifth VOC, revealing that SARS-CoV-2 has the potential to go beyond the available therapies. The high number of mutations harboured on the spike protein make Omicron highly transmissible, less responsive to several of the currently used drugs, as well as potentially able to escape immune protection elicited by both vaccines and previous infection. We reviewed the latest publication and the most recent available literature on the Omicron variant, enlightening both reasons for concern and high hopes for new therapeutic strategies.