COVID-19 in Unvaccinated patients with inherited metabolic disorders: A single center experience

Patients with certain inherited metabolic disorders (IMD) are at high risk for metabolic decompensation with exposure to infections. The COVID-19 pandemic has been particularly challenging for health care providers dealing with IMD patients, in view of its unpredictable consequences in these patients. There is limited data in literature on evaluating the impact and the outcome of COVID-19 infection in these patients. This cross-sectional retrospective study on a large cohort of unvaccinated IMD patients, reviewed the incidence of COVID-19 infection, disease manifestation and outcome during the pandemic between November 2019 and July 2021. In this cohort of 1058 patients, 11.7% (n = 124) were infected with COVID-19. Their median age was 16 years (age range 2–42); 57% (n = 71) were males. Post-exposure positive test was noted in 78% (n = 97) patients, while 19% (n = 24) had symptomatic diagnosis and three patients tested positive during pre-hospital visits screening. Most patients, 68.5% (n = 85) had mild COVID-19 related symptoms such as fever, cough, headache and diarrhea while 13.7% (n = 17) patients had no symptoms. Of twenty-two patients (17.7%) who required hospitalization, 16 were adults with various intoxication and energy metabolism disorders, who developed IMD related complications such as metabolic acidosis, hyperammonemia, acute pancreatitis, hypoglycemia, rhabdomyolysis and thrombosis. Ten patients needed intensive care management. The cohort death rate was 2.4% (3 patients).Overall, the clinical course of COVID-19 infection in these IMD patients was relatively mild except for patients with intoxication and energy metabolism disorders who had high risk of developing acute metabolic decompensation with severe complications.     

Tocilizumab in patients with severe COVID-19: A single-center observational analysis

Patients with coronavirus disease 2019 (COVID-19) may develop severe respiratory distress, thought to be mediated by cytokine release. Elevated proinflammatory markers have been associated with disease severity. Tocilizumab, an interleukin-6 receptor antagonist, may be beneficial for severe COVID-19, when cytokine storm is suspected. This is a retrospective single-center analysis of the records of patients diagnosed with COVID-19 who received tocilizumab. Outcomes, including clinical improvement, mortality and changes in oxygen-support at 24, 48, and 72 hours, and 7, 14, and 28 days post-tocilizumab, are reported. Patients were evaluated by baseline pre-tocilizumab oxygenation status and changes in proinflammatory markers within 7 days post-tocilizumab are reported. Sixty-six patients received tocilizumab at a mean dose of 724 mg (7.4 mg/kg), 3.7 days from admission. At baseline, 53% of patients were on ventilation support and all had elevated proinflammatory markers, including c-reactive protein (CRP). Common comorbidities were diabetes mellitus (43%) and hypertension (74%). Most patients received concomitant glucocorticoids and hydroxychloroquine. Seven days after tocilizumab, ten patients (15.2%) had clinical improvement in their oxygenation status, and there was a 95% decrease in CRP. Within 14 days of treatment, 29% of patients had clinical improvement, 20% had minimal or no improvement, 17% worsened, 27% died, and 7% were transferred to an outside hospital. Ultimately, 42% of all patients that received tocilizumab expired and 49% were discharged. This study found limited clinical improvement in patients that received tocilizumab in the setting of severe COVID-19. Clinical trials are ongoing to further evaluate tocilizumab's benefit in this patient population.     

Tocilizumab challenge: A series of cytokine storm therapy experiences in hospitalized COVID-19 pneumonia patients

To recognize the period of exaggerated cytokine response in patients with coronavirus disease 2019 (COVID-19) pneumonia, and to describe the clinical outcomes of using tocilizumab as a treatment option. The data of 12 adult COVID-19 pneumonia patients who were followed in the inpatient clinics of Biruni University Medical Faculty Hospital (Istanbul, Turkey) were retrospectively analyzed. Diagnostic tests, laboratory examinations, clinical findings, and computed tomography of the thorax imaging results were evaluated. A dramatic laboratory and clinical improvement was observed in 83% (10 out of 12) of patients after tocilizumab. In 17% (2 out of 12) of our patients, short-term ventilator support was required in the intensive care unit. The longest hospital stay was 18 days. However, in the end, all of our patients were discharged home with good health. Although arterial oxygen saturations (87.58 ± 3.12%) dropped in room air in the pre-tocilizumab period, post-tocilizumab they normalized in all patients (94.42 ± 1%). None of them had fever after tocilizumab treatment and the levels of C-reactive protein (13.08 ± 12.89) were almost within normal limits. Eosinophil values were quite low at the time of diagnosis (10 ± 17.06), but increased significantly post-tocilizumab (155.33 ± 192.69). There is currently no proven treatment for COVID-19 induced by novel coronavirus SARS-CoV-2. Based on our experience with twelve adult COVID-19 pneumonia patients, we can say that tocilizumab, an IL-6 inhibitor, is more beneficial in preventing the damage caused by excessive cytokine response in the body if administered at the right time and provides clinical and radiological recovery.     

Inflammation in COVID-19: from pathogenesis to treatment

The coronavirus disease 2019 (COVID-19) was declared a pandemic in March 2020 by the World Health Organization (WHO). To date, there were > 163 million confirmed cases of COVID-19 and the disease has claimed > 3.3 million lives globally. As with many other diseases, inflammation is a key feature of COVID-19. When inflammation is overwhelming, it may lead to unfavorable outcomes or even death. Scientists all over the world are working tirelessly in search of therapeutic strategies to suppress or modulate inflammation in COVID-19. This review gives an overview of the role of inflammation in COVID-19. It also critically examines the various treatment approaches that target the immune system and inflammation in COVID-19, as well as highlights the key findings in the numerous studies conducted thus far.     

Role of IL-6 inhibitor in treatment of COVID-19-related cytokine release syndrome

Cytokine release syndrome (CRS) may be the key factor in the pathology of severe coronavirus disease 2019 (COVID-19). As a major driver in triggering CRS in patients with COVID-19, interleukin-6 (IL-6) appears to be a promising target for therapeutics. The results of inhibiting both trans- and classical- signaling with marketed IL-6 inhibitors (tocilizumab, siltuximab and sarilumab) in severe COVID-19 patients are effective based on several small studies and case reports thus far. In this review, we described the evidence of the IL-6 response in patients with COVID-19, clarified the pathogenesis of the role of IL-6-mediated CRS in severe COVID-19, and highlighted the rationale for the use of anti-IL-6 agents and key information regarding the potential features of these IL-6 inhibitors in COVID-19 patients.     

The role of cytokines and their antagonists in the treatment of COVID-19 patients

The coronavirus disease 2019 (COVID-19) has various presentations, of which immune dysregulation or the so-called cytokine storm syndrome (COVID-CSS) is prominent. Even though cytokines are vital regulators of body immunoinflammatory responses, their exaggerated release can be harmful. This hyperinflammatory response is more commonly observed during severe COVID-19 infections, caused by the excessive release of pro-inflammatory cytokines, such as interleukin-1 (IL-1), IL-6, IL-8, tumour necrosis factor, granulocyte-macrophage colony-stimulating factor, and interferon-gamma, making their blockers and antagonists of great interest as therapeutic options in this condition. Thus, the pathophysiology of excessive cytokine secretion is outlined, and their most important blockers and antagonists are discussed, mainly focussing on tocilizumab, an interleukin-6 receptor blocker approved to treat severe COVID-19 infections.     

Tocilizumab versus baricitinib in hospitalized patients with severe COVID-19: an open label,randomized controlled trial

ObjectiveRandomized controlled trials comparing tocilizumab and baricitinib in patients with coronavirus disease 2019 (COVID-19) are needed. This was an open-label, randomized controlled trial aiming to address this unmet need.MethodsTo determine whether baricitinib was non-inferior to tocilizumab, we assessed whether the upper boundary of the two-sided 95% CI of the hazard ratio (HR) did not exceed 1.50. The primary outcome was mechanical ventilation or death by day 28. Secondary outcomes included time to hospital discharge by day 28 and change in WHO progression scale at day 10.ResultsWe assigned 251 patients with COVID-19 and a PaO_2/FiO₂ ratio of <200 to receive either tocilizumab (n = 126) or baricitinib (n = 125) plus standard of care. Baricitinib was non-inferior to tocilizumab for the primary composite outcome of mechanical ventilation or death by day 28 (mechanical ventilation or death for patients who received baricitinib, 39.2% [n = 49/125]; mechanical ventilation or death for patients who received tocilizumab, 44.4% [n = 56/126]; HR, 0.83; 95% CI, 0.56–1.21; p 0.001 for non-inferiority). Baricitinib was non-inferior to tocilizumab for the time to hospital discharge within 28 days (patients who received baricitinib- discharged alive: 58.4% [n = 73/125] vs. patients who received tocilizumab- discharged alive: 52.4% [n = 66/126]; HR, 0.85; 95% CI, 0.61–1.18; p < 0.001 for non-inferiority). There was no significant difference between the baricitinib and tocilizumab arms in the change in WHO scale at day 10 (0.0 [95% CI, 0.0–0.0] vs. 0.0 [95% CI, 0.0–1.0]; p 0.83).DiscussionIn the setting of this trial, baricitinib was non-inferior to tocilizumab with regards to the composite outcome of mechanical ventilation or death by day 28 and the time to discharge by day 28 in patients with severe COVID-19.     

Effects of tocilizumab on mortality in hospitalized patients with COVID-19: a multicentre cohort study

ObjectivesTocilizumab has been proposed as a candidate therapy for patients with severe coronavirus disease 2019 (COVID-19), especially among those with higher systemic inflammation. We investigated the association between receipt of tocilizumab and mortality in a large cohort of hospitalized patients.MethodsIn this cohort study of patients hospitalized with COVID-19 in Spain, the primary outcome was time to death and the secondary outcome time to intensive care unit (ICU) admission or death. We used inverse probability weighting to fit marginal structural models adjusted for time-varying covariates to determine the causal relationship between receipt of tocilizumab and outcome.ResultsData from 1229 patients were analysed, with 261 patients (61 deaths) in the tocilizumab group and 969 patients (120 deaths) in the control group. In the adjusted marginal structural models, a significant interaction between receipt of tocilizumab and high C-reactive protein (CRP) levels was detected. Tocilizumab was associated with decreased risk of death (adjusted hazard ratio 0.34, 95% confidence interval 0.16–0.72, p 0.005) and ICU admission or death (adjusted hazard ratio 0.39, 95% confidence interval 0.19–0.80, p 0.011) among patients with baseline CRP >150 mg/L but not among those with CRP ≤150 mg/L. Exploratory subgroup analyses yielded point estimates that were consistent with these findings.ConclusionsIn this large observational study, tocilizumab was associated with a lower risk of death or ICU admission or death in patients with higher CRP levels. While the results of ongoing clinical trials of tocilizumab in patients with COVID-19 will be important to establish its safety and efficacy, our findings have implications for the design of future clinical trials.     

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.     

Tocilizumab for coronavirus disease 2019 in pregnancy and lactation: a narrative review

BackgroundTocilizumab is a monoclonal antibody that interrupts interleukin-6 signalling, reducing downstream effects on inflammation and the innate immune response. It was shown to reduce mortality in patients with severe or critical coronavirus disease 2019 (COVID-19). Pregnant and breastfeeding people were largely excluded from clinical trials and hence, the extent to which results can be applied to these populations is not clear.ObjectivesTo synthesize published data on tocilizumab in pregnancy and lactation, highlight important knowledge gaps, and help inform clinical decision-making about tocilizumab's use in these populations with COVID-19.SourcesPubMed was searched for studies evaluating tocilizumab in pregnancy and lactation for COVID-19 and other indications. Literature on pharmacokinetics and reproductive/fetal safety of monoclonal antibodies in general was also sought. The US Food and Drug Administration and the European Medicines Agency guidance for the industry and regulatory approval documents were reviewed.ContentPublished data on tocilizumab in pregnancy include 610 cases (n = 20 with COVID-19) together with seven mother–infant breastfeeding pairs. Higher rates of spontaneous abortion and premature birth have been reported compared with the general population, but multiple confounding variables limit interpretation. There is little data on tocilizumab exposure in the second and third trimesters when transplacental transport is highest. The effects of tocilizumab on the developing immune system are unclear. Pregnant patients with COVID-19 who received tocilizumab were often critically ill and corticosteroid use was uncommon. Neonatal follow up was limited. Tocilizumab appears to be compatible with breastfeeding.ImplicationsAlthough the available data do not raise serious safety signals, they have significant limitations and are not sufficient to delineate the complete spectrum of potential adverse outcomes that may be associated with tocilizumab exposure during pregnancy and lactation. Diligent follow up and documentation of pregnancy outcomes will be important moving forward. A more effective regulatory framework to ensure equitable inclusion of pregnant people in research is clearly needed.     

COVID-19 associated with pulmonary aspergillosis: A literature review

Bacterial or virus co-infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been reported in many studies, however, the knowledge on Aspergillus co-infection among patients with coronavirus disease 2019 (COVID-19) was limited. This literature review aims to explore and describe the updated information about COVID-19 associated with pulmonary aspergillosis. We found that Aspergillus spp. can cause co-infections in patients with COVID-19, especially in severe/critical illness. The incidence of IPA in COVID-19 ranged from 19.6% to 33.3%. Acute respiratory distress syndrome requiring mechanical ventilation was the common complications, and the overall mortality was high, which could be up to 64.7% (n = 22) in the pooled analysis of 34 reported cases. The conventional risk factors of invasive aspergillosis were not common among these specific populations. Fungus culture and galactomannan test, especially from respiratory specimens could help early diagnosis. Aspergillus fumigatus was the most common species causing co-infection in COVID-19 patients, followed by Aspergillus flavus. Although voriconazole is the recommended anti-Aspergillus agent and also the most commonly used antifungal agent, aspergillosis caused by azole-resistant Aspergillus is also possible. Additionally, voriconazole should be used carefully in the concern of complicated drug–drug interaction and enhancing cardiovascular toxicity on anti-SARS-CoV-2 agents. Finally, this review suggests that clinicians should keep alerting the possible occurrence of pulmonary aspergillosis in severe/critical COVID-19 patients, and aggressively microbiologic study in addition to SARS-CoV-2 via respiratory specimens should be indicated.     

Convalescent plasma treatment for COVID-19: Tempering expectations with the influenza experience

The COVID-19 pandemic caused by the zoonotic coronavirus, SARS-CoV-2 has swept the world in 5 months. A proportion of cases develop severe respiratory tract infections progressing to acute respiratory distress syndrome and a diverse set of complications involving different organ systems. Faced with a lack of coronavirus-specific antiviral drugs and vaccines, hundreds of clinical trials have been undertaken to evaluate repurposed drugs. Convalescent plasma from recovered patients is an attractive option because antibodies can have direct or indirect antiviral activity and immunotherapy works well in principle, in animal models, and in anecdotal reports. However, the benefits of convalescent plasma treatment can only be clearly established through carefully designed randomized clinical trials. The experience from investigations of convalescent plasma products for severe influenza offers a cautionary tale. Despite promising pilot studies, large multicenter randomized controlled trials failed to show a benefit of convalescent plasma or hyperimmune intravenous globulin for the treatment of severe influenza A virus infection. These studies provide important lessons that should inform the planning of adequately powered randomized controlled trials to evaluate the promise of convalescent plasma therapy in COVID-19 patients.     

The role of HMGB1 in COVID-19-induced cytokine storm and its potential therapeutic targets: A review

Hyperinflammation characterized by elevated proinflammatory cytokines known as ‘cytokine storms’ is the major cause of high severity and mortality seen in COVID-19 patients. The pathology behind the cytokine storms is currently unknown. Increased HMGB1 levels in serum/plasma of COVID-19 patients were reported by many studies, which positively correlated with the level of proinflammatory cytokines. Dead cells following SARS-CoV-2 infection might release a large amount of HMGB1 and RNA of SARS-CoV-2 into extracellular space. HMGB1 is a well-known inflammatory mediator. Additionally, extracellular HMGB1 might interact with SARS-CoV-2 RNA because of its high capability to bind with a wide variety of molecules including nucleic acids and could trigger massive proinflammatory immune responses. This review aimed to critically explore the many possible pathways by which HMGB1-SARS-CoV-2 RNA complexes mediate proinflammatory responses in COVID-19. The contribution of these pathways to impair host immune responses against SARS-CoV-2 infection leading to a cytokine storm was also evaluated. Moreover, since blocking the HMGB1-SARS-CoV-2 RNA interaction might have therapeutic value, some of the HMGB1 antagonists have been reviewed. The HMGB1- SARS-CoV-2 RNA complexes might trigger endocytosis via RAGE which is linked to lysosomal rupture, PRRs activation, and pyroptotic death. High levels of the proinflammatory cytokines produced might suppress many immune cells leading to uncontrolled viral infection and cell damage with more HMGB1 released. Altogether these mechanisms might initiate a proinflammatory cycle leading to a cytokine storm. HMGB1 antagonists could be considered to give benefit in alleviating cytokine storms and serve as a potential candidate for COVID-19 therapy.     

COVID-19 vaccines: Knowing the unknown

Vaccine development against SARS-CoV-2 has drawn attention around the globe due to the exploding pandemic. Although COVID-19 is caused by a new coronavirus, SARS-CoV-2, previous research on other coronavirus vaccines, such as FIPV, SARS, and MERS, has provided valuable information for the rapid development of COVID-19 vaccine. However, important knowledge gaps remain — some are specific to SARS-CoV-2, others are fundamental to immunology and vaccinology. Here, we discuss areas that need to be addressed for COVID-19 vaccine development, and what can be learned from examples of vaccine development in the past. Since the beginning of the outbreak, the research progress on COVID-19 has been remarkable. We are therefore optimistic about the rapid development of COVID-19 vaccine.     

Quercetin for the treatment of COVID-19 patients: A systematic review and meta-analysis

Currently approved therapies for COVID-19 are mostly limited by their low availability, high costs or the requirement of parenteral administration by trained medical personnel in an in-hospital setting. Quercetin is a cheap and easily accessible therapeutic option for COVID-19 patients. However, it has not been evaluated in a systematic review until now. We aimed to conduct a meta-analysis to assess the effect of quercetin on clinical outcomes in COVID-19 patients. Various databases including PubMed, the Cochrane Library and Embase were searched from inception until 5 October 2022 and results from six randomized controlled trials (RCTs) were pooled using a random-effects model. All analyses were conducted using RevMan 5.4 with odds ratio (OR) as the effect measure. Quercetin decreased the risk of intensive care unit admission (OR = 0.31; 95% confidence interval (CI) 0.10–0.99) and the incidence of hospitalisation (OR = 0.25; 95% CI 0.10–0.62) but did not decrease the risk of all-cause mortality and the rate of no recovery. Quercetin may be of benefit in COVID-19 patients, especially if administered in its phytosome formulation which greatly enhances its bioavailability but large-scale RCTs are needed to confirm these findings.     

Scientific evidence in the COVID-19 treatment: A comprehensive review

In December 2019, cases of unknown origin pneumonia appeared in Wuhan, China; the causal agent of this pneumonia was a new virus of the coronaviridae family called severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). According to the clinical severity, symptoms and response to the different treatments, the evolution of the disease is divided in three phases. We analysed the most used treatments for coronavirus disease 2019 and the phase in which they are supposed to be effective. In the viral phase, remdesivir has demonstrated reduction in recovery time but no mortality reduction. Other drugs proposed for viral phase such as convalescent plasma and lopinavir/ritonavir did not demonstrate to be effective. In the inflammatory phase, corticosteroids demonstrated reduction of 28-d mortality in patients who needed oxygen, establishing that a corticosteroid regimen should be part of the standard treatment of critically ill patients. There are other immunosuppressive and immunomodulatory treatments such as anakinra, sarilumab, tocilizumab, colchicine or baricitinib that are being studied. Other treatments that were proposed at the beginning, like hydroxichloroquine or azithromycin, demonstrated no efficacy and increased mortality when combined.