Treatment of COVID-19 with convalescent plasma in patients with humoral immunodeficiency - Three consecutive cases and review of the literature.

Patients lacking humoral response have been suggested to develop a less severe COVID-19, but there are some reports with a prolonged, relapsing or deadly course. From April 2020, there is growing evidence on the benefits of COVID-19 convalescent plasma (CCP) for patients with humoral immunodeficiency. Most of them had a congenital primary immunodeficiency or were on treatment with anti CD20 antibodies. We report on three patients treated in our hospital and review thirty-one more cases described in the literature. All patients but three resolved clinical picture with CCP. A dose from 200 to 800ml was enough in most cases. Antibody levels after transfusion were negative or low, suggesting consumption of them in SARS-CoV-2 neutralization. These patients have a protracted clinical course shortened after CCP. CCP could be helpful for patients with humoral immunodeficiency. It avoid relapses and chronification. CCP should be transfused as early as possible in patients with COVID-19 and humoral immunodeficiency.

Acute Kidney Injury Associated with Severe SARS-CoV-2 Infection: Risk Factors for Morbidity and Mortality and a Potential Benefit of Combined Therapy with Tocilizumab and Corticosteroids.

BACKGROUND: Acute kidney injury (AKI) is a common complication in patients with severe COVID-19. METHODS: We retrospectively reviewed 249 patients admitted to an intensive care unit (ICU) during the first wave of the pandemic to determine risk factors for AKI. Demographics, comorbidities, and clinical and outcome variables were obtained from electronic medical records. RESULTS: Univariate analysis revealed older age, higher admission serum creatinine, elevated Sequential Organ Failure Assessment (SOFA) score, elevated admission D-Dimer, elevated CRP on day 2, mechanical ventilation, vasopressor requirement, and azithromycin usage as significant risk factors for AKI. Multivariate analysis demonstrated that higher admission creatinine (p = 0.0001, OR = 2.41, 95% CI = 1.56-3.70), vasopressor requirement (p = 0.0001, OR = 3.20, 95% CI = 1.69-5.98), elevated admission D-Dimer (p = 0.008, OR = 1.0001, 95% CI = 1.000-1.001), and elevated C-reactive protein (CRP) on day 2 (p = 0.033, OR = 1.0001, 95% CI = 1.004-1.009) were independent risk factors. Conversely, the combined use of Tocilizumab and corticosteroids was independently associated with reduced AKI risk (p = 0.0009, OR = 0.437, 95% CI = 0.23-0.81). CONCLUSION: This study confirms the high rate of AKI and associated mortality among COVID-19 patients admitted to ICUs and suggests a role for inflammation and/or coagulopathy in AKI development. One should consider the possibility that early administration of anti-inflammatory agents, as is now routinely conducted in the management of COVID-19-associated acute respiratory distress syndrome, may improve clinical outcomes in patients with AKI.

Correction to "Retrospective analysis of anti-inflammatory therapies during the first wave of COVID-19 at a community hospital".

[This corrects the article on p. 244 in vol. 10, PMID: 34616660.].

Treatment of COVID-19 with convalescent plasma in patients with humoral immunodeficiency – Three consecutive cases and review of the literature Tratamiento de la COVID-19 con plasma de convalecientes en pacientes con inmunodeficiencia humoral. Tres casos consecutivos y revisión de la literatura

Patients lacking humoral response have been suggested to develop a less severe COVID-19, but there are some reports with a prolonged, relapsing or deadly course. From April 2020, there is growing evidence on the benefits of COVID-19 convalescent plasma (CCP) for patients with humoral immunodeficiency. Most of them had a congenital primary immunodeficiency or were on treatment with anti CD20 antibodies. We report on three patients treated in our hospital and review thirty-one more cases described in the literature. All patients but three resolved clinical picture with CCP. A dose from 200 to 800 ml was enough in most cases. Antibody levels after transfusion were negative or low, suggesting consumption of them in SARS-CoV-2 neutralization. These patients have a protracted clinical course shortened after CCP. CCP could be helpful for patients with humoral immunodeficiency. It avoid relapses and chronification. CCP should be transfused as early as possible in patients with COVID-19 and humoral immunodeficiency.

New insights into antibody levels against SARS-CoV-2 for healthcare personnel vaccinated with tozinameran (Comirnaty).

AIM: The aim of this study is to determine the levels of spike protein IgG and total antibodies in subjects vaccinated against SARS-CoV-2 (both infected and non-infected) and the titer evolution over time. In addition, we also addressed the performance of each of the included platforms in the study, as they are intended to measure antibody levels in naturally infected patients. MATERIALS AND METHODS: An observational study including 288 volunteer healthcare professionals vaccinated against SARS-CoV-2 (Comirnaty™) at the Andújar Alto Guadalquivir Hospital. Serum samples were obtained in September 2020 and 14 and 90 days after administration of the second dose. The following in vitro methods were used: Elecsys Anti-SARS-CoV-2 N and Elecsys Anti-SARS-CoV-2 S (Roche, Germany) and EliA SARS-CoV-2-Sp1 IgG (Thermo Fisher Scientific, Germany). RESULTS: For the Elecsys S method at 1/10 dilution and for the EliA Sp1 IgG method at 1/5 dilution, 54% and 19% of samples were out of range, respectively. The vaccine activated a high humoral response- 0 to 3000 BAU/mL being the "normal titer range" in all volunteers. Patients vaccinated after COVID-19 exhibited higher total S antibody load values than non-vaccinated volunteers while showing the same response for S IgG isotype. Titers decreased up to 86% in the case of S IgG neutralizing antibodies. CONCLUSIONS: The characterization of human response to SARS-CoV-2 vaccines is still far from being completely elucidated. It is important to increase the methods dynamic range to study humoral response evolution in depth and decide whether booster doses or seasonal vaccination plans will be necessary to definitively control the pandemic.

Treatment of COVID-19 with convalescent plasma in patients with humoral immunodeficiency - Three consecutive cases and review of the literature.

Patients lacking humoral response have been suggested to develop a less severe COVID-19, but there are some reports with a prolonged, relapsing or deadly course. From April 2020, there is growing evidence on the benefits of COVID-19 convalescent plasma (CCP) for patients with humoral immunodeficiency. Most of them had a congenital primary immunodeficiency or were on treatment with anti CD20 antibodies. We report on three patients treated in our hospital and review thirty-one more cases described in the literature. All patients but three resolved clinical picture with CCP. A dose from 200 to 800ml was enough in most cases. Antibody levels after transfusion were negative or low, suggesting consumption of them in SARS-CoV-2 neutralization. These patients have a protracted clinical course shortened after CCP. CCP could be helpful for patients with humoral immunodeficiency. It avoid relapses and chronification. CCP should be transfused as early as possible in patients with COVID-19 and humoral immunodeficiency.

Clot Stiffness Measured By Seer Sonorheometry As a Marker Of Poor Prognosis In Hospitalized COVID-19 Patients.

A high risk of thrombotic complications has been observed among severely ill COVID-19 patients. Viscoelastic tests (VET) have shown a hypercoagulable profile in these patients, although so far there is no clear evidence on the use of these tools as predictors of risk in the clinical course of patients. In this study we aimed to evaluate the association between Quantra® sonorheometry VET parameters, standard coagulation tests and inflammatory markers in 69 patients with COVID-19 on hospital admission with disease severity and outcome. Inflammatory markers were elevated in a high percentage of patients, as were coagulation-related parameters such as fibrinogen and D-dimer levels. Quantra® sonorheometry analysis revealed increased clot stiffness (CS), especially due to increased fibrinogen contribution (FCS) in 63.7%. Analysis of clot stability to lysis (CSL) on the Quantra showed a value of 100%, suggesting hypofibrinolysis, in 32.4%. Age > 65 years, elevated values of fibrinogen, D-dimer, LDH, increased CS and CSL were significantly associated with worsening disease. The combination of elevated FCS and D-dimer values showed a particularly high prognostic value in distinguishing patients with severe symptomatology. In conclusion, FCS measured by Quantra® system and its combination with D-dimer could be established as a powerful tool to identify poor prognosis in COVID-19 patients on hospital admission.

Proliferative Glomerulonephritis With Monotypic Immunoglobulin Deposits: An Unusual Presentation in the Setting of Multiple Inciting Events Including COVID-19 Vaccination

Proliferative glomerulonephritis with monoclonal immunoglobulin (mIg) deposits (PGNMID) is a rare glomerular disease characterized by glomerular deposits of mIg. The pathogenesis of PGNMID without circulating mIg is poorly understood but a role for aberrant immune response to infection or another exogenous stimulus has been proposed. We describe a unique case of PGNMID that presented with multiple episodes of acute kidney injury, nephritic syndrome, and hypocomplementemia, associated with self-limited febrile illnesses or COVID-19 vaccination. Monoclonal IgG lambda was detected in the serum and urine, consistent with monoclonal gammopathy of renal significance (MGRS). Consecutive kidney biopsies demonstrated evolving morphologic and immunohistologic features, with monotypic IgG lambda deposits identified only in the third biopsy. Despite the need for dialysis, renal dysfunction and hypocomplementemia resolved after each episode with corticosteroid therapy. This case illustrates infections or COVID vaccination maybe “second hits” that promote mIg deposition in PGNMID, possibly due to cytokine release by innate immune cells that promote endothelial cell injury. 

Routine Immunization Programs for Children during the COVID-19 Pandemic in Ecuador, 2020-Hidden Effects, Predictable Consequences.

The COVID-19 pandemic has led to a global disruption of several services, including routine immunizations. This effect has been described in several countries, but there are few detailed studies in Latin America and no reports in Ecuador. Therefore, this work aims to quantify the reduction in routine immunizations for infants during the 2020 COVID-19 pandemic in Ecuador. 2018, 2019, and 2020 data were obtained from the Ministry of Health, Ecuador. The number of doses and the extent of immunization coverage was descriptively compared for four vaccines: rotavirus (ROTA), poliovirus (PV), pneumococcal (PCV), and pentavalent (PENTA) vaccines. There was no significant difference in doses applied during the 2018 and 2019 years. However, a significant (p < 0.05) drop of 137,000 delivered doses was observed in 2020 compared to the pre-pandemic years. Reductions in the percentage of coverage were more pronounced for the PENTA vaccine (17.7%), followed by PV (16.4%), ROTA (12%), and PCV vaccines (10.7%). Spatial analysis shows a severe impact on vaccination coverage on provinces from the Coast and Highland regions of the country. The pandemic has significantly impacted the immunization programs for infants across Ecuador. This retrospective analysis shows an urgent need to protect vulnerable zones and populations during public health emergencies.

"MATH+" Multi-Modal Hospital Treatment Protocol for COVID-19 Infection: Clinical and Scientific Rationale.

In December 2019, coronavirus disease 2019 (COVID-19), a severe respiratory illness caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China. The greatest impact that COVID-19 had was on intensive care units (ICUs), given that approximately 20% of hospitalized cases developed acute respiratory failure (ARF) requiring ICU admission. Based on the assumption that COVID-19 represented a viral pneumonia and no anti-coronaviral therapy existed, nearly all national and international health care societies recommended "supportive care only" avoiding other therapies outside of randomized controlled trials, with a specific prohibition against the use of corticosteroids in treatment. However, early studies of COVID-19-associated ARF reported inexplicably high mortality rates, with frequent prolonged durations of mechanical ventilation (MV), even from centers expert in such supportive care strategies. These reports led the authors to form a clinical expert panel called the Front-Line COVID-19 Critical Care Alliance (www.flccc.net). The panel collaboratively reviewed the emerging clinical, radiographic, and pathological reports of COVID-19 while initiating multiple discussions among a wide clinical network of front-line clinical ICU experts from initial outbreak areas in China, Italy, and New York. Based on the shared early impressions of "what was working and what wasn't working", the increasing medical journal publications and the rapidly accumulating personal clinical experiences with COVID-19 patients, a treatment protocol was created for the hospitalized patients based on the core therapies of methylprednisolone, ascorbic acid, thiamine, heparin and non-antiviral co-interventions (MATH+). This manuscript reviews the scientific and clinical rationale behind MATH+ based on published in-vitro, pre-clinical, and clinical data in support of each medicine, with a special emphasis of studies supporting their use in the treatment of patients with viral syndromes and COVID-19 specifically.

Retrospective analysis of anti-inflammatory therapies during the first wave of COVID-19 at a community hospital.

BACKGROUND: Our understanding of the severe acute respiratory syndrome coronavirus 2 has evolved since the first reported cases in December 2019, and a greater emphasis has been placed on the hyper-inflammatory response in severely ill patients. The purpose of this study was to determine risk factors for mortality and the impact of anti-inflammatory therapies on survival. AIM: To determine the impact of various therapies on outcomes in severe coronavirus disease 2019 patients with a focus on anti-inflammatory and immune-modulating agents. METHODS: A retrospective analysis was conducted on 261 patients admitted or transferred to the intensive care unit in two community hospitals between March 12, 2020 and June 17, 2020. Totally 167 patients received glucocorticoid (GC) therapy. Seventy-three patients received GC alone, 94 received GC and tocilizumab, 28 received tocilizumab monotherapy, and 66 received no anti-inflammatory therapy. RESULTS: Patient survival was associated with GC use, either alone or with tocilizumab, and decreased vasopressor requirements. Delayed administration of GC was found to decrease the survival benefit of GC therapy. No difference in survival was found with varying anticoagulant doses, convalescent plasma, tocilizumab monotherapy; prone ventilation, hydroxychloroquine, azithromycin, or intravenous ascorbic acid use. CONCLUSION: This analysis demonstrated the survival benefit associated with anti-inflammatory therapy of GC, with or without tocilizumab, with the combination providing the most benefit. More studies are needed to assess the optimal timing of anti-inflammatory therapy initiation.

A scoping review of the pathophysiology of COVID-19.

COVID-19 is a highly heterogeneous and complex medical disorder; indeed, severe COVID-19 is probably amongst the most complex of medical conditions known to medical science. While enormous strides have been made in understanding the molecular pathways involved in patients infected with coronaviruses an overarching and comprehensive understanding of the pathogenesis of COVID-19 is lacking. Such an understanding is essential in the formulation of effective prophylactic and treatment strategies. Based on clinical, proteomic, and genomic studies as well as autopsy data severe COVID-19 disease can be considered to be the connection of three basic pathologic processes, namely a pulmonary macrophage activation syndrome with uncontrolled inflammation, a complement-mediated endothelialitis together with a procoagulant state with a thrombotic microangiopathy. In addition, platelet activation with the release of serotonin and the activation and degranulation of mast cells contributes to the hyper-inflammatory state. Auto-antibodies have been demonstrated in a large number of hospitalized patients which adds to the end-organ damage and pro-thrombotic state. This paper provides a clinical overview of the major pathogenetic mechanism leading to severe COVID-19 disease.

Catastrophic Thromboembolic Syndrome During the COVID-19 Pandemic.

Since March 2020, the SARS-CoV-2 virus known to cause COVID-19 has presented in many ways and it seems to affect almost all organ systems. One of its detrimental effects is on the coagulation system. Disruption of the coagulation pathway or hypercoagulability has been reported extensively in many articles and studies. It seems there is no specific pattern or location of the coagulopathy. The coagulopathy can present as part of the respiratory disease process or as an isolated phenomenon. Many articles had reported that the thrombus can be a venous thromboembolic phenomenon such as deep venous thrombosis (DVT), portal vein thrombosis, pulmonary embolism (PE), or as arterial thrombosis, for instance, coronary artery thrombosis, cerebrovascular thromboembolic disease (i.e., stroke), or an aortic thrombus. One of the disastrous presentations is what is called "catastrophic thrombosis syndrome." This syndrome is characterized by multiple thromboses that take place in different parts of the vascular system at different parts of the body at the same time. In many studies, D-dimer levels have been shown to predict the risk of increased thromboembolism in SARS-CoV-2. However, an appropriate anticoagulation agent, dosage, and duration are yet to be determined. We are presenting an interesting case of a female who suffered catastrophic thrombosis syndrome despite being on prophylactic anticoagulation. She presented with leg pain and was found to have extensive multiple thrombi starting from the ascending/descending aorta and extending to the distal peroneal arteries.

Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19.

BACKGROUND: After COVID-19 emerged on U.S shores, providers began reviewing the emerging basic science, translational, and clinical data to identify potentially effective treatment options. In addition, a multitude of both novel and repurposed therapeutic agents were used empirically and studied within clinical trials. AREAS OF UNCERTAINTY: The majority of trialed agents have failed to provide reproducible, definitive proof of efficacy in reducing the mortality of COVID-19 with the exception of corticosteroids in moderate to severe disease. Recently, evidence has emerged that the oral antiparasitic agent ivermectin exhibits numerous antiviral and anti-inflammatory mechanisms with trial results reporting significant outcome benefits. Given some have not passed peer review, several expert groups including Unitaid/World Health Organization have undertaken a systematic global effort to contact all active trial investigators to rapidly gather the data needed to grade and perform meta-analyses. DATA SOURCES: Data were sourced from published peer-reviewed studies, manuscripts posted to preprint servers, expert meta-analyses, and numerous epidemiological analyses of regions with ivermectin distribution campaigns. THERAPEUTIC ADVANCES: A large majority of randomized and observational controlled trials of ivermectin are reporting repeated, large magnitude improvements in clinical outcomes. Numerous prophylaxis trials demonstrate that regular ivermectin use leads to large reductions in transmission. Multiple, large "natural experiments" occurred in regions that initiated "ivermectin distribution" campaigns followed by tight, reproducible, temporally associated decreases in case counts and case fatality rates compared with nearby regions without such campaigns. CONCLUSIONS: Meta-analyses based on 18 randomized controlled treatment trials of ivermectin in COVID-19 have found large, statistically significant reductions in mortality, time to clinical recovery, and time to viral clearance. Furthermore, results from numerous controlled prophylaxis trials report significantly reduced risks of contracting COVID-19 with the regular use of ivermectin. Finally, the many examples of ivermectin distribution campaigns leading to rapid population-wide decreases in morbidity and mortality indicate that an oral agent effective in all phases of COVID-19 has been identified.

The time to offer treatments for COVID-19.

Background: COVID-19 has several overlapping phases. Treatments to date have focused on the late stage of disease in hospital. Yet, the pandemic is by propagated by the viral phase in out-patients. The current public health strategy relies solely on vaccines to prevent disease.Methods: We searched the major national registries, pubmed.org, and the preprint servers for all ongoing, completed and published trial results.Results: As of 2/15/2021, we found 111 publications reporting findings on 14 classes of agents, and 9 vaccines. There were 62 randomized controlled studies, the rest retrospective observational analyses. Only 21 publications dealt with outpatient care. Remdesivir and high titer convalescent plasma have emergency use authorization for hospitalized patients in the U.S.A. There is also support for glucocorticoid treatment of the COVID-19 respiratory distress syndrome. Monoclonal antibodies are authorized for outpatients, but supply is inadequate to treat all at time of diagnosis. Favipiravir, ivermectin, and interferons are approved in certain countries.Expert Opinion: Vaccines and antibodies are highly antigen specific, and new SARS-Cov-2 variants are appearing. We call on public health authorities to authorize treatments with known low-risk and possible benefit for outpatients in parallel with universal vaccination.

The Importance of Understanding the Stages of COVID-19 in Treatment and Trials.

COVID-19, caused by SARS-CoV-2, continues to be a major health problem since its first description in Wuhan, China, in December 2019. Multiple drugs have been tried to date in the treatment of COVID-19. Critical to treatment of COVID-19 and advancing therapeutics is an appreciation of the multiple stages of this disease and the importance of timing for investigation and use of various agents. We considered articles related to COVID-19 indexed on PubMed published January 1, 2020-November 15, 2020, and considered papers on the medRxiv preprint server. We identified relevant stages of COVID-19 including three periods: pre-exposure, incubation, and detectable viral replication; and five phases: the viral symptom phase, the early inflammatory phase, the secondary infection phase, the multisystem inflammatory phase, and the tail phase. This common terminology should serve as a framework to guide when COVID-19 therapeutics being studied or currently in use is likely to provide benefit rather than harm.

Clinical and Scientific Rationale for the "MATH+" Hospital Treatment Protocol for COVID-19.

In December 2019, COVID-19, a severe respiratory illness caused by the new coronavirus SARS-CoV-2 (COVID-19) emerged in Wuhan, China. The greatest impact that COVID-19 had was on intensive care units (ICUs), given that approximately 20% of hospitalized cases developed acute respiratory failure (ARF) requiring ICU admission. Based on the assumption that COVID-19 represented a viral pneumonia and no anti-coronaviral therapy existed, nearly all national and international health care societies' recommended "supportive care only" avoiding other therapies outside of randomized controlled trials, with a specific prohibition against the use of corticosteroids in treatment. However, early studies of COVID-19-associated ARF reported inexplicably high mortality rates, with frequent prolonged durations of mechanical ventilation (MV), even from centers expert in such supportive care strategies. These reports led the authors to form a clinical expert panel called the Front-Line COVID-19 Critical Care Alliance (www.flccc.net). The panel collaboratively reviewed the emerging clinical, radiographic, and pathological reports of COVID-19 while initiating multiple discussions among a wide clinical network of front-line clinical ICU experts from initial outbreak areas in China, Italy, and New York. Based on the shared early impressions of "what was working and what wasn't working," the increasing medical journal publications and the rapidly accumulating personal clinical experiences with COVID-19 patients, a treatment protocol was created for the hospitalized patients based on the core therapies of methylprednisolone, ascorbic acid, thiamine, heparin and co-interventions (MATH+). This manuscript reviews the scientific and clinical rationale behind MATH+ based on published in-vitro, pre-clinical, and clinical data in support of each medicine, with a special emphasis of studies supporting their use in the treatment of patients with viral syndromes and COVID-19 specifically. The review concludes with a comparison of published multi-national mortality data with MATH+ center outcomes.

MATH+ protocol for the treatment of SARS-CoV-2 infection: the scientific rationale.

INTRODUCTION: COVID-19 disease progresses through a number of distinct phases. The management of each phase is unique and specific. The pulmonary phase of COVID-19 is characterized by an organizing pneumonia with profound immune dysregulation, activation of clotting, and a severe microvascular injury culminating in severe hypoxemia. The core treatment strategy to manage the pulmonary phase includes the combination of methylprednisolone, ascorbic acid, thiamine, and heparin (MATH+ protocol). The rationale for the MATH+ protocol is reviewed in this paper. AREAS COVERED: We provide an overview on the pathophysiological changes occurring in patients with COVID-19 respiratory failure and a treatment strategy to reverse these changes thereby preventing progressive lung injury and death. EXPERT OPINION: While there is no single 'Silver Bullet' to cure COVID-19, we believe that the severely disturbed pathological processes leading to respiratory failure in patients with COVID-19 organizing pneumonia will respond to the combination of Methylprednisone, Ascorbic acid, Thiamine, and full anticoagulation with Heparin (MATH+ protocol).We believe that it is no longer ethically acceptable to limit management to 'supportive care' alone, in the face of effective, safe, and inexpensive medications that can effectively treat this disease and thereby reduce the risk of complications and death.