Impact of a TLR9 agonist and broadly neutralizing antibodies on HIV-1 persistence: the randomized phase 2a TITAN trial.

Inducing antiretroviral therapy (ART)-free virological control is a critical step toward a human immunodeficiency virus type 1 (HIV-1) cure. In this phase 2a, placebo-controlled, double-blinded trial, 43 people (85% males) with HIV-1 on ART were randomized to (1) placebo/placebo, (2) lefitolimod (TLR9 agonist)/placebo, (3) placebo/broadly neutralizing anti-HIV-1 antibodies (bNAbs) or (4) lefitolimod/bNAb. ART interruption (ATI) started at week 3. Lefitolimod was administered once weekly for the first 8 weeks, and bNAbs were administered twice, 1 d before and 3 weeks after ATI. The primary endpoint was time to loss of virologic control after ATI. The median delay in time to loss of virologic control compared to the placebo/placebo group was 0.5 weeks (P = 0.49), 12.5 weeks (P = 0.003) and 9.5 weeks (P = 0.004) in the lefitolimod/placebo, placebo/bNAb and lefitolimod/bNAb groups, respectively. Among secondary endpoints, viral doubling time was slower for bNAb groups compared to non-bNAb groups, and the interventions were overall safe. We observed no added benefit of lefitolimod. Despite subtherapeutic plasma bNAb levels, 36% (4/11) in the placebo/bNAb group compared to 0% (0/10) in the placebo/placebo group maintained virologic control after the 25-week ATI. Although immunotherapy with lefitolimod did not lead to ART-free HIV-1 control, bNAbs may be important components in future HIV-1 curative strategies. ClinicalTrials.gov identifier: NCT03837756 .

Respiratory dysfunction three months after severe COVID-19 is associated with gut microbiota alterations.

BACKGROUND: Although coronavirus disease 2019 (COVID-19) is primarily a respiratory infection, mounting evidence suggests that the gastrointestinal tract is involved in the disease, with gut barrier dysfunction and gut microbiota alterations being related to disease severity. Whether these alterations persist and are related to long-term respiratory dysfunction remains unknown. METHODS: Plasma was collected during hospital admission and after 3 months from the NOR-Solidarity trial (n = 181) and analyzed for markers of gut barrier dysfunction and inflammation. At the 3-month follow-up, pulmonary function was assessed by measuring the diffusing capacity of the lungs for carbon monoxide (DLCO ). Rectal swabs for gut microbiota analyses were collected (n = 97) and analyzed by sequencing the 16S rRNA gene. RESULTS: Gut microbiota diversity was reduced in COVID-19 patients with respiratory dysfunction, defined as DLCO below the lower limit of normal 3 months after hospitalization. These patients also had an altered global gut microbiota composition, with reduced relative abundance of 20 bacterial taxa and increased abundance of five taxa, including Veillonella, potentially linked to fibrosis. During hospitalization, increased plasma levels of lipopolysaccharide-binding protein (LBP) were strongly associated with respiratory failure, defined as pO2 /fiO2 (P/F ratio) <26.6 kPa. LBP levels remained elevated during and after hospitalization and were associated with low-grade inflammation and respiratory dysfunction after 3 months. CONCLUSION: Respiratory dysfunction after COVID-19 is associated with altered gut microbiota and persistently elevated LBP levels. Our results should be regarded as hypothesis generating, pointing to a potential gut-lung axis that should be further investigated in relation to long-term pulmonary dysfunction and long COVID.

Human Immunodeficiency Virus-Infected Immunological Nonresponders Have Colon-Restricted Gut Mucosal Immune Dysfunction.

BACKGROUND: Human immunodeficiency virus (HIV)-infected immunological nonresponders (INRs) fail to reconstitute their CD4+ T-cell pool after initiation of antiretroviral therapy, and their prognosis is inferior to that of immunological responders (IRs). A prevailing hypothesis is that the INR phenotype is caused by a persistently disrupted mucosal barrier, but assessments of gut mucosal immunology in different anatomical compartments are scarce. METHODS: We investigated circulating markers of mucosal dysfunction, immune activation, mucosal Th17 and Th22 cells, and mucosa-adherent microbiota signatures in gut mucosal specimens from sigmoid colon and terminal ileum of 19 INRs and 20 IRs in addition to 20 HIV-negative individuals. RESULTS: INRs had higher blood levels of the enterocyte damage marker intestinal fatty acid-binding protein than IRs. In gut mucosal biopsies, INRs had lower fractions of CD4+ T cells, higher fractions of interleukin 22, and a tendency to higher fractions of interleukin 17-producing CD4+ T cells. These findings were all restricted to the colon and correlated to circulating markers of enterocyte damage. There were no observed differences in gut microbial composition between INRs and IRs. CONCLUSIONS: Restricted to the colon, enterocyte damage and mucosal immune dysfunction play a role for insufficient immune reconstitution in HIV infection independent of the gut microbiota.

Probiotics to HIV-Infected Immunological Nonresponders: Altered Mucosal Immunity and Microbial Diversity Restricted to Ileum.

BACKGROUND: HIV-infected immunological nonresponders (INRs) have increased risk of non-AIDS morbidity and compromised gut barrier immunity. Probiotics are widely used to improve health. We assessed the effects of probiotics in INRs with a comprehensive analysis of gut immunity and microbiome in terminal ileum and sigmoid colon. METHODS: The study involved clinical intervention with five-strain probiotic capsules (1.2 × 1010 CFUs/d) for 8 weeks in 20 INRs with CD4+ T-cell counts <400 cells/µL and plasma HIV RNA <50 copies/mL for more than 3.5 years. Colonoscopy with sampling of gut biopsies from terminal ileum and sigmoid colon and fecal and blood sampling were performed before and after the intervention. Flow cytometry (cytokine production, immune activation, and exhaustion), ELISA (inflammation, microbial translocation, and enterocyte damage), and 16S rRNA sequencing analyses were applied. RESULTS: In the terminal ileum, increased alpha diversity, increased abundance of Bifidobacterium sp., and decreased frequencies of IL-22+ CD4+ T cells were observed. The increased abundance of Bifidobacterium sp. in the terminal ileum correlated with increased fraction of CD4+ T cells in the same compartment (r = 0.54, P = 0.05) and increased CD4/CD8 ratio in peripheral blood (r = 0.49, P = 0.05). There were no corresponding changes in the sigmoid colon and no changes in fecal microbiome. Probiotic intervention did not affect peripheral blood CD4 count, viral load, or soluble markers of inflammation and microbial translocation. CONCLUSIONS: Probiotics induced segment-specific changes in the terminal ileum but did not affect systemic CD4 counts in INRs. Further clinical studies are warranted to recommend probiotics to INRs.

Persistent pulmonary pathology after COVID-19 is associated with high viral load, weak antibody response, and high levels of matrix metalloproteinase-9.

The association between pulmonary sequelae and markers of disease severity, as well as pro-fibrotic mediators, were studied in 108 patients 3 months after hospital admission for COVID-19. The COPD assessment test (CAT-score), spirometry, diffusion capacity of the lungs (DLCO), and chest-CT were performed at 23 Norwegian hospitals included in the NOR-SOLIDARITY trial, an open-labelled, randomised clinical trial, investigating the efficacy of remdesivir and hydroxychloroquine (HCQ). Thirty-eight percent had a CAT-score ≥ 10. DLCO was below the lower limit of normal in 29.6%. Ground-glass opacities were present in 39.8% on chest-CT, parenchymal bands were found in 41.7%. At admission, low pO2/FiO2 ratio, ICU treatment, high viral load, and low antibody levels, were predictors of a poorer pulmonary outcome after 3 months. High levels of matrix metalloproteinase (MMP)-9 during hospitalisation and at 3 months were associated with persistent CT-findings. Except for a negative effect of remdesivir on CAT-score, we found no effect of remdesivir or HCQ on long-term pulmonary outcomes. Three months after hospital admission for COVID-19, a high prevalence of respiratory symptoms, reduced DLCO, and persistent CT-findings was observed. Low pO2/FiO2 ratio, ICU-admission, high viral load, low antibody levels, and high levels of MMP-9 were associated with a worse pulmonary outcome.

Enhanced Gut-Homing Dynamics and Pronounced Exhaustion of Mucosal and Blood CD4+ T Cells in HIV-Infected Immunological Non-Responders.

Immunological non-responders (INR), a subgroup of people living with HIV (PLHIV) who fail to restore CD4+ T cell numbers upon effective antiretroviral treatment, have impaired gut mucosal barrier function and an inferior clinical prognosis compared with immunological responders (IR). The contribution of gut-homing and exhaustion of mucosal T cells to the INR phenotype was previously unknown. Flow cytometry analysis of mononuclear cells from peripheral blood and ileal and colonic lamina propria showed that INR had higher fractions of gut-homing CD4+ T cells in blood compared with IR. In addition, gut-homing cells were more likely to display signs of exhaustion in INR. The increased CD4+ T cell exhaustion in INR was ubiquitous and not restricted to subpopulations defined by activation, differentiation or regulatory T cell markers. In INR, colon CD4+ T cell exhaustion correlated negatively with the fraction of CD4+ T cells in the same compartment, this was not apparent in the ileum. The fraction of exhausted mucosal CD4+ T cells correlated with I-FABP and REG3α, markers of enterocyte damage. We conclude that alterations of gut-homing and exhaustion of T cells may contribute to impaired gut immune and barrier functions associated with immunological non-response in PLHIV.

Blood neurofilament light concentration at admittance: a potential prognostic marker in COVID-19.

OBJECTIVE: To test the hypotheses that blood biomarkers for nervous system injury, serum concentrations of neurofilament light chain protein (NfL) and glial fibrillary acidic protein (GFAp) can serve as biomarkers for disease severity in COVID-19 patients. METHODS: Forty-seven inpatients with confirmed COVID-19 had blood samples drawn on admission for assessing serum biomarkers of CNS injury by Single molecule array (Simoa), NfL and GFAp. Concentrations of NfL and GFAp were analyzed in relation to symptoms, clinical signs, inflammatory biomarkers and clinical outcomes. We used multivariate linear models to test for differences in biomarker concentrations in the subgroups, accounting for confounding effects. RESULTS: In total, 21% (n = 10) of the patients were admitted to an intensive care unit, and the overall mortality rate was 13% (n = 6). Non-survivors had higher serum concentrations of NfL (p < 0.001) upon admission than patients who were discharged alive both in adjusted analyses (p = 2.6 × 10-7) and unadjusted analyses (p = 0.001). The concentrations of NfL in non-survivors increased over repeated measurements; whereas, the concentrations in survivors were stable. The GFAp concentration was also significantly higher in non-survivors than survivors (p = 0.02). CONCLUSION: Increased concentrations of NfL and GFAp in COVID-19 patients on admission may indicate increased mortality risk. Measurement of blood biomarkers for nervous system injury can be useful to detect and monitor CNS injury in COVID-19.

Probiotics to manage inflammation in HIV infection.

PURPOSE OF REVIEW: To evaluate the current scientific basis for administering probiotics to people living with HIV (PLHIV) to alleviate chronic inflammation and subsequently improve their prognosis. RECENT FINDINGS: The gut microbiome is a potential contributing factor to low-grade inflammation in HIV infection, and there is a scientific rationale for attempting to attenuate inflammation by administering probiotics. Sixteen reports from clinical studies in antiretroviral therapy (ART)-treated PLHIV assessing inflammation after probiotic intervention have been identified; half of them randomized control trials (RCT). Some of the studies report improvement in some parameters of inflammation, but results are inconsistent. No studies report improvement of CD4 counts. None of the RCTs report improvements in any markers of inflammation when analyzed according to protocol. SUMMARY: Current scientific evidence does not support the use of probiotics to alleviate inflammation in HIV infection. The potential effect of probiotic intervention in ART-treated PLHIV with high risk for inflammation remains to be investigated.

Activated dendritic cells and monocytes in HIV immunological nonresponders: HIV-induced interferon-inducible protein-10 correlates with low future CD4+ recovery.

OBJECTIVE: To explore monocyte and dendritic cell immune responses, and their association with future CD4 gain in treated HIV patients with suboptimal CD4 recovery. DESIGN: A cross-sectional study of HIV-infected, virally suppressed individuals on antiretroviral therapy for at least 24 months; 41 immunological nonresponders (INRs) (CD4 cell count <400 cells/µl) and 26 immunological responders (CD4 cell count >600 cells/µl). Ten HIV-infected antiretroviral therapy-naive and 10 HIV-negative healthy persons served as controls. CD4 cell counts were registered after median 2.4 and 4.7 years. METHODS: Monocyte, dendritic-cell and T-cell activation and regulatory T cells (Tregs) were analyzed by flow cytometry. In INR and immunological responder subgroups matched on age and nadir CD4 cell count, upregulation of interferon-inducible protein-10 (IP-10) and indoleamine 2,3-dioxygenase in monocytes and dendritic cells and cytokines in cell supernatants were measured in vitro in peripheral blood mononuclear cells stimulated with aldrithiol-2-inactivated HIV-1. RESULTS: The INR group displayed higher spontaneous activation of both monocytes (HLA-DR) and myeloid and plasmacytoid dendritic cells (HLA-DR, CD83 and CD86) compared with immunological responders, and this was associated with increased T-cell activation (CD38HLA-DR), an effector memory T-cell phenotype and activated Tregs. The IP-10 response in monocytes after in-vitro HIV stimulation was negatively associated with prospective CD4 gain. IP-10, indoleamine 2,3-dioxygenase and cytokines levels were comparable between the groups, but inversely correlated with activated Tregs in INRs. CONCLUSION: HIV-infected individuals with suboptimal immune recovery demonstrated more activated monocytes and in particular dendritic cells, compared with patients with acceptable CD4 gain. A high level of HIV-specific IP-10 expression in monocytes may be predictive of future CD4 recovery.

Microbial translocation revisited: targeting the endotoxic potential of gut microbes in HIV-infected individuals.

OBJECTIVE: Translocation of microbial products such as lipopolysaccharides (LPS) from the gut may contribute to chronic inflammation in HIV-infected individuals. Recent studies indicate that differences in degree of acylation of gut-bacterial-derived LPS may explain variable immune effects, with hexa-acylated rather than penta-acylated LPS having proinflammatory capacity. We investigated whether the degree of acylation of gut-derived LPS associates with systemic inflammation, and the potential effect of probiotic intervention. METHODS: Gut microbiota profiles from a probiotics intervention were investigated and validated in a cohort of HIV-infected individuals commencing antiretroviral therapy. The PiCRUSt software was used to predict overall functional capacity of the microbiota and in-house bioinformatics to distinguish between bacteria producing hexa-acylated and penta-acylated LPS. RESULTS AND CONCLUSION: HIV-infected individuals with the highest ratio of proinflammatory hexa-acylated LPS to noninflammatory penta-acylated LPS-producing bacteria exhibited increased levels of systemic inflammation (neopterin, P < 0.001) and tryptophan catabolism (kynurenine/tryptophan ratio, P = 0.01), indicating a link between proinflammatory LPS, tryptophan catabolism and inflammation. After probiotics for 8 weeks, there was a decrease in Gram-negative bacteria (P = 0.01), related primarily to a reduction in bacteria producing penta-acylated LPS (P = 0.01), but not hexa-acylated LPS. The reduction in Gram-negative bacteria correlated positively with decreased plasma LPS (r = 0.72), mainly related to a reduction in bacteria producing noninflammatory penta-acylated LPS (r = 0.58). Notably, gut bacteria producing hexa-acylated LPS were outnumbered by penta-acylated LPS with a factor of 25 in HIV-infected individuals. Further studies are warranted to determine whether microbes producing hexa-acylated LPS might be a more relevant trigger of systemic inflammation compared with plasma LPS captured by the existing limulus assay.

High neopterin and IP-10 levels in cerebrospinal fluid are associated with neurotoxic tryptophan metabolites in acute central nervous system infections.

BACKGROUND: The host response to intruders in the central nervous system (CNS) may be beneficial but could also be harmful and responsible for neurologic symptoms and sequelae in CNS infections. This immune response induces the activation of the kynurenine pathway (KP) with the production of neuroactive metabolites. Herein, we explored cytokine and KP responses in cerebrospinal fluid (CSF) and serum in patients with encephalitis, aseptic, and bacterial meningitis. METHODS: Cytokines were measured in CSF and serum by multiplex assay in adult patients with encephalitis of infectious, autoimmune or unknown etiology (n = 10), aseptic meningitis (ASM, n = 25), acute bacterial meningitis (ABM, n = 6), and disease control patients with similar symptoms but without pleocytosis in CSF (n = 42). Liquid chromatography-tandem mass spectrometry (LC-MS/ MS) was used to measure KP metabolites in CSF and serum. RESULTS: A characteristic pattern of increasing cytokine levels and KP metabolites was found in CSF from encephalitis to ASM, with the highest levels in ABM. In ASM and ABM, most inflammatory mediators, including IL-6, IL-8, and IFN-inducible protein-10 (IP-10), showed markedly elevated levels in CSF compared with serum, indicating production within the CNS. In contrast to most mediators, the highest level of IP-10 was found in the ASM group, suggesting a potential role for IP-10 in aseptic/viral meningitis. Neopterin and IP-10 were associated with marked changes in KP metabolites in CSF with increasing kynurenine/tryptophan ratio reflecting indoleamine 2,3-dioxygenase activity. Neopterin, a marker of IFN-γ activity, was associated with an unfavorable balance between neuroprotective and neurotoxic tryptophan metabolites. CONCLUSION: We show that parenchymal and meningeal inflammations in CNS share a characteristic cytokine profile with a general immune response in the CSF with limited influence from the systemic circulation. IFN-γ activity, assessed by neopterin and IP-10 levels, may play a role in the activation of the KP pathway in these patients, potentially mediating neurotoxic effects.

Plasma IP-10 Is Increased in Immunological NonResponders and Associated With Activated Regulatory T Cells and Persisting Low CD4 Counts.

OBJECTIVE: To explore immune mechanisms and identify biomarkers associated with an inadequate immune recovery in patients with HIV with efficient antiretroviral therapy. DESIGN: A cross-sectional study of 67 HIV-infected patients on antiretroviral therapy for ≥24 months with HIV RNA ≤20 copies per milliliter; 41 were defined as immunological nonresponders (INR) (CD4 < 400 cells per microliter) and 26 as immunological responders (CD4 > 600 cells per microliter). CD4 counts were also registered 2 years after inclusion. METHODS: Cytokines, soluble markers of microbial translocation, and tryptophan catabolites were measured in plasma by multiplex assay, ELISA, or mass spectrometry. T-cell activation, differentiation, and regulatory T cells (Tregs) were analyzed by flow cytometry in 2 subgroups with comparable nadir CD4 counts. RESULTS: Plasma interferon-inducible protein-10 (IP-10) levels were higher (P < 0.05), the T cells were more activated (CD38HLA-DR) (P < 0.05), the naive/effector memory T-cell ratio was lower (P < 0.01) and the proportion of resting Tregs (CD4CD45RAFoxP3) was reduced (P < 0.001) in INR patients compared with immunological responders. INR patients with CD4 counts ≤300 cells per microliter also demonstrated a higher fraction of activated Tregs (aTreg) (CD4CD147CD25) (P < 0.05). In the INR group, the aTreg percentages correlated with plasma IP-10 levels and inversely with CD4 counts (both P < 0.01). IP-10 levels (P < 0.05) and kynurenine/tryptophan ratio (P < 0.01) were negatively associated with the CD4 count 2 years after inclusion. CONCLUSION: Patients with HIV with inadequate CD4 responses had higher levels of IP-10, more activated and differentiated T-cell phenotypes, as well as aTreg, compared with patients with satisfactory CD4 gain. High IP-10 levels were also associated with lower CD4 counts after 2 years.

Increased Tryptophan Catabolism Is Associated With Increased Frequency of CD161+Tc17/MAIT Cells and Lower CD4+ T-Cell Count in HIV-1 Infected Patients on cART After 2 Years of Follow-Up.

BACKGROUND: HIV infection is associated with increased ratio between kynurenine and tryptophan (KTR) in plasma, increased microbial translocation, expansion of regulatory T cells (Tregs), and depletion of Tc17/mucosa-associated invariant T (MAIT) cells. The association between these parameters and the impact of KTR on CD4 T-cell recovery in HIV-infected patients on combination antiretroviral therapy (cART) after 2 years of follow-up was investigated. METHODS: Forty-one HIV-infected individuals treated with cART for a minimum of 2 years were included. Tregs, CD161Tc17/MAIT cells, naive cells, immune activation, senescence, and apoptosis were measured using flow cytometry. Soluble CD14 (sCD14), lipopolysaccharide, and tryptophan metabolites in plasma were measured retrospectively before cART and at inclusion initiation using Limulus Amebocyte Lysate colometric assay, enzyme-linked immunosorbent assay, and tandem mass spectrometry, respectively. KTR was calculated, and patients were divided into 2 groups defined by high vs. low KTR. CD4 T-cell count was determined at inclusion and after 2 years of follow-up. RESULTS: KTR decreased after cART initiation. Patients on cART with high KTR displayed an immunological profile with high sCD14, high percentage Tregs, low percentage CD161Tc17/MAIT cells, low percentage naive cells, low CD4/CD8 ratio, and poor immune reconstitution after 2 years of follow-up compared with patients with low KTR. CONCLUSIONS: Our results support the hypothesis that tryptophan catabolism, indoleamine 2,3-dioxygenase 1 (IDO1) activation, microbial translocation, and perturbed distribution of Tregs and CD161Tc17/MAIT cells are part of a vicious circle that perpetuates exhaustion of the immune system and progression of untreated HIV infection and challenge immune reconstitution in patients on cART.

Reduced Levels of D-dimer and Changes in Gut Microbiota Composition After Probiotic Intervention in HIV-Infected Individuals on Stable ART.

BACKGROUND: Microbial translocation and chronic inflammation may contribute to non-AIDS morbidity in patients with HIV. This study assessed the impact of probiotic intervention on microbial translocation and inflammation in patients on antiretroviral therapy with viral suppression and subnormal CD4 count. METHODS: Thirty-two patients receiving antiretroviral therapy (CD4 <500 cells/µL) were randomized in a double-blind fashion to multistrain daily probiotics (n = 15), placebo (n = 9), or controls (n = 8) for 8 weeks. Soluble inflammation markers, D-dimer, lipopolysaccharide (LPS), sCD14, T-cell activation, tryptophan metabolites, and gut microbiota composition were analyzed at baseline and end of study. Nonparametric statistics were applied. RESULTS: Twenty-four participants completed the study and were included in as-treated analyses. In patients receiving probiotics, there was a significant reduction in D-dimer levels (median change 33%, P = 0.03) and a tendency to reduced levels of C-reactive protein (CRP) (P = 0.05) and interleukin (IL)-6 (P = 0.06). The changes in CRP and IL-6 were highly correlated (r = 0.95, P < 0.01), whereas changes in D-dimer did not correlate with changes in CRP or IL-6. Increases in Bifidobacteria (P = 0.04) and Lactobacilli (P = 0.06) were observed in the probiotic group, whereas the relative abundance of Bacteroides decreased (P ≤ 0.01). No significant changes were seen in markers of microbial translocation or T-cell activation. However, the expansion of Bifidobacteria correlated negatively with differences in LPS (r = -0.77, P = 0.01), whereas the reduction in Bacteroides correlated positively with changes in LPS during the study period (r = 0.72, P = 0.02). CONCLUSIONS: Probiotic intervention seemed to reduce markers of coagulation and inflammation without overt changes in microbial translocation. These findings warrant further studies in larger cohorts with long-term follow-up.

A one-year observational study of all hospitalized and fatal acute poisonings in Oslo: epidemiology, intention and follow-up.

BACKGROUND: Up to date information on poisoning trends is important. This study reports the epidemiology of all hospitalized acute poisonings in Oslo, including mortality, follow-up referrals, and whether the introduction of over-the-counter sales of paracetamol outside pharmacies had an impact on the frequency of poisonings. METHODS: All acute poisonings of adults (≥16 years) treated at the five hospitals in Oslo from April 2008 to April 2009 were included consecutively in an observational cross-sectional multicentre study. A standardized form was completed by the treating physician, which covered the study aims. All deaths by poisoning in and outside hospitals were registered at the Institute of Forensic Medicine. RESULTS: There were 1065 hospital admissions of 912 individuals; 460 (50%) were male, and the median age was 36 years. The annual incidence was 2.0 per 1000. The most frequent toxic agents were ethanol (18%), benzodiazepines (15%), paracetamol (11%), and opioids (11%). Physicians classified 46% as possible or definite suicide attempts, 37% as accidental overdoses with substances of abuse (AOSA), and 16% as other accidents. Twenty-four per cent were discharged without any follow-up and the no follow-up odds were highest for AOSA. There were 117 deaths (eight in hospital), of which 75% were males, and the median age was 41 years. Thus, the annual mortality rate was 25 per 100 000 and the in-hospital mortality was 0.8%. Opioids were the most frequent cause of death. CONCLUSIONS: The incidence of hospitalized acute poisonings in Oslo was similar to that in 2003 and there was an equal sex distribution. Compared with a study performed in Oslo in 2003, there has been an increase in poisonings with a suicidal intention. The in-hospital mortality was low and nine out of ten deaths occurred outside hospitals. Opioids were the leading cause of death, so preventive measures should be encouraged among substance abusers. The number of poisonings caused by paracetamol remained unchanged after the introduction of over-the-counter sales outside pharmacies and there were no deaths, so over-the-counter sales may be considered safe.

A one-year observational study of all hospitalized acute poisonings in Oslo: complications, treatment and sequelae.

OBJECTIVES: Changes in poisoning trends may affect both complications and outcomes in patients with acute poisoning. This study reports the treatments given and the frequency of complications, also related to treatment, mortality and sequelae related to various toxic agents. METHODS: All acute poisonings in adults (≥ 16 years) admitted to the five hospitals in Oslo were included consecutively during one year (2008 to 2009) in an observational cross-sectional multicenter study. A standardized form was completed by the treating physician, which covered the study aims. RESULTS: There were 1065 admissions in 912 patients. The median length of hospital stay was one day, and 49% were observed in an intensive care unit (ICU). Active treatment was given to 83%, and consisted of supportive therapy (70%), antidote(s) (38%), activated charcoal (16%) and gastric lavage (9%). The most commonly used antidotes were flumazenil (19%), naloxone (17%) and N-acetylcysteine (11%). The rate of treatment-related complications was 2.4% (21/884). Neither flumazenil, naloxone, nor the combination, was associated with convulsions or other complications. Among those receiving N-acetylcysteine, 5% (6/120) developed allergic reactions, one of which mandated discontinuation of treatment. Nineteen percent presented in a coma. Complications developed in 30%, compared with 18% in a 2003 study, mainly respiratory depression (12%), prolonged QTc interval (6%) and hypotension (5%). Eight patients died (0.8%) and five (0.5%) survived with permanent sequelae, mainly anoxic brain damage. DISCUSSION: Few patients stayed more than two days. The use of the ICU was liberal, considering that only one out of five presented in a coma. Antidotes were frequently given diagnostically. Although N-acetylcysteine induced allergic reactions, most were mild and treatment discontinuation was only necessary once. The frequency of complications had almost doubled in five years, although the poisoning pattern was largely unchanged. However, few patients developed permanent sequelae.

Acute child poisonings in Oslo: a 2-year prospective study.

AIM: To study the current epidemiology, clinical course and outcome of poisonings among children in Oslo and compare findings to a similar study from 1980. METHODS: Observational study with prospective inclusion of all children (<15 years of age) with a main diagnosis of acute poisoning treated in hospital or outpatient clinic in Oslo for 2 years. RESULTS: One hundred seventy-five episodes of acute poisoning were included at the outpatient clinic only (n = 65), the paediatric department only (n = 82) or both (n = 28 referrals). Annual incidence was 97 per 100 000, significantly lower than in 1980 (230 per 100 000). Highest incidence was in 1-year-old males (576 per 100 000). In children <8 years of age, the most common toxic agents were pharmaceuticals (39%) and household products (32%); children > or = 8 years ingested mainly ethanol (46%) or pharmaceuticals (36%). Five percent of all children were comatose, and complications were seen in 13%. All children survived without sequelae. Half of the admissions needed treatment; most commonly used treatments were activated charcoal (33%), gastric lavage (9%) and emetics (9%). CONCLUSION: The incidence of child poisonings in Oslo has significantly reduced since 1980. Only half of the poisonings needed treatment, most of the poisonings were mild and the clinical outcome was good.