Enhancing EQ-5D-5L Sensitivity in Capturing the Most Common Symptoms in Post-COVID-19 Patients: An Exploratory Cross-Sectional Study with a Focus on Fatigue, Memory/Concentration Problems and Dyspnea Dimensions.

This study aimed to determine whether the EQ-5D-5L tool captures the most common persistent symptoms, such as fatigue, memory/concentration problems and dyspnea, in patients with post-COVID-19 conditions while also investigating if adding these symptoms improves the explained variance of the health-related quality of life (HRQoL). In this exploratory cross-sectional study, two cohorts of Swedish patients (n = 177) with a history of COVID-19 infection answered a questionnaire covering sociodemographic characteristics and clinical factors, and their HRQoL was assessed using EQ-5D-5L with the Visual Analogue Scale (EQ-VAS). Spearman rank correlation and multiple regression analyses were employed to investigate the extent to which the most common persistent symptoms, such as fatigue, memory/concentration problems and dyspnea, were explained by the EQ-5D-5L. The explanatory power of EQ-5D-5L for EQ-VAS was also analyzed, both with and without including symptom(s). We found that the EQ-5D-5L dimensions partly captured fatigue and memory/concentration problems but performed poorly in regard to capturing dyspnea. Specifically, the EQ-5D-5L explained 55% of the variance in memory/concentration problems, 47% in regard to fatigue and only 14% in regard to dyspnea. Adding fatigue to the EQ-5D-5L increased the explained variance of the EQ-VAS by 5.7%, while adding memory/concentration problems and dyspnea had a comparatively smaller impact on the explained variance. Our study highlights the EQ-5D-5L's strength in capturing fatigue and memory/concentration problems in post-COVID-19 patients. However, it also underscores the challenges in assessing dyspnea in this group. Fatigue emerged as a notably influential symptom, significantly enhancing the EQ-5D-5L's predictive ability for these patients' EQ-VAS scores.

Influenza-associated invasive aspergillosis in patients admitted to the intensive care unit in Sweden: a prospective multicentre cohort study.

BACKGROUND: The purpose of this study was to prospectively investigate the incidence of influenza-associated pulmonary aspergillosis (IAPA) in influenza patients admitted to intensive care units in Sweden. METHODS: The study included consecutive adult patients with PCR-verified influenza A or B in 12 Swedish intensive care units (ICUs) over four influenza seasons (2019-2023). Patients were screened using serum galactomannan and ß-d-glucan tests and fungal culture of a respiratory sample at inclusion and weekly during the ICU stay. Bronchoalveolar lavage was performed if clinically feasible. IAPA was classified according to recently proposed case definitions. RESULTS: The cohort included 55 patients; 42% were female, and the median age was 59 (IQR 48-71) years. All patients had at least one galactomannan test, ß-d-glucan test and respiratory culture performed. Bronchoalveolar lavage was performed in 24 (44%) of the patients. Five (9%, 95% CI 3.8% - 20.4%) patients were classified as probable IAPA, of which four lacked classical risk factors. The overall ICU mortality was significantly higher among IAPA patients than non-IAPA patients (60% vs 8%, p = 0.01). CONCLUSIONS: The study represents the first prospective investigation of IAPA incidence. The 9% incidence of IAPA confirms the increased risk of invasive pulmonary aspergillosis among influenza patients admitted to the ICU. Therefore, it appears reasonable to implement a screening protocol for the early diagnosis and treatment of IAPA in influenza patients receiving intensive care. TRIAL REGISTRATION: ClinicalTrials.gov NCT04172610, registered November 21, 2019.

Anakinra or tocilizumab in patients admitted to hospital with severe covid-19 at high risk of deterioration (IMMCoVA): A randomized, controlled, open-label trial.

BACKGROUND: Anakinra and tocilizumab are used for severe Covid-19, but only one previous randomized controlled trial (RCT) has studied both. We performed a multi-center RCT comparing anakinra or tocilizumab versus usual care (UC) for adults at high risk of deterioration. METHODS: The study was conducted June 2020 to March 2021. Eligibility required ≥ 5 liters/minute of Oxygen to maintain peripheral oxygen saturation at ≥ 93%, CRP > 70 mg/L, ferritin > 500 µg/L and at least two points where one point was awarded for lymphocytes < 1x 109/L; D-dimer ≥ 0.5 mg/L and; lactate dehydrogenase ≥ 8 microkatal/L. Patients were randomly assigned 1:1:1 to receive either a single dose of tocilizumab (8 mg/kg) or anakinra 100 mg IV QID for seven days or UC alone. The primary outcome was time to recovery. RESULTS: Recruitment was ended prematurely when tocilizumab became part of usual care. Out of a planned 195 patients, 77 had been randomized, 27 to UC, 28 to anakinra and 22 to tocilizumab. Median time to recovery was 15, 15 and 11 days. Rate ratio for recovery for UC vs anakinra was 0.91, 0.47 to 1.78, 95% [CI], p = 0.8 and for UC vs tocilizumab 1.13, 0.55 to 2.30; p = 0.7. There were non-significant trends favoring tocilizumab (and to limited degree anakinra) vs UC for some secondary outcomes. Safety profiles did not differ significantly. CONCLUSION: Premature closure of trial precludes firm conclusions. Anakinra or tocilizumab did not significantly shorten time to clinical recovery compared to usual care. (IMMCoVA, NCT04412291, EudraCT: 2020-00174824).

Absenteeism Costs Due to COVID-19 and Their Predictors in Non-Hospitalized Patients in Sweden: A Poisson Regression Analysis.

BACKGROUND: This study aimed to estimate absenteeism costs and identify their predictors in non-hospitalized patients in Sweden. METHODS: This cross-sectional study's data were derived from the longitudinal project conducted at Uppsala University Hospital. The mean absenteeism costs due to COVID-19 were calculated using the human capital approach, and a Poisson regression analysis was employed to determine predictors of these costs. RESULTS: The findings showed that the average absenteeism cost due to COVID-19 was USD 1907.1, compared to USD 919.4 before the pandemic (p < 0.001). Notably, the average absenteeism cost for females was significantly higher due to COVID-19 compared to before the pandemic (USD 1973.5 vs. USD 756.3, p = 0.001). Patients who had not fully recovered at the 12-month follow-up exhibited significantly higher costs than those without symptoms at that point (USD 3389.7 vs. USD 546.7, p < 0.001). The Poisson regression revealed that several socioeconomic factors, including age, marital status, country of birth, educational level, smoking status, BMI, and occupation, along with COVID-19-related factors such as severity at onset, pandemic wave, persistent symptoms at the follow-up, and newly introduced treatment for depression after the infection, were significant predictors of the absenteeism costs. CONCLUSIONS: Our study reveals that the mean absenteeism costs due to COVID-19 doubled compared to the year preceding the pandemic. This information is invaluable for decision-makers and contributes to a better understanding of the economic aspects of COVID-19.

Clustering Analysis Identified Three Long COVID Phenotypes and Their Association with General Health Status and Working Ability.

BACKGROUND/AIM: This study aimed to distinguish different phenotypes of long COVID through the post-COVID syndrome (PCS) score based on long-term persistent symptoms following COVID-19 and evaluate whether these symptoms affect general health and work ability. In addition, the study identified predictors for severe long COVID. METHOD: This cluster analysis included cross-sectional data from three cohorts of patients after COVID-19: non-hospitalized (n = 401), hospitalized (n = 98) and those enrolled at the post-COVID outpatient's clinic (n = 85). All the subjects responded to the survey on persistent long-term symptoms and sociodemographic and clinical factors. K-Means cluster analysis and ordinal logistic regression were used to create PCS scores that were used to distinguish patients' phenotypes. RESULTS: 506 patients with complete data on persistent symptoms were divided into three distinct phenotypes: none/mild (59%), moderate (22%) and severe (19%). The patients with severe phenotype, with the predominating symptoms were fatigue, cognitive impairment and depression, had the most reduced general health status and work ability. Smoking, snuff, body mass index (BMI), diabetes, chronic pain and symptom severity at COVID-19 onset were factors predicting severe phenotype. CONCLUSION: This study suggested three phenotypes of long COVID, where the most severe was associated with the highest impact on general health status and working ability. This knowledge on long COVID phenotypes could be used by clinicians to support their medical decisions regarding prioritizing and more detailed follow-up of some patient groups.

Enhanced bacterial clearance in early secondary sepsis in a porcine intensive care model.

Early secondary sepsis (ESS), occurring after recent inflammatory activation is associated with a reduced inflammatory response. If this attenuation also is associated with decreased bacterial killing, the need for antibiotic efficacy might be greater than in primary sepsis (PS). This prospective, randomised interventional study compares bacterial killing in ESS and PS in a large animal intensive care sepsis model. 38 pigs were intravenously administered live Escherichia coli for 3 h. Before baseline ESS was pre-exposed to endotoxin 24 h, whereas PS was not. Bacterial growth was measured in organs immediately post-mortem, repeatedly during 6 h in blood in vivo and for blood intrinsic bactericidal capacity ex vivo. Splenic growth was lower in ESS animals, than in PS animals (3.31 ± 0.12, vs. 3.84 ± 0.14 log10 CFU/mL, mean ± SEM) (p < 0.01) with a similar trend in hepatic growth (p = NS). Blood bacterial count at 2 h correlated with splenic bacterial count in ESS (ESS: r = 0.71, p < 0.001) and to blood killing capacity in PS (PS: r = 0.69, p < 0.001). Attenuated inflammation in ESS is associated with enhanced antibacterial capacities in the spleen. In ESS blood bacterial count is related to splenic killing and in PS to blood bactericidal capacity. The results suggest no increased need for synergistic antibiotic combinations in ESS.

Predictors of post-COVID-19 and the impact of persistent symptoms in non-hospitalized patients 12 months after COVID-19, with a focus on work ability.

Background: Better knowledge of long-term symptoms following coronavirus disease 2019 (COVID-19), the so-called post-COVID-19, in non-hospitalized patients is needed. The aim of this study was to study persisent symptoms up to 12 months after COVID-19 in non-hospitalized patients and their impact on work ability. We also investigated predictors of persistent symptoms. Methods: This study encompassed non-hospitalized adult subjects with a COVID-19 infection confirmed via positive nasopharyngeal swab polymerase chain reaction test during the first wave of the pandemic in Uppsala, Sweden. In total, 566 subjects were sent a survey via e-mail or post with an invitation to participate in the survey 12 months post-diagnosis. The majority of subjects were healthcare workers, as this group was prioritized for testing. Results: A total of 366 subjects responded, with 47% reporting persistent symptoms 12 months after their COVID-19 diagnosis. The most commonly reported symptoms at this time were impaired sense of smell and/or taste and fatigue. Among the predictors of persistent symptoms were being born abroad, lower physical fitness compared with peers before COVID-19, body mass index >25 kg/m2, cooccurrence of hypertension and chronic pain, and having more than seven of the general COVID-19 symptoms at the onset. Respondents with symptoms after 12 months self-reported negatively about their general health and work ability. Conclusions: This study indicated that many people who had mild COVID-19 might have a variety of long-term symptoms. It highlights the importance of considering work ability after mild COVID-19.

Urine Hydrogen Peroxide Levels and Their Relation to Outcome in Patients with Sepsis, Septic Shock, and Major Burn Injury.

Hydrogen peroxide (H2O2) and oxidative stress have been suggested as possible instigators of both the systemic inflammatory response and the increased vascular permeability associated with sepsis and septic shock. We measured H2O2 concentrations in the urine of 82 patients with severe infections, such as sepsis, septic shock, and infections not fulfilling sepsis-3 criteria, in patients with major burn injury with associated systemic inflammation, and healthy subjects. The mean concentrations of H2O2 were found to be lower in patients with severe infections compared to burn injury patients and healthy subjects. Patients with acute kidney injury (AKI), vs. those without AKI, in all diagnostic groups displayed higher concentrations of urine H2O2 (p < 0.001). Likewise, urine concentrations of H2O2 were higher in non-survivors as compared to survivors (p < 0.001) at day 28 in all diagnostic groups, as well as in patients with severe infections and burn injury (p < 0.001 for both). In this cohort, increased H2O2 in urine is thus associated with mortality in patients with sepsis and septic shock as well as in patients with burn injury.

Patterns and predictors of sick leave among Swedish non-hospitalized healthcare and residential care workers with Covid-19 during the early phase of the pandemic.

Healthcare and residential care workers represent two occupational groups that have, in particular, been at risk of Covid-19, its long-term consequences, and related sick leave. In this study, we investigated the predictors of prolonged sick leave among healthcare and residential workers due to non-hospitalized Covid-19 in the early period of the pandemic. This study is based on a patient register (n = 3209) and included non-hospitalized healthcare or residential care service workers with a positive RT- PCR for SARS-CoV-2 (n = 433) between March and August 2020. Data such as socio-demographics, clinical characteristics, and the length of sick leave because of Covid-19 and prior to the pandemic were extracted from the patient's electronic health records. Prolonged sick leave was defined as sick leave ≥ 3 weeks, based on the Swedish pandemic policy. A generalized linear model was used with a binary distribution, adjusted for age, gender, and comorbidity in order to predict prolonged sick leave. Of 433 (77% women) healthcare and residential care workers included in this study, 14.8% needed longer sick leave (> 3 weeks) due to Covid-19. Only 1.4% of the subjects were on sick leave because of long Covid. The risk of sick leave was increased two-fold among residential care workers (adjusted RR 2.14 [95% CI 1.31-3.51]). Depression/anxiety (adjusted RR 2.09 [95% CI 1.31-3.34]), obesity (adjusted RR 1.96 [95% CI 1.01-3.81]) and dyspnea at symptom onset (adjusted RR 2.47 [95% CI 1.55-3.92]), sick leave prior to the pandemic (3-12 weeks) (adjusted RR 2.23 [95% CI 1.21-4.10]) were associated with longer sick leave. From a public health perspective, considering occupational category, comorbidity, symptoms at onset, and sick leave prior to the pandemic as potential predictors of sick leave in healthcare may help prevent staff shortage.

Human G-MDSCs are neutrophils at distinct maturation stages promoting tumor growth in breast cancer.

Myeloid-derived suppressor cells (MDSCs) are known to contribute to immune evasion in cancer. However, the function of the human granulocytic (G)-MDSC subset during tumor progression is largely unknown, and there are no established markers for their identification in human tumor specimens. Using gene expression profiling, mass cytometry, and tumor microarrays, we here demonstrate that human G-MDSCs occur as neutrophils at distinct maturation stages, with a disease-specific profile. G-MDSCs derived from patients with metastatic breast cancer and malignant melanoma display a unique immature neutrophil profile, that is more similar to healthy donor neutrophils than to G-MDSCs from sepsis patients. Finally, we show that primary G-MDSCs from metastatic breast cancer patients co-transplanted with breast cancer cells, promote tumor growth, and affect vessel formation, leading to myeloid immune cell exclusion. Our findings reveal a role for human G-MDSC in tumor progression and have clinical implications also for targeted immunotherapy.

Systemic Monocytic-MDSCs Are Generated from Monocytes and Correlate with Disease Progression in Breast Cancer Patients.

Myeloid-derived suppressor cells (MDSCs) are highly immunosuppressive myeloid cells, which increase in cancer patients. The molecular mechanism behind their generation and function is unclear. Whereas granulocytic-MDSCs correlate with poor overall survival in breast cancer, the presence and relevance of monocytic-MDSCs (Mo-MDSCs) is unknown. Here we report for the first time an enrichment of functional blood Mo-MDSCs in breast cancer patients before they acquire a typical Mo-MDSC surface phenotype. A clear population of Mo-MDSCs with the typical cell surface phenotype (CD14(+)HLA-DR(low/-)CD86(low/-)CD80(low/-)CD163(low/-)) increased significantly first during disease progression and correlated to metastasis to lymph nodes and visceral organs. Furthermore, monocytes, comprising the Mo-MDSC population, from patients with metastatic breast cancer resemble the reprogrammed immunosuppressive monocytes in patients with severe infections, both by their surface and functional phenotype but also at their molecular gene expression profile. Our data suggest that monitoring the Mo-MDSC levels in breast cancer patients may represent a novel and simple biomarker for assessing disease progression.

A high frequency of MDSCs in sepsis patients, with the granulocytic subtype dominating in gram-positive cases.

The causative microorganisms dictate the type of MDSC generated in sepsis patients, and a large proportion of PMN-MDSCs in gram-positive sepsis includes immunosuppressive myeloid blasts. MDSCs constitute a heterogeneous population of immature myeloid cells that potently suppress immune responses. They were identified originally in cancer patients and have since been reported to occur also in chronic inflammation, autoimmunity, and even bacterial infections. Human MDSCs are commonly divided into Mo-MDSCs and granulocytic (PMN-MDSCs) subtypes. To what extent the bona fide cancer MDSCs are representative of the proposed MDSCs found in other diseases is not well known. PMN-MDSCs have been found previously to be enriched among LDGs in density gradient-centrifuged blood. In this study, we analyzed potential MDSCs in sepsis patients with different causative microorganisms, using total peripheral blood compared with density gradient-centrifuged blood. We found a high frequency of typical CD14(+)HLA-DR(low) Mo-MDSCs in all sepsis patients, whereas the typical PMN-MDSCs, as well as a prominent CD14(low) PMN-MDSC-like population, appeared preferentially in gram-positive cases. The CD14(low) PMN-MDSC variant was demonstrated to suppress T cell proliferation in vitro via a ROS-dependent mechanism, to display an increased IL-10:TNF-α ratio, and to present with signs of immaturity: blast morphology and low cytokine levels. We conclude that a spectrum of cells with MDSC features is enriched in sepsis and that the microbial origin of sepsis contributes to the substantial interindividual patient variation in the MDSC pattern.

Early treatment response evaluated by a clinical scoring system correlates with the prognosis of pulmonary tuberculosis patients in Ethiopia: a prospective follow-up study.

BACKGROUND: In resource-limited settings the monitoring of tuberculosis (TB) patients is challenging, and early identification of TB patients with a high mortality risk is important. The aim of this study was to investigate prospectively whether early changes in a clinical scoring system (TB score) can predict treatment outcome in Ethiopian patients with pulmonary tuberculosis. METHOD: TB patients (n = 250) and blood donors (n = 82) were recruited prospectively at Gondar University Hospital, Ethiopia. Clinical scoring was performed using an interview-based questionnaire and clinical examination. RESULTS: Among TB patients (53.6% of whom were HIV co-infected) the median TB score declined from week 0 to week 2 (8 (interquartile range (IQR) 6-9) vs 4 (IQR 2-6)) and dropped to a low level at week 8, which was still significantly higher than that found in blood donors (2 (IQR 1-4) vs 0 (IQR 0-1), p < 0.0001). Patients who died had a significantly higher TB score at week 0, week 2, and week 8 than survivors. Mortality was associated with a failure to achieve a decrease greater than 25% in the TB score at 2 weeks. Baseline CD4 + cell counts (< 200 cells/mm³) were associated with mortality but not with initial TB score results. CONCLUSIONS: The TB score was increased during the first 2 months of treatment among patients who died. Failure to achieve a greater than 25% decrease in TB score after 2 weeks of treatment was associated with increased mortality. Repeated clinical scoring during the intensive phase of TB treatment could be useful to identify high-risk patients.

Wnt5a induces a tolerogenic phenotype of macrophages in sepsis and breast cancer patients.

A well-orchestrated inflammatory reaction involves the induction of effector functions and, at a later stage, an active downregulation of this potentially harmful process. In this study we show that under proinflammatory conditions the noncanonical Wnt protein, Wnt5a, induces immunosuppressive macrophages. The suppressive phenotype induced by Wnt5a is associated with induction of IL-10 and inhibition of the classical TLR4-NF-κB signaling. Interestingly, this phenotype closely resembles that observed in reprogrammed monocytes in sepsis patients. The Wnt5a-induced feedback inhibition is active both during in vitro LPS stimulation of macrophages and in patients with sepsis caused by LPS-containing, gram-negative bacteria. Furthermore, using breast cancer patient tissue microarrays, we find a strong correlation between the expression of Wnt5a in malignant epithelial cells and the frequency of CD163(+) anti-inflammatory tumor-associated macrophages. In conclusion, our data point out Wnt5a as a potential target for an efficient therapeutic modality in severe human diseases as diverse as sepsis and malignancy.

Lymphocyte and monocyte flow cytometry immunophenotyping as a diagnostic tool in uncharacteristic inflammatory disorders.

BACKGROUND: Patients with uncharacteristic inflammatory symptoms such as long-standing fatigue or pain, or a prolonged fever, constitute a diagnostic and therapeutic challenge. The aim of the present study was to determine if an extended immunophenotyping of lymphocytes and monocytes including activation markers can define disease-specific patterns, and thus provide valuable diagnostic information for these patients. METHODS: Whole blood from patients with gram-negative bacteraemia, neuroborreliosis, tuberculosis, acute mononucleosis, influenza or a mixed connective tissue disorders, as diagnosed by routine culture and serology techniques was analysed for lymphocyte and monocyte cell surface markers using a no-wash, no-lyse protocol for multi-colour flow cytometry method. The immunophenotyping included the activation markers HLA-DR and CD40. Plasma levels of soluble TNF alpha receptors were analysed by ELISA. RESULTS: An informative pattern was obtained by combining two of the analysed parameters: (i), the fractions of HLA-DR-expressing CD4+ T cells and CD8+ T cells, respectively, and (ii), the level of CD40 on CD14+ CD16- monocytes. Patients infected with gram-negative bacteria or EBV showed a marked increase in monocyte CD40, while this effect was less pronounced for tuberculosis, borrelia and influenza. The bacterial agents could be distinguished from the viral agents by the T cell result; CD4+ T cells reacting in bacterial infection, and the CD8+ T cells dominating for the viruses. Patients with mixed connective tissue disorders also showed increased activation, but with similar engagement of CD4+ and CD8+ T cells. Analysis of soluble TNF alpha receptors was less informative due to a large inter-individual variation. CONCLUSION: Immunophenotyping including the combination of the fractions of HLA-DR expressing T cell subpopulations with the level of CD40 on monocytes produces an informative pattern, differentiating between infections of bacterial and viral origin. Furthermore, a quantitative analysis of these parameters revealed the novel finding of characteristic patterns indicating a subacute bacterial infection, such as borreliosis or tuberculosis, or a mixed connective tissue disorder. The employed flow cytometric method is suitable for clinical diagnostic laboratories, and may help in the assessment of patients with uncharacteristic inflammatory symptoms.

Kinetics of the QuantiFERON-TB Gold In-Tube test during treatment of patients with sputum smear-positive tuberculosis in relation to initial TST result and severity of disease.

The QuantiFERON-TB Gold In-Tube test (QFN) measures interferon-gamma production in response to Mycobacterium tuberculosis antigens. Our aim was to assess the kinetics of the QFN and initial tuberculin skin test (TST) result in relation to severity of disease in a tuberculosis (TB) endemic area. Smear-positive TB patients (n = 71) were recruited at Gondar University Hospital, Ethiopia. The TST, QFN, CD4+ cell count and clinical symptoms (TB score) were assessed and followed up during treatment. From baseline to 7 months after treatment, there was a significant decrease in QFN reactivity (93.8% to 62.5% in HIV-negative/TB; 70.3% to 33.3% in HIV-positive/TB patients) down to a level comparable to a control group of blood donors (51.2%). The agreement between TST and QFN was poor in TB patients compared to healthy controls. A negative TST correlated to more advanced TB in contrast to a negative QFN test. We conclude that the QFN reactivity is significantly reduced at the end of treatment against active TB to the background level of healthy blood donors, and that the agreement between TST and QFN is poor including correlation to the severity of disease.

Cerebral malaria in children: serum and cerebrospinal fluid TNF-alpha and TGF-beta levels and their relationship to clinical outcome.

This was a prospective study conducted at the Moi Teaching and Referral Hospital, Eldoret, Kenya. Twenty-three children admitted to the hospital with cerebral (CM) and 10 children with non-cerebral malaria (NCM) were studied. The aim of the study was to establish and compare levels of tumour necrosis factor (TNF-alpha) and transforming growth factor (TGF-beta1) in these children. Serum and cerebrospinal fluid (CSF) cytokine levels were assayed using ELISA kits. In serum, TGF-beta1 and TNF-alpha decreased over 5 days after admission to the hospital in both groups of patients with CM and NCM. In the CSF of cerebral cases the levels of TNF-alpha and TGF-beta1 were low and inversely related. Children in deeper coma had lower levels in serum of TGF-beta and higher levels of TNF-alpha than those in lighter levels of coma. The serum TNF-alpha levels in CM children were the same irrespective of the duration of illness before admission, but children with NCM who had been sick for a shorter duration before admission tended to have higher serum levels of TNF-alpha and higher levels of TGF-beta than those with a longer duration of illness before admission. In conclusion, this study shows that TNF-alpha and TGF-beta1 may not be useful in predicting the outcome for CM. They may, however, be useful in detecting children at risk of developing deep coma. TNF-alpha and TGF-beta levels were inversely related both in serum and CSF.