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Campylobacter concisus has been associated with prolonged mild diarrhoea, but investigations regarding the efficacy of antimicrobial treatment have not been reported previously. We initiated a phase 3, single-centre, randomized, double-blinded, placebo-controlled study comparing the efficacy of 500 mg once-daily dose of azithromycin with a 500 mg once-daily dose of placebo for three days, for the treatment of C. concisus diarrhoea in adult patients with a follow-up period of ten days. If symptoms persisted at day ten, the patient was offered cross-over study treatment of three days and another ten-day follow-up period. The primary efficacy endpoint was the clinical response, defined as time to cessation of diarrhoea (<3 stools/day or reversal of accompanying symptoms). Our estimated sample size was 100 patients. We investigated a total of 10,036 diarrheic stool samples from 7,089 adult patients. Five-hundred and eighty-eight C. concisus positive patients were assessed for eligibility, of which 559 were excluded prior to randomization. The three main reasons for exclusion were duration of diarrhoea longer than 21 days (n = 124), previous antibiotic treatment (n = 113), and co-pathogens in stools (n = 87). Therefore, 24 patients completed the trial with either azithromycin (n = 12) or placebo (n = 12). Both groups presented symptoms of mild, prolonged diarrhoea with a mean duration of 18 days (95% CI: 16-19). One person in the azithromycin group and four from the placebo group chose to continue with crossover medication after the initial ten-day period. In the azithromycin group, there was a mean of seven days (95% CI: 5-9) to clinical cure and for the placebo group it was ten days (95% CI: 6-14) (OR-3 (95% CI: -7-1). We observed no differences in all examined outcomes between azithromycin treatment and placebo. However, due to unforeseen recruitment difficulties we did not reach our estimated sample size of 100 patients and statistical power to conclude on an effect of azithromycin treatment was not obtained., Trial Registration: Clinicaltrials.gov identifier: NCT01531218., Competing Interests: The authors have declared that no competing interests exist.

Objective: Gastroenteritis with Campylobacter concisus is an emerging infection, but the risk of irritable bowel syndrome (IBS) following it is unknown., Material and Methods: In a prospective, community-based study of gastroenteritis with C. concisus and C. jejuni/coli, we invited adult patients to participate in a questionnaire study, including IBS symptoms and psychometric scores, at baseline and at 6 months. We estimated adjusted RR (RRadj) (for age, sex and comorbidity) for IBS as the primary outcome., Results: The development of IBS symptoms at 6 months was reported in 26/106 (25%) patients with C. concisus infection, and in 30/162 (19%) of C. jejuni/coli patients. The baseline predictors for IBS in C. concisus infection were high anxiety scores (RRadj 2.0; 95% CI 1.1-3.6, p<0.05), chills (RRadj 1.9; 95% CI 1.0-3.6, p<0.05), headache (RRadj 2.5; 95% CI 1.1-6.0, p<0.05), dizziness (RRadj 2.6; 95% CI 1.2-5.8, p<0.05) and muscle ache (RRadj 3.6; 95% CI 1.4-8.9, p<0.01). For all Campylobacter patients (n=268), we confirmed previous reports of anxiety (RRadj 2.0; 95% CI 1.3-3.1), depression (RRadj 2.3; 95% CI 1.3-4.0) and high somatization scores (RRadj 3.0; 95% CI 1.5-6.0) as predictors for post-infectious IBS (PI-IBS)., Conclusions: Gastroenteritis with C. concisus carries a 25% risk of IBS at 6-month follow-up. The risk factors for IBS are chills, headache, dizziness and muscle ache in the acute stage, as well as preexisting high psychometric scores for anxiety. Our findings suggest that psychological factors play a role in the development of PI-IBS.

Background: There is only sparse information about the clinical impact of Campylobacter concisus infections in children., Methods: A study was performed during a 2-year period to determine the clinical manifestations in C. concisus-positive children with gastroenteritis. A case patient was defined as a child or teenager (<18 years) with a C. concisus-positive stool sample during the study period. Clinical data were obtained with use of a questionnaire study supplemented with the patients' medical records. The clinical manifestations in these patients were compared with those of patients with Campylobacter jejuni/coli infection., Results: Two thousand three hundred seventy-two diarrheic stool samples from 1867 children were cultured for pathogenic enteric bacteria during the study period, and 85 and 109 children with C. concisus and C. jejuni/coli, respectively, were identified. Comparison of the acute clinical manifestations in 44 C. concisus patients with those in 64 C. jejuni/coli patients showed a significantly lower prevalence of fever, chills and blood in stools in the former. However, half of C. concisus patients compared with one-fourth of C. jejuni/coli patients had prolonged diarrhea for more than 2 weeks and two-thirds of all children with C. concisus reported loose stools after 6-month follow-up., Conclusions: C. concisus infection in children seems to have a milder course of acute gastroenteritis compared with C. jejuni/coli infection but is associated with more prolonged diarrhea. Children with C. concisus have the same degree of late gastrointestinal complaints as children diagnosed with C. jejuni/coli infection.

One thousand seven hundred ninety-one diarrheic stool samples were cultivated for Campylobacter spp. We found a high prevalence of Campylobacter concisus with use of a polycarbonate filter (n = 114) compared to a cellulose acetate filter (n = 79) (P < .0001). The polycarbonate filter is superior to the commonly used cellulose acetate filter for detection of C. concisus., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Calprotectin (CP) is a calcium-binding cytosolic neutrophil protein and the concentration in feces reflects the migration of neutrophils into the gut lumen. Testing for fecal CP (f-CP) in patients with negative cultures for enteric pathogens is widely accepted as a useful screening tool for identifying patients who are most likely to benefit from endoscopy for suspected inflammatory bowel disease (IBD) with the assumption that a negative f-CP is compatible with a functional disorder. Campylobacter concisus has recently been reported to have a high incidence in the Danish population almost equal to Campylobacter jejuni and Campylobacter coli and has been reported to cause prolonged watery diarrhea. However, isolation of C. concisus from feces requires the filter method in a hydrogen-enriched microaerobic atmosphere, which is not commonly used in the laboratory, and the diagnosis may consequently be missed. The aim of this study was to evaluate the f-CP levels, as a marker for the intestinal inflammation in C. jejuni/coli- and C. concisus-infected patients. The authors found a high concentration of f-CP (median 631: IQR 221-1274) among 140 patients with C. jejuni/coli infection, whereas the f-CP level among 99 C. concisus-infected patients was significantly lower (median 53: IQR 20-169). The data correlate to the severe inflammatory gastroenteritis seen in patients infected with C. jejuni/coli, whereas C. concisus-infected patients have a much lower intestinal inflammation which could be compared with viral gastroenteritis. Nevertheless, clinicians should be aware of C. concisus infection, especially in patients with prolonged mild diarrhea, in the differential diagnosis to IBD.

The incidence of non-thermophilic Campylobacter species was assessed in an unselected population-based study in a mixed urban and rural community in North Jutland, Denmark. In a 2-year study period, 11,314 faecal samples from 8302 patients with gastroenteritis were cultured with supplement of the filter method. We recovered a high incidence of Campylobacter concisus (annual incidence 35/100,000 inhabitants), almost as high as the common Campylobacter jejuni/coli. In contrast, there was a very low incidence of other non-thermophilic Campylobacter species, such as Campylobacter upsaliensis. Campylobacter concisus was, unlike C. jejuni/coli, found more frequently among small children (<1 year) and the elderly (≥ 65 years). Around 10% of the patients with C. consisus had co-infections dominated by Clostridium difficile and Salmonella enterica, whereas co-infections occurred in about 5% of C. jejuni/coli patients. We observed a seasonal variation in C. jejuni/coli with a peak incidence in late summer months and autumn, whereas there was an almost constant monthly prevalence of C. concisus. Among patients participating in a questionnaire sub-study, there was a higher degree of close contacts with animals, especially dogs, as well as a higher travel exposure among C. jejuni/coli patients compared with C. concisus patients. We did not culture any C. concisus in stool samples from a small cohort of healthy individuals. Future studies have to focus on the clinical follow-up and the long-term risk of inflammatory bowel diseases in C. concisus-positive patients. We conclude that there is a high incidence of C. concisus in Denmark., (© 2012 The Authors. Clinical Microbiology and Infection © 2012 European Society of Clinical Microbiology and Infectious Diseases.)

There are only sparse data on the short-term and medium-term clinical impacts of Campylobacter concisus infection. A clinical study was performed during a 2-year period to determine the clinical manifestations in C. concisus-positive adult patients. A case patient was defined as an adult patient (≥18 years) with a C. concisus-positive stool sample during the study period. Clinical data were obtained with use of a questionnaire supplemented with the patients' medical records, if any. The short-term and medium-term clinical manifestations in these patients were compared with those of patients with Campylobacter jejuni/Campylobacter coli infection. One hundred and seventy-four C. concisus patients and 196 C. jejuni/C. coli patients participated in the study. Patients with pre-existing inflammatory bowel disease or microscopic colitis or enteric co-infection were excluded from review of the clinical manifestations. Comparison of the short-term clinical manifestations in 139 C. concisus patients with those in 187 C. jejuni/C. coli patients showed a significantly lower prevalence of fever, chills, mucus and blood in stools, and weight loss. However, 80% of C. concisus patients, but only 32% of C. jejuni/C. coli patients, had diarrhoea for >2 weeks. After a 6-month follow-up period, 12% of C. concisus patients were diagnosed with microscopic colitis, whereas no C. jejuni/C. coli patients were diagnosed with non-infective colitis. Irritable bowel symptoms were common in both groups at follow-up. C. concisus infection seems to cause a milder course of acute gastroenteritis than C. jejuni/C. coli infection, but is associated with more prolonged diarrhoea., (© 2012 The Authors. Clinical Microbiology and Infection © 2012 European Society of Clinical Microbiology and Infectious Diseases.)

The risk of infection with Campylobacter jejuni/coli as well as complications may be related to host genetics. We assessed six single-nucleotide polymorphisms in inflammatory cytokine genes in 105 patients with Campylobacter jejuni/coli gastroenteritis. The population distribution of the genes was determined in healthy subjects. The patients responded to mailed questionnaires with regard to reactive arthritis (RA) and irritable bowel syndrome (IBS) in 6-month follow-up. The genotype INFG(+ 874A/A) was less frequent in patients than in controls (20% versus 33%; P = 0.015), whereas the distribution of the other five SNPs did not differ from controls. After 6 months, RA had developed in 15 subjects and IBS in 20 subjects. RA was significant more frequent in patients with IL-18(-137G/G) (22%) than IL-18(-137C/C) (0%), P = 0.03, with INFG(+874 T/T (32%) than INFG(+874A/A) (0%), P = 0.007, and with INFG(+2197 A/A) (22%) than INFG(+2197G/G) (0%), P = 0.02. The development of IBS was not linked to gene polymorphisms. In conclusion, the risk of acquiring clinical gastroenteritis with Campylobacter jejuni/coli is related to the INFG (+ 874A>T) of intron 1. Polymorphisms in IL-18 and INFG are linked to the risk of post-infectious reactive arthritis, but not to irritable bowel syndrome., (© 2012 The Authors. Scandinavian Journal of Immunology © 2012 Blackwell Publishing Ltd.)

The role of bacterial genes in the determination of the clinical spectrum of Campylobacter jejuni infection is unclear. We compared clinical isolates from invasive blood-stream infection with stool isolates from gastroenteritis and found no association of the putative virulence genes iam, capA, virB and cdtB with clinical presentation.

We hypothesized that preceding zoonotic Salmonella or Campylobacter gastroenteritis aggravated the prognosis in cancer patients. Exposed patients comprised all of those diagnosed with first-time Salmonella/Campylobacter gastroenteritis from 1991 and with first-time cancer diagnosis thereafter (through 2003) in two Danish counties. These patients were matched for main cancer type, gender, age and calendar period to unexposed cancer patients, i.e. those without Salmonella/Campylobacter gastroenteritis. We compared cancer stage by age- and comorbidity-adjusted logistic regression analysis, survival by comorbidity-adjusted Cox's regression analysis and mortality dependent on the time period between Salmonella/Campylobacter gastroenteritis and cancer by spline regression curves. The study cohort comprised 272 Salmonella/Campylobacter-exposed cancer patients and 2681 unexposed cancer patients. Prevalence odds ratios [95% confidence intervals (CI)] in exposed as compared with unexposed patients were 0.96 (0.74-1.25) for localized tumours, 1.15 (0.87-1.54) for regional spread and 1.14 (0.84-1.55) for metastases. Adjusted mortality rate ratios (95% CI) were 0.93 (0.75-1.16) for 0-1 year, 1.08 (0.84-1.39) for 2-5 years and 1.02 (0.60-1.73) for the remaining period. Mortality estimates did not change in relation to the time period between gastroenteritis and cancer. Salmonella/Campylobacter gastroenteritis prior to cancer was associated with neither the cancer stage nor a poorer prognosis.

Invasive disease as a result of Campylobacter is rarely reported. We reviewed 46 cases of blood stream infection with Campylobacter in a Danish population with complete follow-up. The incidence was 2.9 per 1 million person-years with a peak incidence in the age group above 80 years. In the population, the ratio of notified bacteraemia/enteritis patients with Campylobacter infection was 0.004. Patients with bacteraemia were older and had higher comorbidity, e.g. alcoholism, immunosuppression, previous gastrointestinal surgery or HIV infection. We found 26% of blood isolates resistant to ciprofloxacin. The length of hospitalization was significantly longer in bacteraemia patients, whereas the outcome was favourable with 28-day mortality of 4% in bacteraemia patients and 1% in enteritis patients. None of the bacteraemia patients relapsed within 365-day follow-up.

Background & Aims: Various commensal enteric and potentially pathogenic bacteria may be involved in the pathogenesis of inflammatory bowel diseases (IBD). We compared the risk of IBD between a cohort of patients with documented Salmonella or Campylobacter gastroenteritis and an age- and gender-matched control group from the same population in Denmark., Methods: We identified 13,324 patients with Salmonella/Campylobacter gastroenteritis from laboratory registries in North Jutland and Aarhus counties, Denmark, from 1991 through 2003, and 26,648 unexposed controls from the same counties. Of these, 176 exposed patients with IBD before the infection, their 352 unexposed controls, and 80 unexposed individuals with IBD before the Salmonella/Campylobacter infection were excluded. The final study cohort of 13,148 exposed and 26,216 unexposed individuals were followed for up to 15 years (mean, 7.5 years)., Results: A first-time diagnosis of IBD was reported in 107 exposed (1.2%) and 73 unexposed individuals (0.5%). By age, gender, and comorbidity adjusted Cox proportional hazards regression analysis, the hazard ratio (95% confidence interval) for IBD was 2.9 (2.2-3.9) for the whole period and 1.9 (1.4-2.6) if the first year after the Salmonella/Campylobacter infection was excluded. The increased risk in exposed subjects was observed throughout the 15-year observation period. The increased risk was similar for Salmonella (n = 6463) and Campylobacter (n = 6685) and for a first-time diagnosis of Crohn's disease (n = 47) and ulcerative colitis (n = 133)., Conclusions: In our population-based cohort study with complete follow-up, an increased risk of IBD was demonstrated in individuals notified in laboratory registries with an episode of Salmonella/Campylobacter gastroenteritis.

We hypothesised that haematological malignancies increase the risk of acquiring zoonotic Salmonella or Campylobacter gastroenteritis. The population-based study comprised all first-time Salmonella/Campylobacter gastroenteritis cases in two Danish counties (1991-2003), with age- and gender-matched controls from the background population. We linked the study cohort to registries to obtain data on malignancies, chemotherapy (yes/no), and main comorbidities diagnosed before Salmonella/Campylobacter gastroenteritis. Based on this design, we determined incidence rate ratios (IRR) in conditional logistic regression analyses, and we used weighted mean regression curves to evaluate fluctuations in risk 0-5 years after the malignancy diagnosis. Sixty-eight of 13,324 cases (0.5%) and 29 of 26,648 controls (0.1%) had haematological malignancy before their Salmonella/Campylobacter gastroenteritis. Comorbidity-adjusted IRR for Salmonella/Campylobacter gastroenteritis in patients with haematological malignancy as compared to patients without malignancy were 4.46 [95% confidence intervals (CI), 2.88-6.90] for all individuals, 8.33 (95% CI, 4.31-16.1) for Salmonella, and 2.17 (95% CI, 1.15-4.08) for Campylobacter. Stratification on chemotherapy treatment did not change these estimates. In time-related analyses, IRR were 7-8 in the first 2 years after the haematological malignancy diagnosis and 4-5 in the following 3 years. Patients with haematological malignancy had increased long-term risk of enquiring Salmonella or Campylobacter gastroenteritis.

Campylobacter jejuni is a frequent cause of bacterial gastroenteritis. Often it causes self-limiting disease but severe or prolonged cases may require antimicrobial treatment. The agricultural use of antimicrobial agents selects for resistance among C. jejuni which is transmitted to humans via food. In Denmark, the use of fluoroquinolones in animal husbandry has been restricted since 2003. The purpose of the present study was to look at trends in occurrence of resistance among C. jejuni from broiler chickens, broiler chicken meat and human domestically acquired or travel associated cases. From 1997 through 2007, C. jejuni isolates were obtained from The Danish Integrated Antimicrobial Resistance Monitoring and Research Programme (DANMAP) and susceptibility tested for ciprofloxacin, erythromycin, nalidixic acid, and tetracycline. Erythromycin resistance was at a low level in all the reservoirs during the study period. Resistance to ciprofloxacin, nalidixic acid and tetracycline was significantly higher in C. jejuni from imported broiler chicken meat compared to Danish broiler chicken meat. In domestically acquired human C. jejuni isolates, resistance to ciprofloxacin and nalidixic acid was for most years significantly higher compared to the level found in isolates from Danish broiler chicken meat, whereas the resistance level was similar to the level found in isolates from imported broiler chicken meat. Imported broiler chicken meat may therefore contribute to the high level of ciprofloxacin and nalidixic acid resistance in C. jejuni isolates from domestically acquired human infections. In 2006 and 2007, the occurrence of resistance to ciprofloxacin, nalidixic acid and tetracycline was significantly higher in travel associated C. jejuni isolates compared to isolates acquired domestically. Even though the use of fluoroquinolones is restricted for animal use in Denmark, Danes are still often infected by fluoroquinolone resistant C. jejuni from imported chicken meat or by travelling.

We hypothesized that patients coinfected with zoonotic Salmonella and Campylobacter were frailer than monoinfected Salmonella or Campylobacter patients. The study cohort included all first-time Salmonella/Campylobacter infections in Aarhus and North Jutland counties, Denmark, from 1991 through 2003. Data on comorbidity, hospitalization in relation to the Salmonella/Campylobacter infection, and 1-year mortality were obtained from electronic registries. Among 13,449 individuals, 114 (0.85%) had Salmonella/Campylobacter coinfection, 6567 (48.8%) had Salmonella monoinfection, and 6768 (50.3%) had Campylobacter monoinfection. There were no major differences in age, gender, comorbidity, hospitalization rates, 1-year mortality, or seasonal variation between coinfected patients on the one hand and each of the monoinfected patient groups on the other. The main difference was encountered between the Salmonella serotype distribution as 49.1% of coinfected patients versus 20.3% of monoinfected Salmonella patients had Salmonella serotypes other than Salmonella Enteritidis and Salmonella Typhimurium (odds ratio [95% confidence interval]: 4.07 [2.73-6.06]). In conclusion, Salmonella/Campylobacter coinfected patients were not frailer than monoinfected patients. The difference in Salmonella serotype distribution was compatible with a higher proportion of coinfections acquired during foreign travel.

Objectives: To evaluate the impact of age and comorbidity on the risk and prognosis of zoonotic Salmonella and Campylobacter gastroenteritis in elderly individuals., Methods: Registry-based study comprising all first-time zoonotic Salmonella/Campylobacter gastroenteritis infections in two Danish counties from 1991 through 2003. Cases were elderly (>or=65 years) Salmonella/Campylobacter patients. Younger Salmonella/Campylobacter patients and age and gender matched individuals were reference persons., Results: There were 13,324 Salmonella/Campylobacter patients (including 1226 elderly patients) and 26,648 matched reference persons. Elderly Salmonella/Campylobacter patients had more comorbidity than their matched reference persons (OR [95% CI]: 1.56 [1.35-1.80]) and comorbidity adjusted mortality rate ratios (95% CI) were 11.4 (5.1-25.4), 1.9 (1.4-2.6), and 1.3 (0.9-1.9) at day 0-30, 31-180, and 181-365, respectively. The differences in crude 365-day mortality increased with age when Salmonella/Campylobacter patients and reference persons without comorbidity were compared. The independent impact of age was less clear for individuals with comorbidity. There were no differences in comorbidity or survival between non-hospitalized elderly patients and their matched reference persons., Conclusions: Elderly hospitalized Salmonella/Campylobacter patients had higher comorbidity and 1-year mortality than the background population. The excess 30-day mortality elucidated the prognostic role of the Salmonella/Campylobacter infection per se.

Preliminary case reports have suggested an association between Campylobacter jejuni infection and occurrence of perimyocarditis. In the present study we analysed the incidence of perimyocarditis requiring hospitalization in a Danish cohort of 6,204 patients with Campylobacter-positive stool cultures and compared it to the incidence in a matched control cohort comprising 62,040 subjects. We found no cases of pericarditis in the Campylobacter population and an incidence rate of 3.2 [95% confidence interval (CI): 0.8-12.9] per 100,000 person-years in the control population. The incidence rate of myocarditis was 16.1 (95% CI: 2.3-114.4) per 100,000 person-years in the Campylobacter population compared to 1.6 (95% CI: 0.2-11.4) per 100,000 person-years in the control cohort. We found no statistically significant difference in perimyocarditis between the two groups.