Balancing evidence and frontline experience in the early phases of the COVID-19 pandemic: current position of the Italian Society of Anti-infective Therapy (SITA) and the Italian Society of Pulmonology (SIP)

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), which has rapidly become epidemic in Italy and other European countries. The disease spectrum ranges from asymptomatic/mildly symptomatic presentations to acute respiratory failure. At the present time the absolute number of severe cases requiring ventilator support is reaching or even surpassing the intensive care unit bed capacity in the most affected regions and countries.ObjectivesTo narratively summarize the available literature on the management of COVID-19 in order to combine current evidence and frontline opinions and to provide balanced answers to pressing clinical questions.SourcesInductive PubMed search for publications relevant to the topic.ContentThe available literature and the authors' frontline-based opinion are summarized in brief narrative answers to selected clinical questions, with a conclusive statement provided for each answer.ImplicationsMany off-label antiviral and anti-inflammatory drugs are currently being administered to patients with COVID-19. Physicians must be aware that, as they are not supported by high-level evidence, these treatments may often be ethically justifiable only in those worsening patients unlikely to improve only with supportive care, and who cannot be enrolled onto randomized clinical trials. Access to well-designed randomized controlled trials should be expanded as much as possible because it is the most secure way to change for the better our approach to COVID-19 patients.     

The Development and Operation of a Home Management System during the COVID-19 Pandemic: Experience of the Local Government Gyeonggi-do in Korea

During the three the coronavirus disease 2019 (COVID-19) surges in South Korea, there was a shortage of hospital beds for COVID-19 patients, and as a result, there were cases of death while waiting for hospitalization. To minimize the risk of death and to allow those confirmed with COVID-19 to safely wait for hospitalization at home, the local government of Gyeonggi-do in South Korea developed a novel home management system (HMS). The HMS team, comprised of doctors and nurses, was organized to operate HMS. HMS provided a two-way channel for the taskforce and patients to monitor the severity of patient''s condition and to provide healthcare counseling as needed. In addition, the HMS team cooperated with a triage/bed assignment team to expedite the response in case of an emergency, and managed a database of severity for real-time monitoring of patients. The HMS became operational for the first time in August 2020, initially managing only 181 patients; it currently manages a total of 3,707 patients. The HMS supplemented the government''s COVID-19 confirmed case management framework by managing patients waiting at home for hospitalization due to lack of hospital and residential treatment center beds. HMS also could contribute a sense of psychological stability in patients and prevented the situation from worsening by efficient management of hospital beds and reduction of workloads on public healthcare centers. To stabilize and improve the management of COVID-19 confirmed cases, governments should organically develop self-treatment and HMS, and implement a decisive division of roles within the local governments.     

Infliximab rescue therapy in a patient with acute severe ulcerative colitis and coronavirus disease 2019 followed by Escherichia coli 0157:H7 infection: a case report

The management of patients with acute severe ulcerative colitis and SARS-CoV-2 presents a clinical challenge. We report on the first case of a patient with acute severe ulcerative colitis and mild coronavirus disease 2019 (COVID-19) who received rescue infliximab therapy, followed by a relapse caused by enterohemorrhagic Escherichia coli 0157:H7. The treatment challenges we faced were biologic therapy administration during active COVID-19, about which little was known at the time, and how to treat EHEC due to the risk of hemolytic uremic syndrome. Acute severe ulcerative colitis was treated with rescue infliximab therapy, and enteric infection with an antibiotic, both with satisfactory clinical response. The decision to induce biologic therapy for inflammatory bowel disease relapse in SARS-CoV-2-positive patients should be made on a case-to-case basis and should be driven by the dominant disease. Our patient tested positive for SARS-CoV-2, but actually had mild disease. At the same time, she had acute severe ulcerative colitis, so we started anti-tumor necrosis factor therapy despite serological tests and the recommendation to delay biological therapy administration for two-weeks. Second, due to severity of the first flare, COVID-19, and the patient''s general condition, we opted for an antibiotic treatment of Escherichia coli 0157:H7 while monitoring the parameters of potential hemolytic uremic syndrome development.

The treatment of patients with acute severe ulcerative colitis (ASUC) and coronavirus disease 2019 (COVID-19) presents a clinical challenge. We report on a patient with ASUC and mild COVID-19 acquired during the hospital stay, followed by enterohemorrhagic Escherichia coli (EHEC) 0157:H7 infection. To our knowledge, this is the first such case described in the literature.     

A severe COVID-19 case with schizophrenia as well as other chronic diseases

The prognosis of COVID-19 (coronavirus disease 2019) is usually poor when it occurs in aged adults or in patients with chronic diseases, which brought a great challenge to clinical practice. Furthermore, widespread depression, anxiety, and panic related to SARS-CoV-2 (severe acute respiratory syndrome-coronavirus 2) infection affected treatment compliance and recovery. Here we report the successful treatment of a 57-year-old male with severe COVID-19, schizophrenia, hypertension, and type 2 diabetes. The patient''s negative emotions (such as tension, panic, and anxiety), particularly his aggression and paranoia, seriously hindered treatment, leading to a deteriorating condition. Psychological counseling and supportive psychotherapy were given but the effect was weak. To improve adherence, risperidone and quetiapine fumarate were replaced by olanzapine for anti-schizophrenic treatment to reduce insomnia and anxiety side effects, associated with sedative-hypnotic drugs as well as psychological counseling. The treatment compliance of the patient improved significantly. The patient''s serum alanine aminotransferase increased abnormally in the late stage of hospitalization, suggesting potential liver damage after complex medication strategies. We also monitored the changes of lymphocyte subsets and retrospectively analyzed the virus-specific antibody response. The results suggested that dynamic monitoring of lymphocyte subsets and virus-specific antibody response could facilitate disease progression evaluation and timely treatment plan adjustments. An effective psychotropic drug intervention associated with psychological counselling and psychotherapy are essential for the successful adherence, treatment, and rehabilitation of psychiatric disorders in COVID-19 patients.     

Potential interventions for novel coronavirus in China: A systematic review

An outbreak of a novel coronavirus (COVID-19 or 2019-CoV) infection has posed significant threats to international health and the economy. In the absence of treatment for this virus, there is an urgent need to find alternative methods to control the spread of disease. Here, we have conducted an online search for all treatment options related to coronavirus infections as well as some RNA-virus infection and we have found that general treatments, coronavirus-specific treatments, and antiviral treatments should be useful in fighting COVID-19. We suggest that the nutritional status of each infected patient should be evaluated before the administration of general treatments and the current children's RNA-virus vaccines including influenza vaccine should be immunized for uninfected people and health care workers. In addition, convalescent plasma should be given to COVID-19 patients if it is available. In conclusion, we suggest that all the potential interventions be implemented to control the emerging COVID-19 if the infection is uncontrollable.     

Risk factors associated with COVID-19-associated pulmonary aspergillosis in ICU patients: a French multicentric retrospective cohort

ObjectivesThe main objective of this study was to determine the incidence of invasive pulmonary aspergillosis (IPA) in patients with coronavirus disease 2019 (COVID-19) admitted to the intensive care unit (ICU), and to describe the patient characteristics associated with IPA occurrence and to evaluate its impact on prognosis.MethodsWe conducted a retrospective cohort study including all successive COVID-19 patients, hospitalized in four ICUs, with secondary deterioration and one or more respiratory samples sent to the mycology department. We used a strengthened IPA testing strategy including seven mycological criteria. Patients were classified as probable IPA according to the European Organization for Research and Treatment of Cancer (EORTC)/Mycoses Study Group Education and Research Consortium (MSGERC) classification if immunocompromised, and according to the recent COVID-19-associated IPA classification otherwise.ResultsProbable IPA was diagnosed in 21 out of the 366 COVID-19 patients (5.7%) admitted to the ICU and in the 108 patients (19.4%) who underwent respiratory sampling for deterioration. No significant differences were observed between patients with and without IPA regarding age, gender, medical history and severity on admission and during hospitalization. Treatment with azithromycin for ≥3 days was associated with the diagnosis of probable IPA (odds ratio 3.1, 95% confidence interval 1.1–8.5, p = 0.02). A trend was observed with high-dose dexamethasone and the occurrence of IPA. Overall mortality was higher in the IPA patients (15/21, 71.4% versus 32/87, 36.8%, p < 0.01).ConclusionIPA is a relatively frequent complication in severe COVID-19 patients and is responsible for increased mortality. Azithromycin, known to have immunomodulatory properties, may contribute to increase COVID-19 patient's susceptibility to IPA.     

Repurposing the antioxidant and anti-inflammatory agent N-acetyl cysteine for treating COVID-19

Although several considerations have been raised suggesting a beneficial effect of N-acetyl cysteine (NAC) for the treatment of severe acute respiratory syndrome coronavirus 2 infection, there is currently no clinical evidence that NAC truly prevents coronavirus disease 2019 (COVID-19), reduces the severity of the disease, or improves the outcome. Appropriately designed clinical trials are warranted to prove or disprove a therapeutic effect of NAC for COVID-19 patients.     

COVID-19 infection and rheumatoid arthritis: Faraway,so close!

The outbreak of the new coronavirus infections COVID-19 in December 2019 in China has quickly become a global health emergency. Given the lack of specific anti-viral therapies, the current management of severe acute respiratory syndrome coronaviruses (SARS-CoV-2) is mainly supportive, even though several compounds are now under investigation for the treatment of this life-threatening disease. COVID-19 pandemic is certainly conditioning the treatment strategy of a complex disorder as rheumatoid arthritis (RA), whose infectious risk is increased compared to the general population because of an overall impairment of immune system typical of autoimmune diseases combined with the iatrogenic effect generated by corticosteroids and immunosuppressive drugs. However, the increasing knowledge about the pathophysiology of SARS-CoV-2 infection is leading to consider some anti-rheumatic drugs as potential treatment options for the management of COVID-19. In this review we will critically analyse the evidences on either positive or negative effect of drugs commonly used to treat RA in this particular scenario, in order to optimize the current approach to RA patients.     

Prevention and treatment of COVID-19 disease by controlled modulation of innate immunity

The recent outbreak of coronavirus disease 2019 (COVID-19), triggered by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses an enormous threat to global public health and economies. Human coronaviruses normally cause no or mild respiratory disease but in the past two decades, potentially fatal coronavirus infections have emerged, causing respiratory tract illnesses such as pneumonia and bronchitis. These include severe acute respiratory syndrome coronavirus (SARS-CoV), followed by the Middle East respiratory syndrome coronavirus (MERS-CoV), and recently the SARS-CoV-2 coronavirus outbreak that emerged in Wuhan, China, in December 2019. Currently, most COVID-19 patients receive traditional supportive care including breathing assistance. To halt the ongoing spread of the pandemic SARS-CoV-2 coronavirus and rescue individual patients, established drugs and new therapies are under evaluation. Since it will be some time until a safe and effective vaccine will be available, the immediate priority is to harness innate immunity to accelerate early antiviral immune responses. Second, since excessive inflammation is a major cause of pathology, targeted anti-inflammatory responses are being evaluated to reduce inflammation-induced damage to the respiratory tract and cytokine storms. Here, we highlight prominent immunotherapies at various stages of development that aim for augmented anti-coronavirus immunity and reduction of pathological inflammation.     

Clinical characteristics,management and in-hospital mortality of patients with coronavirus disease 2019 in Genoa,Italy

ObjectivesTo describe clinical characteristics, management and outcome of individuals with coronavirus disease 2019 (COVID-19); and to evaluate risk factors for all-cause in-hospital mortality.MethodsThis retrospective study from a University tertiary care hospital in northern Italy, included hospitalized adult patients with a diagnosis of COVID-19 between 25 February 2020 and 25 March 2020.ResultsOverall, 317 individuals were enrolled. Their median age was 71 years and 67.2% were male (213/317). The most common underlying diseases were hypertension (149/317; 47.0%), cardiovascular disease (63/317; 19.9%) and diabetes (49/317; 15.5%). Common symptoms at the time of COVID-19 diagnosis included fever (285/317; 89.9%), shortness of breath (167/317; 52.7%) and dry cough (156/317; 49.2%). An ‘atypical’ presentation including at least one among mental confusion, diarrhoea or nausea and vomiting was observed in 53/317 patients (16.7%). Hypokalaemia occurred in 25.8% (78/302) and 18.5% (56/303) had acute kidney injury. During hospitalization, 111/317 patients (35.0%) received non-invasive respiratory support, 65/317 (20.5%) were admitted to the intensive care unit (ICU) and 60/317 (18.5%) required invasive mechanical ventilation. All-cause in-hospital mortality, assessed in 275 patients, was 43.6% (120/275). On multivariable analysis, age (per-year increase OR 1.07; 95% CI 1.04–1.10; p < 0.001), cardiovascular disease (OR 2.58; 95% CI 1.07–6.25; p 0.03), and C-reactive protein levels (per-point increase OR 1.009; 95% CI 1.004–1.014; p 0.001) were independent risk factors for all-cause in-hospital mortality.ConclusionsCOVID-19 mainly affected elderly patients with predisposing conditions and caused severe illness, frequently requiring non-invasive respiratory support or ICU admission. Despite supportive care, COVID-19 remains associated with a substantial risk of all-cause in-hospital mortality.     

Extremely low prevalence of asymptomatic COVID-19 among healthcare workers caring for COVID-19 patients in Israeli hospitals: a cross-sectional study

ObjectivesWe aimed to compare the prevalence of asymptomatic coronavirus disease 19 (COVID-19) among clinical staff in designated COVID-19 units versus that among staff in similar units with no known or suspected COVID-19 patients.MethodsWe conducted a cross-sectional survey of healthcare workers (HCWs) in eight Israeli general hospitals. The survey involved a questionnaire and a PCR test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We surveyed HCWs in COVID-19 units and comparison units (internal medicine and cardiology) between 30th April and 7th May 2020.ResultsThere were 522 participants: 291 from COVID-19 units and 231 from comparison units. Only one participant (0.2%, 95%CI: 0.005–1.1%)—an asymptomatic nurse on a COVID-19 unit—tested positive for SARS-CoV-2. In participating COVID-19 units there were two symptomatic HCWs with confirmed COVID-19 in the 2 weeks before the survey; both were infected by contact with a co-worker outside of the COVID-19 unit.ConclusionsThe low prevalence of asymptomatic COVID-19 among HCWs, coupled with an absence of symptomatic COVID-19 acquired during patient care, suggest that Israel's national guidelines for personal protective equipment, which are consistent with those of the World Health Organization, adequately protect HCWs.     

Genetic predisposition to blood cell indices in relation to severe COVID-19

Despite considerable variation in disease manifestations observed among coronavirus disease 2019 (COVID-19) patients infected with severe acute respiratory syndrome coronavirus 2, the risk factors predicting disease severity remain elusive. Recent studies suggest that peripheral blood cells play a pivotal role in COVID-19 pathogenesis. Here, we applied two-sample Mendelian randomization (MR) analyses to evaluate the potential causal contributions of blood cell indices variation to COVID-19 severity, using single-nucleotide polymorphisms (SNPs) as instrumental variables for 17 indices from the UK Biobank and INTERVAL genome-wide association studies (N = 173 480). Data on the associations between the SNPs and very severe respiratory confirmed COVID-19 were obtained from the COVID-19 host genetics initiative (N = 8779/1 001 875). We observed significant negative association between hematocrit (HCT; odds ratio, OR = 0.775, 95% confidence interval, CI = 0.635–0.915, p = 3.48E−04) or red blood cell count (OR = 0.830, 95% CI = 0.728–0.932, p = 2.19E−03) and very severe respiratory confirmed COVID-19, as well as nominal negative association of hemoglobin concentration (OR = 0.808, 95% CI = 0.673–0.943, p = 3.95E−03) with very severe respiratory confirmed COVID-19 (no effect survived multiple correction). In conclusion, the MR study supports a protective effect of high HCT and red blood cell count from very severe respiratory confirmed COVID-19, suggesting potential strategies to ameliorate/treat clinical conditions in very severe respiratory confirmed COVID-19.     

The role of type I interferon in the treatment of COVID-19

Although significant research has been done to find effective drugs against coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), no definite effective drug exists. Thus, research has now shifted towards immunomodulatory agents other than antivirals. In this review, we aim to describe the latest findings on the role of type I interferon (IFN)-mediated innate antiviral response against SARS-CoV-2 and discuss the use of IFNs as a medication for COVID-19. A growing body of evidence has indicated a promoting active but delayed IFNs response to SARS-CoV-2 and Middle East respiratory syndrome coronavirus in infected bronchial epithelial cells. Studies have demonstrated that IFNs' administration before the viral peak and the inflammatory phase of disease could offer a highly protective effect. However, IFNs' treatment during the inflammatory and severe stages of the disease causes immunopathology and long-lasting harm for patients. Therefore, it is critical to note the best time window for IFNs' administration. Further investigation of the clinical effectiveness of interferon for patients with mild to severe COVID-19 and its optimal timing and route of administration can be beneficial in finding a safe and effective antiviral therapy for the COVID-19 disease.     

Outcomes of Late-Preterm and Term Infants Born to SARS-CoV-2-Positive Mothers

With the spread of coronavirus disease 2019 (COVID-19) in Korea, the number of pregnant women infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is rapidly increasing. A shortage of negative-pressure isolation rooms for newborns makes hospital assignment more difficult for late-pregnant women with COVID-19. Among 34 infants born to SARS-CoV-2-positive mothers, 5 (14.7%) presented with respiratory distress and 1 (2.9%) presented with feeding intolerance that required specialized care. Aerosol-generating procedures were performed in one infant. Overall outcomes of 34 infants were favorable, and no infant tested positive for SARS-CoV-2. Most infants born to SARS-CoV-2-positive mothers did not need to be quarantined in a negative-pressure isolation room, and 17 (50%) mother–infant dyads were eligible for rooming-in. If negative-pressure isolation rooms are selectively used for newborns requiring aerosol-generating procedures or newborns in respiratory distress, resource availability for lower-risk cases may improve.     

A compendium answering 150 questions on COVID-19 and SARS-CoV-2

In December 2019, China reported the first cases of the coronavirus disease 2019 (COVID-19). This disease, caused by the severe acute respiratory syndrome–related coronavirus 2 (SARS-CoV-2), has developed into a pandemic. To date, it has resulted in ~9 million confirmed cases and caused almost 500 000 related deaths worldwide. Unequivocally, the COVID-19 pandemic is the gravest health and socioeconomic crisis of our time. In this context, numerous questions have emerged in demand of basic scientific information and evidence-based medical advice on SARS-CoV-2 and COVID-19. Although the majority of the patients show a very mild, self-limiting viral respiratory disease, many clinical manifestations in severe patients are unique to COVID-19, such as severe lymphopenia and eosinopenia, extensive pneumonia, a “cytokine storm” leading to acute respiratory distress syndrome, endothelitis, thromboembolic complications, and multiorgan failure. The epidemiologic features of COVID-19 are distinctive and have changed throughout the pandemic. Vaccine and drug development studies and clinical trials are rapidly growing at an unprecedented speed. However, basic and clinical research on COVID-19–related topics should be based on more coordinated high-quality studies. This paper answers pressing questions, formulated by young clinicians and scientists, on SARS-CoV-2, COVID-19, and allergy, focusing on the following topics: virology, immunology, diagnosis, management of patients with allergic disease and asthma, treatment, clinical trials, drug discovery, vaccine development, and epidemiology. A total of 150 questions were answered by experts in the field providing a comprehensive and practical overview of COVID-19 and allergic disease.     

Angiotensin-converting enzyme 2 receptors,chronic liver diseases,common medications,and clinical outcomes in coronavirus disease 2019 patients

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), enters affected cells through the angiotensin-converting enzyme 2 (ACE2) receptor, which is highly expressed in type II alveolar cells, enterocytes, and cholangiocytes. SARS-CoV-2 infection causes fever, dry cough, and breathing difficulty, which can progress to respiratory distress due to interstitial pneumonia, and hepatobiliary injury due to COVID-19 is increasingly recognized. The hepatobiliary injury may be evident at presentation of the disease or develop during the disease progression. The development of more severe clinical outcomes in patients with chronic liver diseases (CLD) with or without cirrhosis infected with SARS-CoV-2 has not been elucidated. Moreover, there is limited data related to common medications that affect the disease severity of COVID-19 patients. Additionally, ACE2 receptor expression of hepatobiliary tissue related to the disease severity also have not been clarified. This review summarized the current situation regarding the clinical outcomes of COVID-19 patients with chronic liver diseases who were treated with common medications. Furthermore, the association between ACE2 receptor expression and disease severity in these patients is discussed.     

Anti-SARS-CoV-2 IgG levels in relation to disease severity of COVID-19

The durability of infection-induced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunity has crucial implications for reinfection and vaccine effectiveness. However, the relationship between coronavirus disease 2019 (COVID-19) severity and long-term anti-SARS-CoV-2 immunoglobulin G (IgG) antibody level is poorly understood. Here, we measured the longevity of SARS-CoV-2-specific IgG antibodies in survivors who had recovered from COVID-19 1 year previously. In a cohort of 473 survivors with varying disease severity (asymptomatic, mild, moderate, or severe), we observed a positive correlation between virus-specific IgG antibody titers and COVID-19 severity. In particular, the highest virus-specific IgG antibody titers were observed in patients with severe COVID-19. By contrast, 74.4% of recovered asymptomatic carriers had negative anti-SARS-CoV-2 IgG test results, while many others had very low virus-specific IgG antibody titers. Our results demonstrate that SARS-CoV-2-specific IgG persistence and titer depend on COVID-19 severity.     

Characteristics and roles of severe acute respiratory syndrome coronavirus 2-specific antibodies in patients with different severities of coronavirus 19

The diagnosis of coronavirus 19 (COVID-19) relies mainly upon viral nucleic acid detection, but false negatives can lead to missed diagnosis and misdiagnosis; severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibody detection is convenient, safe and highly sensitive. Immunoglobulin (Ig)M and IgG are commonly used to serologically diagnose COVID-19; however, the role of IgA is not well known. We aimed to quantify the levels of SARS-CoV-2-specific IgM, IgA and IgG antibodies, identify changes in them based on COVID-19 severity, and establish the significance of combined antibody detection. COVID-19 patients, divided into a severe and critical group and a moderate group, and non-COVID-19 patients with respiratory disease were included in this study. A chemiluminescence method was used to detect the levels of SARS-CoV-2-specific IgM, IgA and IgG in the blood samples from the three groups. Epidemiological characteristics, symptoms, blood test results and other data were recorded for all patients. Compared to the traditional IgM–IgG combined antibodies, IgA–IgG combined antibodies are more effective for diagnosing COVID-19. During the disease process, IgA appeared first and disappeared last. All three antibodies had significantly higher levels in COVID-19 patients than in non-COVID-19 patients. IgA and IgG were also higher for severe and critical disease than for moderate disease. All antibodies were at or near low levels at the time of tracheal extubation in critical patients. Detection of SARS-CoV-2-specific combined IgA–IgG antibodies is advantageous in diagnosing COVID-19. IgA detection is suitable during early and late stages of the disease. IgA and IgG levels correspond to disease severity.