Dynamics of peripheral T cell exhaustion and monocyte subpopulations in neurocognitive impairment and brain atrophy in chronic HIV infection.

BACKGROUND: HIV-associated neurocognitive disorders (HAND) is hypothesized to be a result of myeloid cell-induced neuro-inflammation in the central nervous system that may be initiated in the periphery, but the contribution of peripheral T cells in HAND pathogenesis remains poorly understood. METHODS: We assessed markers of T cell activation (HLA-DR + CD38+), immunosenescence (CD57 + CD28-), and immune-exhaustion (TIM-3, PD-1 and TIGIT) as well as monocyte subsets (classical, intermediate, and non-classical) by flow cytometry in peripheral blood derived from individuals with HIV on long-term stable anti-retroviral therapy (ART). Additionally, normalized neuropsychological (NP) composite test z-scores were obtained and regional brain volumes were assessed by magnetic resonance imaging (MRI). Relationships between proportions of immune phenotypes (of T-cells and monocytes), NP z-scores, and brain volumes were analyzed using Pearson correlations and multiple linear regression models. RESULTS: Of N = 51 participants, 84.3% were male, 86.3% had undetectable HIV RNA < 50 copies/ml, median age was 52 [47, 57] years and median CD4 T cell count was 479 [376, 717] cells/uL. Higher CD4 T cells expressing PD-1 + and/or TIM-3 + were associated with lower executive function and working memory and higher CD8 T cells expressing PD-1+ and/or TIM-3+ were associated with reduced brain volumes in multiple regions (putamen, nucleus accumbens, cerebellar cortex, and subcortical gray matter). Furthermore, higher single or dual frequencies of PD-1 + and TIM-3 + expressing CD4 and CD8 T-cells correlated with higher CD16 + monocyte numbers. CONCLUSIONS: This study reinforces evidence that T cells, particularly those with immune exhaustion phenotypes, are associated with neurocognitive impairment and brain atrophy in people living with HIV on ART. Relationships revealed between T-cell immune exhaustion and inflammatory in CD16+ monocytes uncover interrelated cellular processes likely involved in the immunopathogenesis of HAND.

Plasma anti-CD4 IgG is associated with brain abnormalities in people with HIV on antiretroviral therapy.

Anti-CD4 IgG autoantibodies have been implicated in CD4+ T cell reconstitution failure, leaving people with HIV (PWH) at heightened risk of HIV-associated comorbidities, such as neurocognitive impairment. Seventeen PWH on stable anti-retroviral therapy (ART) and 10 HIV seronegative controls had plasma anti-CD4 IgG antibodies measured by enzyme-linked immunosorbent assay. Neuropsychological (NP) tests assessed cognitive performance, and brain volumes were measured by structural magnetic resonance imaging. Anti-CD4 IgG levels were elevated (p = 0.04) in PWH compared with controls. Anti-CD4 IgG correlated with global NP z-scores (rho = - 0.51, p = 0.04). A relationship was observed between anti-CD4 IgG and putamen (ß = - 0.39, p = 0.02), pallidum (ß = - 0.38, p = 0.03), and amygdala (ß = - 0.42, p = 0.05) regional brain volumes. The results of this study suggest the existence of an antibody-mediated relationship with neurocognitive impairment and brain abnormalities in an HIV-infected population.

Are Salt Tablets Effective in the Treatment of Euvolemic Hyponatremia?

OBJECTIVES: There is limited evidence for the use of salt tablets in the treatment of hyponatremia. This retrospective study evaluated the effectiveness of salt tablet administration in euvolemic hyponatremia. METHODS: This was a single-center, retrospective cohort study. Information on patients' demographics, clinical characteristics, and laboratory data were collected for retrospective review. Treatment for hyponatremia, including the amount of salt tablets, fluid restriction, and diuretics was collected. We compared hyponatremic patients with those who received salt tablets versus those who did not receive salt tablets. The primary outcome of interest was the change in serum sodium at 48 hours between the two groups. RESULTS: A total of 1258 medical records were initially screened with inclusion and exclusion criteria. After screening, there were 83 patients included in the study. Forty-two patients received salt tablets and 41 patients were in the group that did not receive salt tablets. Patients treated with salt tablets were older, more often female, and had lower body weight and lower initial serum sodium. The change in serum sodium after 48 hours was higher in the salt tablet group (5.2 mEq/L) than the non-salt tablet group (3.1 mEq/L; P < 0.001). This difference in serum sodium between the two groups remained statistically significant when adjusted for age, sex, weight, and initial serum sodium. CONCLUSIONS: The use of salt tablets in the treatment of euvolemic hyponatremia is associated with a small but significant improvement in serum sodium compared with patients who did not receive such therapy, even after adjusting for age, sex, weight, and initial serum sodium. This study supports the effectiveness of salt tablets in the treatment of euvolemic hyponatremia in medical patients.

Increasing Prevalence of Nontuberculous Mycobacteria in Respiratory Specimens from US-Affiliated Pacific Island Jurisdictions1.

Nontuberculous mycobacteria (NTM) respiratory infections represent a growing public health problem in many countries. However, there are limited published epidemiologic studies for the Western Pacific region. We reviewed respiratory specimens submitted to Diagnostic Laboratory Services in Hawaii, USA, for culture of Mycobacterium tuberculosis during August 2007-December 2011 to determine the NTM isolation rate. We observed a statistically significant increase in the rate of specimens with NTM isolated in respiratory culture (adjusted rate ratio per year 1.65, 95% CI 1.54-1.77; p<0.01). In contrast, the number of patients with respiratory cultures positive for M. tuberculosis showed no increase (adjusted rate ratio per year 0.98, 95% CI 0.94-1.01; p = 0.19). A 6-month subset of NTM isolates was identified by using a nucleic acid probe or 16S rRNA sequencing. M. avium complex and M. fortuitum were the most common NTM identified.

HIV and coronary artery calcium score: comparison of the Hawaii Aging with HIV Cardiovascular Study and Multi-Ethnic Study of Atherosclerosis (MESA) cohorts.

OBJECTIVES: To determine the association of HIV, immunologic, and inflammatory factors on coronary artery calcium (CAC), a marker of subclinical atherosclerosis. METHODS: Cross-sectional study comparing baseline data of males from Hawaii Aging with HIV - Cardiovascular Study (HAHCS) with the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. The cohorts were pooled to determine effects of HIV on CAC and explore immunologic and inflammatory factors that may explain development of CAC in HIV. Multivariable regression models compared CAC prevalence in HAHCS with MESA adjusting for coronary heart disease (CHD) risk profiles. RESULTS: We studied 100 men from HAHCS and 2733 men from MESA. Positive CAC was seen in 58% HAHCS participants and 57% MESA participants. Mean CAC was 260.8 in HAHCS and 306.5 in MESA. Using relative risk (RR) regression, HAHCS participants had a greater risk (RR = 1.20, P < 0.05) of having positive CAC than MESA when adjusting for age, smoking status, diabetes, antihypertensive therapy, BMI, systolic blood pressure, total cholesterol, and HDL cholesterol. Among participants with positive CAC, HIV infection was not associated with larger amounts of CAC. Among HAHCS participants, current HIV viral load, CD4, length of HIV, interleukin 6 (IL-6), fibrinogen, C-reactive protein (CRP), and D-dimer were not associated with the presence or amount of CAC. DISCUSSION: HIV was independently associated with a positive CAC in men with increased likelihood occurring between 45 and 50 years of age. Current HIV viral load, CD4 count, length of HIV, and inflammatory markers were unrelated to either presence or amount of CAC.

Serum amyloid P (SAP) is associated with impaired brachial artery flow-mediated dilation in chronically HIV-1 infected adults on stable antiretroviral therapy.

OBJECTIVE: This study aimed to evaluate the relationship between inflammatory biomarkers and endothelial dysfunction (ED), as measured by brachial artery flow-mediated dilation (FMD). METHODS: We conducted a cross-sectional analysis utilizing baseline data of 135 participants with HIV infection on stable antiretroviral therapy (ART) in the Hawaii Aging with HIV-Cardiovascular (HAHC-CVD) study who had available baseline inflammatory biomarkers and brachial artery FMD measurements. RESULTS: We observed significant associations between brachial artery FMD and baseline brachial artery diameter, age, male gender, traditional cardiovascular disease (CVD) risk factors such as BMI, waist to hip ratio, hypertension, systolic blood pressure (BP), diastolic BP, and LDL cholesterol, and 10-year coronary heart disease (CHD) risk estimated by Framingham risk score (FRS). Of all biomarkers tested, higher level of C-reactive protein (CRP) (beta = - 0.695, P = 0.030) and serum amyloid P (SAP) (beta = - 1.318, P = 0.021) were significantly associated with lower brachial artery FMD in univariable regression analysis. After adjusting for baseline brachial artery diameter, age, and selected traditional CVD risk factors in multivariable model, SAP remained significantly associated with brachial artery FMD (beta = - 1.094, P = 0.030), while CRP was not (beta = - 0.391, P = 0.181). DISCUSSION: Serum amyloid P was independently associated with impaired brachial artery FMD and may potentially relate to ED and increased CVD risk in HIV-infected patients on stable ART.

Treatment intensification with maraviroc (CCR5 antagonist) leads to declines in CD16-expressing monocytes in cART-suppressed chronic HIV-infected subjects and is associated with improvements in neurocognitive test performance: implications for HIV-associated neurocognitive disease (HAND).

HIV-associated neurocognitive disorders (HAND) continues to be prevalent (30-50%) despite plasma HIV-RNA suppression with combination antiretroviral therapy (cART). There is no proven therapy for individuals on suppressive cART with HAND. We have shown that the degree of HIV reservoir burden (HIV DNA) in monocytes appear to be linked to cognitive outcomes. HIV infection of monocytes may therefore be critical in the pathogenesis of HAND. A single arm, open-labeled trial was conducted to examine the effect of maraviroc (MVC) intensification on monocyte inflammation and neuropsychological (NP) performance in 15 HIV subjects on stable 6-month cART with undetectable plasma HIV RNA (<48 copies/ml) and detectable monocyte HIV DNA (>10 copies/10(6) cells). MVC was added to their existing cART regimen for 24 weeks. Post-intensification change in monocytes was assessed using multiparametric flow cytometry, monocyte HIV DNA content by PCR, soluble CD163 (sCD163) by an ELISA, and NP performance over 24 weeks. In 12 evaluable subjects, MVC intensification resulted in a decreased proportion of circulating intermediate (median; 3.06% (1.93, 6.45) to 1.05% (0.77, 2.26)) and nonclassical (5.2% (3.8, 7.9) to 3.2% (1.8, 4.8)) CD16-expressing monocytes, a reduction in monocyte HIV DNA content to zero log10 copies/10(6) cells and in levels of sCD163 of 43% by 24 weeks. This was associated with significant improvement in NP performance among six subjects who entered the study with evidence of mild to moderate cognitive impairment. The results of this study suggest that antiretroviral therapy with potency against monocytes may have efficacy against HAND.

Aerobic fitness levels and validation of a non exercise VO2max prediction equation for HIV-infected patients on HAART.

BACKGROUND: Non-exercise (N-EX) questionnaires have been developed to determine maximal oxygen consumption (VO2max) in healthy populations. There are limited reliable and validated N-EX questionnaires for the HIV+ population that provide estimates of habitual physical activity and not VO2max. OBJECTIVES: To determine how well regression equations developed previously on healthy populations, including N-EX prediction equations for VO2max and age-predicted maximal heart rates (APMHR), worked on an HIV+ population; and to develop a specific N-EX prediction equation for VO2max and APMHR for HIV+ individuals. METHODS: Sixty-six HIV+ participants on stable HAART completed 4 N-EX questionnaires and performed a maximal graded exercise test. RESULTS: Sixty males and 6 females were included; mean (SD) age was 49.2 (8.2) years; CD4 count was 516.0 ± 253.0 cells·mm-3; and 92% had undetectable HIV PCR. Mean VO2max was 29.2 ± 7.6 (range, 14.4-49.4) mL·kg-1·min-1 Despite positive correlations with VO2max, previously published N-EX VO2max equations produced results significantly different than actual VO2 scores (P < .0001). An HIV+ specific N-EX equation was developed and produced similar mean VO2max values, R = 0.71, when compared to achieved VO2max (P = .53). CONCLUSION: HIV+ individuals tend to be sedentary and unfit, putting them at increased risk for the development of chronic diseases associated with a sedentary lifestyle. Based on the level of error associated with utilizing APMHR and N-EX VO2max equations with HIV+ individuals, neither should be used in this population for exercise prescription.

Feasibility and potential role of ferumoxytol-enhanced neuroimaging in HIV-associated neurocognitive disorder.

We assessed ferumoxytol-enhanced brain MRI to identify monocyte/macrophage accumulation in HIV-associated neurocognitive disorder (HAND). Four HIV-infected subjects with undetectable HIV RNA levels on antiretroviral therapy, HIV DNA level in CD14+ cells ≥10 copies/10(6) cells, and cognitive impairment underwent ferumoxytol-enhanced brain MRI. On post-ferumoxytol susceptibility-weighted images, all HIV-infected subjects demonstrated a diffuse "tram track" appearance in the perivascular regions of cortical and deep white matter vessels suggesting ferumoxytol uptake in monocytes/macrophages. This finding was not present in an HIV-seronegative control. While ferumoxytol may have potential as an imaging biomarker for monocyte/macrophage accumulation in patients with HAND, future study is needed.

Health Disparities Investigator Development through a Team-Science Pilot Projects Program.

Profound health disparities are widespread among Native Hawaiians, other Pacific Islanders, and Filipinos in Hawai'i. Efforts to reduce and eliminate health disparities are limited by a shortage of investigators trained in addressing the genetic, socio economic, and environmental factors that contribute to disparities. In this conference proceedings report from the 2022 RCMI Consortium National Conference, we describe our mentoring program, with an emphasis on community-engaged research. Elements include our encouragement of a team-science, customized Pilot Projects Program (PPP), a Mentoring Bootcamp, and a mentoring support network. During 2017-2022, we received 102 PPP preproposals. Of these, 45 (48%) were invited to submit full proposals, and 22 (19%) were awarded (8 basic biomedical, 7 clinical, 7 behavioral). Eighty-three percent of awards were made to early-career faculty (31% ethnic minority, 72% women). These 22 awards generated 77 related publications; 84 new grants were submitted, of which 31 were awarded with a resultant return on investment of 5.9. From 5 to 11 investigators were supported by PPP awards each year. A robust usage of core services was observed. Our descriptive report (as part of a scientific conference session on RCMI specialized centers) focuses on a mentoring vehicle and shows how it can support early-stage investigators in pursuing careers in health disparities research.

Plasma galectin-3 is associated with decreased glomerular filtration rate in chronic HIV.

BACKGROUND: People living with HIV (PLWH) have higher rates of chronic kidney disease (CKD) compared with HIV-uninfected individuals. The pathogenesis of CKD in HIV remains poorly understood but is likely from a combination of various factors, such as traditional comorbidities, prolonged antiretroviral therapy, immune dysregulation, and direct HIV effect on the kidneys. We evaluated plasma galectin-3 (Gal-3), a circulating marker of fibrosis, and its association with renal function. METHODS: Estimated glomerular filtration rate (eGFR) was assessed by CKD-EPI. Plasma galectin-3 was obtained from banked specimens by ELISA. Factors associated with eGFR were analyzed using step-wise multiple linear regression. RESULTS: A total of 45 PLWH and 58 HIV-uninfected participants were included with similar demographic parameters. Among PLWH, majority had undetectable plasma HIV RNA (82.2%). Gal-3 was significantly higher in PLWH than in HIV-uninfected participants (6.4 [IQR 4.0, 8.5] ng/mL and 4.5 [IQR 2.3, 6.5] ng/mL, respectively; p = 0.020) while a trend towards lower eGFR was found in PLWH compared to the HIV-uninfected cohort (86.8 [IQR 71.3, 91.8] and 89.0 [IQR 78.6, 97.4] mL/min/1.73 m2, respectively; p = 0.071). In univariable analysis, HIV status was marginally associated with decreased eGFR (ß coefficient= -0.035, p = 0.051). In the final multivariable regression model adjusted for traditional risk factors of CKD, Gal-3 independently predicted a decrease in eGFR (unstandardized B= -0.008, p < 0.001) while HIV status did not demonstrate any significant association. CONCLUSION: Gal-3 was higher in PLWH compared with HIV-uninfected participants. In multivariable adjusted analyses, Gal-3, but not HIV status, was associated with decreased eGFR. The role of Gal-3 as a biomarker of kidney function needs to be further elucidated.

Platelet and HIV Interactions and Their Contribution to Non-AIDS Comorbidities.

Platelets are anucleate cytoplasmic cell fragments that circulate in the blood, where they are involved in regulating hemostasis. Beyond their normal physiologic role, platelets have emerged as versatile effectors of immune response. During an infection, cell surface receptors enable platelets to recognize viruses, resulting in their activation. Activated platelets release biologically active molecules that further trigger host immune responses to protect the body against infection. Their impact on the immune response is also associated with the recruitment of circulating leukocytes to the site of infection. They can also aggregate with leukocytes, including lymphocytes, monocytes, and neutrophils, to immobilize pathogens and prevent viral dissemination. Despite their host protective role, platelets have also been shown to be associated with various pathophysiological processes. In this review, we will summarize platelet and HIV interactions during infection. We will also highlight and discuss platelet and platelet-derived mediators, how they interact with immune cells, and the multifaceted responsibilities of platelets in HIV infection. Furthermore, we will give an overview of non-AIDS comorbidities linked to platelet dysfunction and the impact of antiretroviral therapy on platelet function.

Low-density granulocytes display immature cells with enhanced NET formation in people living with HIV.

While the protective role of neutrophil extracellular traps (NETs) in limiting human immunodeficiency virus (HIV) spread to susceptible cells has been documented, there is comparatively little insight into whether NET formation is harmful in people living with HIV (PLWH). To gain insight into neutrophil dysregulation and the pathological role of NETs in HIV, we examined expressions of NET-associated markers [cell-free DNA (cfDNA) and citrullinated histone H3 (CitH3)] in the plasmas from a cohort of the Hawaii Aging with HIV-cardiovascular and HIV-seronegative (HIV-) individuals. In a subset of participants, circulating low-density granulocyte (LDG) levels and their maturation and activation status were analyzed via flow cytometry. We demonstrated higher plasma levels of CitH3 in PLWH compared to HIV- individuals. LDGs from PLWH had heightened CD66b, but reduced CD16 expression. The percentages and counts of CD10+ LDGs were significantly decreased in PLWH. In addition, the CD16Lo LDG subsets were enriched in PLWH, compared to HIV- group, indicating that immature LDGs are increased in PLWH. Moreover, LDGs from PLWH exhibited significantly higher NET forming capacity. In summary, our study presents evidence that LDGs from PLWH on ART display an immature and altered phenotype with increased NET formation. Among PLWH, plasma NET levels as well as LDG parameters correlated with blood markers for inflammation and coagulation, suggesting that neutrophil activation and NETs may exert proinflammatory and coagulation effects. Our data provide insights into the pathologic role of LDGs at least in part mediated through NET formation in PLWH.

Corrigendum: Phenotypic alteration of low-density granulocytes in people with pulmonary post-acute sequelae of SARS-CoV-2 infection.

[This corrects the article DOI: 10.3389/fimmu.2022.1076724.].

Elevated circulating monocytes and monocyte activation in COVID-19 convalescent individuals.

Background: Monocytes and macrophages play a pivotal role in inflammation during acute SARS-CoV-2 infection. However, their contribution to the development of post-acute sequelae of SARS-CoV-2 infection (PASC) are not fully elucidated. Methods: A cross-sectional study was conducted comparing plasma cytokine and monocyte levels among three groups: participants with pulmonary PASC (PPASC) with a reduced predicted diffusing capacity for carbon monoxide [DLCOc, <80%; (PG)]; fully recovered from SARS-CoV-2 with no residual symptoms (recovered group, RG); and negative for SARS-CoV-2 (negative group, NG). The expressions of cytokines were measured in plasma of study cohort by Luminex assay. The percentages and numbers of monocyte subsets (classical, intermediate, and non-classical monocytes) and monocyte activation (defined by CD169 expression) were analyzed using flow cytometry analysis of peripheral blood mononuclear cells. Results: Plasma IL-1Ra levels were elevated but FGF levels were reduced in PG compared to NG. Circulating monocytes and three subsets were significantly higher in PG and RG compared to NG. PG and RG exhibited higher levels of CD169+ monocyte counts and higher CD169 expression was detected in intermediate and non-classical monocytes from RG and PG than that found in NG. Further correlation analysis with CD169+ monocyte subsets revealed that CD169+ intermediate monocytes negatively correlated with DLCOc%, and CD169+ non-classical monocytes positively correlated with IL-1α, IL-1ß, MIP-1α, Eotaxin, and IFN-γ. Conclusion: This study present evidence that COVID convalescents exhibit monocyte alteration beyond the acute COVID-19 infection period even in convalescents with no residual symptoms. Further, the results suggest that monocyte alteration and increased activated monocyte subsets may impact pulmonary function in COVID-19 convalescents. This observation will aid in understanding the immunopathologic feature of pulmonary PASC development, resolution, and subsequent therapeutic interventions.

Increased transmigration of intermediate monocytes associated with atherosclerotic burden in people with HIV on antiretroviral therapy.

This study evaluated the association between the transmigration of monocyte subpopulations that contributes to atherosclerosis development, along with surrogate biomarkers of inflammation and atherosclerosis, through carotid intima-media thickness (cIMT) measurements of 72 people with HIV (PWH) on suppressive antiretroviral therapy (ART). We found that the transmigration of intermediate monocytes was positively correlated with D-dimer and cIMT, suggesting that intermediate monocytes may have a greater propensity to promote cardiovascular disease (CVD) in PWH on ART.

Accuracy and Precision of 3-dimensional Optical Imaging for Body Composition by Age, BMI, and Ethnicity.

BACKGROUND: The obesity epidemic brought a need for accessible methods to monitor body composition, as excess adiposity has been associated with cardiovascular disease, metabolic disorders, and some cancers. Recent 3-dimensional optical (3DO) imaging advancements have provided opportunities for assessing body composition. However, the accuracy and precision of an overall 3DO body composition model in specific subgroups are unknown. OBJECTIVES: This study aimed to evaluate 3DO's accuracy and precision by subgroups of age, body mass index, and ethnicity. METHODS: A cross-sectional analysis was performed using data from the Shape Up! Adults study. Each participant received duplicate 3DO and dual-energy X-ray absorptiometry (DXA) scans. 3DO meshes were digitally registered and reposed using Meshcapade. Principal component analysis was performed on 3DO meshes. The resulting principal components estimated DXA whole-body and regional body composition using stepwise forward linear regression with 5-fold cross-validation. Duplicate 3DO and DXA scans were used for test-retest precision. Student's t tests were performed between 3DO and DXA by subgroup to determine significant differences. RESULTS: Six hundred thirty-four participants (females = 346) had completed the study at the time of the analysis. 3DO total fat mass in the entire sample achieved R2 of 0.94 with root mean squared error (RMSE) of 2.91 kg compared to DXA in females and similarly in males. 3DO total fat mass achieved a % coefficient of variation (RMSE) of 1.76% (0.44 kg), whereas DXA was 0.98% (0.24 kg) in females and similarly in males. There were no mean differences for total fat, fat-free, percent fat, or visceral adipose tissue by age group (P > 0.068). However, there were mean differences for underweight, Asian, and Black females as well as Native Hawaiian or other Pacific Islanders (P < 0.038). CONCLUSIONS: A single 3DO body composition model produced accurate and precise body composition estimates that can be used on diverse populations. However, adjustments to specific subgroups may be warranted to improve the accuracy in those that had significant differences. This trial was registered at clinicaltrials.gov as NCT03637855 (Shape Up! Adults).

Single-cell RNA sequencing reveals characteristics of myeloid cells in pulmonary post-acute sequelae of SARS-CoV-2.

Background: Although our understanding of the immunopathology and subsequent risk and severity of COVID-19 disease is evolving, a detailed account of immune responses that contribute to the long-term consequences of pulmonary complication in COVID-19 infection remain unclear. Few studies have detailed the immune and cytokine profiles associated with post-acute sequalae of SARS-CoV-2 infection with persistent pulmonary symptoms (PPASC). However, the dysregulation of the immune system that drives pulmonary sequelae in COVID-19 survivors and PASC sufferers remains largely unknown. Results: To characterize the immunological features of pulmonary PASC (PPASC), we performed droplet-based single-cell RNA sequencing to study the transcriptomic profiles of peripheral blood mononuclear cells (PBMCs) from participants naïve to SARS-CoV-2 (Control) and infected with SARS-CoV-2 with chronic pulmonary symptoms (PPASC). We analyzed more than 34,139 PBMCs by integrating our dataset with previously reported control datasets (GSM4509024) cell distribution. In total, 11 distinct cell populations were identified based on the expression of canonical markers. The proportion of myeloid-lineage cells ([MLCs]; CD14 + /CD16 + monocytes and dendritic cells) was increased in PPASC compared to controls. MLCs from PPASC displayed up-regulation of genes associated with pulmonary symptoms/fibrosis, while glycolysis metabolism-related genes were downregulated. Similarly, pathway analysis showed that fibrosis- related ( VEGF , WNT , and SMAD ) and cell death pathways were up-regulated, but immune pathways were down-regulated in PPASC. In PPASC, we observed interactive VEGF ligand- receptor pairs among MLCs, and network modules in CD14 + (cluster 4) and CD16 + (Cluster 5) monocytes displayed a significant enrichment for biological pathways linked to adverse COVID- 19 outcomes, fibrosis, and angiogenesis. Further analysis revealed a distinct metabolic alteration in MLCs with a down-regulation of glycolysis/gluconeogenesis in PPASC compared to SARS- CoV-2 naïve samples. Conclusion: This study offers valuable insights into the immune response and cellular landscape in PPASC. The presence of elevated MLC levels and their corresponding gene signatures associated with fibrosis, immune response suppression, and altered metabolic states suggests their potential role as a driver of PPASC.