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3.  Irritable Bowel Syndrome and Chronic Fatigue 6 Years After Giardia Infection: A Controlled Prospective Cohort Study 
Giardia infection in a nonendemic setting is associated with an increased risk for irritable bowel syndrome and chronic fatigue 6 years later. These conditions should be considered a differential diagnosis in patients with persisting symptoms after eradication of the parasite.
Background. Functional gastrointestinal disorders and fatigue may follow acute infections. This study aimed to estimate the persistence, prevalence, and risk of irritable bowel syndrome and chronic fatigue 6 years after Giardia infection.
Methods. We performed a controlled prospective study of a cohort of 1252 individuals who had laboratory-confirmed Giardia infection during a waterborne outbreak in 2004. In total, 748 cohort cases (exposed) and 878 matched controls responded to a postal questionnaire 6 years later (in 2010). Responses were compared to data from the same cohort 3 years before (in 2007).
Results. The prevalences of irritable bowel syndrome (39.4%) by Rome III criteria and chronic fatigue (30.8%) in the exposed group 6 years after giardiasis were significantly elevated compared with controls, with adjusted relative risks (RRs) of 3.4 (95% confidence interval [CI], 2.9–3.9) and 2.9 (95% CI, 2.3–3.4), respectively. In the exposed group, the prevalence of irritable bowel syndrome decreased by 6.7% (RR, 0.85 [95% CI, .77–.93]), whereas the prevalence of chronic fatigue decreased by 15.3% from 3 to 6 years after Giardia infection (RR, 0.69 [95% CI, .62–.77]). Giardia exposure was a significant risk factor for persistence of both conditions, and increasing age was a risk factor for persisting chronic fatigue.
Conclusions. Giardia infection in a nonendemic setting is associated with an increased risk for irritable bowel syndrome and chronic fatigue 6 years later. The prevalences of both conditions decrease over time, indicating that this intestinal protozoan parasite may elicit very long-term, but slowly self-limiting, complications.
PMCID: PMC4207419  PMID: 25115874
Giardia; irritable bowel syndrome; chronic fatigue; postinfectious
4.  A Novel Fibrosis Index Comprising a Non-Cholesterol Sterol Accurately Predicts HCV-Related Liver Cirrhosis 
PLoS ONE  2014;9(4):e93601.
Diagnosis of liver cirrhosis is essential in the management of chronic hepatitis C virus (HCV) infection. Liver biopsy is invasive and thus entails a risk of complications as well as a potential risk of sampling error. Therefore, non-invasive diagnostic tools are preferential. The aim of the present study was to create a model for accurate prediction of liver cirrhosis based on patient characteristics and biomarkers of liver fibrosis, including a panel of non-cholesterol sterols reflecting cholesterol synthesis and absorption and secretion. We evaluated variables with potential predictive significance for liver fibrosis in 278 patients originally included in a multicenter phase III treatment trial for chronic HCV infection. A stepwise multivariate logistic model selection was performed with liver cirrhosis, defined as Ishak fibrosis stage 5–6, as the outcome variable. A new index, referred to as Nordic Liver Index (NoLI) in the paper, was based on the model: Log-odds (predicting cirrhosis) = −12.17+ (age×0.11) + (BMI (kg/m2)×0.23) + (D7-lathosterol (μg/100 mg cholesterol)×(−0.013)) + (Platelet count (x109/L)×(−0.018)) + (Prothrombin-INR×3.69). The area under the ROC curve (AUROC) for prediction of cirrhosis was 0.91 (95% CI 0.86–0.96). The index was validated in a separate cohort of 83 patients and the AUROC for this cohort was similar (0.90; 95% CI: 0.82–0.98). In conclusion, the new index may complement other methods in diagnosing cirrhosis in patients with chronic HCV infection.
PMCID: PMC3974766  PMID: 24699777
5.  Fever in the tropics: aetiology and case-fatality - a prospective observational study in a tertiary care hospital in South India 
BMC Infectious Diseases  2013;13:355.
The objective of this study was to describe aetiology and case fatality of fever among inpatients in a tertiary care hospital in South India.
This was an observational, prospective study conducted in a tertiary care hospital in Vellore, Tamil Nadu, India. Between July 2nd 2007 and August 2nd in 2007, adult patients admitted to the hospital with temperature ≥ 38.0°C were included consecutively and followed during the hospitalisation period. Demographic and clinical data were collected and analysed for each patient. Associations were sought between death and various clinical and demographic variables.
One hundred patients were included, 61 male and 39 female. Mean age was 37.5 (range: 16 to 84) years. Mean fever duration was 5.4 (range: 0.1 to 42.9) weeks.
The following infectious aetiologies were recorded: tuberculosis (19%), lower respiratory infection (11%) including three with sepsis, urinary tract infection (10%) including three with E. coli sepsis, Plasmodium falciparum malaria (5%) including three patients with mixed P. vivax infection, scrub typhus (5%), typhoid fever (4%), cryptococcal meningitis (4%) including three HIV positive patients, endocarditis (3%) including two patients with Staphylococcus aureus sepsis, spleen abscess (2%), amoebic liver abscess (2%), sepsis undefined focus (1%), HIV infection (1%), hepatitis B (1%), rubella (1%), peritonitis (1%) and cholecystitis (1%).
Non-infectious causes of fever were diagnosed in 15%, including systemic lupus erythematosus in four and malignancy in six patients. Cause of fever remained unknown in 13%.
Case fatality during hospitalisation was 7% (7/100). Six of those who died were male. Five fatalities had bacterial sepsis, one spleen abscess and malignancy, and one had lymphomalignant disorder.
Diabetes and increasing age were significant risk factors for fatal outcome in unadjusted analyses, but only increasing age was a risk factor for death in adjusted analysis.
A high number of tuberculosis and bacterial infections and a high case fatality rate from sepsis were found in this cohort, underlining the importance of microbiological diagnostics and targeted antimicrobial treatment in the management of fever. P. falciparum was identified in all malaria cases, and this rapidly fatal infection should be considered in patients with acute undifferentiated fever in India.
PMCID: PMC3750507  PMID: 23899336
Fever; Aetiology; Tropics; Case-fatality; Sepsis; Malaria; Tuberculosis
6.  Chronic fatigue syndrome 5 years after giardiasis: differential diagnoses, characteristics and natural course 
BMC Gastroenterology  2013;13:28.
A high prevalence of chronic fatigue has previously been reported following giardiasis after a large waterborne outbreak in Bergen, Norway in 2004. The aim of this study was to describe and evaluate differential diagnoses and natural course of fatigue five years after giardiasis among patients who reported chronic fatigue three years after the infection.
Patients who three years after Giardia infection met Chalder’s criteria for chronic fatigue (n=347) in a questionnaire study among all patients who had laboratory confirmed giardiasis during the Bergen outbreak (n=1252) were invited to participate in this study five years after the infection (n=253). Structured interviews and clinical examination were performed by specialists in psychiatry, neurology and internal medicine/infectious diseases. Fukuda et al’s 1994 criteria were used to diagnose chronic fatigue syndrome (CFS) and idiopathic chronic fatigue (ICF). Self-reported fatigue recorded with Chalder Fatigue Questionnaire three and five years after infection were compared.
53 patients were included. CFS was diagnosed in 41.5% (22/53) and ICF in 13.2% (7/53). Chronic fatigue caused by other aetiology was diagnosed in 24.5% (13/53); five of these patients had sleep apnoea/hypopnoea syndrome, six had depression and five anxiety disorder, and among these two had more than one diagnosis. Fatigue had resolved in 20.8% (11/53). Self-reported fatigue score in the cohort was significantly reduced at five years compared to three years (p<0.001).
The study shows that Giardia duodenalis may induce CFS persisting as long as five years after the infection. Obstructive sleep apnoea/hypopnoea syndrome, depression and anxiety were important differential diagnoses, or possibly comorbidities, to post-infectious fatigue in this study. Improvement of chronic fatigue in the period from three to five years after giardiasis was found.
PMCID: PMC3598369  PMID: 23399438
Giardia; Chronic fatigue syndrome; Depression; Anxiety; Sleep apnoea hypopnea syndrome
7.  A novel, single-amplification PCR targeting mitochondrial genome highly sensitive and specific in diagnosing malaria among returned travellers in Bergen, Norway 
Malaria Journal  2013;12:26.
Nested PCR is a commonly used technique in diagnosis of malaria owing to its high sensitivity and specificity. However, it is time-consuming, open to considerable risk of contamination and has low cost-efficiency. Using amplification targets presented in multiple copies, such as rRNA 18S, or mitochondrial targets with an even higher copy number, might increase sensitivity.
The sensitivity and specificity of two newly designed Plasmodium genus-specific single-round amplification PCR programmes, based on previously published primers targeting 18S and mitochondrial genome, were compared with a widely used nested 18S PCR. Analyses of dilution series from Plasmodium falciparum reference material were performed, as well as retrospective analyses of 135 blood samples, evaluated by routine microscopy, from 132 fever patients with potential imported malaria. Sequencing of the 220 bp mitochondrial PCR products was performed.
At the threshold dilution 0.5 parasites/μl, the sensitivity of the mitochondrial PCR was 97% (29/30 parallels), that of the single-round 18S PCR 93% and the reference nested 18S PCR 87%. All three assays detected as low as 0.05 p/μl, though not consistently. In the patient cohort, malaria was diagnosed in 21% (28/135) samples, defined as positive by at least two methods. Both single-round amplification assays identified all malaria positives diagnosed by nested PCR that had sensitivity of 96% (27/28). The mitochondrial PCR detected one additional sample, also positive by microscopy, and was the only method with 100% sensitivity (28/28). The sensitivity and specificity of the mitochondrial PCR were statistically non-inferior to that of the reference nested PCR. Microscopy missed two infections detected by all PCR assays. Sequencing of the genus-specific mitochondrial PCR products revealed different single nucleotide polymorphisms which allowed species identification of the 28 sequences with following distribution; 20 P. falciparum, six Plasmodium vivax, one Plasmodium ovale and one Plasmodium malariae.
In this study, design of PCR programmes with suitable parameters and optimization resulted in simpler and faster single-round amplification assays. Both sensitivity and specificity of the novel mitochondrial PCR was 100% and proved non-inferior to that of the reference nested PCR. Sequencing of genus-specific mitochondrial PCR products could be used for species determination.
PMCID: PMC3556099  PMID: 23336125
Malaria; Diagnostics; PCR; Amplification; Sequencing; Mitochondrial DNA; 18S; Sensitivity; Gametocytes; Returned travellers
9.  Immunophenotyping in post-giardiasis functional gastrointestinal disease and chronic fatigue syndrome 
BMC Infectious Diseases  2012;12:258.
A Giardia outbreak was associated with development of post-infectious functional gastrointestinal disorders (PI-FGID) and chronic fatigue syndrome (PI-CFS). Markers of immune dysfunction have given conflicting results in CFS and FGID patient populations. The aim of this study was to evaluate a wide selection of markers of immune dysfunction in these two co-occurring post-infectious syndromes.
48 patients, reporting chronic fatigue in a questionnaire study, were clinically evaluated five years after the outbreak and grouped according to Fukuda criteria for CFS (n=19) and idiopathic chronic fatigue (n=5) and Rome II criteria for FGIDs (n=54). 22 Giardia exposed non-fatigued individuals and 10 healthy unexposed individuals were recruited as controls. Peripheral blood lymphocyte subsets were analyzed by flow cytometry.
In peripheral blood we found significantly higher CD8 T-cell levels in PI-FGID, and significantly lower NK-cell levels in PI-CFS patients. Severity of abdominal and fatigue symptoms correlated negatively with NK-cell levels. A tendency towards lower T-cell CD26 expression in FGID was seen.
Patients with PI-CFS and/or PI-FGID 5 years after Giardia lamblia infection showed alterations in NK-cell and CD8-cell populations suggesting a possible immunological abnormality in these conditions. We found no significant changes in other markers examined in this well-defined group of PI-CFS and PI-FGID elicited by a gastrointestinal infection. Controlling for co-morbid conditions is important in evaluation of CFS-biomarkers.
PMCID: PMC3553045  PMID: 23061432
Giardia lamblia; Functional gastrointestinal disorder; Chronic fatigue syndrome; Irritable bowel syndrome; NK-cells; CD8 T-cells
10.  PNPLA 3 I148M genetic variant associates with insulin resistance and baseline viral load in HCV genotype 2 but not in genotype 3 infection 
BMC Medical Genetics  2012;13:82.
Hepatic steatosis in HCV patients has been postulated as a risk factor associated with a higher frequency of fibrosis and cirrhosis. A single genetic variant, PNPLA3 I148M, has been widely associated with increased hepatic steatosis. Previous studies of the PNPLA3 I148M sequence variant in HCV infected individuals have reported an association between this variant and prevalence of steatosis, fibrosis, and cirrhosis. To evaluate the impact of PNPLA3 I148M variant on metabolic traits and treatment response in HCV genotype 2 and 3 infected patients.
Three hundred and eighty-two treatment naïve HCV genotype 2 or 3 infected patients were included in a phase III, open label, randomized, multicenter, investigator-initiated trial (the NORDynamIC study), in which pretreatment liver biopsies were mandatory. PNPLA3I148M genotyping was performed in a total of 359 Caucasian patients.
In HCV genotype 2 infected patients carrying the PNPLA3 148M allele, there was significantly increased insulin resistance (P = 0.023) and lower viral load (P = 0.005) at baseline as well as the first seven days of antiviral treatment. These results were not observed in HCV genotype 3 infected patients.
Our results suggest a possible association between the PNPLA3 148M allele and insulin resistance as well as baseline viral load in HCV genotype 2, but not in genotype 3.
PMCID: PMC3495049  PMID: 22978414
Hepatitis C; PNPLA 3; Insulin resistance; Viral load
11.  Impact of Obesity on the Bioavailability of Peginterferon-α2a and Ribavirin and Treatment Outcome for Chronic Hepatitis C Genotype 2 or 3 
PLoS ONE  2012;7(5):e37521.
Background and Aims
Having a body mass index above or equal to 30 kg/m2 in conjunction with chronic hepatitis C virus infection is associated with non-responsiveness to treatment with interferon and ribavirin, but details regarding the mechanisms whereby obesity reduces the efficacy of therapy remain unclear.
This study evaluated impact of obesity on outcome as well as interferon and ribavirin concentrations following standard-of-care fixed dosing with peginterferon-α2a 180 µg once weekly and ribavirin 800 mg daily among 303 HCV genotype 2/3-infected patients enrolled in the per-protocol analysis of a recently completed phase III trial (NORDynamIC).
Patients with BMI ≥30 kg/m2 showed poorer outcome following 24 weeks of therapy (SVR 62% vs. 89% for BMI ≥30 vs. <30; P = 0.006) along with significantly higher steatosis grade (P = 0.002), HOMA-IR (P<0.0001), triglyceride levels (P = 0.0002), and baseline viral load (P = 0.028). Obesity was also significantly associated with lower plasma interferon concentrations on days 3, 7, and 29 (P = 0.02, P = 0.0017, and P<0.0001, respectively) and lower plasma ribavirin concentrations day 29 (P = 0.025), and lower concentration of interferon in turn was associated with a poorer first phase reduction in HCV RNA (P<0.0001). In multivariate analysis, ribavirin concentrations week 12, interferon concentrations day 29, and baseline HCV RNA levels were independent predictors of achieving SVR among patients treated for 24 weeks (n = 140).
Reduced bioavailability of interferon and ribavirin along with higher baseline viral load are dominant risk factors for treatment failure in obese patients with chronic hepatitis C.
PMCID: PMC3360051  PMID: 22655053
12.  Impact of IL28B-Related Single Nucleotide Polymorphisms on Liver Histopathology in Chronic Hepatitis C Genotype 2 and 3 
PLoS ONE  2012;7(1):e29370.
Background and Aims
Recently, several genome-wide association studies have revealed that single nucleotide polymorphisms (SNPs) in proximity to IL28B predict spontaneous clearance of HCV infection as well as outcome following peginterferon and ribavirin therapy among HCV genotype 1 infected patients. The present study aimed to evaluate the impact of IL28B SNP variability on liver histology in the context of a phase III treatment trial (NORDynamIC) for treatment-naïve patients with chronic HCV genotype 2 or 3 infection, where pretreatment liver biopsies were mandatory.
Three hundred and thirty-nine Caucasian patients had samples available for IL28B genotyping (rs12979860) of whom 314 had pretreatment liver biopsies that were evaluated using the Ishak protocol, allowing for detailed grading and staging of liver histopathology.
IL28B CCrs12979860 genotype in HCV genotype 3 infected patients was associated with higher ALT levels (p<0.0001), higher AST to platelet ratio index (APRI; p = 0.001), and higher baseline viral load (p<0.0001) as compared to patients with the CT or TT genotypes. Additionally the CCrs12979860 genotype entailed more pronounced portal inflammation (p = 0.02) and steatosis (p = 0.03). None of these associations were noted among HCV genotype 2 infected patients.
This study shows that the CCrs12979860 SNP is associated with more pronounced liver histopathology in patients chronically infected with HCV genotype 3, which may be secondary to higher viral load. The finding that IL28B variability did not impact on liver pathology or viral load among genotype 2 infected patients implies that IL28B may differentially regulate the course of genotype 2 and 3 infection.
PMCID: PMC3258245  PMID: 22253715
13.  Intravenous Artesunate for Severe Malaria in Travelers, Europe 
Emerging Infectious Diseases  2011;17(5):771-777.
Multicenter trials in Southeast Asia have shown better survival rates among patients with severe malaria, particularly those with high parasitemia levels, treated with intravenous (IV) artesunate than among those treated with quinine. In Europe, quinine is still the primary treatment for severe malaria. We conducted a retrospective analysis for 25 travelers with severe malaria who returned from malaria-endemic regions and were treated at 7 centers in Europe. All patients survived. Treatment with IV artesunate rapidly reduced parasitemia levels. In 6 patients at 5 treatment centers, a self-limiting episode of unexplained hemolysis occurred after reduction of parasitemia levels. Five patients required a blood transfusion. Patients with posttreatment hemolysis had received higher doses of IV artesunate than patients without hemolysis. IV artesunate was an effective alternative to quinine for treatment of malaria patients in Europe. Patients should be monitored for signs of hemolysis, especially after parasitologic cure.
PMCID: PMC3321768  PMID: 21529383
artesunate; Plasmodium falciparum; parasites; malaria; hemolysis; critical care; travelers; Europe; synopsis
14.  Severity of Giardia infection associated with post-infectious fatigue and abdominal symptoms two years after 
A high rate of post-infectious fatigue and abdominal symptoms two years after a waterborne outbreak of giardiasis in Bergen, Norway in 2004 has previously been reported. The aim of this report was to identify risk factors associated with such manifestations.
All laboratory confirmed cases of giardiasis (n = 1262) during the outbreak in Bergen in 2004 received a postal questionnaire two years after. Degree of post-infectious abdominal symptoms and fatigue, as well as previous abdominal problems, was recorded. In the statistical analyses number of treatment courses, treatment refractory infection, delayed education and sick leave were used as indices of protracted and severe Giardia infection. Age, gender, previous abdominal problems and symptoms during infection were also analysed as possible risk factors. Simple and multiple ordinal logistic regression models were used for the analyses.
The response rate was 81% (1017/1262), 64% were women and median age was 31 years (range 3-93), compared to 61% women and 30 years (range 2-93) among all 1262 cases. Factors in multiple regression analysis significantly associated with abdominal symptoms two years after infection were: More than one treatment course, treatment refractory infection, delayed education, bloating and female gender. Abdominal problems prior to Giardia infection were not associated with post-infectious abdominal symptoms. More than one treatment course, delayed education, sick leave more than 2 weeks, and malaise at the time of infection, were significantly associated with fatigue in the multiple regression analysis, as were increasing age and previous abdominal problems.
Protracted and severe giardiasis seemed to be a risk factor for post-infectious fatigue and abdominal symptoms two years after clearing the Giardia infection.
PMCID: PMC2808308  PMID: 20003489
15.  Severe Malaria and Artesunate Treatment, Norway 
Emerging Infectious Diseases  2008;14(11):1816-1818.
PMCID: PMC2630751  PMID: 18976584
Plasmodium falciparum malaria; artesunate; artemisinin; letter

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