Although COVID-19 is most well known for causing substantial respiratory pathology, it can also result in several extrapulmonary manifestations. These conditions include thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, neurologic illnesses, ocular symptoms, and dermatologic complications. Given that ACE2, the entry receptor for the causative coronavirus SARS-CoV-2, is expressed in multiple extrapulmonary tissues, direct viral tissue damage is a plausible mechanism of injury. In addition, endothelial damage and thromboinflammation, dysregulation of immune responses, and maladaptation of ACE2-related pathways might all contribute to these extrapulmonary manifestations of COVID-19. Here we review the extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.

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Extrapulmonary manifestations of COVID-19.

Key Clinical Points Mild or Moderate Covid-19 Covid-19 (the illness caused by SARS-CoV-2) has a range of clinical manifestations, including cough, fever, malaise, myalgias, gastrointestinal symptom...

https://www.nejm.org/doi/pdf/10.1056/NEJMcp2009249

Mild or Moderate Covid-19.

BACKGROUND: There is currently very limited information on the nature and prevalence of post-COVID-19 symptoms after hospital discharge. METHODS: A purposive sample of 100 survivors discharged from a large University hospital were assessed 4 to 8 weeks after discharge by a multidisciplinary team of rehabilitation professionals using a specialist telephone screening tool designed to capture symptoms and impact on daily life. EQ-5D-5L telephone version was also completed. RESULTS: Participants were between 29 and 71 days (mean 48 days) postdischarge from hospital. Thirty-two participants required treatment in intensive care unit (ICU group) and 68 were managed in hospital wards without needing ICU care (ward group). New illness-related fatigue was the most common reported symptom by 72% participants in ICU group and 60.3% in ward group. The next most common symptoms were breathlessness (65.6% in ICU group and 42.6% in ward group) and psychological distress (46.9% in ICU group and 23.5% in ward group). There was a clinically significant drop in EQ5D in 68.8% in ICU group and in 45.6% in ward group. CONCLUSIONS: This is the first study from the United Kingdom reporting on postdischarge symptoms. We recommend planning rehabilitation services to manage these symptoms appropriately and maximize the functional return of COVID-19 survivors.

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Postdischarge symptoms and rehabilitation needs in survivors of COVID-19 infection: A cross-sectional evaluation.

Gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA are frequently observed in COVID-19 patients. However, it is unclear whether SARS-CoV-2 replicates in the human intestine and contributes to possible fecal-oral transmission. Here, we report productive infection of SARS-CoV-2 in ACE2+ mature enterocytes in human small intestinal enteroids. Expression of two mucosa-specific serine proteases, TMPRSS2 and TMPRSS4, facilitated SARS-CoV-2 spike fusogenic activity and promoted virus entry into host cells. We also demonstrate that viruses released into the intestinal lumen were inactivated by simulated human colonic fluid, and infectious virus was not recovered from the stool specimens of COVID-19 patients. Our results highlight the intestine as a potential site of SARS-CoV-2 replication, which may contribute to local and systemic illness and overall disease progression.

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TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes.

https://research.birmingham.ac.uk/portal/files/100722606/manu_lancet_GH_clean_4_16_copy.pdf

Manifestations and prognosis of gastrointestinal and liver involvement in patients with COVID-19: a systematic review and meta-analysis.

Abstract Mutations in the GJB2 gene (encoding Connexin26(Cx26)) are the most common cause of hereditary deafness, accounting for about a quarter of all cases. Sensory epithelial damage is considered to be one of the main causes of deafness caused by GJB2 gene mutation. Dexamethasone (DEX) is widely used in the treatment of a variety of inner ear diseases including sudden sensorineural hearing loss (SSNHL), noise-induced hearing loss (NIHL), and deafness caused by ototoxic drugs. Whether DEX has a direct therapeutic effect on hereditary deafness, especially GJB2 -related deafness, remains unclear. In this study, we revealed that DEX can effectively prevent hair cell death caused by oxidative stress in cochlear explants. Additionally, two distinct Cx26-null mouse models were established to investigate whether systemic administration of DEX alleviate the cochlear sensory epithelial injury or deafness in these models. In a specific longitudinally Cx26-null model that does not cause deafness, systemic administration of DEX prevents the degeneration of outer hair cells (OHCs) induced by Cx26 knockout. Similarly, in a targeted-Deiter’s cells (DCs) Cx26-null mouse model that causes deafness, treatment with DEX can almost completely prevent OHCs loss and alleviates auditory threshold shifts at some frequencies. Additionally, we observed that DEX inhibited the recruitment of CD45-positive cells in the targeted-DCs Cx26-null mice. Taken together, our results suggest that the protective effect of dexamethasone on cochlear sensory epithelial damage and partially rescue auditory function may be related to the regulation of inner ear immune response in Cx26 deficiency mouse models. 

/pdf/the-protective-effects-of-systemic-dexamethasone-on-sensory-3pie7yry.pdf

The protective effects of systemic dexamethasone on sensory epithelial damage and hearing loss in targeted Cx26-null mice

Waardenburg syndrome (WS), also known as auditory-pigmentary syndrome, is the most common cause of syndromic hearing loss. It is responsible for 2-5% of congenital deafness. WS is classified into four types depending on the clinical phenotypes. Currently, pathogenic mutation of PAX3, MITF, EDNRB, EDN3, SNAI2, or SOX10 can cause corresponding types of WS. Among them, SOX10 mutation is responsible for approximately 15% of type II WS or 50% of type IV WS. We report the case of a proband in a Chinese family who was diagnosed with WS type II. Whole exome sequencing (WES) of the proband detected a novel heterozygous spontaneous mutation: SOX10 c.246delC. According to analysis based on nucleic acid and amino acid sequences, this mutation may produce a truncated protein, with loss of the HMG structure domain. Therefore, this truncated protein may fail to activate the expression of the MITF gene, which regulates melanocytic development and plays a key role in WS. Our finding expands the database of SOX10 mutations associated with WS and provides more information regarding the molecular mechanism of WS.

/pdf/a-novel-spontaneous-mutation-of-the-sox10-gene-associated-kydynye2ro.pdf

A Novel Spontaneous Mutation of the SOX10 Gene Associated with Waardenburg Syndrome Type II.

Auditory neuropathy spectrum disorder (ANSD), also called auditory neuropathy (AN), is a unique type of prelingual hearing impairment. Up to 10% of deaf infants and children are affected by this disease. Mutation of the OTOF gene which encodes otoferlin is the common cause of congenital nonsyndromic ANSD. To date, over 110 mutations have been identified in the OTOF gene according to the Human Gene Mutation Database (HGMD). Here, next-generation sequencing (NGS) revealed that the compound heterozygous mutations c.4748G>A/c.2523+1G>T and c.5248G>C/c.5098G>C of the OTOF gene were present in two Chinese ANSD patients. Each patient had a known pathogenic mutation (c.4748G>A or c.5098G>C) and a novel mutation (c.2523+1G>T or c.5248G>C). Comparative amino acid sequence analysis across different species revealed that the residues at these novel mutation sites are evolutionarily highly conservative. This indicated that the novel mutations were possible causes of the disorder in the patients. Our findings extend the OTOF mutation spectrum and further confirm the role of the OTOF gene in ANSD.

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Auditory Neuropathy Spectrum Disorder due to Two Novel Compound Heterozygous OTOF Mutations in Two Chinese Families

Genetic testing is widely used in diagnosing genetic hearing loss in patients. Other than providing genetic etiology, the benefits of genetic testing in pediatric patients with hearing loss are less investigated.From 2018-2020, pediatric patients who initially presented isolated hearing loss were enrolled. Comprehensive genetic testing, including GJB2/SLC26A4 multiplex amplicon sequencing, STRC/OTOA copy number variation analysis, and exome sequencing, were hierarchically offered. Clinical follow-up and examinations were performed.A total of 80 pediatric patients who initially presented isolated hearing loss were considered as nonsyndromic hearing loss and enrolled in this study. The definitive diagnosis yield was 66% (53/80) and the likely diagnosis yield was 8% (6/80) through comprehensive genetic testing. With the aid of genetic testing and further clinical follow-up and examinations, the clinical diagnoses and medical management were altered in eleven patients (19%, 11/59); five were syndromic hearing loss; six were nonsyndromic hearing loss mimics.Syndromic hearing loss and nonsyndromic hearing loss mimics are common in pediatric patients who initially present with isolated hearing loss. The comprehensive genetic testing provides not only a high diagnostic yield but also valuable information for clinicians to uncover subclinical or pre-symptomatic phenotypes, which allows early diagnosis of SHL, and leads to precise genetic counseling and changes the medical management. 

/pdf/comprehensive-genetic-testing-improves-the-clinical-ktlyirvh.pdf

Comprehensive genetic testing improves the clinical diagnosis and medical management of pediatric patients with isolated hearing loss

/pdf/comprehensive-genetic-testing-improves-the-clinical-2tlyam1l.pdf

Yuan Jin

Papers

The protective effects of systemic dexamethasone on sensory epithelial damage and hearing loss in targeted Cx26-null mice

A Novel Spontaneous Mutation of the SOX10 Gene Associated with Waardenburg Syndrome Type II.

Auditory Neuropathy Spectrum Disorder due to Two Novel Compound Heterozygous OTOF Mutations in Two Chinese Families

Comprehensive genetic testing improves the clinical diagnosis and medical management of pediatric patients with isolated hearing loss

Comprehensive genetic testing improves the clinical diagnosis and medical management of pediatric patients with isolated hearing loss