Multi-organ Damage Research Articles

Association of Elevated Tricuspid Regurgitation Velocity with Kidney and Cerebrovascular Disease in Children with Sickle Cell Disease

Introduction: Adult patients with sickle cell disease (SCD) develop progressive end-organ injury leading to multi-organ disease and increased mortality. It is plausible that this multi-organ damage begins in pediatric patients. Tricuspid regurgitation velocity (TRV), measured by echocardiography is a surrogate marker for pulmonary hypertension that is a poor prognostic factor in adults with SCD. The utility of screening echocardiograms as a marker of disease severity is being studied in pediatrics. In this study, we assessed associations between elevated TRV with early development of chronic kidney disease (albuminuria), and cerebrovascular disease (CVD). Methods: We performed an IRB approved cross-sectional study to evaluate the prevalence of elevated TRV ≥ 2.5 m/s and its associations with albuminuria and CVD in patients with SCD ages 1-21 years. We included children with a diagnosis of SCD who had at least one echocardiogram performed during an outpatient clinic visit at steady-state for screening for pulmonary hypertension. We categorized patients as receiving either transfusion therapy (chronic transfusion for >12 months), SCD modifying therapy (hydroxyurea, voxelotor, crizanlizumab, or L-glutamine), or no therapy. Patients on both transfusion and a SCD modifying therapy were defined as being on transfusion therapy. We defined albuminuria as patients with two of three consecutive albumin creatinine ratios ≥30mg/g measured during standard clinic visits. Cerebrovascular disease was defined as having either 1) an overt stroke, 2) silent cerebral stroke defined by MRI, 3) vasculopathy by abnormal magnetic resonance angiography (MRA), 4) transient ischemic event defined by stroke symptoms that resolved within 24 hours, or 5) abnormal TCD (>200 cm/second). We performed bivariate analysis utilizing t-test (or Kruskal-Wallis test) and Cochran-Mantel-Haenszel test for continuous and categorical variables respectively. To determine the association between elevated TRV and albuminuria, and elevated TRV and CVD, logistic regression was fit and adjusted for variables that were significant in the bivariate analysis. Using the TRV <2.5m/sec as the reference group, adjusted odds ratios with their accompanying confidence intervals were calculated for those with albuminuria and those with CVD in separate models. All reported P values were 2-sided. Statistical significance was defined as p<0.05. All analyses were performed using Statistical Analysis Software 9.4, (SAS Institute, Cary, NC). Results: Among 166 children with echocardiography, the prevalence of an elevated TRV was 21%. On bivariate analysis, elevated TRV was significantly associated with persistent albuminuria (OR 2.85 (95% CI: 1.27-6.43) and cerebrovascular disease (OR: 2.46 (95% CI: 1.09-5.53) (Table 1). An elevated TRV was also significantly associated with increased age (15.6 vs 12.9 yrs, p=0.005), lower hemoglobin F% (2.5 vs 4.6%, p=0.01), higher absolute reticulocyte count (0.5 vs 0.4 x 106/ µL p=0.005) and chronic transfusion therapy (p=0.04). After adjusting for age, absolute reticulocyte count, HbF and treatment in a multivariable logistic regression, the associations between elevated TRV with either persistent albuminuria (OR: 1.82 (0.71 - 4.67)) and cerebrovascular disease (OR: 1.15 (0.43-3.10)) were no longer statistically significant (Table 1). Our data suggests that with an odds ratio of 2.9 and a prevalence of elevated TRV of 20%, a prospective study of 166 adolescent patients with SCD would be needed to detect the association between elevated TRV and persistent albuminuria with 80% power and 233 children would be needed to detect this difference with 90% power. Conclusion: This data provides additional evidence that around 20% of pediatric patients have an elevated TRV and those patients may also have an increased risk for developing chronic kidney disease and cerebrovascular disease. A larger, prospective cohort study should be conducted to confirm these findings and determine the role of screening echocardiography in pediatric SCD. At minimum, our data suggests that pediatric patients with known chronic kidney disease or cerebrovascular disease should be screened for cardiac complications. Furthermore, longitudinal studies are needed to evaluate the association between elevated TRV in children with early end-organ complications in adults. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Protective effect of total saponins of ginseng stems and leaves (GSLS) on chlorpyrifos-induced brain toxicity in mice through the PTEN/PI3K/AKT axis.

Chlorpyrifos (CPF) is a class of toxic compounds which has been widely used in agriculture that can cause multi-organ damage to the liver, kidneys, testes, and nervous system. Currently, most studies on ginseng have concentrated on the roots and rhizomes, and less research has been conducted on the above-ground parts. Our laboratory found that ginseng stem and leaf total saponin (GSLS) features strong antioxidant activity. In this experiment, we selected different concentrations of CPF to induce hippocampal neuronal cell injury model in mice, conducted a cell survival screening test, and also selected appropriate concentrations of CPF to induce brain injury model in mice. CCK-8, flow cytometry, Elisa, Hoechst 33258 staining, Annexin V-FITC/PI staining, HE staining, Morris water maze, and qRT-PCR were adopted for detecting the effects of GSLS treatment on CPF-induced cell viability, mitochondrial membrane potential, reactive oxygen species (ROS) levels, Ca2+ concentration and GSLS treatment on CPF-induced brain injury and related signaling in mice, respectively. The effects of GSLS treatment on CPF-induced brain injury and the related signaling pathways in mice were examined. The results showed that GSLS at 60 μg/ml and 125 μg/ml concentrations elevated the viability of CPF-induced HT22 cells, increased mitochondrial membrane potential, depleted ROS, decreased Ca2+ concentration, and decreased apoptosis rate. Meanwhile, GSLS treatment significantly reduced CPF-induced escape latency in mice, elevated the number of entries into the plateau and effective area, increased the effective area and target quadrant residence time, as well as improved the pathological damage of mouse hippocampal neurons. The results of mouse brain sections demonstrated that GSLS treatment significantly increased SOD and CAT activities and lowered MDA accumulation in CPF-induced mice. qRT-PCR revealed that PTEN mRNA expression was significantly decreased with PI3K and AKT expression being significantly increased in GSLS-treated CPF-induced mice. Thus, the obtained results indicate that GSLS can effectively antagonize CPF-induced brain toxicity in mice through regulating PTEN/PI3K/AKT pathway.

Paeoniflorin improves cognitive dysfunction, restores glutamate receptors, attenuates gliosis and maintains synaptic plasticity in cadmium-intoxicated mice

Toxic metals exposed to the environment in industrial and agricultural production, such as cadmium (Cd), Plumbum (Pb) and aluminium (Al), are neurotoxic and harmful to brain functions such as learning and memory, and may contribute to neurological disease. In this study, we investigated the neuronal protective effects of Paeoniflorin (PF) in a mouse model of Cd poisoning that showed cognitive dysfunction. PF attenuated Cd-induced multi-organ damage and brain neurotoxicity, consistent with improved behavioral performances in mice. At the molecular level, Cd-induced toxicity attenuated the phosphorylation of glutamate receptors NMDAR2A, NMDAR2B, and GluR2, but increased the phosphorylation of GluR1. In addition, gliosis after Cd toxicity showed an increase in the number of IBA1 or GFAP-positive cells, which contrasted with the loss of neurons and synapses. However, PF treatment alleviated gliosis and maintained glutamate receptor and neuronal activity, as evidenced by the recovery of marker proteins MAP2, PSD95 and synaptophysin. Also, Cd-induced upregulation of CD68, a lysosomal protein that scavenges damaged cellular components in active microglia, was also restored by PF. In conclusion, PF is a potential neuroprotective natural product.

Мультисистемный воспалительный синдром, ассоциированный с SARS-CoV-2, у детей: этиопатогенез, клиническая картина, диагностика, лечение (обзор)

This article discusses current ideas about the etiology, pathogenesis, clinical picture, diagnosis, differential diagnosis, and approaches to the treatment of multisystem inflammatory syndrome in children (MIS-C) associated with the novel coronavirus infection (COVID-19). The causative agent of COVID-19 is the SARS-CoV-2 RNA virus that causes severe acute respiratory syndrome. Multisystem inflammatory syndrome is a symptom complex associated with COVID-19 that occurs in children and adolescents and includes signs of Kawasaki disease and toxic shock. It debuts 2–6 weeks after COVID-19 exposure and, as a rule, is observed in children older than 5 years. The main pathogenetic mechanism of MIS-C is a pathological hyperimmune response to the virus, activation of neutrophils, macrophages, proinflammatory interleukins and, as a result, an intense cytokine storm leading to the development of multisystem inflammation. Postinfectious multi-organ damage is associated with the prevalence of target organs for autoantibodies. Target antigens are expressed in mucosal tissues, endothelial cells, and myocardium. Clinical and laboratory signs of MIS-C include: fever, skin rash, abdominal symptoms, damage to the nervous and cardiovascular systems, increased levels of inflammatory markers in the blood, myocardial damage, and hypercoagulability. Echocardiography shows signs of myocarditis, coronary artery anomalies, and pericarditis. Abdominal ultrasound and computed tomography reveal signs of ascites, colitis, ileitis, and hepatosplenomegaly. Differential diagnosis should be made to distinguish MIS-C from Kawasaki disease and toxic shock syndrome. MIS-C requires a comprehensive pathogenetic treatment, which includes antibacterial therapy (initially, until a bacterial infection is ruled out), anticoagulants, antiplatelet agents, systemic glucocorticosteroids, monoclonal antibodies, and oxygen therapy. The best way to prevent MIS-C is to vaccinate adolescents against COVID-19.

A Rare Case of Amyloid Light Chain Amyloidosis with Extensive Hepatic Involvement

Abstract Introduction/Objective Amyloid light chain (AL) amyloidosis is a life-threatening disease entity, with an incidence of 10–15 per million per year in the USA. Amyloidosis is caused by the extracellular deposition of insoluble fibrillary amyloid protein resulting in multiorgan damage. Though amyloidosis is primarily a systemic disease, 10%-20% of cases can be localized. Methods/Case Report We present a case of a 37-year-old male admitted with predominant hepatic manifestations, whose liver biopsy led to the diagnosis of amyloidosis. The patient presented with intermittent abdominal pain, weight loss, persistent hypoglycemia, hepatomegaly, and raised liver enzymes. Imaging studies showed hepatomegaly with a heterogeneous lace like appearance of the liver parenchyma. Liver biopsy revealed an extensive deposition of amyloid protein in peri-sinusoidal spaces. The amyloid protein is highlighted by crystal violet stain and revealed apple- green birefringence on polarized microscopy after Congo red staining. On further evaluation, elevated kappa and lambda free light chains with increased kappa-lambda ratio were identified by serum protein electrophoresis. Subsequent bone marrow aspirate and biopsy identified a monoclonal kappa positive plasma cell neoplasm with an amorphous eosinophilic infiltrate. Liquid chromatography-tandem mass spectrometry on bone marrow biopsy detected a peptide profile consistent with AL (kappa) type amyloid deposition. Results (if a Case Study enter NA) NA. Conclusion AL amyloidosis patients with predominant hepatic involvement have a worse prognosis. Rapid diagnosis and prompt clinical intervention prevents further organ damage. This case study aims to promote awareness of the unusual presentations of amyloidosis.

PSAT066 Adrenal Insufficiency Associated with Amyloidosis and Sickle Cell Disease

Abstract Background Amyloidosis causes chronic inflammation by the deposition of amyloid protein fragments in multiple organs, such as kidneys, adrenal, and pituitary glands. It is a challenge to access adrenocortical function in renal amyloidosis patients due to heavy proteinuria induced hypoproteinemia and low corticosteroid-binding globulin (CBG) which may cause false positive adrenocorticotropin (ACTH) test and the reduced cortisol level uncorrelated with free cortisol. On the other hand, adrenal insufficiency also frequently occurs in Sickle Cell Disease (SCD) patients. The hypothalamic-pituitary-adrenal (HPA) axis can be affected by tissue hypoxia during recurrent small vessel occlusion, chronic anemia, and iron-overload related oxidative stress. We report a SCD patient with nephrotic syndrome due to amyloidosis, who has adrenal insufficiency. Case Presentation A 41 years old female with Nephrotic syndrome secondary to Amyloid A (AA) amyloidosis, Adrenal insufficiency, Sickle cell disease (HbSC), Graves’ Hyperthyroidism, CVA, and bilateral femoral head avascular necrosis, presented with sickle cell pain crisis and anasarca with hypotension. She was on Hydrocortisone for 12 years but was not compliant for 2 months. She was on Methimazole for several years before it was discontinued one year ago. She has amenorrhea, severe edema with anasarca from the lower extremities to the abdomen. Labs showed morning cortisol 5.46 ug/dL, low albumin 2.4 g/dL, high TSH 5.43 uIU/mL, normal FT4 1.60 ng/dL, high urine protein 996.2 mg/dL, and eGFR 21.2. CT revealed pericardial effusion, free pelvic fluid, splenomegaly, edema, and thyroid goiter. Previous labs showed persistent low cortisol 0.9 to 3.5 ug/dL, high ferritin 1007 ng/mL, and pituitary workup was normal for Prolactin 4.6 ug/L, LH 5.02 mIU/mL, FSH 9.9 mIU/mL, IGF1 216 ng/mL, and ACTH 13.1 pg/mL. NM thyroid uptake elevated 51.7% and positive TPO 79.7 IU/mL. CT head was unremarkable. The patient was managed with Lasix and Albumin infusion for anasarca, Cyclosporine for amyloidosis, and Midodrine 10 mg TID for hypotension. Hydrocortisone stress dose was given followed by Prednisone 30 mg BID. Her symptoms improved. Discussion In Amyloidosis patients with heavy proteinuria, the low serum CBG levels affect total cortisol level. Therefore, the proper assessment for the adrenal function should be used with albumin-calculated free cortisol or cortisol/CBG ratio in addition to the ACTH stimulation tests. It is essential to differentiate between adrenal insufficiency and amyloidosis-related symptoms to prevent adrenal crisis and refrain from glucocorticoid side effects by unnecessary steroid use. On the other hand, endocrine manifestations of SCD may include hypogonadism, thyroid, adrenal, and pituitary dysfunction due to vaso-occlusive episodes induced multi-organ ischemic damage. This patient has amenorrhea, adrenal insufficiency, and normalized thyroid function test in Graves’ disease. It is crucial to avoid iron-overload induced oxidative stress which would worsen endocrine dysfunctions as well. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Major Burns After Lightning Strikes at Field: Case Report

Lightning injuries can cause multi-organ damage such as burns, ear damage, and nervous system damage. The type of Burns in this trauma consists of linear or flash burns, punctate burns, thermal injuries, Lichtenburg figures, and combination wounds which are generally superficial and heal faster. Lightning strikes also cause ear damage in the form of perforation of the tympanic membrane, bleeding, and micro fractures in the cochlea. The sequelae in lightning injury survivors consist of permanent brain injury, chronic pain syndrome, peripheral neuropathy, and blindness. This case is a man, 20 years old, working as a farmer, referred to the hospital because he was struck by lightning while working in the middle of the rice fields during heavy rain. There were complaints of pain, heat throughout the body, and decreased hearing in both ears in the anamnesis. Physical examination showed a general condition within normal limits. Local status examination found burns as large as 31.5% of the body area, with 2a degree burns (partial thickness) on the chest, back, upper and lower limbs. Examination of the outer and middle ear revealed no abnormalities. The principle of the treatment refers to the electric burns treatment with initial therapy in fluid resuscitation, evaluation of ECG, adequate analgesia, and wound care. The advanced phase of the treatment focuses on treating the burns and evaluating the hearing loss. Adequate care for nine days showed that the wound was epithelialized by 60% of the total wound area and without any other complaints. This case is essential to be studied considering that Indonesia's natural conditions allow for lightning strikes, especially during the rainy season, so lightning is a threat to farmers as a part of the agro-industrial community.&#x0D; Keywords: Lightning injuries, burns, agroindustrial

Rare penetrating abdominal injury caused by falling from height: Miraculously good prognosis.

Fall from height causing penetrating abdominal visceral injuries is rare condition leading to abdominal multiorgan damage. It carries high mortality. A case of construction site worker sustaining penetrating visceral injuries by falling from height leading to impalement of steal bar from anus presented to our hospital and managed by timely evacuation from site of accident to hospital, resuscitations, radiological investigations and multi-Disciplinary team management lead to successful outcome. Our protocol for such cases will be discussed with references.

Chlorogenic Acid Relieves the Lupus Erythematosus-like Skin Lesions and Arthritis in MRL/lpr Mice.

Chlorogenic acid (CGA) is a phenylpropyl substance synthesized through the shikimic acid pathway. In addition to its anti-tumor, anti-inflammatory, and antioxidant abilities, CGA also has immunomodulatory effects. The aim of the present study is to investigate the therapeutic effects of CGA on the skin damage and arthritis caused by systemic lupus erythematosus (SLE) in an MRL/lpr mouse model. In the SLE model, female MRL/lpr mice at the age of 10 weeks old were treated with CGA daily or cyclophosphamide (CTX) weekly via intraperitoneal injection for three months. After treatment, CGA can significantly alleviate the skin and mucous membrane damage caused by SLE and has a certain improvement effect on arthritis. CGA could inhibit dsDNA expression to a certain extent but has no obvious regulation on ANA concentration. The ELISA and BioMAP results indicated that CGA might play an anti-inflammatory role by down-regulating the interleukin (IL)-17 level. In conclusion, our study demonstrates that CGA can alleviate multiorgan damage in MRL/lpr mice by reducing IL-17.

Clinical features and prognosis of MPO-ANCA and anti-GBM double-seropositive patients.

Several lines of evidence implicate that there are distinct differences between patients with myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA) and anti-glomerular basement membrane (GBM) antibody double-seropositive patients (DPPs) and single-positive patients. Hence, we conducted a retrospective study from a single center in China to analyze the clinical and pathological features, and prognosis of DPPs. 109 patients with MPO-ANCA-associated vasculitis (MPO-AAV), 20 DPPs and 23 patients diagnosed with anti-GBM disease from a large center in China were included in this study. The ratio of patients with renal biopsy in three groups were 100%, 50% and 100%, respectively. Their clinical and pathological characteristics, and outcomes were analyzed. The intensity of immune deposits in the kidney at diagnosis was detected by immunofluorescence (IF). Furthermore, multivariate Cox hazard model analysis was used to assess the clinical and histological predictors of end-stage renal disease (ESRD) and death for DPPs. In our study, we found that patients in the DPPs group were older than the other two groups (p = 0.007, MPO-AAV vs. DPPs; p < 0.001, DPPs vs. anti-GBM). The DPPs group had a higher value of serum creatinine (p = 0.041) and lower estimated glomerular filtration rate (eGFR) (p = 0.032) compared with MPO-AAV patients. On the contrary, the DPPs group had a lower serum creatinine (p = 0.003) compared with patients with anti-GBM group. The proportion of patients with cardiac system involvement in the DPPs group was higher than anti-GBM patients (p = 0.014). Cellular crescents could be generally observed in renal biopsy of DPPs and patients with anti-GBM glomerulonephritis. In addition, Bowman's capsule rupture was more common in DPPs than MPO-AAV patients (p = 0.001). MPO-AAV had a better renal and overall survival outcome than DPPs (p < 0.001). There was no significant difference of renal and overall survival outcome between DPPs and patients with anti-GBM disease. The incidence of ESRD in DPPs was negatively associated with lymphocyte count (HR 0.153, 95% CI 0.027 to 0.872, p = 0.034) and eGFR (HR 0.847, 95% CI 0.726 to 0.989, p = 0.036). Elevated serum creatinine was confirmed as a risk factor of both renal (HR 1.003, 95% CI 1.000 to 1.005, p = 0.019) and patient survival in DPPs (HR1.461, 95% CI 1.050 to 2.033, p = 0.024). In summary, compared with anti-GBM disease, DPPs tended to involve multi-organ damage rather than limited to the kidney. It is highlighted that serologic DPPs have a worse renal and patient prognosis than MPO-AAV. Moreover, we found that the risk factors of renal survival of DPPs include low lymphocyte count, elevated serum creatinine and reduced eGFR, and serum creatinine can predict patient survival.

Progress in the application of body fluid and tissue level mRNAs-non-coding RNAs for the early diagnosis and prognostic evaluation of systemic lupus erythematosus.

The diagnosis and differential classification of systemic lupus erythematosus (SLE) is difficult, especially in patients with early-onset SLE who are susceptible to systemic multi-organ damage and serious complications and have difficulties in individualized treatment. At present, diagnosis is based mainly on clinical manifestations and the detection of serological antinuclear antibodies. The pathogenesis of SLE involves multiple factors, is clinically heterogeneous, and lacks specific biomarkers. Therefore, it is necessary to identify new biomarkers for the diagnosis and subtype classification of SLE. Non-coding RNAs (ncRNAs) are composed of microRNAs, long non-coding RNAs, small nucleolar RNAs, circular RNAs, and transfer RNAs. They play an important role in the occurrence and development of diseases and are used widely in the early diagnosis and prognosis of autoimmune diseases. In this review, we focus on the research progress in the diagnosis and prognostic assessment of SLE using humoral to tissue level ncRNAs.

The role of organ-deposited IgG in the pathogenesis of multi-organ and tissue damage in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE), often known simply as lupus, is a severe chronic autoimmune disease that is characterized by multi-organ and tissue damage and high levels of autoantibodies in serum. We have recently investigated, using animal models, the role of organ-deposited IgG autoantibodies in the pathogenesis of organ and tissue damage in SLE. We found that intra-organ injection of serum from mice with lupus (i.e., lupus mice) into healthy mice triggered inflammation in tissue and organs but that serum from other healthy mice did not, and that the severity of inflammation was related to the dose of serum injected. Immunohistochemistry showed that a large number of IgG molecules are deposited at the site of organ and tissue damage in lupus mice, and that IgG is a major contributor to the development of tissue inflammation triggered by serum from lupus mice or patients. The development of tissue inflammation induced by IgG in serum from lupus mice requires the presence of monocytes/macrophages, but not of lymphocytes or neutrophils; tumor necrosis factor (TNF)/tumor necrosis factor receptor 1 (TNFR1) and interleukin 1 (IL-1) also play essential roles in the development of tissue inflammation triggered by IgG. In addition, it has been found that TNFR1 inhibitors can suppress skin injury in lupus mice and that spleen tyrosine kinase (Syk) inhibitors, which can block the signaling transduction of IgG/Fc gamma receptors (FcγRs), can prevent and treat skin injury and kidney damage in lupus mice. We have also observed that lupus IgG might protect against bone erosion. Based on these results, we conclude that IgG plays a crucial role in the development of organ and tissue damage in SLE and in protecting bone erosion and arthritis, and we suggest that the IgG/FcγR signaling pathway is an important therapeutic target in SLE.

Vernodalin regulated the NF-κβp65 signaling in inflammation of lipopolysaccharide -induced sepsis rats

Sepsis, systemic inflammatory responses in western medicine stimulated by infections various sources and traditionally in Chinese medicine belong the poison heat syndrome. Vernodalin (VN) is a well-known cytotoxic sesquiterpene that has been renowned as anti-cancer, anti-inflammatory, and anti-bacterial properties. However, the molecular mechanism of VN on sepsis has not been studied. Therefore, we investigated the anti-inflammatory and antioxidant potential of VN against LPS-prompted sepsis in rats and also assess the impact of the NF-κBp65 signaling cascade. Rats were alienated into four groups: Group-I normal control, given 1 ml DMSO; while group-II rats were injected with LPS (100 μg/kg b.w., i.p.); Group-III rats were LPS (100 μg/kg b.w., i.p.) + VN (50 mg/kg b.w. in DMSO); Group- IV rats were given VN (50 mg/kg b.w. in DMSO) alone. We examined hepatic toxic markers, inflammatory cytokines, antioxidants, histopathology, and western blot analysis. Inflammatory markers, oxidative stress, and toxicity markers were significantly (p < 0.05) enhanced in the LPS-persuaded rats, whereas VN significantly (p < 0.05) prevented oxidative stress, lipid peroxides, toxic markers, pro-inflammatory cytokines, histological changes, and thereby multi-organ damage. VN significantly (p < 0.05) suppressed the NF-κβp65 signaling pathway and inhibited the Iκβα degradation. Thus, VN exerts a promising anti-septic natural agent for LPS-induced sepsis rats.

The effects of COVID-19 on respiratory muscle performance: making the case for respiratory muscle testing and training.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection results in multiorgan damage primarily mediated by viral infiltration via angiotensin-converting enzyme-2 receptors on the surface of cells. A primary symptom for many patients is exertional dyspnoea which may persist even beyond recovery from the viral infection. Respiratory muscle (RM) performance was hypothesised as a contributing factor to the severity of coronavirus disease 2019 (COVID-19) symptoms, such as dyspnoea, and outcomes. This was attributed to similarities between patient populations at elevated risk for severe COVID-19 symptoms and those with a greater likelihood of baseline RM weakness and the effects of prolonged mechanical ventilation. More recent evidence suggests that SARS-CoV-2 infection itself may cause damage to the RM, and many patients who have recovered report persistent dyspnoea despite having mild cases, normal lung function or undamaged lung parenchyma. These more recent findings suggest that the role of RM in the persistent dyspnoea due to COVID-19 may be more substantial than originally hypothesised. Therefore, screening for RM weakness and providing interventions to improve RM performance appears to be important for patients with COVID-19. This article will review the impact of SARS-CoV-2 infection on RM performance and provide clinical recommendations for screening RM performance and treatment interventions.

The Impact of COVID-19 (SARS-CoV-2) Virus Infection on the Endocrine System: A Review Study

The global coronavirus disease 2019 (COVID-19) pandemic is rapidly growing, and high mortality rates are reported in this regard. Coronaviruses are known to cause multi-organ system damage. Few data are available on the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on different endocrine glands. As angiotensin-converting enzyme-2 (ACE2) receptor is extensively expressed in the endocrine organs, and thus several important questions have arisen regarding whether the function of the endocrine organ changes in COVID-19 disease and patients with the SARS-CoV-2 infection develop endocrine disorders. Databases including PubMed, Web of Sciences, Scopus, and Google Scholar were searched for studies published from 1996 to February 15, 2021. New-onset diabetes mellitus has been reported by different studies at rates ranging from 5.8% to 35%. Hypercortisolism in admission time could predict disease severity. Tissues from the hypothalamus and the pituitary gland in animals are rich in ACE2, and some endocrinopathy may be secondary. Thyroiditis and thyrotoxicosis have also been recognized in the COVID-19 infection. Hypocalcemia and vitamin D deficiency may be correlated with disproportionate parathormone levels. Patients with decreased serum calcium levels had worse clinical variables and higher incidences of complications such as septic shock. Men are more susceptible to hypogonadism, and differences in the COVID-19 infection and mortality rates between males and females are due to the differential effects of estradiol and testosterone on the immune system. Considering that different glands have the ACE2 receptor, the coronavirus may be able to alter their function. Hence, this review mainly focused on COVID-19-associated endocrinopathy.

S3431 Intestinal Strongyloidiasis and Hyperinfection Syndrome in an Immunocompetent Patient

Introduction: Strongylodiasis is a term attributed to the many pathologies caused by the nematode helminth Strongyloides stercoralis. The condition is prevalent in around 70 countries with endemicity in tropical and subtropical climates, including the Southern United States. In chronically infected and immunocompetent individuals, the disease is generally asymptomatic with eosinophilia and stool larvae being the only indication of infection. A more disseminated form of the disease can lead to a debilitating condition known as Strongyloides hyperinfection syndrome (SHS), caused by a high intestinal parasitic load leading to multi-organ damage. SHS may reach 2% of patients with strongyloidiasis, typically occurring in the immunocompromised with underlying conditions such as hematologic neoplasias, advanced HIV, and organ transplantation. The risk of SHS in immunocompetent patients is not zero, however, as other conditions such as malnutrition, diabetes, chronic obstructive pulmonary disease, alcoholism, and chronic kidney disease are identifiable predisposing conditions for SHS. Case Description/Methods: A 73-year-old South Asian male with well-controlled asthma and diabetes presented with worsening shortness of breath, cramping abdominal pain, and distension for the past month accompanied by a productive cough and constipation with no bowel movement for the last 4 days. Twenty years earlier, he had emigrated from Bangladesh to his current residence in the northeast United States. Initial exam was notable for wheezing and diffuse, mild abdominal tenderness. Workup showed a leukocytosis with eosinophilic predominance and computed tomography showed a short segment of mural thickening in the sigmoid colon/rectum. Treatment with nebulizers and bowel regimens failed to relieve his symptoms initially. Stool analysis was notable for the presence of rare Strongyloides stercoralis larvae and the patient was started on ivermectin with complete relief of pulmonary and gastrointestinal symptoms (Figure). Discussion: SHS varies widely in symptomatology with gastrointestinal complaints ranging from abdominal pain to vomiting and watery diarrhea. Strongyloides is unique among intestinal nematodes in its ability to persist in humans for many years. Most cases of infection in diabetics are in those individuals with poor sugar control. Our case appears to be a waning of immunity in a likely chronic, asymptomatic strongyloidiasis patient housing the parasite since emigration from South Asia leading to SHS requiring urgent medical care.Figure 1.: (a) Iodine contrast staining of stool showing rhabditiform larva of Strongyloides stercoralis (b) Fecal agar plate culture showing rhabditiform larva of Strongyloides stercoralis.

Co-infection associated with SARS-CoV-2 and their management.

SARS-CoV-2was discovered in Wuhan, China and quickly spread throughout the world. This deadly virus moved from person to person, resulting in severe pneumonia, fever, chills and hypoxia. Patients are still experiencing problems after recovering from COVID-19. This review covers COVID-19 and associated issues following recovery from COVID-19, as well as multiorgan damage risk factors and treatment techniques. Several unusual illnesses, including mucormycosis, white fungus infection, happy hypoxia and other systemic abnormalities, have been reported in recovered individuals. In children, multisystem inflammatory syndrome with COVID-19 (MIS-C) is identified. The reasons for this might include uncontrollable steroid usage, reduced immunity, uncontrollable diabetes mellitus and inadequate care following COVID-19 recovery.

Severity of SARS-CoV-2 infection is associated with high numbers of alveolar mast cells and their degranulation.

BackgroundThe systemic inflammatory response post-SARS-CoV-2 infection increases pro-inflammatory cytokine production, multi-organ damage, and mortality rates. Mast cells (MC) modulate thrombo-inflammatory disease progression (e.g., deep vein thrombosis) and the inflammatory response post-infection.ObjectiveTo enhance our understanding of the contribution of MC and their proteases in SARS-CoV-2 infection and the pathogenesis of the disease, which might help to identify novel therapeutic targets.MethodsMC proteases chymase (CMA1), carboxypeptidase A3 (CPA3), and tryptase beta 2 (TPSB2), as well as cytokine levels, were measured in the serum of 60 patients with SARS-CoV-2 infection (30 moderate and 30 severe; severity of the disease assessed by chest CT) and 17 healthy controls by ELISA. MC number and degranulation were quantified by immunofluorescent staining for tryptase in lung autopsies of patients deceased from either SARS-CoV-2 infection or unrelated reasons (control). Immortalized human FcεR1+c-Kit+ LUVA MC were infected with SARS-CoV-2, or treated with its viral proteins, to assess direct MC activation by flow cytometry.ResultsThe levels of all three proteases were increased in the serum of patients with COVID-19, and strongly correlated with clinical severity. The density of degranulated MC in COVID-19 lung autopsies was increased compared to control lungs. The total number of released granules and the number of granules per each MC were elevated and positively correlated with von Willebrand factor levels in the lung. SARS-CoV-2 or its viral proteins spike and nucleocapsid did not induce activation or degranulation of LUVA MC in vitro.ConclusionIn this study, we demonstrate that SARS-CoV-2 is strongly associated with activation of MC, which likely occurs indirectly, driven by the inflammatory response. The results suggest that plasma MC protease levels could predict the disease course, and that severe COVID-19 patients might benefit from including MC-stabilizing drugs in the treatment scheme.

Urinary lipid profile of patients with coronavirus diseases 2019.

The coronavirus diseases 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is ongoing. Over 490 million people have been infected with this virus worldwide. Although many patients present with lower respiratory symptoms, some may progress to acute respiratory distress syndrome and even multi-organ damage. Therefore, there is an urgent need to establish treatment and management methods for this infectious disease. Here, we comprehensively analyzed urinary lipid mediators and their metabolites to identify non-invasive biomarkers that reflect the disease status of COVID-19 patients. We diagnosed 16 patients by polymerase chain reaction (PCR) analysis, who presented with mild-to-moderate symptoms, including fever and cough, between May and October 2020 in Japan, and collected their urine samples. Using mass spectrometry, we analyzed the lipid metabolites in these urine samples. In all the urine samples from the patients, 21 types of fatty acids and their metabolites were consistently detected in the samples among the 214 metabolites which were analyzed. Interestingly, urinary levels of fatty acids, docosahexaenoic acid was increased by approximately 3-fold in patients with COVID-19 compared to those in healthy subjects. Metabolites of major proinflammatory lipid mediators, PGE2, TXA2, and PGF2α, were also detected at significantly higher levels in the urine of patients with COVID-19. These observations suggest that urinary lipids can reflect the inflammatory status of patients with COVID-19, which can be a useful index to manage this disease.

3D engineered tissue models for studying human-specific infectious viral diseases.

Viral infections cause damage to various organ systems by inducing organ-specific symptoms or systemic multi-organ damage. Depending on the infection route and virus type, infectious diseases are classified as respiratory, nervous, immune, digestive, or skin infections. Since these infectious diseases can widely spread in the community and their catastrophic effects are severe, identification of their causative agent and mechanisms underlying their pathogenesis is an urgent necessity. Although infection-associated mechanisms have been studied in two-dimensional (2D) cell culture models and animal models, they have shown limitations in organ-specific or human-associated pathogenesis, and the development of a human-organ-mimetic system is required. Recently, three-dimensional (3D) engineered tissue models, which can present human organ-like physiology in terms of the 3D structure, utilization of human-originated cells, recapitulation of physiological stimuli, and tight cell–cell interactions, were developed. Furthermore, recent studies have shown that these models can recapitulate infection-associated pathologies. In this review, we summarized the recent advances in 3D engineered tissue models that mimic organ-specific viral infections. First, we briefly described the limitations of the current 2D and animal models in recapitulating human-specific viral infection pathology. Next, we provided an overview of recently reported viral infection models, focusing particularly on organ-specific infection pathologies. Finally, a future perspective that must be pursued to reconstitute more human-specific infectious diseases is presented.