Associations between blood cultures after surgery for colorectal cancer and long-term oncological outcomes.

BACKGROUND: Systemic inflammation following curative surgery for colorectal cancer may be associated with increased risk of recurrence. [Correction added on 29 November 2019, after first online publication: text amended for accuracy.] This study investigated whether a clinically suspected infection, for which blood cultures were sent within 30 days after surgery for colorectal cancer, was associated with long-term oncological outcomes. METHODS: This register-based national cohort study included all Danish residents undergoing surgery with curative intent for colorectal cancer between January 2003 and December 2013. Patients who developed recurrence or died within 180 days after surgery were not included. Associations between blood cultures taken within 30 days after primary surgery and overall survival, disease-free survival and recurrence-free survival were analysed using Cox regression models adjusted for relevant clinical confounders, including demographic data, cancer stage, co-morbidity, blood transfusion, postoperative complications and adjuvant chemotherapy. RESULTS: The study included 21 349 patients, of whom 3390 (15·9 per cent) had blood cultures taken within 30 days after surgery. Median follow-up was 5·6 years. Patients who had blood cultures taken had an increased risk of all-cause mortality (hazard ratio (HR) 1·27, 95 per cent c.i. 1·20 to 1·35; P < 0·001), poorer disease-free survival (HR 1·22, 1·16 to 1·29; P < 0·001) and higher risk of recurrence (HR 1·15, 1·07 to 1·23; P < 0·001) than patients who did not have blood cultures taken. CONCLUSION: A clinically suspected infection requiring blood cultures within 30 days of surgery for colorectal cancer was associated with poorer oncological outcomes.

ANTECEDENTES: La inflamación sistémica en el cáncer colorrectal puede asociarse con un aumento del riesgo de recidiva. En este estudio se investigó si la sospecha clínica de infección, en la que se obtuvieron cultivos de sangre periférica durante los primeros 30 días de la cirugía por cáncer colorrectal, se asociaba con los resultados oncológicos a largo plazo. MÉTODOS: Se trata de un estudio de cohortes de un registro de una base de datos nacional, que incluyía todos los sujetos residentes en Dinamarca sometidos a cirugía por cáncer colorrectal con intención curativa desde enero de 2003 a diciembre de 2013. Los pacientes con recidiva o que fallecieron durante los primeros 180 días después de la cirugía fueron excluidos. Se estimaron las asociaciones entre los cultivos de sangre periférica efectuados en los primeros 30 días tras la cirugía primaria y la supervivencia global, supervivencia libre de enfermedad y supervivencia libre de recidiva mediante modelos de regresión de Cox, ajustados por variables clínicas confusoras relevantes (incluyendo datos demográficos, estadio del cáncer, comorbilidad, transfusión de sangre, complicaciones postoperatorias y quimioterapia adyuvante). RESULTADOS: El estudio incluyó 21.349 pacientes, de los cuales en 3.390 (16%) se habían obtenido cultivos de sangre periférica durante los primeros 30 días tras la cirugía. La mediana de seguimiento fue de 5,6 años. Los pacientes en los que se había obtenido cultivos de sangre periférica presentaron un riesgo aumentado de mortalidad por cualquier causa (cociente de riesgos instantáneos, hazard ratio, HR 1,27, i.c. del 95% 1,20-1,35; P < 0.0001), peor supervivencia libre de enfermedad (HR 1,22, i.c. del 95% 1,16-1,29; P < 0,0001) y mayor riesgo de recidiva (HR 1,15, i.c. del 95% 1,07-1,23; P < 0,0001) que los pacientes en los que no se habían obtenido cultivos. CONCLUSIÓN: La presencia de una infección sospechada clínicamente para la cual se requiere obtener cultivos de sangre periférica en los primeros 30 días tras cirugía por cancer colorrectal se asoció con peores resultados oncológicos.

Associations between functional polymorphisms and response to biological treatment in Danish patients with psoriasis.

Biological agents including anti-tumor necrosis factor (anti-TNF; adalimumab, infliximab, etanercept) and anti-interleukin-12/13 (IL12/23; ustekinumab) are essential for treatment of patients with severe psoriasis. However, a significant proportion of the patients do not respond to a specific treatment. Pharmacogenetics might be a way to predict treatment response. Using a candidate gene approach, 62 mainly functional single-nucleotide polymorphisms (SNPs) in 44 different genes were evaluated in 478 Danish patients with psoriasis undergoing 376 series of anti-TNF treatment and 230 series of ustekinumab treatment. Associations between genetic variants and treatment outcomes (drug survival and Psoriasis Area Severity Index reduction) were assessed using logistic regression analyses (crude and adjusted for gender, age, psoriatic arthritis and previous treatment). After correction for multiple testing controlling the false discovery rate, six SNPs (IL1B (rs1143623, rs1143627), LY96 (rs11465996), TLR2 (rs11938228, rs4696480) and TLR9 (rs352139)) were associated with response to anti-TNF treatment and 4 SNPs (IL1B (rs1143623, rs1143627), TIRAP (rs8177374) and TLR5 (rs5744174)) were associated with response to ustekinumab treatment (q<0.20). The results suggest that genetic variants related to increased IL-1ß levels may be unfavorable when treating psoriasis with either anti-TNF or ustekinumab, whereas genetic variants related to high interferon-γ levels may be favorable when treating psoriasis with ustekinumab.

The diagnostic accuracy of serological tests for Lyme borreliosis in Europe: a systematic review and meta-analysis.

BACKGROUND: Interpretation of serological assays in Lyme borreliosis requires an understanding of the clinical indications and the limitations of the currently available tests. We therefore systematically reviewed the accuracy of serological tests for the diagnosis of Lyme borreliosis in Europe. METHODS: We searched EMBASE en MEDLINE and contacted experts. Studies evaluating the diagnostic accuracy of serological assays for Lyme borreliosis in Europe were eligible. Study selection and data-extraction were done by two authors independently. We assessed study quality using the QUADAS-2 checklist. We used a hierarchical summary ROC meta-regression method for the meta-analyses. Potential sources of heterogeneity were test-type, commercial or in-house, Ig-type, antigen type and study quality. These were added as covariates to the model, to assess their effect on test accuracy. RESULTS: Seventy-eight studies evaluating an Enzyme-Linked ImmunoSorbent assay (ELISA) or an immunoblot assay against a reference standard of clinical criteria were included. None of the studies had low risk of bias for all QUADAS-2 domains. Sensitivity was highly heterogeneous, with summary estimates: erythema migrans 50% (95% CI 40% to 61%); neuroborreliosis 77% (95% CI 67% to 85%); acrodermatitis chronica atrophicans 97% (95% CI 94% to 99%); unspecified Lyme borreliosis 73% (95% CI 53% to 87%). Specificity was around 95% in studies with healthy controls, but around 80% in cross-sectional studies. Two-tiered algorithms or antibody indices did not outperform single test approaches. CONCLUSIONS: The observed heterogeneity and risk of bias complicate the extrapolation of our results to clinical practice. The usefulness of the serological tests for Lyme disease depends on the pre-test probability and subsequent predictive values in the setting where the tests are being used. Future diagnostic accuracy studies should be prospectively planned cross-sectional studies, done in settings where the test will be used in practice.

Diagnosis of Clostridium difficile: real-time PCR detection of toxin genes in faecal samples is more sensitive compared to toxigenic culture.

The diagnosis of Clostridium difficile infection (CDI) requires the detection of toxigenic C. difficile or its toxins and a clinical assessment. We evaluated the performance of four nucleic acid amplification tests (NAATs) detecting toxigenic C. difficile directly from faeces compared to routine toxigenic culture. In total, 300 faecal samples from Danish hospitalised patients with diarrhoea were included consecutively. Culture was performed in duplicate (routine and 'expanded toxigenic culture': prolonged and/or re-culture) and genotypic toxin profiling by polymerase chain reaction (PCR), PCR ribotyping and toxinotyping (TT) were performed on culture-positive samples. In parallel, the samples were analysed by four NAATs; two targeting tcdA or tcdB (illumigene C. difficile and PCRFast C. difficile A/B) and two multi-target real-time (RT) PCR assays also targeting cdt and tcdC alleles characteristic of epidemic and potentially more virulent PCR ribotypes 027, 066 and 078 (GeneXpert C. difficile/Epi and an 'in-house RT PCR' two-step algorithm). The multi-target assays were significantly more sensitive compared to routine toxigenic culture (p < 0.05) and significantly more robust to inhibition compared to PCRFast (p < 0.001). Duplicate 'expanded toxigenic culture' increased the culture-positive rate by 29% compared to routine culture. The ability of the GeneXpert and in-house assays to correctly classify PCR ribotype 027 was high (>95%), and in-house PCR displayed 100% correct identification of PCR ribotypes 066 and 078. Furthermore, the presence of the PCR enhancer bovine serum albumin (BSA) was found to be related to high sensitivity and low inhibition rate. Rapid laboratory diagnosis of toxigenic C. difficile by RT PCR was accurate.

Improving national surveillance of Lyme neuroborreliosis in Denmark through electronic reporting of specific antibody index testing from 2010 to 2012.

Our aim was to evaluate the results of automated surveillance of Lyme neuroborreliosis (LNB) in Denmark using the national microbiology database (MiBa), and to describe the epidemiology of laboratory-confirmed LNB at a national level. MiBa-based surveillance includes electronic transfer of laboratory results, in contrast to the statutory surveillance based on manually processed notifications. Antibody index (AI) testing is the recommend laboratory test to support the diagnosis of LNB in Denmark. In the period from 2010 to 2012, 217 clinical cases of LNB were notified to the statutory surveillance system, while 533 cases were reported AI positive by the MiBa system. Thirty-five unconfirmed cases (29 AI-negative and 6 not tested) were notified, but not captured by MiBa. Using MiBa, the number of reported cases was increased almost 2.5 times. Furthermore, the reporting was timelier (median lag time: 6 vs 58 days). Average annual incidence of AI-confirmed LNB in Denmark was 3.2/100,000 population and incidences stratified by municipality ranged from none to above 10/100,000. This is the first study reporting nationwide incidence of LNB using objective laboratory criteria. Laboratory-based surveillance with electronic data-transfer was more accurate, complete and timely compared to the surveillance based on manually processed notifications. We propose using AI test results for LNB surveillance instead of clinical reporting.

Does Alzheimer's disease with early onset progress faster than with late onset? A case-control study of clinical progression and cerebrospinal fluid biomarkers.

BACKGROUND: Early-onset Alzheimer's disease (EOAD) is generally thought to have a more rapid course compared to late-onset Alzheimer's disease (LOAD). The faster progression of EOAD observed in some studies has also been thought to correlate with cerebrospinal fluid (CSF) biomarkers. Our clinical experience has not been suggestive of any difference in disease progression; therefore, we decided to investigate whether differences in clinical progression and CSF biomarkers between EOAD and LOAD could be demonstrated. METHODS: Case-control study with 42 patients, 21 EOAD and 21 matched LOAD patients. Rates of progression were calculated and these, as well as CSF biomarker levels, were statistically compared. RESULTS: There were no statistically significant differences in clinical progression between the EOAD group and the LOAD group. There was no significant difference in the absolute values of CSF biomarkers, but a tendency towards lower levels of ß-amyloid in patients with EOAD was observed. CONCLUSIONS: Our findings did not converge with results from the majority of previous studies, which have been suggestive of a faster clinical progression in EOAD. Possibly, the very strict algorithm by which our patients were matched explains our findings. However, the findings should be repeated in a larger study population.

Commercial bacterial and fungal broad-range PCR (Micro-Dx™) used on culture-negative specimens from normally sterile sites: diagnostic value and implications for antimicrobial treatment.

The aim of this study was to evaluate the clinical value of partial 16S/18S rRNA gene sequencing with the commercial kit Micro-Dx™ used with the SelectNA™plus instrument on culture-negative samples. A retrospective study of microbiological and clinical data from a 2.5-year period was performed. Assessment of the clinical relevance of the 16S/18S rRNA gene sequencing results was based on evaluation of the results in the clinical context and changes in antimicrobial therapy. Included were 529 samples from 223 patients, representing 251 episodes. In 191 samples (36.1%), bacterial/fungal DNA was detected. Positive results were judged clinically relevant in 79 (31.5%) episodes. Antimicrobial treatment was adjusted according to the 16S/18S rRNA gene sequence analysis result in 42 (16.7%) episodes. The results from 16S/18S rRNA gene sequence analysis were highly clinically relevant. These findings support the use of this analysis in a routine setting.

Pseudomonas aeruginosa and risk of death and exacerbations in patients with chronic obstructive pulmonary disease: an observational cohort study of 22 053 patients.

OBJECTIVES: The role of Pseudomonas aeruginosa in the long-term prognosis of chronic obstructive pulmonary disease (COPD) is unknown. The purpose of this study was to determine whether P. aeruginosa is associated with increased risk of exacerbations or death in patients with COPD. METHODS: This is a multiregional epidemiological study based on complete data on COPD outpatients between 1 January 2010 and 31 October 2017 and corresponding microbiology and national register data. Time-dependent Cox proportional hazards models and propensity matching was used to estimate hospitalization-demanding exacerbations and death after 2 years, separately and in combination. RESULTS: A total of 22 053 COPD outpatients were followed for a median of 1082 days (interquartile-range: 427-1862). P. aeruginosa was present in 905 (4.1%) patients. During 730 days of follow-up, P. aeruginosa strongly and independently predicted an increased risk of hospitalization for exacerbation or all-cause death (HR 2.8, 95%CI 2.2-3.6; p <0.0001) and all-cause death (HR 2.7, 95%CI 2.3-3.4; p <0.0001) in analyses adjusted for known and suspected confounders. The signal remained unchanged in unadjusted analyses as well as propensity-matched subgroup analyses. Among patients 'ever colonized' with P. aeruginosa, the incidence of hospital-demanding exacerbations doubled after the time of the first colonization. CONCLUSIONS: COPD patients in whom P. aeruginosa can be cultured from the airways had a markedly increased risk of exacerbations and death. It is still not clear whether this risk can be reduced by offering patients targeted antipseudomonal antibiotics. A randomized trial is currently recruiting patients to clarify this (ClinicalTrials.gov: NCT03262142).

To test or not to test? Laboratory support for the diagnosis of Lyme borreliosis: a position paper of ESGBOR, the ESCMID study group for Lyme borreliosis.

BACKGROUND: Lyme borreliosis (LB) is a tick-borne infection caused by Borrelia burgdorferi sensu lato. The most frequent clinical manifestations are erythema migrans and Lyme neuroborreliosis. Currently, a large volume of diagnostic testing for LB is reported, whereas the incidence of clinically relevant disease manifestations is low. This indicates overuse of diagnostic testing for LB with implications for patient care and cost-effective health management. AIM: The recommendations provided in this review are intended to support both the clinical diagnosis and initiatives for a more rational use of laboratory testing in patients with clinically suspected LB. SOURCES: This is a narrative review combining various aspects of the clinical and laboratory diagnosis with an educational purpose. The literature search was based on existing systematic reviews, national and international guidelines and supplemented with specific citations. IMPLICATIONS: The main recommendations according to current European case definitions for LB are as follows. Typical erythema migrans should be diagnosed clinically and does not require laboratory testing. The diagnosis of Lyme neuroborreliosis requires laboratory investigation of the spinal fluid including intrathecal antibody production, and the remaining disease manifestations require testing for serum antibodies to B. burgdorferi. Testing individuals with non-specific subjective symptoms is not recommended, because of a low positive predictive value.

Selecting PCR for the Diagnosis of Intestinal Parasitosis: Choice of Targets, Evaluation of In-House Assays, and Comparison with Commercial Kits.

Microscopy of stool samples is a labour-intensive and inaccurate technique for detection of intestinal parasites causing diarrhoea and replacement by PCR is attractive. Almost all cases of diarrhoea induced by parasites over a nine-year period in our laboratory were due to Giardia lamblia, Cryptosporidium species, or Entamoeba histolytica detected by microscopy. We evaluated and selected in-house singleplex real-time PCR (RT-PCR) assays for these pathogens in 99 stool samples from patients suspected of having intestinal parasitosis tested by microscopy. The strategy included a genus-specific PCR assay for C. parvum and C. hominis, with subsequent identification by a PCR that distinguishes between the two species. G. lamblia was detected in five and C. parvum in one out of 68 microscopy-negative samples. The performance of the in-house RT-PCR assays was compared to three commercially available multiplex test (MT-PCR) kit systems in 81 stool samples, collected in 28 microscopy-positive and 27 microscopy-negative samples from individuals suspected of intestinal parasitosis and in 26 samples from individuals without suspicion of parasitic infection. The in-house assays detected parasites in more samples from patients suspected of having parasitosis than did any of the kits. We conclude that commercial kits are targeting relevant parasites, but their performance may vary.

Utilization of blood cultures in Danish hospitals: a population-based descriptive analysis.

This national population-based study was conducted as part of the development of a national automated surveillance system for hospital-acquired bacteraemia and ascertains the utilization of blood cultures (BCs). A primary objective was to understand how local differences may affect interpretation of nationwide surveillance for bacteraemia. From the Danish Microbiology Database, we retrieved all BCs taken between 2010 and 2013 and linked these to admission data from the National Patient Registry. In total, 4 587 295 admissions were registered, and in 11%, at least one BC was taken. Almost 50% of BCs were taken at admission. The chance of having a BC taken declined over the next days but increased after 4 days of admission. Data linkage identified 876 290 days on which at least one BC was taken; 6.4% yielded positive results. Ten species, Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Enterococcus faecium, Enterococcus faecalis, Pseudomonas aeruginosa, Candida albicans, Enterobacter cloacae and Klebsiella oxytoca, accounted for 74.7% of agents for this purpose classified as pathogenic. An increase in BCs and positive BCs was observed over time, particularly among older patients. BCs showed a seasonal pattern overall and for S. pneumoniae particularly. A predominance of male patients was seen for bacteraemias due to S. aureus, E. faecium and K. pneumoniae. Minor differences in BCs and positive BCs between departments of clinical microbiology underpin the rationale of a future automated surveillance for bacteraemia. The study also provides important knowledge for interpretation of surveillance of invasive infections more generally.

Polymerase chain reaction as a rapid diagnostic assay for cytomegalovirus infection in renal transplant patients.

The aim of this study was to apply a polymerase chain reaction for diagnosis of CMV infection and determine its clinical value in renal transplant recipients. We have applied the PCR to urine and blood specimens collected from 27 renal transplant recipients as well as blood from 49 normal blood donors. Ten of twenty-seven patients, compared to 3 of 49 normal blood donors, had CMV-DNA present in one or more samples. Six of the ten CMV-DNA-positive patients had positive CMV serology, and 3 of the 10 had severe clinical symptoms of active CMV infection. In four additional patients with positive CMV serology - but without clinical signs of active CMV infection - no CMV-DNA could be detected by the PCR. In the three patients with severe symptoms, PCR could detect CMV-DNA before serology became positive, and in one of these three patients, serology remained negative despite the patient's death from clinically obvious CMV pneumonia. PCR thus appears capable of detecting active CMV infection at a time when CMV serology is inconclusive, but cannot substitute for serology as the only routine analysis since a transient viraemia might be missed. However, in immunosuppressed patients with severe CMV infection, PCR could provide an early diagnosis, enabling the clinician to implement early specific treatment.

[Respiratory syncytial virus infection. A frequent child disease in Denmark with annual outbreaks]. / Respiratorisk syncytial virus infektion. En hyppig børnesygdom i Danmark med årlige epidemier.

Infection with respiratory syncytial virus (RSV) is an important cause of illness in infants often leading to hospital admission during the winter months. Diagnosis of RSV by direct detection of virus antigen has been implemented in a number of departments of clinical microbiology, and on this background a descriptive study of the seasonal incidence, sex and age distribution of RSV in two Danish counties was undertaken. A total of 5533 clinical episodes of respiratory infection were registered from October 1988 to September 1992 in the two counties and 1421 (26%) were positive for RSV. The incidence of hospital admission for RSV infection was 14 per 1000 below three years of age in Copenhagen County in the winter season 1991-1992. The seasonal peak of RSV infection was postponed about one month in Northern Jutland as compared to the capital area. Only 10 episodes (three positive) were from primary care, the remainder from hospitals and other institutions. RSV-testing was rarely requested in general practice. The study confirmed the importance of RSV infection in young children admitted with lower respiratory tract infection. We recommend the establishment of a surveillance system incorporating the local departments of clinical microbiology for warning of the yearly epidemics during which RSV infections may also be a risk outside the paediatric age span.

[Psychogenic polydipsia: pronounced cerebral edema after exaggerated consumption of boiled water]. / Psykogen polydipsi: Udtalt cerebralt ødem efter overdreven indtagelse af kogt vand.

A case of psychogenic polydipsia is presented. A 40 year old female was brought to the emergency room after a sudden seizure at home. The patient had spontaneous eye opening, was making incomprehensible sounds and had abnormal and agitated flexion of the limbs. Severe cerebral edema was seen on the computed tomogram. The patient was found to have hypotonic polyuria and hyponatremia. Two months previously, the patient had stopped taking bromazepam (a benzodiazepine) and on the advice of a neighbour had taken plenty of water to avoid withdrawal symptoms. The diagnosis and therapy are discussed.

[Ampicillin-resistant Haemophilus influenzae. Prevalence in isolates from Danish children]. / Ampicillinresistente Haemophilus influenzae. Forekomst i isolater fra danske børn.

The prevalence of ampicillin-resistance was assessed among a total of 2766 strains of H. influenzae isolated from lower respiratory tract secretions, middle ear secretions, spinal fluid specimens, and blood cultures from children 0-15 years of age tested in two separate counties in Denmark during the period from 1986 to May, 1993. All strains were tested for susceptibility to ampicillin with disc or tablet diffusion technique and strains were examined for beta-lactamase production with a chromogenic cephalosporinase test. In the county of Northern Jutland the rate of beta-lactamase production in non-encapsulated H. influenzae was 2.5% in 1986 rising to 9.3% in 1993. The rate of beta-lactamase production in H. influenzae type b was 4.1% without any rise. In the county of Copenhagen the rate of beta-lactamase production in non-encapsulated H. influenzae rose from 6.3% in 1986 to 10.6% in 1992. In 1993 a further increase to 20.7% was noticed. This year the number of specimens sent to the laboratory and the number of H. influenzae isolated were lower compared to previous years. Thus a different selection of patients may explain the increase in the rate of beta-lactamase production in 1993. The rate of beta-lactamase production in H. influenzae type b was 8.5%. No strains were resistant to ampicillin in diffusion test other than the beta-lactamase producers.

[Reproducibility of a rapid test for HIV antibody]. / Reproducerbarheden af hurtigtest for HIV-antistoffer.

This study evaluated three rapid test kits for HIV antibody detection. Thirty consecutive blood specimens from the infectious diseases outpatient clinic were examined by three house officers who tested each specimen twice in a blind and randomized experiment. HIV-Chek (Du Pont) and HIV-1/HIV-2 TestPack (Abbott) were easy to handle and gave good intra- and interobserver agreement and good agreement with routine ELISA. Recombigen (BioScience) was difficult to interpret and gave poorer intra- and inter-observer variation. We suggest that HIV-Chek and TestPack can be used for assessment of patients' HIV antibody status in emergency circumstances with only minimal instruction of the staff.