Characterizing Long COVID: Deep Phenotype of a Complex Condition

Importance: Since late 2019, the novel coronavirus SARS-CoV-2 has given rise to a global pandemic and introduced many health challenges with economic, social, and political consequences. In addition to a complex acute presentation that can affect multiple organ systems, there is mounting evidence of various persistent long-term sequelae. The worldwide scientific community is characterizing a diverse range of seemingly common long-term outcomes associated with SARS-CoV-2 infection, but the underlying assumptions in these studies vary widely making comparisons difficult. Numerous publications describe the clinical manifestations of post-acute sequelae of SARS-CoV-2 infection (PASC or long COVID), but they are difficult to integrate because of heterogeneous methods and the lack of a standard for denoting the many phenotypic manifestations of long COVID. Observations: We identified 303 articles published before April 29, 2021, curated 59 relevant manuscripts that described clinical manifestations in 81 cohorts of individuals three weeks or more following acute COVID-19, and mapped 287 unique clinical findings to Human Phenotype Ontology (HPO) terms. Conclusions and Relevance: Patients and clinicians often use different terms to describe the same symptom or condition. Addressing the heterogeneous and inconsistent language used to describe the clinical manifestations of long COVID combined with the lack of standardized terminologies for long COVID will provide a necessary foundation for comparison and meta-analysis of different studies. Translating long COVID manifestations into computable HPO terms will improve the analysis, data capture, and classification of long COVID patients. If researchers, clinicians, and patients share a common language, then studies can be compared or pooled more effectively. Furthermore, mapping lay terminology to HPO for long COVID manifestations will help patients assist clinicians and researchers in creating phenotypic characterizations that are computationally accessible, which may improve the stratification and thereby diagnosis and treatment of long COVID.

Download Full-text

Challenges in defining Long COVID: Striking differences across literature, Electronic Health Records, and patient-reported information

10.1101/2021.03.20.21253896 ◽

2021 ◽

Author(s):

Halie M. Rando ◽

Tellen D. Bennett ◽

James Brian Byrd ◽

Carolyn Bramante ◽

Tiffany J. Callahan ◽

...

Keyword(s):

Electronic Health Records ◽

Multiple Organ ◽

Health Records ◽

Health Crisis ◽

Organ Systems ◽

Wide Range ◽

Patient Reported ◽

Electronic Health ◽

Novel Coronavirus

Since late 2019, the novel coronavirus SARS-CoV-2 has introduced a wide array of health challenges globally. In addition to a complex acute presentation that can affect multiple organ systems, increasing evidence points to long-term sequelae being common and impactful. As the worldwide scientific community forges ahead with efforts to characterize a wide range of outcomes associated with SARS-CoV-2 infection, the proliferation of available data has made it clear that formal definitions are needed in order to design robust and consistent studies of Long COVID that consistently capture variation in long-term outcomes. In the present study, we investigate the definitions used in the literature published to date and compare them against data available from electronic health records and patient-reported information collected via surveys. Long COVID holds the potential to produce a second public health crisis on the heels of the pandemic. Proactive efforts to identify the characteristics of this heterogeneous condition are imperative for a rigorous scientific effort to investigate and mitigate this threat.

Download Full-text

Leukoencephalopathy and cerebral edema as the presenting manifestations of SLE in an ANA-negative adolescent female: A case report and review of literature.

10.21203/rs.2.22477/v1 ◽

2020 ◽

Author(s):

Alexandra Theisen ◽

Paroma Bose ◽

Christina Knight ◽

Melissa Oliver

Keyword(s):

Cerebral Edema ◽

Lupus Erythematosus ◽

Primary Care Physicians ◽

Neuropsychiatric Symptoms ◽

Clinical Manifestations ◽

Central Nervous System Involvement ◽

Multiple Organ ◽

Small Subset ◽

Adolescent Female ◽

Organ Systems

Abstract Background: Systemic lupus erythematosus (SLE) is an autoimmune disease with various clinical manifestations involving multiple organ systems. Neuropsychiatric manifestations of SLE has been associated with increased morbidity and mortality, thus it is important to recognize and diagnosis the disease entity and treat early. When neuropsychiatric symptoms are involved, typically there are many other systemic features to aid in the diagnosis of SLE. Many autoantibodies have been discovered and are used to help diagnose SLE. The antibody present in most cases of pediatric SLE, as well as in many other rheumatic diseases, is the nonspecific antinuclear antibody (ANA), making it a commonly used screening tool by primary care physicians when evaluating a patient with a possible rheumatic disorder. However, a small subset of SLE patients, 1-5%, present with a negative ANA, and it is important to keep SLE on the differential diagnosis in specific instances when a thorough infectious and neurological workup has been completed and proven to be inconclusive. Case Presentation: This case involves a Hispanic adolescent female with a negative ANA who presented with diffuse cerebral edema secondary to leukoencephalopathy due to SLE with central nervous system involvement. She had an extensive workup while inpatient involving metabolism, infectious disease, rheumatology, and neurology prior to obtaining the diagnosis of SLE. She was treated with both cyclophosphamide and rituximab and showed improvement. Conclusions: A review of the literature revealed 8 cases with SLE presenting with or developing diffuse cerebral edema and/or leukoencephalopathy. Our patient’s case differs in that she was also ANA negative despite other autoantibody positivity. While she did have low complements and transient leukopenia, she did not present with other signs of organ involvement, which made the diagnosis of SLE with neuropsychiatric involvement quite challenging. We discuss the importance of keeping SLE on the differential despite a negative ANA in complex cases without any other cause and to consider initial screening with not only the ANA but also dsDNA and complements to avoid missed diagnoses.

Download Full-text

Biologics in the Treatment of Lupus Erythematosus: A Critical Literature Review

BioMed Research International ◽

10.1155/2019/8142368 ◽

2019 ◽

Vol 2019 ◽

pp. 1-17 ◽

Cited By ~ 12

Author(s):

Dominik Samotij ◽

Adam Reich

Keyword(s):

Clinical Trials ◽

Lupus Erythematosus ◽

Unmet Need ◽

Clinical Manifestations ◽

Immunosuppressive Drugs ◽

Multiple Organ ◽

Biologic Agents ◽

Drug Induced ◽

Treatment Regimes ◽

Organ Systems

Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease affecting multiple organ systems that runs an unpredictable course and may present with a wide variety of clinical manifestations. Advances in treatment over the last decades, such as use of corticosteroids and conventional immunosuppressive drugs, have improved life expectancy of SLE sufferers. Unfortunately, in many cases effective management of SLE is still related to severe drug-induced toxicity and contributes to organ function deterioration and infective complications, particularly among patients with refractory disease and/or lupus nephritis. Consequently, there is an unmet need for drugs with a better efficacy and safety profile. A range of different biologic agents have been proposed and subjected to clinical trials, particularly dedicated to this subset of patients whose disease is inadequately controlled by conventional treatment regimes. Unfortunately, most of these trials have given unsatisfactory results, with belimumab being the only targeted therapy approved for the treatment of SLE so far. Despite these pitfalls, several novel biologic agents targeting B cells, T cells, or cytokines are constantly being evaluated in clinical trials. It seems that they may enhance the therapeutic efficacy when combined with standard therapies. These efforts raise the hope that novel drugs for patients with refractory SLE may be available in the near future. This article reviews the current biological therapies being tested in the treatment of SLE.

Download Full-text

A clinicopathologic correlation of the idiopathic hypereosinophilic syndrome. II. Clinical manifestations

Blood ◽

10.1182/blood.v58.5.1021.1021 ◽

1981 ◽

Vol 58 (5) ◽

pp. 1021-1026 ◽

Cited By ~ 73

Author(s):

RT Schooley ◽

MA Flaum ◽

HR Gralnick ◽

AS Fauci

Keyword(s):

Hypereosinophilic Syndrome ◽

Clinical Manifestations ◽

Initial Therapy ◽

Multiple Organ ◽

Cytotoxic Agents ◽

Grading System ◽

Idiopathic Hypereosinophilic Syndrome ◽

Splenic Enlargement ◽

Organ Systems ◽

Clinical Grading

Abstract The idiopathic hypereosinophilic syndrome, a disorder characterized by peripheral blood and bone marrow eosinophilia associated with single or multiple organ system dysfunction attributable to tissue invasion by eosinophils has, in the past, been associated with an extremely poor prognosis. Recently, we reported the favorable impact of a therapeutic protocol consisting of prednisone and/or hydroxyurea on the morbidity and mortality of this syndrome. We have reviewed the clinical and hematologic features upon admission and the subsequent clinical courses of 32 patients with this disease referred to the NIH between 1965 and 1979 in an effort to determine which features suggest a more rapidly progressive course. A grading system based on 22 clinical features involving the 8 organ systems commonly affected by the illness was devised. The disease followed a more aggressive course in patients with evidence of cardiac or neurologic dysfunction at the time of initial NIH evaluation. Although splenomegaly, in and of itself, caused little morbidity, splenic enlargement at presentation appeared to be a predictor of a more aggressive course. The clinical grading system accurately predicted which patients would require no specific antihypereosinophilic therapy, which patients would respond adequately to corticosteroids, and which patients would require therapy with cytotoxic agents. It is proposed that this clinical grading system, and the hematologic grading system outlined in the accompanying report be used as aids in the selection of initial therapy in this group of patients.

Download Full-text

Neurological, neuropsychiatric and neurodevelopmental complications of COVID-19

Australian & New Zealand Journal of Psychiatry ◽

10.1177/0004867420961472 ◽

2020 ◽

pp. 000486742096147

Author(s):

Christos Pantelis ◽

Mahesh Jayaram ◽

Anthony J Hannan ◽

Robb Wesselingh ◽

Jess Nithianantharajah ◽

...

Keyword(s):

Organ Damage ◽

Multiple Organ ◽

Global Pandemic ◽

Organ Systems ◽

Future Challenges ◽

The Central Nervous System ◽

The Impact ◽

Collaborative Efforts ◽

The Brain

Although COVID-19 is predominantly a respiratory disease, it is known to affect multiple organ systems. In this article, we highlight the impact of SARS-CoV-2 (the coronavirus causing COVID-19) on the central nervous system as there is an urgent need to understand the longitudinal impacts of COVID-19 on brain function, behaviour and cognition. Furthermore, we address the possibility of intergenerational impacts of COVID-19 on the brain, potentially via both maternal and paternal routes. Evidence from preclinical models of earlier coronaviruses has shown direct viral infiltration across the blood–brain barrier and indirect secondary effects due to other organ pathology and inflammation. In the most severely ill patients with pneumonia requiring intensive care, there appears to be additional severe inflammatory response and associated thrombophilia with widespread organ damage, including the brain. Maternal viral (and other) infections during pregnancy can affect the offspring, with greater incidence of neurodevelopmental disorders, such as autism, schizophrenia and epilepsy. Available reports suggest possible vertical transmission of SARS-CoV-2, although longitudinal cohort studies of such offspring are needed. The impact of paternal infection on the offspring and intergenerational effects should also be considered. Research targeted at mechanistic insights into all aspects of pathogenesis, including neurological, neuropsychiatric and haematological systems alongside pulmonary pathology, will be critical in informing future therapeutic approaches. With these future challenges in mind, we highlight the importance of national and international collaborative efforts to gather the required clinical and preclinical data to effectively address the possible long-term sequelae of this global pandemic, particularly with respect to the brain and mental health.

Download Full-text

HCMV Infection and Apoptosis: How Do Monocytes Survive HCMV Infection?

Viruses ◽

10.3390/v10100533 ◽

2018 ◽

Vol 10 (10) ◽

pp. 533 ◽

Cited By ~ 10

Author(s):

Donna Collins-McMillen ◽

Liudmila Chesnokova ◽

Byeong-Jae Lee ◽

Heather Fulkerson ◽

Reynell Brooks ◽

...

Keyword(s):

Gene Expression ◽

Cell Survival ◽

Hcmv Infection ◽

Viral Gene Expression ◽

Multiple Organ ◽

Viral Gene ◽

Blood Monocytes ◽

Induced Differentiation ◽

Organ Systems

Human cytomegalovirus (HCMV) infection of peripheral blood monocytes plays a key role in the hematogenous dissemination of the virus to multiple organ systems following primary infection or reactivation of latent virus in the bone marrow. Monocytes have a short life span of 1–3 days in circulation; thus, HCMV must alter their survival and differentiation to utilize these cells and their differentiated counterparts—macrophages—for dissemination and long term viral persistence. Because monocytes are not initially permissive for viral gene expression and replication, HCMV must control host-derived factors early during infection to prevent apoptosis or programmed cell death prior to viral induced differentiation into naturally long-lived macrophages. This review provides a short overview of HCMV infection of monocytes and describes how HCMV has evolved to utilize host cell anti-apoptotic pathways to allow infected monocytes to bridge the 48–72 h viability gate so that differentiation into a long term stable mature cell can occur. Because viral gene expression is delayed in monocytes following initial infection and only occurs (begins around two to three weeks post infection in our model) following what appears to be complete differentiation into mature macrophages or dendritic cells, or both; virally-encoded anti-apoptotic gene products cannot initially control long term infected cell survival. Anti-apoptotic viral genes are discussed in the second section of this review and we argue they would play an important role in long term macrophage or dendritic cell survival following infection-induced differentiation.

Download Full-text

SARS-CoV-2, ACE2 expression, and systemic organ invasion

Physiological Genomics ◽

10.1152/physiolgenomics.00087.2020 ◽

2020 ◽

Author(s):

Usman M Ashraf ◽

Ahmed A Abokor ◽

Jonnelle M. Edwards ◽

Emily W. Waigi ◽

Rachel S. Royfman ◽

...

Keyword(s):

Respiratory Illness ◽

Normal Function ◽

Multiple Organ ◽

Angiotensin Converting Enzyme 2 ◽

Multiple Organs ◽

Global Pandemic ◽

Organ Systems ◽

Novel Coronavirus ◽

Severe Respiratory Illness ◽

Organ Invasion

A novel coronavirus disease, COVID-19, has created a global pandemic in 2020, posing an enormous challenge to healthcare systems and affected communities. COVID-19 is caused by Severe Acute Respiratory Syndrome (SARS)-CoronaVirus-2 (CoV-2) that manifests as bronchitis, pneumonia, or a severe respiratory illness. SARS-CoV-2 infects human cells via binding a "spike" protein on its surface to angiotensin-converting enzyme 2 (ACE2) within the host. ACE2 is crucial for maintaining tissue homeostasis and negatively regulates the renin-angiotensin-aldosterone system (RAAS) in the humans. The RAAS is paramount for normal function in multiple organ systems including the lungs, heart, kidney, and vasculature. Given that SARS-CoV-2 internalizes via ACE2, the resultant disruption in ACE2 expression can lead to altered tissue function and exacerbate chronic diseases. The widespread distribution and expression of ACE2 across multiple organs is critical to our understanding of the varied clinical outcomes of COVID-19. This perspective review based on the current literature was prompted to show how disruption of ACE2 by SARS-CoV-2 can affect different organ systems.

Download Full-text

The Role of MSC Therapy in Attenuating the Damaging Effects of the Cytokine Storm Induced by COVID-19 on the Heart and Cardiovascular System

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2020.602183 ◽

2020 ◽

Vol 7 ◽

Author(s):

Georgina M. Ellison-Hughes ◽

Liam Colley ◽

Katie A. O'Brien ◽

Kirsty A. Roberts ◽

Thomas A. Agbaedeng ◽

...

Keyword(s):

Cardiovascular System ◽

Cardiovascular Complications ◽

Multiple Organ ◽

Cytokine Storm ◽

Cell Therapies ◽

Tissue Repair And Regeneration ◽

Global Pandemic ◽

Organ Systems

The global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has led to 47 m infected cases and 1. 2 m (2.6%) deaths. A hallmark of more severe cases of SARS-CoV-2 in patients with acute respiratory distress syndrome (ARDS) appears to be a virally-induced over-activation or unregulated response of the immune system, termed a “cytokine storm,” featuring elevated levels of pro-inflammatory cytokines such as IL-2, IL-6, IL-7, IL-22, CXCL10, and TNFα. Whilst the lungs are the primary site of infection for SARS-CoV-2, in more severe cases its effects can be detected in multiple organ systems. Indeed, many COVID-19 positive patients develop cardiovascular complications, such as myocardial injury, myocarditis, cardiac arrhythmia, and thromboembolism, which are associated with higher mortality. Drug and cell therapies targeting immunosuppression have been suggested to help combat the cytokine storm. In particular, mesenchymal stromal cells (MSCs), owing to their powerful immunomodulatory ability, have shown promise in early clinical studies to avoid, prevent or attenuate the cytokine storm. In this review, we will discuss the mechanistic underpinnings of the cytokine storm on the cardiovascular system, and how MSCs potentially attenuate the damage caused by the cytokine storm induced by COVID-19. We will also address how MSC transplantation could alleviate the long-term complications seen in some COVID-19 patients, such as improving tissue repair and regeneration.

Download Full-text

Loss of Functional Osteoprotegerin: More Than a Skeletal Problem

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2016-2905 ◽

2016 ◽

Vol 102 (1) ◽

pp. 210-219 ◽

Cited By ~ 7

Author(s):

Corinna Grasemann ◽

Nicole Unger ◽

Matthias Hövel ◽

Diana Arweiler-Harbeck ◽

Ralf Herrmann ◽

...

Keyword(s):

Short Stature ◽

Family Members ◽

Clinical Signs ◽

Multiple Organ ◽

Heterozygous Mutation ◽

Human Phenotype ◽

Recessive Mutations ◽

Organ Systems ◽

Juvenile Paget’S Disease ◽

Turnover Markers

Abstract Introduction: Juvenile Paget’s disease (JPD), an ultra-rare, debilitating bone disease due to loss of functional osteoprotegerin (OPG), is caused by recessive mutations in TNFRFSF11B. A genotype–phenotype correlation spanning from mild to very severe forms is described. Aim: This study aimed to describe the complexity of the human phenotype of OPG deficiency in more detail and to investigate heterozygous mutation carriers for clinical signs of JPD. Patients: We investigated 3 children with JPD from families of Turkish, German, and Pakistani descent and 19 family members (14 heterozygous). Results: A new disease-causing 4 bp-duplication in exon 1 was detected in the German patient, and a microdeletion including TNFRFSF11B in the Pakistani patient. Skeletal abnormalities in all affected children included bowing deformities and fractures, contractures, short stature and skull involvement. Complex malformation of the inner ear and vestibular structures (2 patients) resulted in early deafness. Patients were found to be growth hormone deficient (2), displayed nephrocalcinosis (1), and gross motor (3) and mental (1) retardation. Heterozygous family members displayed low OPG levels (12), elevated bone turnover markers (7), and osteopenia (6). Short stature (1), visual impairment (2), and hearing impairment (1) were also present. Conclusion: Diminished OPG levels cause complex changes affecting multiple organ systems, including pituitary function, in children with JPD and may cause osteopenia in heterozygous family members. Diagnostic and therapeutic measures should aim to address the complex phenotype.

Download Full-text

Consensus guidelines for the diagnosis and clinical management of Erdheim-Chester disease

Blood ◽

10.1182/blood-2014-03-561381 ◽

2014 ◽

Vol 124 (4) ◽

pp. 483-492 ◽

Cited By ~ 285

Author(s):

Eli L. Diamond ◽

Lorenzo Dagna ◽

David M. Hyman ◽

Giulio Cavalli ◽

Filip Janku ◽

...

Keyword(s):

Clinical Management ◽

Clinical Laboratory ◽

Clinical Manifestations ◽

Multiple Organ ◽

Future Research ◽

Consensus Guidelines ◽

Erdheim Chester Disease ◽

Organ Systems ◽

Erdheim Chester ◽

Chester Disease

Abstract Erdheim-Chester disease (ECD) is a rare, non-Langerhans histiocytosis. Recent findings suggest that ECD is a clonal disorder, marked by recurrent BRAFV600E mutations in >50% of patients, in which chronic uncontrolled inflammation is an important mediator of disease pathogenesis. Although ∼500 to 550 cases have been described in the literature to date, increased physician awareness has driven a dramatic increase in ECD diagnoses over the last decade. ECD frequently involves multiple organ systems and has historically lacked effective therapies. Given the protean clinical manifestations and the lack of a consensus-derived approach for the management of ECD, we provide here the first multidisciplinary consensus guidelines for the clinical management of ECD. These recommendations were outlined at the First International Medical Symposium for ECD, comprised of a comprehensive group of international academicians with expertise in the pathophysiology and therapy of ECD. Detailed recommendations on the initial clinical, laboratory, and radiographic assessment of ECD patients are presented in addition to treatment recommendations based on critical appraisal of the literature and clinical experience. These formalized consensus descriptions will hopefully facilitate ongoing and future research efforts in this disorder.

Download Full-text