Invasive cryptococcal disease in COVID-19: systematic review of the literature and analysis

SUMMARY During the Coronavirus Disease 2019 (COVID-19) pandemic, an increasing number of fungal infections associated with SARS-CoV-2 infection have been reported. Among them, cryptococcosis could be a life-threatening disease. We performed a Systematic Review (PRISMA Statement) of cryptococcosis and COVID-19 co-infection, case report/series were included: a total of 34 cases were found, then we added our case report. We collected patients' data and performed a statistical analysis comparing two groups of patients sorted by outcome: "dead” and "alive”. Three cases were excluded for lack of information. To compare categorical data, we used a Fisher-exact test (α=0.05). To compare quantitative variables a U Mann-Whitney test was used (α=0.05), with a 95% Confidence Interval. A total of 32 co-infected patients were included in the statistical analysis. Mortality rate was 17/32 (53.1%): these patients were included in "dead” group, and 15/32 (46.9%) patients survived and were included in "alive” group. Overall, males were 25/32 (78.1%), the median age was 60 years (IQR 53–70) with non-statistically significant difference between groups (p=0.149 and p=0.911, respectively). Three variables were associated with mortality: ARDS, ICU admission and inadequate treatment. Overall, 21 out of 24 (87.5%) patients were in ARDS with a statistically significant difference among two groups (p=0.028). ICU admission for COVID-19 was observed in 18/26 (69.2%), more frequently among dead group (p=0.034). Finally, 15/32 (46.9%) patients had adequate treatment (amphotericin B + flucytosine for invasive cryptococcosis) mostly among alive patients (p=0.039). In conclusion, mortality due to cryptococcal infection among COVID-19 patients remains high but an early diagnosis and appropriate treatment could reduce mortality.

Outcomes of Thoracoscopic Lobectomy after Recent COVID-19 Infection.

BACKGROUND: The COVID-19 outbreak had a massive impact on lung cancer patients with the rise in the incidence and mortality of lung cancer. METHODS: We evaluated whether a recent COVID-19 infection affected the outcome of patients undergoing thoracoscopic lobectomy for lung cancer using a retrospective observational mono-centric study conducted between January 2020 and August 2022. Postoperative complications and 90-day mortality were reported. We compared lung cancer patients with a recent history of COVID-19 infection prior to thoracoscopic lobectomy to those without recent COVID-19 infection. Univariable and multivariable analyses were performed. RESULTS: One hundred and fifty-three consecutive lung cancer patients were enrolled. Of these 30 (19%), had a history of recent COVID-19 infection prior to surgery. COVID-19 was not associated with a higher complication rate or 90-day mortality. Patients with recent COVID-19 infection had more frequent pleural adhesions (p = 0.006). There were no differences between groups regarding postoperative complications, conversion, drain removal time, total drainage output, and length of hospital stay. CONCLUSIONS: COVID-19 infection did not affect the outcomes of thoracoscopic lobectomy for lung cancer. The treatment of these patients should not be delayed in case of recent COVID-19 infection and should not differ from that of the general population.

Invasive cryptococcal disease in COVID-19: systematic review of the literature and analysis.

During the Coronavirus Disease 2019 (COVID-19) pandemic, an increasing number of fungal infections associated with SARS-CoV-2 infection have been reported. Among them, cryptococcosis could be a life-threatening disease. We performed a Systematic Review (PRISMA Statement) of cryptococcosis and COVID-19 co-infection, case report/series were included: a total of 34 cases were found, then we added our case report. We collected patients' data and performed a statistical analysis comparing two groups of patients sorted by outcome: "dead" and "alive". Three cases were excluded for lack of information. To compare categorical data, we used a Fisher-exact test (α=0.05). To compare quantitative variables a U Mann-Whitney test was used (α=0.05), with a 95% Confidence Interval. A total of 32 co-infected patients were included in the statistical analysis. Mortality rate was 17/32 (53.1%): these patients were included in "dead" group, and 15/32 (46.9%) patients survived and were included in "alive" group. Overall, males were 25/32 (78.1%), the median age was 60 years (IQR 53-70) with non-statistically significant difference between groups (p=0.149 and p=0.911, respectively). Three variables were associated with mortality: ARDS, ICU admission and inadequate treatment. Overall, 21 out of 24 (87.5%) patients were in ARDS with a statistically significant difference among two groups (p=0.028). ICU admission for COVID-19 was observed in 18/26 (69.2%), more frequently among dead group (p=0.034). Finally, 15/32 (46.9%) patients had adequate treatment (amphotericin B + flucytosine for invasive cryptococcosis) mostly among alive patients (p=0.039). In conclusion, mortality due to cryptococcal infection among COVID-19 patients remains high but an early diagnosis and appropriate treatment could reduce mortality.

Epidemiological and clinical aspects of hepatitis B virus infection in Italy over the last 50 years.

A relevant gradual reduction of both the incidence rate of acute hepatitis B (AHB) and prevalence of chronic hepatitis B has occurred in Italy in the last 50 years, due to substantial epidemiological changes: Improvement in socioeconomic and hygienic conditions, reduction of the family unit, accurate screening of blood donations, abolition of re-usable glass syringes, hepatitis B virus (HBV)-universal vaccination started in 1991, use of effective well tolerated nucleo(t)side analogues able to suppress HBV replication available from 1998, and educational mediatic campaigns against human immunodeficiency virus infection focusing on the prevention of sexual and parenteral transmission of infections. As an example, AHB incidence has gradually decreased from 10/100000 inhabitants in 1985 to 0.21 in 2020. Unfortunately, the coronavirus disease 2019 (COVID-19) pandemic has interrupted the trend towards HBV eradication. In fact, several HBV chronic carriers living in the countryside have become unable to access healthcare facilities for screening, diagnosis, clinical management, and nucleo(t)side analogue therapy in the COVID-19 pandemic, mainly for anxiety of becoming infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), movement restrictions, and reduced gains from job loss. In addition, one-third of healthcare facilities and personnel for HBV patients have been devolved to the COVID-19 assistance.

COVID-19 as Another Trigger for HBV Reactivation: Clinical Case and Review of Literature.

Universal hepatitis B virus (HBV) vaccination has been applied for years in most countries, but HBV infection remains an unresolved public health problem worldwide, with over one-third of the world's population infected during their lifetime and approximately 248 million hepatitis B surface antigen (HBsAg) chronic carriers. HBV infection may reactivate with symptomatic and sometimes life-threatening clinical manifestations due to a reduction in the immune response of various origins, due to chemotherapy or immunosuppressive therapy, treatments increasingly practiced worldwide. SARS-CoV-2 and its COVID-19 associated disease have introduced new chances for HBV reactivation due to the use of dexamethasone and tocilizumab to counteract the cytokine storm. This could and should be prevented by accurate screening of HBV serologic markers and adequate pharmacologic prophylaxis. This article describes the case of a patient with COVID-19 who developed HBV reactivation and died of liver failure and analyzes published data on this setting to provide useful information to physicians who manage these patients during the SARS-CoV-2 pandemic.

Alveolar-Arterial Gradient Is an Early Marker to Predict Severe Pneumonia in COVID-19 Patients.

BACKGROUND: One of the main challenges in the management of COVID-19 patients is to early assess and stratify them according to their risk of developing severe pneumonia. The alveolar-arterial oxygen gradient (D(A-a)O2) is defined as the difference between the alveolar and arteriolar concentration of oxygen, an accurate index of the ventilatory function. The aim of this study is to evaluate D(A-a)O2 as a marker for predicting severe pneumonia in COVID-19 patients, in comparison to the PaO2/FiO2. METHODS: This retrospective, multicentric cohort study included COVID-19 patients admitted to two Italian hospitals between April and July 2020. Clinical and laboratory data were retrospectively collected at the time of hospital admission and during hospitalization. The presence of severe COVID-19 pneumonia was evaluated, as defined by the Infectious Diseases Society of America (IDSA) criteria for community-acquired pneumonia (CAP). Patients were divided in severe and non-severe groups. RESULTS: Overall, 53 COVID-19 patients were included in the study: male were 30/53 (57%), and 10/53 (19%) had severe pneumonia. Patients with severe pneumonia reported dyspnea more often than non-severe patients (90% vs. 39.5%; p = 0.031). A history of chronic obstructive pulmonary disease (COPD) was recalled by 5/10 (50%) patients with severe pneumonia, and only in 6/43 (1.4%) of non-severe cases (p = 0.023). A ROC curve, for D(A-a)O2 >60 mmHg in detecting severe pneumonia, showed an area under the curve (AUC) of 0.877 (95% CI: 0.675-1), while the AUC of PaO2/FiO2 < 263 mmHg resulted 0.802 (95% CI: 0.544-1). D(A-a)O2 in comparison to PaO2/FiO2 had a higher sensibility (77.8% vs. 66.7%), positive predictive value (75% vs. 71.4%), negative predictive value (94% vs. 91%), and similar specificity (94.4% vs. 95.5%). CONCLUSIONS: Our study suggests that the D(A-a)O2 is more appropriate than PaO2/FiO2 to identify COVID-19 patients at risk of developing severe pneumonia early.

Prevention of HBV Reactivation in Hemato-Oncologic Setting during COVID-19.

Onco-hematologic patients are highly susceptible to SARS-CoV-2 infection and, once infected, frequently develop COVID-19 due to the immunosuppression caused by tumor growth, chemotherapy and immunosuppressive therapy. In addition, COVID-19 has also been recognized as a further cause of HBV reactivation, since its treatment includes the administration of corticosteroids and some immunosuppressive drugs. Consequently, onco-hematologic patients should undergo SARS-CoV-2 vaccination and comply with the rules imposed by lockdowns or other forms of social distancing. Furthermore, onco-hematologic facilities should be adapted to new needs and provided with numerically adequate health personnel vaccinated against SARS-CoV-2 infection. Onco-hematologic patients, both HBsAg-positive and HBsAg-negative/HBcAb-positive, may develop HBV reactivation, made possible by the support of the covalently closed circular DNA (cccDNA) persisting in the hepatocytic nuclei of patients with an ongoing or past HBV infection. This occurrence must be prevented by administering high genetic barrier HBV nucleo(t)side analogues before and throughout the antineoplastic treatment, and then during a long-term post-treatment follow up. The prevention of HBV reactivation during the SARS-CoV-2 pandemic is the topic of this narrative review.

Phylogeography and genomic epidemiology of SARS-CoV-2 in Italy and Europe with newly characterized Italian genomes between February-June 2020.

The aims of this study were to characterize new SARS-CoV-2 genomes sampled all over Italy and to reconstruct the origin and the evolutionary dynamics in Italy and Europe between February and June 2020. The cluster analysis showed only small clusters including < 80 Italian isolates, while most of the Italian strains were intermixed in the whole tree. Pure Italian clusters were observed mainly after the lockdown and distancing measures were adopted. Lineage B and B.1 spread between late January and early February 2020, from China to Veneto and Lombardy, respectively. Lineage B.1.1 (20B) most probably evolved within Italy and spread from central to south Italian regions, and to European countries. The lineage B.1.1.1 (20D) developed most probably in other European countries entering Italy only in the second half of March and remained localized in Piedmont until June 2020. In conclusion, within the limitations of phylogeographical reconstruction, the estimated ancestral scenario suggests an important role of China and Italy in the widespread diffusion of the D614G variant in Europe in the early phase of the pandemic and more dispersed exchanges involving several European countries from the second half of March 2020.

SARS-CoV-2 infection: a hurricane that does not ignore chronic hepatitis.

BACKGROUND: The COVID-19 pandemic significantly compromised screening, laboratory controls, clinical surveillance and treatment of chronic hepatitis patients and worsened their outcome, as evidenced by its significant correlation with advanced cirrhosis, liver decompensation and mortality. RESULTS: This pandemic significantly impaired also the sector of liver transplantation, whose wards, operating rooms, outpatients' facilities, and healthcare personnel have been dedicated to patients with COVID-19. In addition, screening and treatment for HBV infection have been delayed or suspended in in most countries, with an increased risk of viral reactivation. Similar delay or suspension have also occurred for universal hepatitis B vaccination programs in many countries. Likewise, COVID-19 pandemic has made unreachable the goal of elimination of HCV infection as a worldwide public-health issue predicted for 2030 by the WHO. CONCLUSION: This review article demonstrates how COVID-19 pandemic is causing serious damage to the sector of liver disease, which has quickly lost the beneficial effects of years of study, research, and clinical and technological application, as well as considerable financial investments.

Hepatitis B virus/hepatitis D virus epidemiology: Changes over time and possible future influence of the SARS-CoV-2 pandemic.

Hepatitis D virus (HDV) is a defective liver-tropic virus that needs the helper function of hepatitis B virus (HBV) to infect humans and replicate. HDV is transmitted sexually or by a parenteral route, in co-infection with HBV or by super-infection in HBV chronic carriers. HDV infection causes acute hepatitis that may progress to a fulminant form (7%-14% by super-infection and 2%-3% by HBV/HDV co-infection) or to chronic hepatitis (90% by HDV super-infection and 2%-5% by HBV/HDV co-infection), frequently and rapidly progressing to cirrhosis or hepatocellular carcinoma (HCC). Peg-interferon alfa the only recommended therapy, clears HDV in only 10%-20% of cases and, consequently, new treatment strategies are being explored. HDV endemicity progressively decreased over the 50 years from the identification of the virus, due to improved population lifestyles and economic levels, to the use of HBV nuclei(t)side analogues to suppress HBV replication and to the application of universal HBV vaccination programs. Further changes are expected during the severe acute respiratory syndrome coronavirus-2 pandemic, unfortunately towards increased endemicity due to the focus of healthcare towards coronavirus disease 2019 and the consequently lower possibility of screening and access to treatments, lower care for patients with severe liver diseases and a reduced impulse to the HBV vaccination policy.

Renal involvement in COVID-19: focus on kidney transplant sector.

INTRODUCTION: Kidney transplant recipients and patients on the waiting list for kidney transplant who acquire SARS-CoV-2 infection are at serious risk of developing severe COVID-19, with an increased risk of mortality for the their immunosuppressive state; other risk factors for mortality have been identified in some comorbidities such as obesity, diabetes, asthma and chronic lung disease. MATERIALS AND METHODS: The COVID-19 pandemic has led to a sharp reduction in kidney transplants in most countries, mainly due to the concern of patients on the waiting list for their potential increased susceptibility to acquire SARS-CoV-2 infection in healthcare facilities and for the difficulties of transplant centers to ensure full activity as hospitals have had to focus most of their attention on COVID-19 patients. Indeed, while the infection curve continued its exponential rise, there was a vertical decline in kidney donation/transplant activity. CONCLUSION: This review article focuses on the damage induced by SARS-CoV-2 infection on kidney and on the adverse effect of this pandemic on the entire kidney transplant sector.

SARS-CoV-2 shifting transmission dynamics and hidden reservoirs potentially limit efficacy of public health interventions in Italy.

We investigated SARS-CoV-2 transmission dynamics in Italy, one of the countries hit hardest by the pandemic, using phylodynamic analysis of viral genetic and epidemiological data. We observed the co-circulation of multiple SARS-CoV-2 lineages over time, which were linked to multiple importations and characterized by large transmission clusters concomitant with a high number of infections. Subsequent implementation of a three-phase nationwide lockdown strategy greatly reduced infection numbers and hospitalizations. Yet we present evidence of sustained viral spread among sporadic clusters acting as "hidden reservoirs" during summer 2020. Mathematical modelling shows that increased mobility among residents eventually catalyzed the coalescence of such clusters, thus driving up the number of infections and initiating a new epidemic wave. Our results suggest that the efficacy of public health interventions is, ultimately, limited by the size and structure of epidemic reservoirs, which may warrant prioritization during vaccine deployment.

More Severe COVID-19 in Patients With Active Cancer: Results of a Multicenter Cohort Study.

BACKGROUND: The aim of the study was to compare coronavirus disease 2019 (COVID-19) severity presentation between oncologic and non-oncologic patients and to evaluate the impact of cancer type and stage on COVID-19 course. METHODS: We performed a multicentre, retrospective study involving 13 COVID-19 Units in Campania region from February to May 2020. We defined as severe COVID-19 presentation the cases that required mechanical ventilation and/or admission to Intensive Care Units (ICU) and/or in case of death. RESULTS: We enrolled 371 COVID-19 patients, of whom 34 (9.2%) had a history or a diagnosis of cancer (24 solid, 6 onco-hematological). Oncologic patients were older (p<0.001), had more comorbidities (p<0.001) and showed a higher rate of severe COVID-19 presentation (p=0.001) and of death (p<0.001). Compared to 12 patients with non-active cancer and to 337 without cancer, the 17 patients with active cancer had more comorbidities and showed a higher rate of severe COVID-19 and of mortality (all p values <0.001). Compared to the 281 non-severe patients, the 90 subjects with a severe presentation of COVID-19 were older (p<0.01), with more comorbidities (p<0.001) and with a higher rate of cancer (p=0.001). At multivariate analysis, age (OR 1.08, 95% CI: 1.04-1.11) and suffering from cancer in an active stage (OR 5.33, 95% CI: 1.77-16.53) were independently associated with severe COVID-19. CONCLUSIONS: Since the higher risk of severe evolution of COVID-19, cancer patients, especially those with an active malignancy, should be candidates for early evaluation of symptoms and early treatment for COVID-19.

SARS-CoV-2 infection affects the lower urinary tract and male genital system: A systematic review.

PubMed, Scopus, and ISI Web of Knowledge databases were searched to identify studies published up to December 2020 on the involvement of urinary and male genital systems in COVID-19. Sixteen studies involving a total of 575 patients (538 males and 37 females) were included in this systematic review. The COVID-19 phase was available for 479 patients: 426 in the acute and 53 in the recovery phase. De novo lower urinary tract symptoms (LUTS) were observed in 43 patients and deterioration of pre-existing LUTS in 7. Bladder hemorrhage was observed in three patients and acute urinary retention in one. Regarding the male genital system, scrotal discomfort was observed in 8 patients, swelling in 14, pain in 16, and erythema in 1; low flow priapism was observed in 2 patients. Ultrasound examination identified acute orchitis in 10 patients, acute epididymitis in 7, and acute epididymo-orchitis in 16. A case-control study reported that patients with moderate COVID-19 show a significant reduction in sperm concertation, the total number of sperms per ejaculate, progressive motility, and complete motility. In contrast to what is known from the first studies on the subject, this review also includes subsequent studies that give evidence of the involvement of the lower urinary tract and male genital system in COVID-19.

The impact of the SARS-CoV-2 infection, with special reference to the hematological setting.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a disease known from a few months, caused by a recently arisen virus and, consequently, it is little known. The disease has a benign course in most infected subjects (children and young adults), is often symptomatic in adults over the age of 50 and often serious and life threatening in people with comorbidities and the elderly. The few data published on coronavirus disease-2019 (COVID-19) in the blood-oncology field report a serious clinical presentation, a serious course of the disease, and a high mortality rate, as has also been reported for other cancer contexts. The current strategy for treating patients with SARS-CoV-2 includes antivirals that are effective against other viral infections and drugs that can moderate the cytokine storm. There is no specific vaccine and consequently all possible precautions must be taken to prevent SARS-CoV-2 infection in the areas of oncology, oncohematology, and bone marrow transplantation. In this reviewer's article, we report the information currently available on SARS-CoV-2 infection to help young doctors and hematologists to successfully manage patients with COVID-19.

Management of SARS-CoV-2 pneumonia.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has rapidly spread throughout the world since December 2019 to become a global public health emergency for the elevated deaths and hospitalizations in Intensive Care Units. The severity spectrum of SARS-CoV-2 pneumonia ranges from mild to severe clinical conditions. The clinical course of SARS-CoV-2 disease is correlated with multiple factors including host characteristics (genetics, immune status, age, and general health), viral load and, above all, the host distribution of the airways and lungs of the viral receptor cells. In this review, we will briefly summarize the current knowledge of the characteristics and management of coronavirus disease 2019-pneumonia. However, other studies are needed to better understand the pathogenetic mechanisms induced by SARS-Cov-2 infection, and to evaluate the long-term consequences of the virus on the lungs.

How Fear of COVID-19 Can Affect Treatment Choices for Anaplastic Large Cell Lymphomas ALK+ Therapy: A Case Report.

BACKGROUND: The t (2; 5) chromosomal rearrangement of the ALK gene with nucleophosmin 1 gene (NPM1), resulting in an NPM1-ALK fusion, was first demonstrated in 1994 in anaplastic large cell lymphoma, (ALCL), a T-cell lymphoma responsive to cyclophosphamide, abriblastine, vincristine and prednisone in approximately 80% of cases; refractory cases usually respond favorably to brentuximab vedotin. These treatments are regarded as a bridge to allogeneic hematopoietic stem cell transplantation (allo-SCT). Nowadays, transplant procedures and the monitoring of chemotherapy patients proceed very slowly because the SARS-CoV-2 pandemic has heavily clogged the hospitals in all countries. RESULTS: A 40-year-old Caucasian woman was first seen at our clinical center in June 2020. She had ALCL ALK+, a history of failure to two previous therapeutic lines and was in complete remission after 12 courses of brentuximab, still pending allo-SCT after two failed donor selections. Facing a new therapeutic failure, we requested and obtained authorization from the Italian drug regulatory agency to administer 250 mg of crizotinib twice a day, a drug incomprehensibly not registered for ALCL ALK +. CONCLUSIONS: The response to crizotinib was optimal since no adverse event occurred, and CT-PET scans persisted negative; this drug has proved to be a valid bridge to allo-SCT.

Rescue Therapy of Refractory Diffuse Large B-Cell Lymphomas BCL2 with Venetoclax: Case Report.

Eleven years ago, a 64-year-old Caucasian man had LNH Follicular 3a, IV A stage, FLIPI 2 as a prognostic index of follicular lymphoma. He received 8 cycles of RCHOP followed by rituximab maintenance, with complete remission. Due to a systemic recurrence, a new treatment schedule (RCOMP, 6 cycles) was introduced with partial remission persisting during a long-term maintenance treatment with rituximab. Three years ago, LNH Follicular 3a progressed into GC type diffuse large B-cell lymphomas (DLBCL); 6 cycles of rituximab and bendamustine were followed by R-ICE and R OXALI DHAP treatments without beneficial effect. Due to the worse general condition (ECOG 3-4), the patient was treated with pixantrone (6 cycles) until July 10, 2019, with a partial response. On Jan 13, 2020, an extreme compassioned treatment with venetoclax alone was started; this drug was well tolerated and provided a satisfactory clinical and laboratory improvement. In June 2020, however, he developed bone marrow toxicity and septic fever. Nasal and pharyngeal secretions were SARS-CoV-2 RNA negative. Blood cultures for mycotic agents and Gram-positive, Gram-negative, and anaerobic bacteria were negative, but few days later, the patients died of sepsis due to unidentified agents. The use of venetoclax as a single drug to treat DLBCL BCL2 patients deserves further investigation.

Therapeutic strategies for severe COVID-19: a position paper from the Italian Society of Infectious and Tropical Diseases (SIMIT).

SCOPE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become pandemic, reaching almost one million death worldwide. At present standard treatment for coronavirus disease 2019 (COVID-19) is not well defined because the evidence, either from randomized or observational studies, with conflicting results, has led to rapid changes in treatment guidelines. Our aim was to narratively summarize the available literature on the management of COVID-19 in order to combine current evidence and interpretation of the data by experts who are treating patients in the frontline setting. METHODS: The panel conducted a detailed review of the literature and eventual press releases from randomized clinical trials for each possible available treatment. Inductive PubMed search waws performed for publications relevant to the topic, including all clinical trials conducted. The result was a flowchart with treatment indications for patients with COVID-19. IMPLICATIONS: After 6 months of a pandemic situation and before a possible second coronavirus wave descends on Europe, it is important to evaluate which drugs proved to be effective while also considering that results from many randomized clinical trials are still awaited. Indeed, among treatments for COVID-19, only glucocorticoids have resulted in an association with a significant decrease in mortality in published randomized controlled trials. New therapeutic strategies are urgently needed.