Excessive Matrix Metalloproteinase-1 and Hyperactivation of Endothelial Cells Occurred in COVID-19 Patients and Were Associated With the Severity of COVID-19.

BACKGROUND: Systemic vascular injury occurs in coronavirus disease 2019 (COVID-19) patients; however, the underlying mechanisms remain unknown. METHODS: To clarify the role of inflammatory factors in COVID-19 vascular injury, we used a multiplex immunoassay to profile 65 inflammatory cytokines/chemokines/growth factors in plasma samples from 24 hospitalized (severe/critical) COVID-19 patients, 14 mild/moderate cases, and 13 healthy controls (HCs). RESULTS: COVID-19 patients had significantly higher plasma levels of 20 analytes than HCs. Surprisingly, only 1 cytokine, macrophage migration inhibitory factor (MIF), was among these altered analytes, while the rest were chemokines/growth factors. Additionally, only matrix metalloproteinase-1 (MMP-1) and vascular endothelial growth factor A (VEGF-A) were significantly elevated in hospitalized COVID-19 patients when compared to mild/moderate cases. We further studied MMP-1 enzymatic activity and multiple endothelial cell (EC) activation markers (soluble forms of CD146, intercellular adhesion molecule 1 [ICAM-1], and vascular cell adhesion molecule 1 [VCAM-1]) and found that they were highly dysregulated in COVID-19 patients. CONCLUSIONS: COVID-19 patients have a unique inflammatory profile, and excessive MMP-1 and hyperactivation of ECs are associated with the severity of COVID-19.

Vitamin D as Supplemental Therapy for Pneumocystis Pneumonia.

The combination of all-trans retinoic acid (ATRA) and primaquine (PMQ) has been shown to be effective for therapy of Pneumocystis pneumonia (PCP). Since a high concentration of ATRA has significant adverse effects, the possibility that vitamin D can be used to replace ATRA for PCP therapy was investigated. C57BL/6 mice were immunosuppressed by depleting CD4(+) cells and infected with Pneumocystis murina 1 week after initiation of immunosuppression. Three weeks after infection, the mice were treated orally for 3 weeks with vitamin D3 (VitD3) alone, PMQ alone, a combination of VitD3 and PMQ (VitD3-PMQ), or a combination of trimethoprim and sulfamethoxazole (TMP-SMX). Results showed that VitD3 (300 IU/kg/day) had a synergistic effect with PMQ (5 mg/kg/day) for therapy of PCP. Flow cytometric studies showed that this VitD3-PMQ combination recovered the CD11b(low) CD11c(high) alveolar macrophage population in mice with PCP as effectively as TMP-SMX. The VitD3-PMQ combination also reduced the massive infiltration of inflammatory cells into the lungs and the severity of lung damage. VitD3 was also shown to reduce the dose of TMP-SMX required for effective treatment of PCP. Taken together, results of this study suggest that a VitD3-PMQ combination can be used as an alternative therapy for PCP.

Serum from COVID-19 patients early in the pandemic shows limited evidence of cross-neutralization against variants of concern.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) results in a variety of clinical symptoms ranging from no or mild to severe disease. Currently, there are multiple postulated mechanisms that may push a moderate to severe disease into a critical state. Human serum contains abundant evidence of the immune status following infection. Cytokines, chemokines, and antibodies can be assayed to determine the extent to which a patient responded to a pathogen. We examined serum and plasma from a cohort of patients infected with SARS-CoV-2 early in the pandemic and compared them to negative-control sera. Cytokine and chemokine concentrations varied depending on the severity of infection, and antibody responses were significantly increased in severe cases compared to mild to moderate infections. Neutralization data revealed that patients with high titers against an early 2020 SARS-CoV-2 isolate had detectable but limited neutralizing antibodies against the emerging SARS-CoV-2 Alpha, Beta and Delta variants. This study highlights the potential of re-infection for recovered COVID-19 patients.

Excessive matrix metalloproteinase-1 and hyperactivation of endothelial cells occurred in COVID-19 patients and were associated with the severity of COVID-19.

COVID-19 starts as a respiratory disease that can progress to pneumonia, severe acute respiratory syndrome (SARS), and multi-organ failure. Growing evidence suggests that COVID-19 is a systemic illness that primarily injures the vascular endothelium, yet the underlying mechanisms remain unknown. SARS-CoV-2 infection is believed to trigger a cytokine storm that plays a critical role in the pathogenesis of endothelialitis and vascular injury, eventually leading to respiratory and multi-organ failure in COVID-19 patients. We used a multiplex immunoassay to systematically profile and compare 65 inflammatory cytokines/chemokines/growth factors in plasma samples from 24 hospitalized (severe/critical) COVID-19 patients, 14 mild/moderate cases, and 13 healthy controls (HCs). Patients with severe/critical and mild/moderate COVID-19 had significantly higher plasma levels of 20 analytes than HCs. Surprisingly, only one cytokine (MIF) was among these altered analytes, while the rest were chemokines and growth factors. In addition, only MMP-1 and VEGF-A were significantly elevated in hospitalized COVID-19 patients when compared to mild/moderate cases. Given that excessive MMP-1 plays a central role in tissue destruction in a wide variety of vascular diseases and that elevated VEGF-A, an EC activation marker, increases vascular permeability, we further studied MMP-1 enzymatic activity and other EC activation markers such as soluble forms of CD146, ICAM-1, and VCAM-1. We found that plasma MMP-1 enzymatic activity and plasma levels of MMP-1 and EC activation markers were highly dysregulated in COVID-19 patients. Some dysregulations were associated with patients' age or gender, but not with race. Our results demonstrate that COVID-19 patients have distinct inflammatory profiles that are distinguished from the cytokine storms in other human diseases. Excessive MMP-1 and hyperactivation of ECs occur in COVID-19 patients and are associated with the severity of COVID-19.

Serum from COVID-19 patients early in the pandemic shows limited evidence of cross-neutralization against variants of concern.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) results in a variety of clinical symptoms ranging from no or mild to severe disease. Currently, there are multiple postulated mechanisms that may push a moderate to severe disease into a critical state. Human serum contains abundant evidence of the immune status following infection. Cytokines, chemokines, and antibodies can be assayed to determine the extent to which a patient responded to a pathogen. We examined serum and plasma from a cohort of patients infected with SARS-CoV-2 early in the pandemic and compared them to negative-control sera. Cytokine and chemokine concentrations varied depending on the severity of infection, and antibody responses were significantly increased in severe cases compared to mild to moderate infections. Neutralization data revealed that patients with high titers against an early 2020 isolate had detectable but limited neutralizing antibodies against newly circulating SARS-CoV-2 variants of concern. This study highlights the potential of re-infection for recovered COVID-19 patients.

Seroprevalence of severe acute respiratory coronavirus virus 2 (SARS-CoV-2) antibodies among healthcare workers with differing levels of coronavirus disease 2019 (COVID-19) patient exposure.

Healthcare employees were tested for antibodies against severe acute respiratory coronavirus virus 2 (SARS-CoV-2). Among 734 employees, the prevalence of SARS-CoV-2 antibodies was 1.6%. Employees with heavy coronavirus disease 2019 (COVID-19) exposure had similar antibody prevalence as those with limited or no exposure. Guidelines for PPE use seem effective for preventing COVID-19 infection in healthcare workers.

Concomitant lymphoplasmacytic lymphoma and plasma cell myeloma, a diagnostic challenge.

BACKGROUND: Lymphoplasmacytic lymphoma and plasma cell myeloma are two B cell lymphoproliferative neoplasms derived from mature B-lymphocytes in different differentiation stages. The coexistence of these two tumors in the same patient is exceedingly rare and can be difficult to diagnose. CASE PRESENTATION: A 76-year-old male presented with a pathologic fracture after a fall. Radiography showed a lytic lesion in the pelvis. Serum immunofixation showed distinct IgM kappa and IgA kappa monoclonal protein bands. Bone marrow examination revealed aggregates of small, mature lymphoid cells with admixed plasma cells. Immunohistochemical studies and flow cytometric analysis showed the lymphoid cells were CD10-/CD5- kappa restricted monoclonal B cells. The plasma cells were monoclonal with kappa light chain restriction. The majority of plasma cells were positive for IgA and cyclin D1 with a few plasma cells positive for IgM. Additional studies showed the presence of both a positive MYD88 L265P mutation and a CCND1/IGH fusion. A diagnosis of concomitant lymphoplasmacytic lymphoma and plasma cell myeloma was rendered. CONCLUSION: Concomitant lymphoplasmacytic lymphoma and plasma cell myeloma can be rarely encountered and is diagnostic challenging. It is commonly associated with biclonal monoclonal proteins. This case demonstrates the importance of a comprehensive work-up in the diagnosis of this disease combination and highlights the diagnostic role of MYD88 mutation study.

Low Serum Pancreatic Amylase and Lipase Values Are Simple and Useful Predictors to Diagnose Chronic Pancreatitis.

Background/Aims: This study aimed to evaluate the diagnostic role of low serum amylase and lipase values in the detection of chronic pancreatitis. Methods: Patients underwent endoscopic retrograde cholangiopancreatography and were diagnosed with non-calcific chronic pancreatitis (NCCP; n=99) and calcific chronic pancreatitis (CCP; n=112). Patient serum amylase and lipase values were compared with those of healthy controls (H; n=170). Results: The median serum amylase (normal range, 19 to 86 U/L) and lipase values (7 to 59 U/L) (P25-P75) were 47.0 (39.8 to 55.3) and 25.0 (18.0 to 35.0) for H, 34.0 (24.5 to 49.0) and 19.0 (9.0 to 30.0) for NCCP, and 30.0 (20.0 to 40.8) and 10.0 (3.0 to 19.0) for CCP, respectively. The cutoff values with the highest diagnostic accuracy for discriminating NCCP from H were 40 U/L for amylase and 20 U/L for lipase, respectively, and for CCP from H were 38 U/L for amylase and 15 U/L for lipase, respectively. For the diagnosis of NCCP with a criterion of serum amylase <40 and lipase <20 U/L, the sensitivity, specificity, positive predictive value, and negative predictive values were 37.4%, 88.8%, 66.1%, and 70.9%, respectively. Conclusions: Serum amylase and/or lipase levels below the normal serum range are highly specific for chronic pancreatitis patients. Clinicians should not ignore low serum pancreatic enzyme values.

Can We Detect Chronic Pancreatitis With Low Serum Pancreatic Enzyme Levels?

OBJECTIVES: The aims of this study were to evaluate whether serum pancreatic enzyme levels could be used to aid screening for chronic pancreatitis (CP). METHODS: 170 healthy volunteers were screened and prospectively enrolled in the control group. 150 patients who were diagnosed with calcific CP were enrolled in the patient group by retrospective review. Serum amylase and lipase levels were compared between the 2 groups. RESULTS: The mean values ± SD of the control group were compared with those of the patient group for serum amylase level (48.1 ± 13.2 vs 34.8 ± 17.2 U/L, P < 0.001) and serum lipase level (26.4 ± 11.3 vs 16.3 ± 11.2 U/L, P < 0.001). On the receiver operating characteristic curve analysis for amylase level, area under the curve was 0.740 (95% confidence interval), and sensitivity and specificity were 38.7% and 94.1%, respectively, with a cutoff value of 27.5 U/L. On the receiver operating characteristic curve analysis for lipase level, area under the curve was 0.748 (95% confidence interval), and sensitivity and specificity were 33.3% and 95.9%, respectively, with a cutoff value of 10.5 U/L. CONCLUSIONS: Our results suggest that low serum pancreatic enzyme levels can be used to aid in detection of CP.

Case report: serial percutaneous cholangioscopy with laser ablation for the management of locally recurrent biliary intraductal papillary mucinous tumor.

We present a case of serial cholangioscopic laser fulguration of a biliary recurrence of pancreatic intraductal papillary mucinous tumor in a 76-year-old man. Through established percutaneous biliary drain tracts, the aseptic use of a standard 6.9 F ureteroscope and holmium laser fiber facilitated visual ablation within the biliary tree. Quarterly cholangioscopic laser ablation provided safe and effective local control without biliary infectious complications. This case appears to be the first treatment of recurrent intrabiliary intraductal papillary mucinous tumor by serial antegrade choledocoscopy and laser photocoagulation. Effective local control appears possible with minimal morbidity. Standard ureteroscopic equipment facilitates safe and efficient percutaneous antegrade choledocoscopy.

Pulmonary hemorrhage syndrome associated with an autochthonous case of dengue hemorrhagic fever.

Dengue fever is a major public health problem worldwide. Dengue hemorrhagic fever, a much rarer form of the disease, occurs when a person previously infected with dengue is re-infected with a different viral serotype. In recent years the infection rates of dengue and both clinical syndromes have increased along the United States-Mexico border. We present the case of a 61-year-old Laotian female who presented with a 1-week history of fever, altered mental status, oral ulceration, and rash. The patient developed diffuse pulmonary hemorrhage and anemia requiring multiple transfusions. She eventually sustained multi-organ system failure and expired. Both the titer data and serologies were consistent with the diagnosis of dengue hemorrhagic fever. We hypothesize that this syndrome was the result of re-infection occurring within the United States. This case is also unusual in that it is the second reported in the literature of pulmonary hemorrhages associated with dengue hemorrhagic fever.