Clinical features of gastroenteritis during a large waterborne Campylobacter outbreak in Askøy, Norway.

PURPOSE: Outbreaks of Campylobacter infection are common, but studies exploring the clinical features of acute illness in the outbreak setting are scarce in existing literature. The main purpose of the present study was to investigate the clinical features of self-reported acute illness in gastroenteritis cases during a large waterborne Campylobacter outbreak in Askøy municipality, Norway, in 2019. METHODS: A web-based self-administered questionnaire, and invitation to participate was sent by the municipality of Askøy as text message to mobile phones using the municipality's warning system to the inhabitants during the ongoing outbreak. RESULTS: Out of 3624 participants, 749 (20.7%) were defined as cases, of which 177 (23.6%) reported severe gastroenteritis. The most common symptoms were loose stools (90.7%), abdominal pain (89.3%) and diarrhea (88.9%), whereas 63.8% reported fever, 50.2% joint pain and 14.2% bloody stools. Tiredness, a symptom non-specific to gastroenteritis, was the overall most common symptom (91.2%). CONCLUSION: About one in four of the cases reported symptoms consistent with severe gastroenteritis. We found more joint pain and less bloody stools than reported in published studies of laboratory confirmed campylobacteriosis cases. Tiredness was common in the current study, although rarely described in previous literature of acute illness in the outbreak setting.

An observational study of community-acquired severe sepsis comparing intensive care and non-intensive care patients.

BACKGROUND: Most studies of sepsis are from intensive care units (ICUs). We aimed to investigate community-acquired severe sepsis in a broader population, in order to compare patients treated in or outside an ICU . METHODS: We performed a 1-year prospective observational study with enrollment of patients from three units; a general ICU, a combined ICU/non-ICU and a medical ward with limited surveillance facilities. Hospital survivors were followed up for 5 years. RESULTS: Overall, 220 patients were included, of which 107 received ICU treatment. The majority of abdominal (77%, P = 0.003) and genitourinary (81%, P < 0.001) infections were found in ICU and non-ICU patients, respectively. Time to first antibiotic administration was longer in ICU-patients (median 3.5 vs. 2.0 h in non-ICU patients, P = 0.011). ICU developed more organ dysfunctions than non-ICU patients (P < 0.001), nevertheless supportive therapy with vasoactive drugs and non-invasive ventilation was documented in 22% and 27% of the latter. Median hospital length of stay was 15 vs. 9 days (P = 0.001), and hospital and 5-year mortality rates 35% vs. 16% (P = 0.002) and 57% vs. 58% (P = 0.892) among ICU and non-ICU patients, respectively. Increasing age (HR 1.06 (1.04, 1.07) per year, P < 0.001), not care level during hospitalization (HR 1.19 (0.70, 2.02), P = 0.514), influenced long-term survival. CONCLUSION: Half of the subjects with community-acquired severe sepsis never received ICU treatment. Still, use of organ supportive therapy outside the ICU was considerable. Hospital mortality was higher, whereas 5-year survival was similar when comparing ICU with non-ICU patients.

Postinfectious and sporadic functional gastrointestinal disorders have different prevalences and rates of overlap: results from a controlled cohort study 3 years after acute giardiasis.

BACKGROUND: Irritable bowel syndrome (IBS) is a common complication following gastroenteritis, and a high prevalence of postgiardiasis IBS has previously been reported. This study aims to investigate the prevalence, adjusted relative risk (RRadj), and overlap of different functional gastrointestinal disorders (FGID) according to Rome III criteria following infection with Giardia lamblia. METHODS: All patients ≥18 years of age with verified giardiasis during an outbreak in 2004, and a control group matched by age and gender, were mailed a questionnaire 3 years later. KEY RESULTS: The prevalence of functional dyspepsia (FD) was 25.9% in the exposed and 6.9% in the control group, RRadj: 3.9 (95% confidence intervals [CI]: 3.1-4.8). The prevalence of IBS was 47.9% and 14.3%, respectively, with RRadj: 3.4 (95% CI: 3.0-3.8). Prevalence of other gastrointestinal symptoms ranged from 70.0% vs 39.7% for bloating (RRadj: 1.8) to 8.3% vs 2.9% for nausea (RRadj: 3.0) in the Giardia and the control group, respectively. Among individuals fulfilling criteria for IBS 44% in the exposed group and 29% in the control group also fulfilled criteria for FD. IBS subtypes based on Rome III criteria (stool consistency) showed poor agreement with subtypes based on frequency of bowel movements (Kappa-values: 0.17 and 0.27). CONCLUSIONS & INFERENCES: There were high prevalences and RRs of IBS, FD and other gastrointestinal symptoms following acute giardiasis, and a high degree of overlap between the disorders. The agreement between different IBS subtype criteria varied, and there were also differences between the exposed and control group.

Salivary IgA from the sublingual compartment as a novel noninvasive proxy for intestinal immune induction.

Whole-saliva IgA appears like an attractive noninvasive readout for intestinal immune induction after enteric infection or vaccination, but has failed to show consistent correlation with established invasive markers and IgA in feces or intestinal lavage. For reference, we measured antibodies in samples from 30 healthy volunteers who were orally infected with wild-type enterotoxigenic Escherichia coli. The response against these bacteria in serum, lavage, and lymphocyte supernatants (antibody-in-lymphocyte-supernatant, ALS) was compared with that in targeted parotid and sublingual/submandibular secretions. Strong correlation occurred between IgA antibody levels against the challenge bacteria in sublingual/submandibular secretions and in lavage (r=0.69, P<0.0001) and ALS (r=0.70, P<0.0001). In sublingual/submandibular secretions, 93% responded with more than a twofold increase in IgA antibodies against the challenge strain, whereas the corresponding response in parotid secretions was only 67% (P=0.039). With >twofold ALS as a reference, the sensitivity of a >twofold response for IgA in sublingual/submandibular secretion was 96%, whereas it was only 67% in the parotid fluid. To exclude that flow rate variations influenced the results, we used albumin as a marker. Our data suggested that IgA in sublingual/submandibular secretions, rather than whole saliva with its variable content of parotid fluid, is a preferential noninvasive proxy for intestinal immune induction.

Whole genome sequencing of clinical isolates of Giardia lamblia.

Clinical isolates from protozoan parasites such as Giardia lamblia are at present practically impossible to culture. By using simple cyst purification methods, we show that Giardia whole genome sequencing of clinical stool samples is possible. Immunomagnetic separation after sucrose gradient flotation gave superior results compared to sucrose gradient flotation alone. The method enables detailed analysis of a wide range of genes of interest for genotyping, virulence and drug resistance.

Sequence diversity of sicG among group C and G Streptococcus dysgalactiae subspecies equisimilis isolates associated with human infections in western Norway.

Streptococcal inhibitor of complement (SIC) and distantly related to SIC (DRS) are well-characterized extracellular virulence factors produced by only a few emm types among group A streptococci. The prevalence and sequence variations of the sic-like gene (sicG) in clinical samples of group C and G Streptococcus dysgalactiae subspecies equisimilis (SDSE), however, have not been widely investigated. We constructed primers targeting sicG and screened 129 geographically matched and previously emm-typed non-invasive (n = 64) and invasive (n = 65) SDSE isolates for the presence of this gene. sicG was detected in seven non-invasive and eight invasive isolates belonging to eight different emm types. Within five of these emm types, sicG-negative isolates were also detected. All three isolates of stG2078.0 possessed sicG and were associated with severe soft tissue infections. Altogether, six sicG alleles (sicG1-6) were identified, and sequence variations were mainly caused by single nucleotide polymorphisms and deletion/insertion mutations. sicG1-6 were predicted to encode SICG proteins of varying length, composition, and homology with SIC and DRS proteins of group A streptococci. Our findings indicate an unpredictable association between sicG and emm type, a limited distribution and substantial sequence diversity of sicG, and no obvious relation between its presence and disease severity.

Necrotizing soft tissue infections caused by Streptococcus pyogenes and Streptococcus dysgalactiae subsp. equisimilis of groups C and G in western Norway.

Streptococcus pyogenes (group A streptococcus, GAS) is a major cause of necrotizing soft tissue infection (NSTI). On rare occasions, other ß-haemolytic streptococci may also cause NSTI, but the significance and nature of these infections has not been thoroughly investigated. In this study, clinical and molecular characteristics of NSTI caused by GAS and ß-haemolytic Streptococcus dysgalactiae subsp. equisimilis of groups C and G (GCS/GGS) in western Norway during 2000-09 are presented. Clinical data were included retrospectively. The bacterial isolates were subsequently emm typed and screened for the presence of genes encoding streptococcal superantigens. Seventy cases were identified, corresponding to a mean annual incidence rate of 1.4 per 100 000. Sixty-one of the cases were associated with GAS, whereas GCS/GGS accounted for the remaining nine cases. The in-hospital case fatality rates of GAS and GCS/GGS disease were 11% and 33%, respectively. The GCS/GGS patients were older, had comorbidities more often and had anatomically more superficial disease than the GAS patients. High age and toxic shock syndrome were associated with mortality. The Laboratory Risk Indicator for Necrotizing Fasciitis laboratory score showed high values (≥6) in only 31 of 67 cases. Among the available 42 GAS isolates, the most predominant emm types were emm1, emm3 and emm4. The virulence gene profiles were strongly correlated to emm type. The number of superantigen genes was low in the four available GCS/GGS isolates. Our findings indicate a high frequency of streptococcal necrotizing fasciitis in our community. GCS/GGS infections contribute to the disease burden, but differ from GAS cases in frequency and predisposing factors.

Early quantification of HCV core antigen may help to determine the duration of therapy for chronic genotype 2 or 3 HCV infection.

The aim of the present study was to evaluate the utility of hepatitis C virus (HCV) core antigen (coreAg) assessment for the identification of candidates for short-term therapy. Plasma samples from HCV genotype 2 or 3-infected patients participating in the NORDynamIC trial (n=382) comparing 12 and 24 weeks of combination treatment with pegylated interferon-α2a and a fixed dose of 800 mg ribavirin daily were analyzed for coreAg. Among the 126 patients (33% of the intention-to-treat population) achieving HCV coreAg levels in plasma below 0.2 pg/mL when assayed on treatment day 3, sustained viral response (SVR) rates of 86% and 84% were achieved in the 12- and 24-week arms, respectively. Similarly, among patients having received at least 80% of the target dose of both pegylated interferon α-2a and of ribavirin for at least 80% of the target treatment duration (per-protocol analysis), the SVR rates were 89% and 95%, respectively. Twelve weeks of combination treatment may be sufficient for genotype 2 or 3-infected patients achieving HCV coreAg levels below 0.2 pg/mL by day 3, signaling a rapid clearance of HCV viremia.

Ribavirin plasma concentration is a predictor of sustained virological response in patients treated for chronic hepatitis C virus genotype 2/3 infection.

In hepatitis C virus (HCV) genotype 1 infection, the likelihood of obtaining sustained virological response (SVR) is associated with higher ribavirin exposure. Such an association has not been demonstrated for HCV genotype 2/3 infection, where a fixed 800 mg daily dosing of ribavirin is generally recommended. The primary aim of this study was to investigate the correlation between ribavirin concentration at day 29 and therapeutic response in patients with HCV genotype 2/3 infection. A total of 382 patients were randomized to 12 or 24 weeks of treatment with pegylated interferon-alfa 2a 180 µg weekly and 800 mg ribavirin daily. Trough plasma concentration of ribavirin was measured at day 29 and week 12 and the primary outcome was SVR (HCV-RNA undetectable 24 weeks after treatment). Of the 382 patients, 355 had a ribavirin concentration available at day 29. SVR was 84% among patients with a ribavirin concentration ≥2 mg/L at day 29 compared to 66% in those with concentrations <2 mg/L (P = 0.002). The corresponding figures in the 12-week treatment group were 74% and 57% (P = 0.12), and in the 24-week treatment group 91% and 75% (P = 0.02), respectively. In a multivariate analysis, ribavirin concentration at day 29 was an independent predictor of SVR (P = 0.002). In conclusion, a higher plasma ribavirin concentration is associated with an increased likelihood of achieving SVR in HCV genotype 2/3 infection. Individualization of ribavirin dosing may be helpful in improving outcome, especially in the presence of unfavourable baseline characteristics. This, however, requires evaluation in a prospective trial.

Hepatitis C treatment response kinetics and impact of baseline predictors.

The optimal duration of treatment for hepatitis C virus (HCV) infections is highly variable but critical for achieving cure (sustained virological response, SVR). We prospectively investigated the impact of age, fibrosis, baseline viraemia and genotype on the early viral kinetics and treatment outcome. Patients treated with peginterferon alfa-2a and ribavirin in standard dosing were included: 49 with genotype 1 treated for 48weeks and 139 with genotype 2 or 3 treated for 24weeks. The reduced SVR rates in patients older than 45years, with severe liver fibrosis or pretreatment viraemia above 400,000IU/mL were strongly associated with slower second phase declines of HCV RNA. Genotype 2/3 infections responded more rapidly than genotype 1, reaching week 4 negativity (RVR) in 59%vs 22%. We conclude that baseline response predictors such as age, fibrosis and viral load were well reflected by the early viral kinetics as assessed by repeated HCV RNA quantifications. The kinetic patterns and the high relapse rate in genotype 2/3 patients without RVR suggest that this group might benefit from treatment durations longer than 24weeks.

Invasive group A, C and G streptococcal disease in western Norway: virulence gene profiles, clinical features and outcomes.

Invasive group A streptococcal (iGAS) disease is endemic in Norway, but data on invasive group C and group G streptococcal (iGCS/GGS) disease are lacking. We investigated the characteristics of iGAS and iGCS/GGS infections in western Norway from March 2006 to February 2009. Clinical information was retrospectively obtained from medical records. GAS and GCS/GGS isolates were emm typed and screened for the presence of 11 superantigen (SAg) genes and the gene encoding streptococcal phospholipase A2 (SlaA). GCS/GGS isolates were also subjected to PCR with primers targeting speG(dys) . Sixty iGAS and 50 iGCS/GGS cases were identified, corresponding to mean annual incidence rates of 5.0 per 100,000 and 4.1 per 100,000 inhabitants, respectively. Skin and soft tissue infections were the most frequent clinical manifestations of both iGAS and iGCS/GGS disease, and 14 iGAS patients (23%) developed necrotizing fasciitis. The 30-day case fatality rates of iGAS and iGCS/GGS disease were 10% and 2%, respectively. emm1, emm3 and emm28 accounted for 53% of the GAS isolates, and these types were associated with severe clinical outcome. SAg gene and SlaA profiles were conserved within most of the GAS emm types, although five profiles were obtained within isolates of emm28. stG643 was the most prevalent GCS/GGS emm type, and speG(dys) was identified in 73% of the GCS/GGS isolates. Neither GAS SAg genes nor SlaA were detected in GCS/GGS. Our findings indicate a considerable burden of both iGAS and iGCS/GGS disease and a high frequency of necrotizing fasciitis caused by GAS in our community.

emm gene diversity, superantigen gene profiles and presence of SlaA among clinical isolates of group A, C and G streptococci from western Norway.

In order to investigate molecular characteristics of beta-hemolytic streptococcal isolates from western Norway, we analysed the entire emm gene sequences, obtained superantigen gene profiles and determined the prevalence of the gene encoding streptococcal phospholipase A2 (SlaA) of 165 non-invasive and 34 contemporary invasive group A, C and G streptococci (GAS, GCS and GGS). Among the 25 GAS and 26 GCS/GGS emm subtypes identified, only emm3.1 was significantly associated with invasive disease. M protein size variation within GAS and GCS/GGS emm types was frequently identified. Two non-invasive and one invasive GGS possessed emm genes that translated to truncated M proteins as a result of frameshift mutations. Results suggestive of recombinations between emm or emm-like gene segments were found in isolates of emm4 and stG485 types. One non-invasive GGS possessed speC, speG, speH, speI and smeZ, and another non-invasive GGS harboured SlaA. speA and SlaA were over-represented among invasive GAS, probably because they were associated with emm3. speG(dys) was identified in 83% of invasive and 63% of non-invasive GCS/GGS and correlated with certain emm subtypes. Our results indicate the invasive potential of isolates belonging to emm3, and show substantial emm gene diversity and possible lateral gene transfers in our streptococcal population.

High rate of fatigue and abdominal symptoms 2 years after an outbreak of giardiasis.

The aim of this study was to evaluate the prevalence of fatigue and abdominal symptoms 2 years after Giardia lamblia infection. All 1262 cases who had Giardia-positive stool samples during an outbreak in 2004 in Norway received a questionnaire in 2006 asking about fatigue and abdominal symptoms. Fatigue was reported by 41%, whereas 38% reported abdominal symptoms, and there was a highly significant association between these symptoms. Increasing age was a highly significant risk factor for fatigue. The symptoms were not due to chronic infection in this cohort. Our data warrant further investigations into the late effects of giardiasis.

Molecular epidemiological investigation of an outbreak of invasive beta-haemolytic streptococcal infection in western Norway.

During a decade-long, high endemic situation with severe group A streptococcal disease in western Norway, a cluster of 16 patients with invasive streptococcal disease was hospitalized during a period of 11 weeks. A study including clinical characteristics and molecular epidemiology of the outbreak was initiated. Relevant clinical information was obtained from the medical records of the patients. Nine of the 16 patients had soft tissue infection, and seven of these had streptococcal toxic shock syndrome (STSS). Mortality, both overall and among those with STSS, was 25%. Streptococcal isolates from these patients were characterized by serogrouping and emm sequence typing. The emm amplicons were further characterized by sequence analysis and restriction fragment length polymorphism (emm RFLP) analysis. The streptococci were identified as group A streptococcus (GAS) in 11 patients and group G streptococcus (GGS) in four patients. The patients with GGS infection were older than the patients with GAS infection, and all patients infected with GGS had predisposing comorbidities. Isolates from 13 patients were available for emm gene analysis and found to belong to nine different emm types. Similar differentiation was obtained with emm RFLP in GAS. Hence, the outbreak was polyclonal. Results suggestive of horizontal gene transfer and recombination between the emm genes of GAS, group C streptococcus and GGS were found in the isolates from seven patients. Such genetic recombination events suggest a possible role in pathogenesis.

Sensitivity of a Giardia antigen test in persistent giardiasis following an extensive outbreak.

The utility of a rapid antigen test for diagnosing cases of persistent giardiasis, as defined by detection of cysts by conventional microscopy following standard formalin-ether concentration or the positive rapid antigen test, was investigated following a large, waterborne outbreak of giardiasis. The sensitivity and specificity of the rapid test as compared with microscopy were 60.7% and 96.7%, respectively, in this patient group. The low sensitivity contrasts with previous reports, and may be partly explained by low cyst numbers.

Treatment-ladder and genetic characterisation of parasites in refractory giardiasis after an outbreak in Norway.

OBJECTIVES: To evaluate the efficacy of a treatment ladder in metronidazole-refractory giardiasis, and to compare genetic characteristics of the parasites. METHODS: A clinical observational study was carried out in 38 adult patients with metronidazole-refractory giardiasis, during an outbreak in Norway with more than 1200 cases. All patients were treated with albendazole in combination with metronidazole. Those who failed were treated with paromomycin. Those who failed on paromomycin were treated with quinacrine in combination with metronidazole. Giardia isolates from 17 patients were characterised by PCR and sequencing at two separate genes. RESULTS: Metronidazole in combination with albendazole was effective in 30 (79%) out of 38 patients. Paromomycin was effective in three out of six patients. Quinacrine in combination with metronidazole was effective in 3 patients. Molecular characterisation of the Giardia isolates revealed that these parasites were identical at two different gene segments, while sequence profiles from isolates at the peak of the outbreak were more heterogenous. CONCLUSIONS: Albendazole and quinacrine both in combination with metronidazole were effective in treating metronidazole-refractory giardiasis in this cohort. Paromomycin was less effective. Particular Giardia sub-genotypes may have been associated with the treatment-refractory giardiasis in these patients, although other undefined factors are probably also of importance.

Changes in pain, stiffness and physical function in patients with osteoarthritis waiting for hip or knee joint replacement surgery.

OBJECTIVE: Little has been reported on changes in health status in patients with osteoarthritis (OA) while waiting for hip or knee replacement surgery. In this study we assessed (1) changes in self-reported pain, stiffness and physical function in patients with OA of the hip or knee, from the decision to undergo surgery to 14 days prior to surgery, and (2) the determinants of these changes. METHODS: Among 353 baseline respondents, 170 waited >30 days for surgery, completed the Western Ontario and McMaster Universities Arthritis Index (WOMAC) before surgery and were included in the analysis of changes; 120 with OA of the hip and 50 of the knee. We analyzed changes in WOMAC scores using the paired t test and determinants of the changes using multiple linear regression. RESULTS: Patients with OA of the hip did not change on any WOMAC scale before surgery. Knee patients deteriorated with time on the WOMAC stiffness and total scales, but not on the pain or physical function subscales. In both patient categories, higher baseline WOMAC scores were associated with smaller changes on all subscales and the total score, and female sex was associated with deterioration on the pain subscale. CONCLUSIONS: Patients with OA of the hip reported no change in pain, stiffness or physical function while waiting for joint replacement surgery, whereas patients with OA of the knee deteriorated on the stiffness and total scales of the WOMAC. This suggests a difference in patient selection, referral pattern or disease development between the patient categories.

Molecular characterisation of Giardia isolates from clinical infections following a waterborne outbreak.

OBJECTIVES: During autumn/winter 2004/2005 an outbreak of waterborne giardiasis occurred in Bergen, Norway. Genetic characterisation at 2 genes of Giardia duodenalis isolates from samples from the outbreak peak showed significant variations between isolates. Characterisation of further isolates from patients diagnosed in the subsequent months was conducted to determine whether isolates with particular sequences might predominate, or whether the sequence variation would continue. METHODS: Genetic characterisation was conducted on 63 isolates from patients diagnosed in the 12 months subsequent to the outbreak peak. RESULTS: At the beta-giardin gene and glutamate dehydrogenase gene, particular isolate sequences within Assemblage B, gradually predominated over time. These sequences had not been the most frequently identified amongst 21 isolates from the outbreak peak. Nor were they apparently associated with a particular sequence at the triose phosphate isomerase gene. CONCLUSIONS: The predominance of particular sequences at the beta-giardin gene and glutamate dehydrogenase gene over time suggests that these sequences may be associated with enhanced transmission characteristics such as higher virulence, greater cyst environmental resistance, increased proliferation, or a combination of these factors. Alternatively greater association with clinical disease may have led to increased submission of samples with these sequences. Whether these sequences may be associated with particular symptom characteristics such as overt clinical disease, infection persistence or unresponsiveness to treatment warrants further study.