ABSTRACTThe determinants of varicella‐zoster virus (VZV)‐associated central nervous system (CNS) infection have not been fully elucidated. This study aimed to investigate the incidence and risk factors, including immunosuppression, for different manifestations of VZV‐associated CNS infection. Patient registers were used to include adults diagnosed with VZV‐associated CNS infections between 2010 and 2019 in Sweden. Nationwide registers covering specialized care, and regional registers covering primary care, were used. Controls without a VZV diagnosis during the study period were matched by age and sex. Risk factors were calculated using multivariable logistic regression. A total of 1488 adult cases with VZV‐associated CNS infection were identified, yielding an incidence of 1.92/100 000 person‐years, which increased over the study period. Meningitis was the most frequent (45%), followed by encephalitis (38%), and Ramsay Hunt syndrome (17%). The highest incidence was observed in individuals over 70 years of age (4.15/100 000 person‐years), in whom encephalitis was most common. Statistically significant risk factors for VZV‐associated CNS infection were HIV, hematological cancer, treatment with specific immunosuppressants or glucocorticoids, chronic obstructive pulmonary disease, diabetes, solid cancer, stroke, and congestive heart failure. Encephalitis was associated with older age, more immunosuppressive conditions, and more comorbidities than other manifestations. In conclusion, VZV is a common cause of adult viral CNS infection, for which elderly individuals with immunosuppressive or comorbid conditions are at the highest risk. The strongest risk factors found were HIV, hematological cancer, and treatment with specific immunosuppressants or high‐dose glucocorticoids.

BACKGROUND:A retrospective study was conducted in people with HIV (PWH) to explore potential cerebrospinal fluid (CSF) biomarkers linked to CSF neurofilament light levels (NfL), indicative of neuronal injury. METHODS:A sample of 168 participants was tested, including 43 HIV-negative controls and PWH who were classified into subgroups based on HIV and treatment status. Twenty CSF protein biomarkers were analyzed for their association with CSF NfL concentrations using a linear regression forward selection strategy, adjusted for age and sex. Regression trees were utilized to visualize feature relationships. RESULTS:Age-adjusted average concentrations of CSF NfL ranged from 427 pg/mL (SD = 190) in HIV- participants to 6456 pg/mL (SD = 46,024) in participants with HIV-associated dementia. Significant associations were found between specific biomarkers and CSF NfL levels in different participant subgroups. Noteworthy findings included correlations between CSF t-tau, CSF MCP-1, CSF TNF-α, and albumin ratio with CSF NfL levels in untreated PWH, and CSF IL-21 with CSF NfL in treated, virally suppressed PWH. Association between age and CSF NfL concentrations was a general finding. CONCLUSION:We identified specific CSF biomarkers, including CSF t-tau protein, CSF MCP-1, and CSF TNF-α that associated with CSF NfL concentrations in untreated PWH and CSF IL-21 that associated with CSF NfL in PWH with effective treatment, shedding light on neuroinflammatory processes which may underlie HIV-related neuronal injury and the impact of antiviral therapy. Further investigations are needed to validate if elevated CSF IL-21 concentrations persist during long-term treatment, and if particular drug combinations are optimal for decreasing inflammatory latency.

BACKGROUND:The incidence and clinical relevance of asymptomatic cerebrospinal fluid escape (CSFE) during antiretroviral therapy (ART) is uncertain. We examined the impact and incidence of asymptomatic CSFE in a Swedish HIV cohort. METHODS:Neuroasymptomatic people with HIV (PWH) who have been on ART for at least 6 months with suppressed plasma viral load were followed longitudinally. CSFE was defined as either increased CSF HIV-1 RNA with concurrent plasma suppression or CSF HIV-1 RNA exceeding that in plasma when both were quantifiable. Paired CSF and plasma were analyzed for HIV-1 RNA, neopterin, neurofilament light protein (NfL), white blood cell (WBC) count, and albumin ratio. RESULTS:Asymptomatic CSFE (cutoff 50 copies/mL) was found in 4 of 173 PWH (2%) and 5 of 449 samples (1%). The corresponding proportions were 8% of PWH and 4% for samples using a 20 copies/mL cutoff for CSF HIV-1 RNA. CSFE samples (cutoff 20 copies/mL) had a 25% higher geometric mean of CSF neopterin (P = .01) and 8% higher albumin ratio (P = .04) compared to samples without CSFE. No differences were observed in CSF NfL levels (P = .8). The odds ratio for increased CSF WBC (≥ 3 cells/μL) in samples with CSFE was 3.9 (P = .004), compared to samples without elevated CSF viral load. CONCLUSIONS:Asymptomatic CSFE was identified in only 4 (2%) PWH, with no cases of continuous CSFE observed. Increased CSF HIV-1 RNA was associated with biomarkers of CNS immune activation and blood-brain barrier impairment, but not with biomarkers of neuronal injury.

BACKGROUND:Residual immune activation is common in people living with HIV (PWH) despite antiretroviral therapy (ART) and may be associated with HIV-specific, as well as lifestyle-related factors. OBJECTIVE:We aimed to investigate markers of immune activation and neuronal injury in PWH on ART compared with controls with similar lifestyle. METHODS:Cerebrospinal fluid (CSF) and blood were collected from 50 men who have sex with men (MSM) with HIV on ART, 50 HIV-negative MSM on preexposure prophylaxis (PrEP), and 25 HIV-negative controls without PrEP. β2-microglobulin, neopterin, and neurofilament light protein (NfL) were analyzed. Cytomegalovirus and herpes simplex virus-2 serostatus, as well as sexually transmitted bacterial infections were registered. RESULTS:Serum and CSF β2-microglobulin and neopterin did not differ significantly between MSM with HIV and MSM on PrEP. However, both groups had significantly higher serum levels of β2-microglobulin and neopterin compared with HIV-negative controls without PrEP. Age-adjusted CSF NfL levels were also similar in MSM with HIV and MSM on PrEP, but higher than in controls without PrEP. A recent syphilis infection was associated with increased immune activation in CSF and blood. CONCLUSION:Increased levels of immune activation and neuronal injury markers were found in virologically suppressed MSM with HIV and MSM on PrEP compared with controls. These findings imply that other factors than HIV contribute to the residual immune activation and impact on neurons observed in MSM with HIV on ART, and emphasize the importance of appropriate controls with similar lifestyle in studies of biomarkers in PWH.

INTRODUCTION:In this special report, we summarize studies of cerebrospinal fluid and plasma/serum biomarker neurofilament light chain (NfL) concentrations, a key structural component of myelinated axons in neuroinfections. AREAS COVERED:The following infections were searched for in PubMed; Neuroinfection and biomarkers, herpes simplex encephalitis and neurofilament light chain, tick-borne encephalitis and neurofilament light chain, Lyme neuroborreliosis and neurofilament light chain, bacterial meningitis and neurofilament light chain, malaria and neurofilament light chain, COVID-19 and neurofilament light chain, HIV infection and neurofilament light chain. EXPERT OPINION:NfL can serve as a valuable biomarker for assessing disease severity and neurological complications in the acute stage of neuroinfections and can also be useful in evaluating patients with residual symptoms following acute illness.

Objectives To study intrathecal kappa free light chain (KFLC) synthesis in people living with HIV (PLWH) in comparison with multiple sclerosis (MS). Methods Cross-sectional analysis including 56 untreated and 150 well treated PLWH, and compared with 58 controls, and 223 MS patients. Results Elevated serum/cerebrospinal fluid (CSF) IgG and KFLC indices were observed in untreated PLWH. Seventy percent of untreated PLWH had KFLC index above 6.1, a threshold associated with clinically isolated syndrome/MS diagnosis. No association was found between KFCL index and CSF markers of neuronal injury in either PLWH or MS patients. Conclusions HIV-related immune system dysfunction is often associated with an elevated KFLC index akin to those observed in MS. HIV infection should be considered as a differential diagnosis for patients presenting with neurological symptoms and increased intrathecal immunoglobulin synthesis.

BACKGROUND:Alcoholism increases the risk of skin and skin structure infections (SSSIs). Furthermore, in complicated SSSIs (cSSSIs) alcoholism is associated with delayed treatment response and a higher risk of blood culture positivity, suggesting poor outcomes. In pneumonia and bacteremia alcoholism is linked with higher mortality, longer hospital treatment and more ICU treatment. METHODS:We conducted a population-based retrospective cohort study including all cases of complicated skin and skin structure infections (n = 460) treated in Gothenburg, Sweden and Helsinki, Finland from 2008 - 2011. Patients were stratified as alcoholics (9%) and non-alcoholics (91%) and patient and disease factors, treatment, and outcomes were compared. RESULTS:Alcoholics were comparatively younger and more often male, with more liver diseases. We observed higher rates of bacteraemia, intensive care unit admission, surgical intervention, and clinical failure in alcoholics. Alcoholism was associated with longer length of stay and more interdepartmental transfers. We did not observe differences in infection type or time from symptom onset to diagnosis. Mortality was low and equivalent in alcoholics and non-alcoholics. CONCLUSIONS:Alcoholism is associated with increased cSSSI disease severity and resource utilisation.

Using the Olink Explore 1536 platform, we measured 1,463 unique proteins in 303 cerebrospinal fluid (CSF) specimens from four clinical centers contributed by uninfected controls and 12 groups of people living with HIV-1 infection representing the spectrum of progressive untreated and treated chronic infection. We present three initial analyses of these measurements: an overview of the CSF protein features of the sample; correlations of the CSF proteins with CSF HIV-1 RNA and neurofilament light chain protein (NfL) concentrations; and comparison of CSF proteins in HIV-associated dementia (HAD) and neurosymptomatic CSF escape (NSE). These reveal a complex but coherent picture of CSF protein changes with highest concentrations of many proteins during CNS injury in the HAD and NSE groups and variable protein changes across the course of systemic HIV-1 progression that included two common patterns, designated as lymphoid and myeloid patterns, related to principal involvement of their underlying inflammatory cell lineages. Antiretroviral therapy reduced CSF protein perturbations, though not always to control levels. The dataset of these CSF protein measurements, along with background clinical information, is posted online. Extended studies of this unique dataset will supplement this report to provide more detailed characterization of the dynamic impact of HIV-1 infection on the CSF proteome across the spectrum of HIV-1 infection, advancing the mechanistic understanding of HIV-1-related CNS pathobiology.

AbstractBackgroundAntiretroviral therapy (ART) initiated during acute infection can potentially impact the central nervous system (CNS) reservoir, but the differential long-term effects of ART initiation during early or late chronic infection are unknown.MethodsWe included neuroasymptomatic people with human immunodeficiency virus (HIV) with suppressive ART initiated during chronic (>1 year since transmission) HIV with archived cerebrospinal fluid (CSF) and serum samples after 1 and/or ≥3 years of ART from a cohort study. CSF and serum neopterin was measured using a commercial immunoassay (BRAHMS, Germany).ResultsIn total, 185 people with HIV (median, 79 [interquartile range, 55–128] months on ART) were included. A significant inverse correlation was found between CD4+ T-cell count and CSF neopterin only at baseline (r = −0.28, P = .002), but not after 1 (r = −0.026, P = .8) or ≥3 (r −0.063, P = .5) years of ART. No significant differences were seen in CSF or serum neopterin concentrations between different pretreatment CD4+ T-cell strata after 1 or ≥3 (median, 6.6) years of ART.ConclusionsIn people with HIV initiating ART during chronic infection, occurrence of residual CNS immune activation was not correlated with pretreatment immune status, even when treatment was initiated at high CD4+ T-cell counts, suggesting that the CNS reservoir, once established, is not differentially affected by the timing of ART initiation during chronic infection.

Purpose In order to enable long-term follow-up of the natural course of HIV infection in the central nervous system, a longitudinal cohort study with repeated cerebrospinal fluid (CSF) analyses at intervals over time was initiated in 1985. When antiretrovirals against HIV were introduced in the late 1980s, short-term and long-term effects of various antiretroviral treatment (ART) regimens were added to the study.Participants All adult people living with HIV (PLWH) who were diagnosed at or referred to the Department of Infectious Diseases, Sahlgrenska University Hospital, Gothenburg, Sweden were asked to participate in the Gothenburg HIV CSF Study Cohort. PLWH with neurological symptoms or other clinical symptoms of HIV, as well as those with no symptoms of HIV infection, were included. Most participants were asymptomatic, which distinguishes this cohort from most other international HIV CSF studies. In addition, HIV-negative controls were recruited. These included people on HIV pre-exposure prophylaxis who served as lifestyle-matched controls to HIV-infected men who have sex with men. Since lumbar puncture (LP) is an invasive procedure, some PLHW only consented to participate in one examination. Furthermore, at the beginning of the study, several participants were lost to follow-up having died from AIDS. Of 662 PLWH where an initial LP was done, 415 agreed to continue with follow-up. Among the 415, 56 only gave permission to be followed with LP for less than 1 year, mainly to analyse the short-term effect of ART. The remaining 359 PLWH were followed up with repeated LP for periods ranging from >1 to 30 years. This group was defined as the ‘longitudinal cohort’. So far, on 7 April 2022, 2650 LP and samplings of paired CSF/blood had been performed, providing a unique biobank.Findings to date A general finding during the 37-year study period was that HIV infection in the central nervous system, as mirrored by CSF findings, appears early in the infectious course of the disease and progresses slowly in the vast majority of untreated PLWH. Combination ART has been highly effective in reducing CSF viral counts, inflammation and markers of neural damage. Minor CSF signs of long-term sequels or residual inflammatory activity and CSF escape (viral CSF blips) have been observed during follow-up. The future course of these changes and their clinical impact require further studies.Future plans PLWH today have a life expectancy close to that of non-infected people. Therefore, our cohort provides a unique opportunity to study the long-term effects of HIV infection in the central nervous system and the impact of ART and is an ongoing study.

Although clinical examinations, neuroimaging, and cerebrospinal fluid analyses are the most important ways to evaluate the impact of HIV infection on the brain and in diagnosis of opportunistic infections, several blood biomarkers including HIV RNA concentrations, CD4 +T-cell count, and neurofilament light chain protein (NfL) concentration, along with tests for opportunistic infections can provide important information for clinical decisions.

IMPORTANCE Neurologic symptoms are common in COVID-19, but the central nervous system (CNS) pathogenesis is unclear, and viral RNA is rarely detected in cerebrospinal fluid (CSF). OBJECTIVE To measure viral antigen and inflammatory biomarkers in CSF in relation to neurologic symptoms and disease severity. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study was performed from March 1, 2020, to June 30, 2021, in patients 18 years or older who were admitted to Sahlgrenska University Hospital, Gothenburg, Sweden, with COVID-19. All patients had CSF samples taken because of neurologic symptoms or within a study protocol. Healthy volunteer and prepandemic control groups were included. EXPOSURE SARS-CoV-2 infection. MAIN OUTCOMES AND MEASURES Outcomes included CSF SARS-CoV-2 nucleocapsid antigen (N-Ag) using an ultrasensitive antigen capture immunoassay platform and CSF biomarkers of immune activation (neopterin, beta(2)-microglobulin, and cytokines) and neuronal injury (neurofilament light protein [NfL]). RESULTS Forty-four patients (median [IQR] age, 57 [48-69] years; 30 [68%] male; 26 with moderate COVID-19 and 18 with severe COVID-19 based on theWorld Health Organization Clinical Progression Scale), 10 healthy controls (median [IQR] age, 58 [54-60] years; 5 [50%] male), and 41 patient controls (COVID negative without evidence of CNS infection) (median [IQR] age, 59 [49-70] years; 19 [46%] male) were included in the study. Twenty-one patients were neuroasymptomatic and 23 were neurosymptomatic (21 with encephalopathy). In 31 of 35 patients for whom data were available (89%), CSF N-Ag was detected; viral RNA test results were negative in all. Nucleocapsid antigen was significantly correlated with CSF neopterin (r = 0.38; P =.03) and interferon. (r = 0.42; P =.01). No differences in CSF N-Ag concentrations were found between patient groups. Patients had markedly increased CSF neopterin, beta(2)-microglobulin, interleukin (IL) 2, IL-6, IL-10, and tumor necrosis factor a compared with controls. Neurosymptomatic patients had significantly higher median (IQR) CSF interferon. (86 [47-172] vs 21 [17-81] fg/mL; P =.03) and had a significantly higher inflammatory biomarker profile using principal component analysis compared with neuroasymptomatic patients (0.54; 95% CI, 0.03-1.05; P =.04). Age-adjusted median (IQR) CSF NfL concentrations were higher in patients compared with controls (960 [673-1307] vs 618 [489-786] ng/L; P =.002). No differences were seen in any CSF biomarkers in moderate compared with severe disease. CONCLUSIONS AND RELEVANCE In this study of Swedish adults with COVID-19 infection and neurologic symptoms, compared with control participants, viral antigen was detectable in CSF and correlated with CNS immune activation. Patients with COVID-19 had signs of neuroaxonal injury, and neurosymptomatic patients had a more marked inflammatory profile that could not be attributed to differences in COVID-19 severity. These results highlight the clinical relevance of neurologic symptoms and suggest that viral components can contribute to CNS immune responses without direct viral invasion.

Effective antiretroviral therapy has radically changed the course of the HIV pandemic. However, despite efficient therapy, milder forms of neurocognitive symptoms are still present in people living with HIV. Plasma homocysteine is a marker of vitamin B deficiency and has been associated with cognitive impairment. People living with HIV have higher homocysteine concentrations than HIV-negative controls, and we have previously found an association between plasma homocysteine concentration and CSF concentration of neurofilament light protein, a sensitive marker for ongoing neuronal injury in HIV. This prompted us to perform this randomized controlled trial, to evaluate the effect of vitamin B supplementation on neuronal injury in a cohort of people living with HIV on stable antiretroviral therapy. At the Department of Infectious Diseases at Sahlgrenska University Hospital in Gothenburg, Sweden, 124 virally suppressed people living with HIV were screened to determine eligibility for this study. Sixty-one fulfilled the inclusion criteria by having plasma homocysteine levels at or above 12 mu mol/l. They were randomized (1:1) to either active treatment (with cyanocobalamin 0.5 mg, folic acid 0.8 mg and pyridoxine 3.0 mg) q.d. or to a control arm with a cross over to active treatment after 12 months. Cognitive function was measured repeatedly during the trial, which ran for 24 months. We found a significant correlation between plasma neurofilament light protein and plasma homocysteine at screening (n = 124, r = 0.35, P < 0.0001). Plasma homocysteine levels decreased by 35% from a geometric mean of 15.7 mu mol/l (95% confidence interval 14.7-16.7) to 10.3 mu mol/l (95% confidence interval 9.3-11.3) in the active treatment arm between baseline and Month 12. No significant change was detected in the control arm during the same time period [geometric mean 15.2 (95% confidence interval 14.3-16.2) versus geometric mean 16.5 mu mol/l (95% confidence interval 14.7-18.6)]. A significant difference in change in plasma homocysteine levels was seen between arms at 12 months [-40% (95% confidence interval -48 to -30%), P < 0.001]. However, no difference between arms was seen in either plasma neurofilament light protein levels [-6.5% (-20 to 9%), P = 0.39], or cognitive measures [-0.08 (-0.33 to 0.17), P = 0.53]. Our results do not support a vitamin B-dependent cause of the correlation between neurofilament light protein and homocysteine. Additional studies are needed to further elucidate this matter. Tyrberg et al. report the results of a randomized controlled trial investigating the effect of vitamin B supplementation on neuronal injury in people living with HIV with effective antiretroviral therapy. Supplementation decreased levels of homocysteine but not neuronal injury measured by neurofilament light protein.

Objective To characterize the evolution of central nervous system (CNS) inflammation in HIV-1 infection applying a panel of cerebrospinal fluid (CSF) inflammatory biomarkers to grouped subjects representing a broad spectrum of systemic HIV-1 immune suppression, CNS injury and viral control. Methods This is a cross-sectional analysis of archived CSF and blood samples, assessing concentrations of 10 functionally diverse soluble inflammatory biomarkers by immunoassays in 143 HIV-1-infected subjects divided into 8 groups: untreated primary HIV-1 infection (PHI); four untreated groups defined by their blood CD4+ T lymphocyte counts; untreated patients presenting with subacute HIV-associated dementia (HAD); antiretroviral-treated subjects with ≥1 years of plasma viral suppression; and untreated elite controllers. Twenty HIV-1-uninfected controls were included for comparison. Background biomarkers included blood CD4+ and CD8+ T lymphocytes, CSF and blood HIV-1 RNA, CSF white blood cell (WBC) count, CSF/blood albumin ratio, CSF neurofilament light chain (NfL), and CSF t-tau. Findings HIV-1 infection was associated with a broad compartmentalized CSF inflammatory response that developed early in its course and changed with systemic disease progression, development of neurological injury, and viral suppression. CSF inflammation in untreated individuals without overt HAD exhibited at least two overall patterns of inflammation as blood CD4+ T lymphocytes decreased: one that peaked at 200–350 blood CD4+ T cells/μL and associated with lymphocytic CSF inflammation and HIV-1 RNA concentrations; and a second that steadily increased through the full range of CD4+ T cell decline and associated with macrophage responses and increasing CNS injury. Subacute HAD was distinguished by a third inflammatory profile with increased blood-brain barrier permeability and robust combined lymphocytic and macrophage CSF inflammation. Suppression of CSF and blood HIV-1 infections by antiretroviral treatment and elite viral control were associated with reduced CSF inflammation, though not fully to levels found in HIV-1 seronegative controls.

OBJECTIVE:Persistent immune activation in the central nervous system and systemically are common in people living with HIV (PLHIV) despite antiretroviral therapy. It is not known whether this is generated by HIV replication or by other components such as coinfections and lifestyle-related factors.DESIGN:The aim of this study was to determine the importance of different factors; it is crucial to find well matched HIV-negative controls. In this context, HIV-negative persons on preexposure prophylaxis (PrEP) may constitute a suitable control group to PLHIV with similar lifestyle-related factors.METHODS:Cerebrospinal fluid (CSF) and blood were collected from 40 HIV-negative persons on PrEP and 20 controls without PrEP. Biomarkers of immune activation, blood--brain barrier (BBB) integrity and neuronal injury were analysed.RESULTS:CSF and serum β2-microglobulin, serum neopterin and CSF neurofilament light protein were higher in persons on PrEP compared with controls. Furthermore, persons on PrEP had higher CSF/plasma albumin ratio, and matrix metalloproteinase-3 concentrations, indicating BBB dysfunction. Of persons on PrEP, 90% were cytomegalovirus (CMV)-positive compared to 65% of the controls. CMV-positive individuals as a group had higher levels of serum β2-microglobulin than CMV-negative individuals (P < 0.05). Drug users had higher serum β2-microglobulin compared to nonusers (P < 0.01).CONCLUSION:HIV-negative persons on PrEP had higher levels of biomarkers for immune activation, BBB impairment and neuronal injury, compared with volunteers without PrEP. Moreover, serum β2-microglobulin was higher in CMV-positive than in CMV-negative individuals and in drug users compared with nonusers. These findings are important to consider when analysing immune activation and CNS injury in PLHIV, and emphasize the importance of appropriate controls.

Abstract Background The aim of this large multicenter study was to determine variations in cerebrospinal fluid (CSF) HIV-RNA in different phases of untreated human immunodeficiency virus type 1 (HIV-1) infection and its associations with plasma HIV-RNA and other biomarkers. Methods Treatment naive adults with available CSF HIV-RNA quantification were included and divided into groups representing significant disease phases. Plasma HIV-RNA, CSF white blood cell count (WBC), neopterin, and albumin ratio were included when available. Results In total, 1018 patients were included. CSF HIV-RNA was in median (interquartile range [IQR]) 1.03 log10 (0.37–1.86) copies/mL lower than in plasma, and correlated with plasma HIV-RNA (r = 0.44, P < .01), neopterin concentration in CSF (r = 0.49, P < .01) and in serum (r = 0.29, P < .01), CSF WBC (r = 0.34, P < .01) and albumin ratio (r = 0.25, P < .01). CSF HIV-RNA paralleled plasma HIV-RNA in all groups except neuroasymptomatic patients with advanced immunodeficiency (CD4 < 200) and patients with HIV-associated dementia (HAD) or opportunistic central nervous system (CNS) infections. Patients with HAD had the highest CSF HIV-RNA (in median [IQR] 4.73 (3.84–5.35) log10 copies/mL). CSF > plasma discordance was found in 126 of 972 individuals (13%) and varied between groups, from 1% in primary HIV, 11% in neuroasymptomatic groups, up to 30% of patients with HAD. Conclusions Our study confirms previous smaller observations of variations in CSF HIV-RNA in different stages of HIV disease. Overall, CSF HIV-RNA was approximately 1 log10 copies/mL lower in CSF than in plasma, but CSF discordance was found in a substantial minority of subjects, most commonly in patients with HAD, indicating increasing CNS compartmentalization paralleling disease progression.

HIV cerebrospinal fluid (CSF) escape is defined by a concentration of HIV-1 RNA in CSF above the lower limit of quantification of the employed assay and equal to or greater than the plasma HIV-1 RNA level in the presence of treatment-related plasma viral suppression, while CSF discordance is similarly defined by equal or higher CSF than plasma HIV-1 RNA in untreated individuals. During secondary CSF escape or discordance, disproportionate CSF HIV-1 RNA develops in relation to another infection in addition to HIV-1. We performed a retrospective review of people living with HIV receiving clinical care at Sahlgrenska Infectious Diseases Clinic in Gothenburg, Sweden who developed uncomplicated herpes zoster (HZ) and underwent a research lumbar puncture (LP) within the ensuing 150 days. Based on treatment status and the relationship between CSF and plasma HIV-1 RNA concentrations, they were divided into 4 groups: i) antiretroviral treated with CSF escape (N = 4), ii) treated without CSF escape (N = 5), iii) untreated with CSF discordance (N = 8), and iv) untreated without CSF discordance (N = 8). We augmented these with two additional cases of secondary CSF escape related to neuroborreliosis and HSV-2 encephalitis and analyzed these two non-HZ cases for factors contributing to CSF HIV-1 RNA concentrations. HIV-1 CSF escape and discordance were associated with higher CSF white blood cell (WBC) counts than their non-escape (P = 0.0087) and non-discordant (P = 0.0017) counterparts, and the CSF WBC counts correlated with the CSF HIV-1 RNA levels in both the treated (P = 0.0047) and untreated (P = 0.002) group pairs. Moreover, the CSF WBC counts correlated with the CSF:plasma HIV-1 RNA ratios of the entire group of 27 subjects (P = <0.0001) indicating a strong effect of the CSF WBC count on the relation of the CSF to plasma HIV-1 RNA concentrations across the entire sample set. The inflammatory response to HZ and its augmenting effect on CSF HIV-1 RNA was found up to 5 months after the HZ outbreak in the cross-sectional sample and, was present for one year after HZ in one individual followed longitudinally. We suggest that HZ provides a 'model' of secondary CSF escape and discordance. Likely, the inflammatory response to HZ pathology provoked local HIV-1 production by enhanced trafficking or activation of HIV-1-infected CD4+ T lymphocytes. Whereas treatment and other systemic factors determined the plasma HIV-1 RNA concentrations, in this setting the CSF WBC counts established the relation of the CSF HIV-1 RNA levels to this plasma set-point.

Objective To explore whether hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and neurologic symptoms have evidence of CNS infection, inflammation, and injury using CSF biomarker measurements. Methods We assessed CSF SARS-CoV-2 RNA along with CSF biomarkers of intrathecal inflammation (CSF white blood cell count, neopterin, β2-microglobulin, and immunoglobulin G index), blood-brain barrier integrity (albumin ratio), and axonal injury (CSF neurofilament light chain protein [NfL]) in 6 patients with moderate to severe coronavirus disease 2019 (COVID-19) and neurologic symptoms who had undergone a diagnostic lumbar puncture. Neurologic symptoms and signs included features of encephalopathies (4 of 6), suspected meningitis (1 of 6), and dysgeusia (1 of 6). SARS-CoV-2 infection was confirmed by real-time PCR analysis of nasopharyngeal swabs. Results SARS-CoV-2 RNA was detected in the plasma of 2 patients (cycle threshold [Ct] value 35.0–37.0) and in CSF at low levels (Ct 37.2, 38.0, 39.0) in 3 patients in 1 but not in a second real-time PCR assay. CSF neopterin (median 43.0 nmol/L) and β2-microglobulin (median 3.1 mg/L) were increased in all. Median immunoglobulin G index (0.39), albumin ratio (5.35), and CSF white blood cell count (<3 cells/µL) were normal in all, while CSF NfL was elevated in 2 patients. Conclusion Our results in patients with COVID-19 and neurologic symptoms suggest an unusual pattern of marked CSF inflammation in which soluble markers were increased but white cell response and other immunologic features typical of CNS viral infections were absent. While our initial hypothesis centered on CNS SARS-CoV-2 invasion, we could not convincingly detect SARS-CoV-2 as the underlying driver of CNS inflammation. These features distinguish COVID-19 CSF from other viral CNS infections and raise fundamental questions about the CNS pathobiology of SARS-CoV-2 infection.

Objective To explore changes in CSF sTREM2 concentrations in the evolving course of HIV-1 infection. Methods In this retrospective cross-sectional study, we measured concentrations of the macrophage/microglial activation marker sTREM2 in CSF samples from 121 HIV-1–infected adults and 11 HIV-negative controls and examined their correlations with other CSF and blood biomarkers of infection, inflammation, and neuronal injury. Results CSF sTREM2 increased with systemic and CNS HIV-1 disease severity, with the highest levels found in patients with HIV-associated dementia (HAD). In untreated HIV-1–infected patients without an HAD diagnosis, levels of CSF sTREM2 increased with decreasing CD4+ T-cell counts. CSF concentrations of both sTREM2 and the neuronal injury marker neurofilament light protein (NFL) were significantly associated with age. CSF sTREM2 levels were also independently correlated with CSF NFL. Notably, this association was also observed in HIV-negative controls with normal CSF NFL. HIV-infected patients on suppressive antiretroviral treatment had CSF sTREM2 levels comparable to healthy controls. Conclusions Elevations in CSF sTREM2 levels, an indicator of macrophage/microglial activation, are a common feature of untreated HIV-1 infection that increases with CD4+ T-cell loss and reaches highest levels in HAD. The strong and independent association between CSF sTREM2 and CSF NFL suggests a linkage between microglial activation and neuronal injury in HIV-1 infection. CSF sTREM2 has the potential of being a useful biomarker of innate CNS immune activation in different stages of untreated and treated HIV-1 infection.

Skin and skin structure infection (SSSI) is classified as complicated (cSSSI) if it involves deep subcutaneous tissue or requires surgery. Factors associated with blood culture sampling and bacteremia have not been established in patients with cSSSI. Moreover, the benefit of information acquired from positive blood culture is unknown. The aim of this study was to address these important issues. In this retrospective population-based study from two Nordic cities, a total of 460 patients with cSSSI were included. Blood cultures were drawn from 258 (56.1%) patients and they were positive in 61 (23.6%) of them. Factors found to be associated with more blood culture sampling in multivariate analysis were diabetes, duration of symptoms shorter than 2 days and higher C-reactive protein (CRP) level. Whereas factors associated with less frequent blood culture sampling were peripheral vascular disease and a surgical wound infection. In patients from whom blood cultures were taken, alcohol abuse was the only factor associated with culture positivity, as CRP level was not. Patients with a positive blood culture had antibiotic streamlining more often than non-bacteremic patients. A high rate of blood culture positivity in patients with cSSSI was observed. Factors related to more frequent blood culture sampling were different from those associated with a positive culture.