Assessment of serum neopterin levels in patients hospitalized with severe COVID-19

Background: COVID-19 has caused a considerable number of hospital admissions in China since December 2019. Many COVID-19 patients experience signs of acute respiratory distress syndrome, and some are even in danger of dying. Background: to measure the serum levels of D-dimer, Neutrophil-Lymphocyte count ratio (NLR), and neopterin in patients hospitalized with severe COVID-19 in Baghdad, Iraq. And to determine the cut-off values (critical values) of these markers for the distinction between the severe patients diagnosed with COVID-19 and the controls. Materials and methods: In this case-control study, we collect blood from 89 subjects, 45 were severe patients hospitalized in many Baghdad medical centers who were diagnosed with COVID-19 infection, and 44 were apparently healthy subjects as a control. The time of collection is from September 15 th to December 31 th, 2021. The optimal cut-off points (critical values) and prognostic relevance of D-dimer, Neutrophil-Lymphocyte count ratio (NLR), and neopterin were investigated using (ROC) curves analysis. Results: In severe patients hospitalized with COVID-19 the levels of D-dimer, NLR, and neopterin were statistically significantly higher than in control participants (P < 0.005). The D-dimer, NLR, and neopterin tests have areas under the receiver operating characteristic (ROC) curves of 0.920, 0.90, and 0.74 respectively, and their critical values for the differentiation between the severe patients and control were 0.22 micro g/ml, 2.56, and 3.02 nmol/L. Conclusions: D-dimer, NLR, and neopterin levels in sever COVID-19 patients were higher than control, with values of greater than 0.22 micro g/ml, 2.56 and 3.02 nmol/L respectively was linked to a severe COVID-19 infection with good sensitivity and selectivity.

Neopterin and kynurenine in serum and urine as prognostic biomarkers in hospitalized patients with delta and omicron variant SARS-CoV-2 infection.

OBJECTIVES: Currently, no biomarker or scoring system could clearly identify patients at risk of progression to a severe coronavirus disease (COVID)-19. Even in patients with known risk factors, the fulminant course cannot be predicted with certainty. Analysis of commonly determined clinical parameters (frailty score, age, or body mass index) together with routine biomarkers of host response (C-reactive protein and viral nucleocapsid protein) in combination with new biomarkers neopterin, kynurenine, and tryptophan, could aid in predicting the patient outcome. METHODS: In 2021 and 2022, urine and serum samples were prospectively collected on 1st to 4th day after hospital admission in 108 consecutive COVID-19 patients hospitalized at the University Hospital Hradec Králové, Czech Republic. Delta and omicron virus variants were studied. Neopterin, kynurenine and tryptophan were determined by liquid chromatography. RESULTS: A significant correlation was observed between urinary and serum biomarker concentrations. Urinary and serum neopterin, kynurenine and kynurenine/tryptophan ratio were significantly (p≤0.05) higher in patients who subsequently needed oxygen therapy vs. patients without oxygen therapy. These parameters were also significantly increased in patients who died during the hospitalization compared to survivors. Complex equations have been derived using the investigated biomarkers and other clinical or laboratory parameters to predict the risk of subsequent oxygen therapy or death during hospitalization. CONCLUSIONS: Present data demonstrate that neopterin, kynurenine and kynurenine/tryptophan ratio in the serum or in the urine represent promising biomarkers in the management of COVID-19 that may help to guide important therapeutic decisions.

Csf & Plasma Soluble Biomarkers in Neuro-Pasc: Preliminary Results from Covid Mind

Background: It is unknown whether individuals with neurological post-acute sequelae of COVID-19 (NeuroPASC) display altered levels of neuroimmune activity or neuronal injury. Method(s): Participants with new or worsened neurologic symptoms at least 3 months after laboratory-confirmed COVID-19 were enrolled in The COVID Mind Study at Yale. Never COVID controls (no history of COVID-19;nucleocapsid (N) antibody negative) were pre-pandemic or prospectively enrolled volunteers. CSF and plasma were assessed for neopterin and for IL-1beta, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p40, IL-12p70, IL-13, MCP-1, TNFalpha by bead-based multiplex assay;and for anti-SARS-CoV-2 N antibodies by Luminex-based multiplex assay in technical replicate, normalized against bovine serum albumin conjugated beads. Plasma concentrations of D-dimer, C-reactive protein, neurofilament light chain (NFL), and glial fibrillary acid protein (GFAP) were measured using high-sensitivity immunoassays. Group comparisons used non-parametric tests. Result(s): NeuroPASC participants (n=38) were studied 329 (median) days (range 81-742) after first positive test for acute COVID-19. Cognitive impairment (84%) and fatigue (82%) were the most frequent post-COVID symptoms. NeuroPASC and controls (n=22) were median 49 vs 52 yrs old (p=0.9), 74% vs 32% female (p< 0.001), 76% vs 23% white race (p< 0.001), and 6% vs 57% smokers (p< 0.001). CSF white blood cells/mL, CSF protein, and serum:CSF albumin ratio were normal in both groups. CSF TNFalpha (0.66 vs 0.55 pg/ul) and plasma IL12p40 were higher (103.3 vs 42.7);and MCP-1 (503 vs 697 pg/ul) and IL-6 (1.32 vs 1.84 pg/ul;p < 0.05 for IL-6) were lower in NeuroPASC vs controls (p< 0.05);but none of these differences were significant after adjusting for multiple comparisons. Plasma GFAP was elevated in NeuroPASC vs controls (54.4 vs 42.3 pg/ml;adjusted p< 0.03). There were no differences in the other biomarkers tested. 10/31 and 7/31 NeuroPASC had anti-N antibodies in CSF and plasma, respectively. Conclusion(s): When comparing NeuroPASC to never COVID controls, we found no evidence of neuroinflammation (normal CSF cell count, inflammatory cytokines) or blood-brain barrier dysfunction (normal albumin ratio), and no support for ongoing neuronal damage (normal plasma NFL). Future studies should include better gender and race matched controls and should explore the significance of a persistent CNS humoral immune response to SARS-CoV-2 and elevated plasma GFAP after COVID-19. (Figure Presented).

Changes in Juvenile Dermatomyositis after the Covid-19 Pandemic

Background. Prior research has shown that viruses may trigger JDM, although the degree to which COVID-19 may serve as a trigger for JDM remains unknown. We present two case reports of JDM occurring after COVID-19 infection. We also provide case numbers of new JDM diagnoses pre-and post-COVID-19 as well as an analysis of JDM population characteristics pre-and post-COVID-19. A 5year-old female developed upper respiratory infection (URI) symptoms and was diagnosed with COVID-19 in December of 2020. She developed Gottron's sign, heliotrope rash, and weakness resulting in admission in February of 2021. She had elevated CK, AST, ALT, LDH, and aldolase. Her CMAS (childhood myositis assessment scale) was 24. An MRI showed diffuse myositis. Myositis specific antibody (MSA) testing revealed a positive MJ antibody. She was diagnosed with JDM and started on steroids, methotrexate, hydroxychloroquine, and IVIG with improvement. The second patient was a 4year-old female who was diagnosed with COVID-19 in October 2020. In January 2021, she developed heliotrope rash and Gottron's papules. She developed decreased exercise tolerance in May 2021 found to have elevated Aldolase and LDH. Her CMAS was 34. An MRI showed diffuse myositis. MSA testing was significant for a positive P155/140 antibody. She was started on hydroxychloroquine, steroids, IVIG and methotrexate with improvement. Due to the aforementioned cases a retrospective analysis was performed assessing the characteristics of JDM pre-and post-COVID-19 at Lurie Children's Hospital. Methods. The Cure JM biorepository houses clinical data, laboratory data, and patient samples obtained at the onset of JDM. The following information was obtained from newly diagnosed JDM patients: MSA, DAS (disease activity score), flow cytometry results, vWF antigen, neopterin, CMAS, capillary end row loop(ERL), LDH, Aldolase, ESR, CRP, IgG, complements, ANA, and age at diagnosis. We identified 10 patients with a diagnosis of JDM from January 1st 2020 -July 1st 2021 who were designated as the post-COVID-19 group. This population was compared to a total of 51 patients diagnosed with JDM between Jan 1st 2010 and December 31st 2019 who were designated as the pre-COVID-19 group. Data analysis was performed using Welch T-testing. Research enrollment was impacted due to the COVID-19 pandemic. To better assess JDM rates, chart review and EMR reports were obtained to determine the total number of JDM diagnoses. Results. T-testing showed no significant change in DAS, ERL count, T or B cell flow cytometry, vWF antigen, CK, CMAS, CRP, Aldolase, LDH, IgG, complements or ANA titer between the pre-and post-COVID-19 JDM groups. The analysis showed a significant change in NK cell population with a decrease in the absolute NK cell number (pre 163, post 90.75. P value 0.03), and NK cell percentage (pre 6.6%, post 3.625%, P value 0.008). Both of the patients presented in this case report showed a low NK cell number (1% and 3% respectively). The total number of new JDM cases rose from an average of 6.3 cases per year to an average 9 cases per year from January 1st 2020 to December 31st 2021. Conclusion. This study provides two case reports of COVID-19 likely triggering JDM. This study also shows a modest increase in the number of new JDM cases since the onset of the pandemic. Interestingly, the NK cell population in the post-COVID-19 JDM patients were significantly decreased. NK cells have multiple roles in not only immune regulation, but also the immune response to viruses. This study suggests that NK cells play a role in the development of in virally mediated JDM, specifically in cases triggered by COVID-19. Future studies will be important to further delineate the function of NK cells in these patients. Markers of JDM disease severity, including DAS, Neopterin, CK, and CMAS, did not significantly change in our institution's JDM population after the onset of the COVID-19 pandemic.

Interferon-gamma Mediated Metabolic Pathways in Hospitalized Patients During Acute and Reconvalescent COVID-19.

Background: Fatigue, sleep disturbance, and neurological symptoms during and after COVID-19 are common and might be associated with inflammation-induced changes in tryptophan (Trp) and phenylalanine (Phe) metabolism. Aim: This pilot study investigated interferon gamma inducible biochemical pathways (namely Trp catabolism, neopterin, tyrosine [Tyr], and nitrite formation) during acute COVID-19 and reconvalescence. Patients and methods: Thirty one patients with moderate to severe COVID-19 admitted to the University Hospital of Innsbruck in early 2020 (March-May) were followed up. Neurotransmitter precursors Trp, Phe, Tyr as well as kynurenine (Kyn), neopterin, nitrite, and routine laboratory parameters were analyzed during acute infection and at a follow-up (FU) 60 days thereafter. Clinical symptoms of patients (neurological symptoms, fatigue, sleep disturbance) were recorded and associations with concentrations of laboratory parameters investigated. Results and conclusion: Almost half of the patients suffered from neurological symptoms (48.4%), the majority of patients experienced sleep difficulties (56.7%) during acute COVID-19. Fatigue was present in nearly all patients. C-reactive protein (CRP), interleukin-6 (IL-6), neopterin, Kyn, Phe concentrations were significantly increased, and Trp levels depleted during acute COVID-19. Patients with sleep impairment and neurological symptoms during acute illness presented with increased CRP and IL-6 concentrations, Trp levels were lower in patients with sleep disturbance. In general, inflammatory markers declined during reconvalescence. A high percentage of patients suffered from persistent symptoms at FU (neurological symptoms: 17.2%, fatigue: 51.7%, sleeping disturbance: 34.5%) and had higher CRP concentrations. Nitrite and Phe levels were lower in patients with sleeping difficulties at FU and Kyn/Trp ratio, as indicator of IDO activity, was significantly lower in patients with neurological symptoms compared to patients without them at FU. In summary, inflammation induced alterations of amino acid metabolism might be related to acute and persisting symptoms of COVID-19.

COVID-19 Mimics Pulmonary Dysfunction in Muscular Dystrophy as a Post-Acute Syndrome in Patients.

Although progressive wasting and weakness of respiratory muscles are the prominent hallmarks of Duchenne muscular dystrophy (DMD) and long-COVID (also referred as the post-acute sequelae of COVID-19 syndrome); however, the underlying mechanism(s) leading to respiratory failure in both conditions remain unclear. We put together the latest relevant literature to further understand the plausible mechanism(s) behind diaphragm malfunctioning in COVID-19 and DMD conditions. Previously, we have shown the role of matrix metalloproteinase-9 (MMP9) in skeletal muscle fibrosis via a substantial increase in the levels of tumor necrosis factor-α (TNF-α) employing a DMD mouse model that was crossed-bred with MMP9-knockout (MMP9-KO or MMP9-/-) strain. Interestingly, recent observations from clinical studies show a robust increase in neopterin (NPT) levels during COVID-19 which is often observed in patients having DMD. What seems to be common in both (DMD and COVID-19) is the involvement of neopterin (NPT). We know that NPT is generated by activated white blood cells (WBCs) especially the M1 macrophages in response to inducible nitric oxide synthase (iNOS), tetrahydrobiopterin (BH4), and tetrahydrofolate (FH4) pathways, i.e., folate one-carbon metabolism (FOCM) in conjunction with epigenetics underpinning as an immune surveillance protection. Studies from our laboratory, and others researching DMD and the genetically engineered humanized (hACE2) mice that were administered with the spike protein (SP) of SARS-CoV-2 revealed an increase in the levels of NPT, TNF-α, HDAC, IL-1ß, CD147, and MMP9 in the lung tissue of the animals that were subsequently accompanied by fibrosis of the diaphragm depicting a decreased oscillation phenotype. Therefore, it is of interest to understand how regulatory processes such as epigenetics involvement affect DNMT, HDAC, MTHFS, and iNOS that help generate NPT in the long-COVID patients.

Comparison of the levels of neopterin, CRP, and IL-6 in patients infected with and without SARS-CoV-2.

Background: Neopterin (NP) is a biomarker for activated cellular immunity and is elevated in diseases including viral and bacterial infections, autoimmune diseases, and cancer. However, the clinical assessment of neopterin has not been used for these disorders because the physiological significance of measuring NP is obscure. It would be important to compare the NP profiles with those of other inflammation markers especially in relatively early phase of patients to reveal the significance of NP measurements in pathological states. Methods: Plasma NP, biopterin, CRP, and IL-6 levels were measured in 46 patients with Coronavirus Disease 2019 (COVID-19) and 23 patients with non-COVID-19 disorders. The correlations between these markers were analyzed in the COVID-19 and non-COVID-19 patients independently. Results: The NP levels were significantly higher in the COVID-19 patients than in the non-COVID-19 patients, while biopterin, CRP and IL-6 were not changed significantly. The NP levels were found to show a weak negative correlation against the days after onset in the COVID-19 patients (rs = -0.348, p = 0.0192), suggesting that the elevation of NP would be an early event of viral infection. Correlations between NP and CRP, or between NP and IL-6 in COVID-19 patients were weaker than that between CRP and IL-6. Conclusions: The elevation of NP levels was supposed to be distinct from those of CRP and IL-6 in relatively early and mild COVID-19 patients. Our data suggest that NP is produced at the early phase of infection by different signaling pathways and/or cells from those of CRP and IL-6. Further study on the signaling pathway to induce NP is expected.

Cytokine patterns of fatal hyperinflammatory conditions, caused by secondary hemophagocytic lymphohistiocytosis, bacterial sepsis and COVID-19

Introduction. In severe cases of coronavirus disease 2019 (COVID-19) pulmonary infiltration is accompanied by cytokine storm syndrome (CSS) development. Besides COVID-19, CSS can be triggered by the range of pathologies, which include hemophagocytic lymphohistiocytosis (sHLH) and septic shock (SS). The aim of this study was to compare immunological profiles in fatal cases of COVID-19, sHLH and SS. Material and methods. Serum levels of IL-1β, IL-2, IL-6, IL-8, IL-10, IL-17A, IL-18, IFN-γ, TNF-α, procalcitonin, neopterin, ferritin with percent of glycosylated fraction (% GF) were measured in 37 COVID-19 fatal cases, collected during 2020 year prospectively;and in 39 sHLH and 47 SS fatal cases, collected within 2018–2019 years retrospectively. Comparison groups also included 194 non-fatal COVID-19 cases and 20 healthy donors, collected during 2020 year. Cytokine concentrations, procalcitonin and neopterin were measured by enzyme-linked immunosorbent assay;the ferritin level was determined by the turbidimetry method. The percent of glycosylated ferritin fraction (% GF) was calculated by the modified method of M. Worwood et al. Results. Deceased patients with COVID-19 had higher IL-6, IL-8, IL-10, IL-18, procalcitonin median levels compared to the survived. Meanwhile IL-8, IL-18, IFN-γ, TNFα and ferritin concentrations were significantly lower in deceased COVID-19 patients compared to sHLH and SS. The levels of IL-6 and procalcitonin in fatal COVID-19 were comparable to SS, but significantly higher than in sHLH. Leucocytes were higher in COVID-19 compared to both SS and sHLH. Conclusion. Each fatal condition was accompanied by specific features of the cytokine profile: high IL-6 combined with low IFN-γ, TNFα in COVID-19;high IL-8, IL-6 with low IL-17A, IL-2 in SS;high IL-18, ferritin, IFN-γ with low IL-6, procalcitonin, % GF in sHLH.

CSF and BLOOD ANALYSES in PARTICIPANTS with POST-COVID-19 NEUROPSYCHIATRIC SYMPTOMS

Background: The pathogenesis of neuropsychiatric symptoms persisting months after acute SARS-CoV-2 infection is poorly understood. We examined clinical and laboratory parameters in participants with post-acute COVID-19 neuropsychiatric symptom to assess for systemic and nervous system immune perturbations. Methods: Participants with a history of laboratory confirmed COVID-19 and ongoing neurologic symptoms were enrolled in an observational study that collected medical history;detailed post-COVID symptom survey;and paired cerebrospinal fluid (CSF) and blood. In addition to standard clinical labs, neopterin and anti-SARS-CoV-2 antibodies (anti-spike, RBD, and nucleocapsid) were measured by ELISA. Non-parametric tests were used to compare CSF and blood findings between the post-COVID participants and pre-COVID-19 era healthy controls. Results: Post-COVID participants (n=27) and controls (n=21) were similar in age (median 51 and 46 years), but there was a greater proportion of females (67% vs 24%;p=0.004) and white participants in the post-COVID cohort (63% vs 24%;p=0.04). The post-COVID study visit was a median of 264 days (IQR 59-332) after acute COVID-19 symptom onset. 35% were hospitalized during their acute illness;12% required intensive care. 33% had previously been treated with medications for mental health conditions. The most frequent neuropsychiatric symptoms were cognitive impairment (67%), mood symptoms (67%), headache (56%), and neuropathy (41%). Blood c-reactive protein, T cell count, and T cell subset frequency (CD4% and CD8%) were similar between groups, while D-dimer was higher in the post-COVID cohort (median 0.48 vs 0.27 mg/L;p = 0.019) (Figure). CSF WBC, protein, neopterin, and CSF/blood albumin ratio were similar between the groups;the frequency of CSF lymphocytes was lower in the post-COVID cohort (p = 0.05) (Figure 1). Antibodies against at least one SARS-CoV-2 antigen were detected in 7/10 CSF and 8/9 blood samples in the post-COVID CSF (antibody reactivity range 1.5 to 55-fold greater than to control antigens). Conclusion: In this small cohort of post-COVID participants with neurologic symptoms, we found limited differences in CSF and blood markers when compared to pre-pandemic healthy controls. Deeper immunophenotyping in a larger number of participants may provide greater insight into subtle differences. The presence of anti-SARS-CoV-2 antibodies in CSF months after acute infection warrants further investigation.

SARS-CoV-2 CSF N-ANTIGEN DETECTION IS ASSOCIATED with CNS INFLAMMATION in NEUROCOVID

Background: The underlying CNS pathogenesis in COVID-19 is not clear and viral RNA is rarely detected in cerebrospinal fluid (CSF). We measured viral antigen and biomarker profiles in CSF in relation to neurological symptoms and disease severity. Methods: We included 44 (32% female) hospitalized patients (26 moderate, 18 severe COVID-19) and 10 healthy controls (HC). 21 patients were neuroasymptomatic (NA), 23 neurosymptomatic (NS;encephalopathy=21, encephalitis=1, GBS=1). For antigen and cytokine analyses, a patient control (PC;n=41) group (COVID-negative with no sign of CNS infection in clinical CSF samples) was used. CSF nucleocapsid antigen (N-Ag) was analyzed using an ultrasensitive antigen capture immunoassay platform, S-PLEX direct detection assay, S-PLEX SARS-CoV-2 N Kit (MesoScale Diagnostics, LLC. Rockville, MD). Additional analyses included CSF neopterin, β2-microglobulin, cytokines and neurofilament light (NfL). Results: CSF N-Ag was detected in 31/35 patients (0/41 controls) while viral RNA was negative in all. CSF N-Ag was significantly correlated with CSF neopterin (r=0.38;p=0.03) and IFN-γ (r=0.42;p=0.01) adjusted for sampling day. No differences in CSF N-Ag concentrations were found between patient groups. All patient groups had markedly increased CSF neopterin, β2M, IL-6, IL-10 and TNF-α compared to controls, while IL-2, IL-1β and IFN-γ were significantly increased only in the NS group. CSF biomarkers were associated with time from symptom onset to CSF sampling. After adjusting for time of sampling, the NS group had significantly higher CSF IFN-γ (p=0.03), and showed a statistical trend towards significantly higher CSF neopterin, IL-6 and TNF-α (p=0.056-0.06) than the NA group. Additionally, age-adjusted CSF NfL was higher in the NS compared to the HC (p=0.01) group. No differences were seen in any CSF biomarkers in moderate compared to severe disease. Conclusion: Viral antigen is detectable in CSF in a majority of patients with COVID-19 despite the absence of detectable viral RNA, and is correlated to CNS immune activation markers. Patients with neurological symptoms had a more marked immune activation profile compared to NA patients, as well as signs of neuroaxonal injury compared to controls. These observations could not be attributed to a difference in COVID-19 severity. Our results highlight the importance of neurological symptoms and indicate that the CNS immune response and CNS pathogenesis can be initiated by viral components without direct viral invasion of the CNS.

The importance of neopterin in COVID-19: The prognostic value and relation with the disease severity.

Coronavirus Disease 2019 [COVID-19], caused by severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2], has rapidly evolved into a global health emergency. Neopterin [NPT], produced by macrophages when stimulated with interferon [IFN-]gamma, is an essential cytokine in the antiviral immune response. NPT has been used as a marker for the early assessment of disease severity in different diseases. The leading cause of NPT production is the pro-inflammatory cytokine IFN-. Macrophage activation has also been revealed to be linked with disease severity in SARS-CoV-2 patients. We demonstrate the importance of NPT in the pathogenesis of SARS-CoV-2 and suggest that targeting NPT in SARS-CoV-2 infection may be critical in the early prediction of disease progression and provision of timely management of infected individuals.

Elevated Neopterin Levels Predict Fatal Outcome in SARS-CoV-2-Infected Patients.

Highlights: Innate immune activation during Covid-19 infection is associated with pernicious clinical outcome. Background: Coronavirus disease 2019 (Covid-19) is a worldwide threat that has already caused more than 3 000 000 deaths. It is characterized by different patterns of disease evolution depending on host factors among which old-age and pre-existing comorbidities play a detrimental role. Previous coronavirus epidemics, notably SARS-CoV, were associated with increased serum neopterin levels, which can be interpreted as a sign of acute innate immunity in response to viral infection. Here we hypothesize that neopterin may serve as a biomarker of SARS-CoV-2 viral infection and Covid-19 disease severity. Methods: We measured neopterin blood levels by ELISA. Seric concentration was quantified from 256 healthy donors and 374 Covid-19 patients at hospital admission. Enrolled Covid-19 patients were all symptomatic and displayed a large spectrum of comorbidities. Patients were followed until disease resolution or death. Results: Severe and critically ill SARS-CoV-2 infected patients were characterized by a profound exacerbation of immune activation characterized by elevated neopterin blood levels. Systemic neopterin levels above 19nM stratified healthy individuals from Covid-19 patients with 87% specificity and 100% sensitivity. Moreover, systemic neopterin levels above 53nM differentiated non-survivors from survivors with 64% specificity and 100% sensitivity. Conclusion: We propose that neopterin concentration measured at arrival to hospital is a hallmark of severe Covid-19 and identifies a high-risk population of pernicious clinical outcome with a need for special medical care.

The potential role of neopterin in Covid-19: a new perspective.

Neopterin (NPT) is a member of pteridines group, synthesized by macrophages when stimulated by interferon gamma (INF-γ). NPT is regarded as a macrophage stimulation indicator, marker of cellular immune activation and T helper 1 (Th1) type 1 immune response. Here, we aimed to provide a view point on the NPT features and role in Covid-19. Serum NPT level is regarded as an independent prognostic factor for Covid-19 severity, with levels starting to increase from the 3rd day of SARS-CoV-2 infection, being associated with severe dyspnea, longer hospitalization period and complications. Also, early raise of NPT reflects monocytes/macrophages activation before antibody immune response, despite the NPT level may also remain high in Covid-19 patients or at the end of incubation period before the onset of clinical symptoms. On the other hand, NPT attenuates the activity of macrophage foam cells and is linked to endothelial inflammation through inhibition of adhesion molecules and monocytes migration. However, NPT also exerts anti-inflammatory and antioxidant effects by suppressing NF-κB signaling and NLRP3 inflammasomes. NPT can be viewed as a protective compensatory mechanism to counterpoise hyper-inflammation, oxidative stress, and associated organ damage.

The prognostic role of neopterin in COVID-19 patients.

In Coronavirus disease-2019 (COVID-19) cases, hyper inflammation is associated with the severity of the disease. High levels of circulating cytokines were reported in severe COVID-19 patients. Neopterin produced by macrophages on stimulation with interferon-gamma, which is an important cytokine in the antiviral immune response, hence it can be used to predict the severity of disease in COVID-19 cases. In this study, it was aimed to determine the prognostic value of the neopterin for the prediction of severe disease in patients with COVID-19. This single-center, prospective study was conducted in hospitalized COVID-19 patients and healthy volunteers. Severe and mild COVID-19 cases were compared in terms of clinical and laboratory findings as well as serum neopterin levels on hospital admission. To assess the prognostic utility of neopterin between the severe and mild COVID-19 groups, a receiver-operating characteristic (ROC) curve was generated, and the area under the curve (AUC) was calculated. The median serum neopterin level was four times higher in COVID-19 patients than the healthy controls (46 vs. 12 nmol/L; p < .001). The AUC value of serum neopterin was 0.914 (95% confidence interval, 0.85-0.97). The sensitivity and specificity of serum neopterin for the cut-off value of 90 nmol/L to identify severe COVID-19 cases were 100% and 76%, respectively. Serum neopterin levels on hospitalization were significantly higher in severe COVID-19 disease than mild COVID-19 patients. Neopterin levels can be used as an early prognostic biomarker for COVID-19 on admission.

Neopterin: A Promising Candidate Biomarker for Severe COVID-19.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has rapidly spread across the world since its first emergence in China in late 2019. It is a major public health concern with no effective treatct 3ments. The immunopathology of SARS-CoV-2 is associated with an excessive inflammatory response. Macrophage activation syndrome (MAS) is also associated with the severity of the disease in SARS-CoV-2-infected patients. Neopterin is a macrophage activation marker produced by monocytes and macrophages upon activation by interferon-gamma (IFN-γ). Neopterin is a well-established marker in a variety of diseases, and recent evidence indicates that it could be helpful in early prediction of the severity of COVID-19 disease and serve as a prognostic marker. Here, we outline the role of macrophage activation syndrome in the pathogenesis of SARS-CoV-2 and suggest that neopterin could be used as a biomarker for progression of COVID-19.

Serum neopterin levels in relation to mild and severe COVID-19.

BACKGROUND: The COVID-19 pandemic, caused by the coronavirus SARS-CoV-2, is rapidly spreading worldwide. There is limited information about prognostic markers that could help clinicians to identify COVID-19 patients with a poor prognosis. Serum levels of the immune activation marker neopterin has shown to be of prognostic value in patients with SARS. The aim of this study was to investigate whether serum neopterin is associated with the severity of COVID-19. METHODS: We included 34 patients with confirmed COVID-19 between March 3 and March 30, 2020. Fifteen patients had mild disease and did not require hospitalization, whereas 19 patients developed severe COVID-19 requiring intensive care. Concentrations of serum neopterin, tryptophan, and kynurenine were measured at and repeatedly after inclusion. RESULTS: We found a more than two-fold higher mean concentration of neopterin in severely ill patients (mean value 42.0 nmol/L (SD 18.2)) compared to patients with mild symptoms (16.9 nmol/L (SD 11.0)). All of the severe cases had elevated neopterin concentrations (> 9.1 nmol/L) at the initial sampling with values ranging from 17.2 to 86.7 nmol/L. In comparison, 10 of 15 patients with mild disease had neopterin levels above 9.1 nmol/L, with concentrations in the range from 4.9 to 31.6 nmol/L. Neopterin levels gradually decreased during the course of COVID-19, but severe cases maintained elevated levels for a longer period. Moreover, lower levels of tryptophan and higher levels of kynurenine, indicating an increased tryptophan catabolism, were seen in the group with severe cases. CONCLUSIONS: In conclusion, we found that serum neopterin levels are associated with the severity of COVID-19. Our findings suggest that neopterin could be used as a prognostic marker, but further studies are needed to elucidate how it can be used in the clinic.

Neopterin Predicts Disease Severity in Hospitalized Patients With COVID-19.

This study evaluates the predictive value of circulating inflammatory markers, especially neopterin, in patients with coronavirus disease 2019 (COVID-19). Within this retrospective analysis of 115 hospitalized COVID-19 patients, elevated neopterin levels upon admission were significantly associated with disease severity, risk for intensive care unit admission, need for mechanical ventilation, and death. Therefore, neopterin is a reliable predictive marker in patients with COVID-19 and may help to improve the clinical management of patients.