Clinical trial: An open-label, randomised trial of different re-start strategies after treatment withdrawal in HBeAg negative chronic hepatitis B.

BACKGROUND: Stopping nucleos(t)ide analogue (NA) therapy in patients with chronic hepatitis B (CHB) may trigger a beneficial immune response leading to HBsAg loss, but clinical trials on re-start strategies are lacking. AIM: To assess whether it is beneficial to undergo a prolonged flare after NA cessation. METHODS: One-hundred-and-twenty-seven patients with HBeAg negative, non-cirrhotic CHB with at least 24 months of viral suppression on NA therapy were included. All study participants stopped antiviral therapy and were randomised to either low-threshold (ALT > 80 U/L and HBV DNA > 2000 IU/mL) or high-threshold (ALT > 100 U/L for >4 months, or ALT > 400 U/L for >2 months) for the re-start of therapy. The primary endpoint was HBsAg loss within 36 months of stopping antiviral treatment. The primary analysis was based on intention-to-treat allocation with last observation carried forward. RESULTS: There was a numerical but not statistically significant difference in HBsAg loss between the low-threshold (3 of 64; 4.7%) and the high-threshold (8 of 63; 12.7%) group (risk difference: 8.0%, 95% CI: -2.3 to 19.6, p = 0.123). None of the patients with end-of-treatment HBsAg > 1000 IU/mL achieved HBsAg loss; among those with end-of-treatment HBsAg < 1000 IU/mL, 8 of 15 (53.3%) achieved HBsAg loss in the high-threshold group compared to 3 of 26 (11.5%) in the low-threshold group. CONCLUSIONS: We could not confirm our hypothesis that a higher threshold for restart of therapy after NA withdrawal improves the likelihood of HBsAg loss within 36 months in patients with HBeAg negative CHB. Further studies including only patients with HBsAg level <1000 IU/mL and/or larger sample size and longer follow-up duration are recommended.

Clinical characteristics and factors affecting disease severity in hospitalized tick-borne encephalitis patients in Norway from 2018 to 2022.

PURPOSE: To describe the clinical characteristics and factors associated with disease severity in a Norwegian cohort of hospitalized patients with tick-borne encephalitis (TBE). METHODS: This observational multicenter study included hospitalized patients with TBE in the endemic area in the southeastern region of Norway from 2018 to 2022. Clinical signs and findings from laboratory tests, EEG, CT and MRI scans were recorded. Patient characteristics were compared among those with mild, moderate, and severe TBE, and factors associated with disease severity were identified. RESULTS: Nearly all eligible patients were included in the final cohort (153/189 participants, 81%). The median age was 56 years, 63% were men, and 7% were vaccinated against TBE; no participants were fully vaccinated. TBE presented as mild (meningeal) disease in 31% of patients and as moderate or severe (encephalitic) disease in 54% and 14% of patients, respectively. We found that 46% of the patients had a monophasic course, 64% had hyponatremia, and 7% presented with central nervous system (CNS) symptoms without pleocytosis in cerebrospinal fluid (CSF). Dysesthesia, a symptom previously not described, was reported in 10% of the patients. Most objective findings were related to the CNS. Preexisting comorbidities, CRP and CSF protein levels were predictors of more severe disease. CONCLUSION: This novel presentation of a large Norwegian cohort supports TBE as a serious disease in the southeastern region of Norway. The majority of hospitalized patients presented with encephalitis, and fewer presented with meningitis. Comorbidities, CRP and CSF protein levels were associated with more severe disease. TRIAL REGISTRATION: Prosjekt #2,296,959 - The Norwegian Tick-borne Encephalitis Study - NOTES. Acute phase characteristics and long-term outcomes. - Cristin.

Corticosteroids and superinfections in COVID-19 patients on invasive mechanical ventilation.

OBJECTIVES: To determine the incidence and characteristics of superinfections in mechanically ventilated COVID-19 patients, and the impact of dexamethasone as standard therapy. METHODS: This multicentre, observational, retrospective study included patients ≥ 18 years admitted from March 1st 2020 to January 31st 2021 with COVID-19 infection who received mechanical ventilation. Patient characteristics, clinical characteristics, therapy and survival were examined. RESULTS: 155/156 patients (115 men, mean age 62 years, range 26-84 years) were included. 67 patients (43%) had 90 superinfections, pneumonia dominated (78%). Superinfections were associated with receiving dexamethasone (66% vs 32%, p<0.0001), autoimmune disease (18% vs 5.7%, p<0.016) and with longer ICU stays (26 vs 17 days, p<0,001). Invasive fungal infections were reported exclusively in dexamethasone-treated patients [8/67 (12%) vs 0/88 (0%), p<0.0001]. Unadjusted 90-day survival did not differ between patients with or without superinfections (64% vs 73%, p=0.25), but was lower in patients receiving dexamethasone versus not (58% vs 78%, p=0.007). In multiple regression analysis, superinfection was associated with dexamethasone use [OR 3.7 (1.80-7.61), p<0.001], pre-existing autoimmune disease [OR 3.82 (1.13-12.9), p=0.031] and length of ICU stay [OR 1.05 p<0.001]. CONCLUSIONS: In critically ill COVID-19 patients, dexamethasone as standard of care was strongly and independently associated with superinfections.

The efficacy of pivmecillinam in oral step-down treatment in hospitalised patients with E. coli bacteremic urinary tract infection; a single-arm, uncontrolled treatment study.

BACKGROUND: The role of oral beta-lactam antibiotics in treating febrile urinary tract infections (UTI) is not yet definite. Today, fluoroquinolones together with trimethoprim-sulfamethoxazole (TMP-MTX) are considered standard of care and often the only available evidence-based oral treatment for febrile UTI. This study clarifies the efficacy and safety of pivmecillinam (PIV) used as step-down therapy for bacteremic urinary tract infection (UTI). METHODS: A single-arm, uncontrolled treatment trial was conducted in the period September 2017-March 2020. Candidates for inclusion were men and women suffering from E. coli bacteremia due to UTI and were consecutively included in a Norwegian hospital. Exclusion criteria were among others: other ongoing bacterial infection, septic shock, pyonephrosis/abscess and pregnancy. After 3 days of parenteral antibiotic, the treatment was converted to the study drug; oral PIV 400 mg QID for 1 week. Primary endpoint was a combination of three elements; afebrility, no need for retreatment and improvement in self-reported health status. Test Of Cure (TOC) was 1 week post-treatment. Secondary endpoints included among others microbiological efficacy and CRP value < 30 mg/L. RESULTS: Of 476 screened subjects, 53 patients were included. Median age was 67 years, 28 (56%) were women. 50 patients were evaluated for per-protocol analysis. 44 of 50 patients (88%) (95% CI [75.7-95.5]) reached the primary endpoint on TOC. 14 of 48 patients (29.2%) had significant growth (> 103 CFU/mL) of E.coli on TOC. CRP-level was strongly associated to treatment outcome, (OR 0.006 [95% CI 0.00-0.11], p < 0.001). CONCLUSIONS: This trial documents that PIV 400 mg QID given for 1 week following 3 days of parenteral antibiotics, is a suitable treatment option in patients suffering from bacteremic UTI due to E. coli. Randomised clinical trials studying the efficacy of PIV vs standard of care of febrile UTI are warranted. Trial registration The trial was registered at ClinicalTrials.gov under the identifier: NCT03282006 13/09/2017 and approved by The Regional Committees for Medical Research Ethics South East Norway (2015/2384/REK sør-øst) and the Norwegian Medicines Agency (SLV; reference No 16/06018-09; EudraCT No 2016-000984-18) before initiation.

Investigating the human jejunal microbiota.

Descriptions of the small intestinal microbiota are deficient and conflicting. We aimed to get a reliable description of the jejunal bacterial microbiota by investigating samples from two separate jejunal segments collected from the luminal mucosa during surgery. Sixty patients with morbid obesity selected for elective gastric bypass surgery were included in this survey. Samples collected by rubbing a swab against the mucosa of proximal and mid jejunal segments were characterized both quantitatively and qualitatively using a combination of microbial culture, a universal quantitative PCR and 16S deep sequencing. Within the inherent limitations of partial 16S sequencing, bacteria were assigned to the species level. By microbial culture, 53 patients (88.3%) had an estimated bacterial density of < 1600 cfu/ml in both segments whereof 31 (51.7%) were culture negative in both segments corresponding to a bacterial density below 160 cfu/ml. By quantitative PCR, 46 patients (76.7%) had less than 104 bacterial genomes/ml in both segments. The most abundant and frequently identified species by 16S deep sequencing were associated with the oral cavity, most often from the Streptococcus mitis group, the Streptococcus sanguinis group, Granulicatella adiacens/para-adiacens, the Schaalia odontolytica complex and Gemella haemolysans/taiwanensis. In general, few bacterial species were identified per sample and there was a low consistency both between the two investigated segments in each patient and between patients. The jejunal mucosa of fasting obese patients contains relatively few microorganisms and a core microbiota could not be established. The identified microbes are likely representatives of a transient microbiota and there is a high degree of overlap between the most frequently identified species in the jejunum and the recently described ileum core microbiota.

The cultivable microbiota of the human distal ileum.

OBJECTIVES: The existing literature on the microbiota of the ileum is inconsistent. To further characterize the microbiota, we analysed samples obtained directly from resected ileums used for urinary diversion after radical cystectomy. METHODS: We included 150 patients with bladder cancer operated on from March 2016 to March 2019. Samples obtained by rubbing a swab against the ileal mucosa 25 cm from the ileocecal valve were cultivated at the local laboratory. Microbial colonies were identified by matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF). RESULTS: The microbial density of the distal ileum was low. Among our samples, 79% (95% confidence interval (CI) 71%, 84%) harboured less than 1.6 × 104 cfu/mL, whereas 36% (95% CI 28%, 44%) harboured less than 1.6 × 103 cfu/mL. The flora was dominated by viridans streptococci, Candida, Actinomyces, Rothia and Lactobacillus species. Colon-related bacteria i.e. strict anaerobic bacteria, Enterobacteriales and enterococci, were recovered from 14% of the samples. Constipation was associated with increased recovery of colon-related bacteria. Antibiotic treatment prior to surgical procedures did not affect culture results. Increased age was significantly associated with more substantial fungal growth and use of proton pump inhibitors seemed to increase both bacterial and fungal growth. CONCLUSIONS: The microbiota of the human distal ileum is sparse and differs significantly from the colonic microbiota both quantitatively and by composition. These findings contradict recent metagenomics studies based on samples collected by retrograde colonoscopy and emphasize the crucial importance of adequate sampling techniques.

Species Level Description of the Human Ileal Bacterial Microbiota.

The small bowel is responsible for most of the body's nutritional uptake and for the development of intestinal and systemic tolerance towards microbes. Nevertheless, the human small bowel microbiota has remained poorly characterized, mainly owing to sampling difficulties. Sample collection directly from the distal ileum was performed during radical cystectomy with urinary diversion. Material from the ileal mucosa were analysed using massive parallel sequencing of the 16S rRNA gene. Samples from 27 Caucasian patients were included. In total 280 unique Operational Taxonomic Units were identified, whereof 229 could be assigned to a species or a species group. The most frequently detected bacteria belonged to the genera Streptococcus, Granulicatella, Actinomyces, Solobacterium, Rothia, Gemella and TM7(G-1). Among these, the most abundant species were typically streptococci within the mitis and sanguinis groups, Streptococcus salivarius, Rothia mucilaginosa and Actinomyces from the A. meyeri/odontolyticus group. The amounts of Proteobacteria and strict anaerobes were low. The microbiota of the distal part of the human ileum is oral-like and strikingly different from the colonic microbiota. Although our patient population is elderly and hospitalized with a high prevalence of chronic conditions, our results provide new and valuable insights into a lesser explored part of the human intestinal ecosystem.

[An outbreak of Yersinia enterocolitica O:9-infection]. / Et utbrudd av Yersinia enterocolitica O:9-infeksjon.

BACKGROUND: Yersiniosis is a zoonosis that is transmitted from pigs to humans. In January 2006 more cases of Yersinia enterocolitica enterocolitis than expected were reported in Norway. The fact that the isolates belonged to the O:9 serogroup, which is rare in Norway, and the geographical and temporal clustering of the cases, pointed to an outbreak. We have conducted a retrospective study of 11 patients who were diagnosed during this outbreak. MATERIAL AND METHODS: The material is based upon applicants' information, patient journals and a questionnaire. In order to disclose the source of infection, a case-control survey was performed. RESULTS: Nine of the 11 patients had enterocolitis and two had septicaemia, both of whom died following a few days of treatment. One patient presented with pseudo- appendicitis while another developed monoarthritis, which persisted for more than three months after the debut of symptoms Treatment with antibiotics was offered in six cases. The case-control analysis indicated that brawn was the probable source of infection. INTERPRETATION: This is the first reported Norwegian outbreak of Y. enterocolitica O:9 disease. The incubation time, disease duration and frequency of intestinal and immunological complications corresponds with previously published data. The frequency of septicaemia exceeds several previously reported outbreaks and retrospective studies of sporadic cases.

Fascioliasis imported to Norway.

We report 3 cases of fascioliasis imported to Norway: a 24-y-old male Vietnamese immigrant and a 51-y-old female Vietnamese immigrant with acute fascioliasis, and a 2-y-old male Ethiopian adoptee with chronic fascioliasis. Diagnosis was confirmed by detection of specific antibodies to Fasciola hepatica in the 2 first cases and by demonstration of Fasciola hepatica eggs in stool samples in the latter case. Treatment with oral triclabendazole led to prompt cure in all 3 patients. Imported fascioliasis is rarely reported but should be suspected in patients with a travel history to endemic areas, abdominal symptoms and hypereosinophilia of the blood.