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.

Successful control of a hospital-wide outbreak of OXA-48 producing Enterobacteriaceae in the Netherlands, 2009 to 2011.

On 31 May 2011, after notification of Klebsiella pneumoniae (KP)(OXA-48;CTX-M-15) in two patients, nosocomial transmission was suspected in a Dutch hospital. Hospital-wide infection control measures and an outbreak investigation were initiated. A total of 72,147 patients were categorised into groups based on risk of OXA-48 colonisation or infection, and 7,527 were screened for Enterobacteriaceae(OXA-48) by polymerase chain reaction (PCR). Stored KP isolates (n=408) were retrospectively tested for OXA-48 and CTX-M-1 group extended-spectrum beta-lactamases (ESBL). 285 KP isolates from retrospective and prospective patient screening were genotyped by amplified fragment length polymorphism (AFLP). 41 isolates harbouring different Enterobacteriaceae species were analysed by plasmid multilocus sequence typing (pMLST). No nosocomial transmission of Enterobacteriaceae(OXA-48) was detected after 18 July 2011. Enterobacteriaceae(OXA-48) were found in 118 patients (KP (n=99), Escherichia coli (n=56), ≥1 Enterobacteriaceae(OXA-48) species (n=52)), of whom 21 had clinical infections. 39/41 (95%) of OXA-48 containing plasmids were identical in pMLST. Minimum inhibitory concentrations (MICs) of KP(OXA-48) and E. coli(OXA-48) for imipenem and meropenem ranged from ≤1 to ≥16 mg/L, and 153/157 (97%) had MIC >0.25 mg/L for ertapenem. AFLP identified a cluster of 203 genetically linked isolates (62 KP(OXA-48;CTX-M15); 107 KP(CTX-M-15); 34 KP(OXA-48)). The 'oldest' KP(CTX-M-15) and KP(OXA-48) clonal types originated from February 2009 and September 2010, respectively. The last presumed outbreak-related KP(OXA-48) was detected in April 2012. Uncontrolled transmission of KP(CTX-M-15) evolved into a nosocomial outbreak of KP(OXA-48;CTX-M15) with large phenotypical heterogeneity. Although the outbreak was successfully controlled, the contribution of individual containment measures and of the hospital relocating into a new building just before outbreak notification was impossible to quantify.

A dynamic case definition is warranted for adequate notification in an extended epidemic setting: the Dutch Q fever outbreak 2007-2009 as exemplar.

Q fever is a notifiable disease in the Netherlands:laboratories are obliged to notify possible cases to the Municipal Health Services. These services then try to reconfirm cases with additional clinical and epidemiological data and provide anonymised reports to the national case register of notifiable diseases. Since the start of the 2007­2009 Dutch Q fever outbreak,notification rules remained unchanged, despite new laboratory insights and altered epidemiology. In this study, we retrospectively analysed how these changes influenced the proportion of laboratory-defined acute Q fever cases (confirmed, probable and possible)that were included in the national case register, during(2009) and after the outbreak (2010 and 2011).The number of laboratory-defined cases notified to the Municipal Health Services was 377 in 2009, 96 in 2010 and 50 in 2011. Of these, 186 (49.3%) in 2009, 12(12.5%) in 2010 and 9 (18.0%) in 2011 were confirmed as acute infection by laboratory interpretation. The proportion of laboratory-defined acute Q fever cases that was reconfirmed by the Municipal Health Services and that were included in the national case register decreased from 90% in 2009, to 22% and 24% in 2010 and 2011, respectively. The decrease was observed in all categories of cases, including those considered to be confirmed by laboratory criteria. Continued use ofa pre-outbreak case definition led to over-reporting of cases to the Municipal Health Services in the post-epidemic years. Therefore we recommend dynamic laboratory notification rules, by reviewing case definitions periodically in an ongoing epidemic, as in the Dutch Q fever outbreak.

Shifting priorities in the aftermath of a Q fever epidemic in 2007 to 2009 in The Netherlands: from acute to chronic infection.

From 2007 to 2009, the Netherlands faced large seasonal outbreaks of Q fever, in which infected dairy goat farms were identified as the primary sources. Veterinary measures including vaccination of goats and sheep and culling of pregnant animals on infected farms seem to have brought the Q fever problem under control. However, the epidemic is expected to result in more cases of chronic Q fever among risk groups in the coming years. In the most affected area, in the south of the country, more than 12% of the population now have antibodies against Coxiella burnetii. Questions remain about the follow-up of acute Q fever patients, screening of groups at risk for chronic Q fever, screening of donors of blood and tissue, and human vaccination. There is a considerable ongoing research effort as well as enhanced veterinary and human surveillance.

A Dutch nationwide evaluation of serological assays for detection of Borrelia antibodies in clinically well-defined patients.

Numerous tests for the detection of antibodies against Borrelia burgdorferi are commercially available. Manufacturer-derived data invariably report a high sensitivity and specificity, but comparative studies demonstrate large differences in clinical practice, especially with regard to specificity. We retrospectively collected data from validation studies for B. burgdorferi antibody assays from 8 laboratories in the Netherlands. The total number of samples was 809. Samples were selected based on clinical and laboratory parameters. We included samples from patients with erythema migrans, acrodermatitis chronicum atrophicans, and neuroborreliosis; cross-reactivity controls; and healthy controls. Data are presented from 10 enzyme-linked immunosorbent assays and 5 immunoblots. For manifestations of B. burgdorferi infection with short disease duration, the positivity rate of the assays varied significantly. In patients with long disease duration, the positivity rate differed only marginally. In cross-reactivity controls, there was significant variation in the reactivity rate. The majority of false-positive reactions are of the IgM isotype.

Molecular epidemiology of Haemophilus influenzae type b.

Ninety-five percent of systemic Haemophilus influenzae infections in childhood are caused by serotype b organisms. The high risk for mortality and serious sequelae and the increase in antibiotic resistance of H influenzae type b are strong arguments for vaccination. Incidences and age distribution of disease caused by H influenzae type b vary considerably among countries. Compiled data for meningitis show the highest incidences to be among Alaskan Eskimos, Navajo and White Mountain Indians, and aboriginals in Australia. High incidences coincide with a peak incidence in a younger age group. This differs from Finland, where 95% of the cases of disease caused by H influenzae type b occur in children older than 7 months of age. In general, incidences are low in industrial and high in nonindustrial areas. For example, in Gambia the highest age-specific incidence is at 4 to 5 months after birth (H.A.B., unpublished data, 1988). This implies that a vaccine and regimen similar to that used in Finland would not be as efficacious if used in Gambia because of differences in demographics and incidence. Vaccines that confer protection at 3 to 4 months of age are, therefore, strongly desired. Outer membrane proteins and lipopolysaccharides of H influenzae type b have been suggested as alternative vaccine candidates in conjugation with the capsular polysaccharide because they apparently can contribute to the virulence of H influenzae type b. The occurrence and immunogenicity of various outer membrane proteins and lipopolysaccharides among H influenzae type b in industrial and nonindustrial countries and their significance as epidemiologic markers for the spread of disease, the type of disease, the age of acquisition, and their association with antibiotic resistance will be reviewed in this article.(ABSTRACT TRUNCATED AT 250 WORDS)

Upper respiratory tract infection, heterologous immunisation and meningococcal disease.

To test the hypothesis that an episode of upper respiratory tract infection or heterologous immunisation is a predisposing factor for the occurrence of meningococcal disease, data from 377 cases of meningococcal disease and their household contacts (n = 1124) were analysed by conditional logistic regression analysis with stratification for household. The odds ratio for a recent upper respiratory tract infection for patients versus household contacts, adjusted for age and the presence of an underlying predisposing disease, was 2.8 and that for recent heterologous immunisation 1.0. These results support previous observations regarding the association between a preceding upper respiratory tract infection and the occurrence of meningococcal disease; however, no association was found between preceding heterologous immunisation and meningococcal disease. Therefore, increased alertness after heterologous immunisation does not seem warranted.

Prognostic indicators of the outcome of meningococcal disease: a study of 562 patients.

To assess prognostic indicators of a fatal outcome in patients with meningococcal disease, data from 562 patients with culture-proven meningococcal disease, reported in the Netherlands between 1 April 1989 and 30 April 1990, were collected prospectively by means of a questionnaire completed by the specialist in attendance. Analysis was done by the chi2 test and multiple logistic regression. During the study period 43 patients (7.7%) died. The risk of a fatal outcome was increased in patients aged 0-5 months, 10-19 years, and > or = 50 years, in female patients and in patients presenting with coma, temperature < or = 38.0 degrees C, mean arterial pressure < or = 70 mmHg, white blood cell count < or = 10 x 10(9)/L and platelet count < or = 100 x 10(9)/L. Predisposing factors and duration of disease before admission were significantly associated with outcome, but these associations disappeared in the multivariate analysis. Race, the administration of antibiotics prior to admission, seizures and haemorrhagic skin lesions were not associated with outcome. In conclusion age, gender, coma, temperature, mean arterial pressure, white blood cell count and platelet count were independent prognostic indicators of the outcome of meningococcal disease. The assessment of these characteristics may be helpful for the identification of high risk patients, whose prognosis might be improved by prompt transfer to an intensive care unit.

Carriage of Haemophilus influenzae in healthy Gambian children.

1240 throat samples were processed during different seasons in 11 different communities of The Gambia (West Africa). The carriage rate for Haemophilus influenzae type b ranged from 0 to 33%, but often attained 10% or more, higher than that reported from other open communities. The duration of carriage was short (less than 3 months) and H. influenzae b was found in only 10% of the carriers isolated during the previous or the following survey. Children less than 5 years old carried H. influenzae b in their throat significantly more often than children older than 14 years (P less than 0.05). A high carriage rate did not correlate with the wet or dry season. The carriage rate of children in rural areas was similar to that of children in urban areas. Children in day-care centres or nurseries had a surprisingly low carriage rate (2%). The carriage rate of H. influenzae b was compared to the presence of H. influenzae subspecies in a random sample, which revealed that H. influenzae subspecies was found in 90% of the children under 5 years old. Encapsulated strains of H. influenzae were found in 25% of the same sample, two-thirds of which were not type b. All capsule types were represented. No meningitis cases occurred in the survey populations. We conclude that the prevalence of H. influenzae b in open Gambian communities is similar to that in closed communities elsewhere, but that the kinetics are different from those in closed communities, as persistence of infection in Gambian children is short-lived.

[Secondary cases of meningococcal disease in The Netherlands, 1989-1990; a reappraisal of chemoprophylaxis]. / Secundaire gevallen van meningokokkenziekte in Nederland, 1989-1990; chemoprofylaxe opnieuw bezien.

OBJECTIVE: To assess the secondary attack rate (SAR) of meningococcal disease among the household contacts of primary patients and to describe the use of chemoprophylaxis in the Netherlands. DESIGN: Descriptive, nation-wide survey. METHODS: Information was collected of patients with meningococcal disease, reported between April 1st, 1989 and April 30th, 1990, and their household contacts. A household contact suffering from meningococcal disease between 24 hours and 1 month after hospital admission of the primary patient, was considered to be a secondary case. Chemoprophylaxis was considered appropriate if rifampicin or minocycline had been prescribed to all household contacts within a maximum of one day after admission of the primary patient. RESULTS: There were 5 secondary cases (SAR: 0.3%). Chemoprophylaxis was prescribed to 627 of 1130 household contacts (55%). Of those the prophylaxis was considered appropriate in 46%. 2 secondary cases were not given any prophylaxis, 2 received penicillin and 1 rifampicin. Of the primary patients, 6% were given prophylaxis during their hospital stay. All meningococci, isolated from pairs of secondary and primary patients, were rifampicin sensitive. CONCLUSIONS: The SAR of meningococcal disease in the Netherlands is similar to that in other countries. Although prescription of chemoprophylaxis is not recommended by the government, it is prescribed to 55% of the household contacts, and in almost half of these instances it was considered to be appropriate. Chemoprophylaxis is rarely prescribed to primary patients. Recommendations concerning chemoprophylaxis in the Netherlands are in need of reappraisal. Based on the results from this study and the literature, the prescription of chemoprophylaxis to all household contacts of a patient with meningococcal disease, and to the index patient, is recommended.

[Myiasis caused by Dermatobia hominis]. / Myiasis door Dermatobia hominis.

In two patients, a woman of 35 and a man of 62 years old, myiasis caused by the larvae of the fly Dermatobia hominis was diagnosed. Both patients had recently returned from a visit to Central America. This ectoparasitosis is found in Central and South America. Patients present themselves with an insect bite which fails to heal. If the clinical presentation is unknown, the disease may well be mistaken for furunculosis. The condition may be easily treated by applying vaseline to the insect bite, which causes extrusion of the larva.

[Meningococcal disease in the winter season 1988-1989]. / Meningokokkenziekte in het winterseizoen 1988-1989.

We describe the 304 cases of meningococcal disease notified from week 45 of 1988 and up to week 21 of 1989, and compare these data with those for 1966, the year of the last epidemic in The Netherlands. During the epidemic the interval between the first day of illness and the moment of reporting shortened.

[Campylobacter infections in pregnancy]. / Campylobacter-infecties in de zwangerschap.

In two pregnant women aged 39 and 35, who presented with fever and diarrhoea, Campylobacter was cultured from a blood sample. They were treated with antibiotics. One had a healthy neonate, in the other intrauterine foetal death had occurred. Campylobacter species have increasingly been recognized as possible causes of septic abortion, premature labour and neonatal sepsis. Early recognition and treatment of maternal Campylobacter infection may reduce the risk of serious foetal or neonatal complications.

A combination of interferon-gamma and interleukin-2 production by Coxiella burnetii-stimulated circulating cells discriminates between chronic Q fever and past Q fever.

Infection with Coxiella burnetii may lead to life-threatening chronic Q fever endocarditis or vascular infections, which are often difficult to diagnose. The present study aims to investigate whether measurement of in-vitro interferon-gamma (IFN-γ) production, a key cytokine in the immune response against C. burnetii, differentiates chronic from a past cleared infection, and whether measurement of other cytokines would improve the discriminative power. First, C. burnetii-specific IFN-γ production was measured in whole blood of 28 definite chronic Q fever patients and compared with 135 individuals with past Q fever (seropositive controls) and 908 seronegative controls. IFN-γ production was significantly higher in chronic Q fever patients than in controls, but with overlapping values between patients and seropositives. Secondly, the production of a series of other cytokines was measured in a subset of patients and controls, which showed that interleukin (IL)-2 production was significantly lower in patients than in seropositive controls. Subsequently, measuring IL-2 in all patients and all controls with substantial IFN-γ production showed that an IFN-γ/IL-2 ratio >11 had a sensitivity and specificity of 79% and 96%, respectively, to diagnose chronic Q fever. This indicates that a high IFN-γ/IL-2 ratio is highly suggestive for chronic Q fever. In an additional group of 25 individuals with persistent high anti-Coxiella phase I IgG titres without definite chronic infection, all but six showed an IFN-γ/IL-2 ratio <11. In conclusion, these findings hold promise for the often difficult diagnostic work-up of Q fever and the IFN-γ/IL-2 ratio may be used as an additional diagnostic marker.

Evaluation of commonly used serological tests for detection of Coxiella burnetii antibodies in well-defined acute and follow-up sera.

In this study, we compared Coxiella burnetii IgG phase I, IgG phase II, and IgM phase II detection among a commercially available enzyme-linked immunosorbent assay (ELISA) (Virion/Serion), an indirect fluorescent antibody test (IFAT) (Focus Diagnostics), and a complement fixation test (CFT) (Virion/Serion). For this, we used a unique collection of acute- and convalescent-phase sera from 126 patients with acute Q fever diagnosed by positive Coxiella burnetii PCR of blood. We were able to establish a reliable date of onset of disease, since DNA is detectable within 2 weeks after the start of symptoms. In acute samples, at t = 0, IFAT demonstrated IgM phase II antibodies in significantly more sera than did ELISA (31.8% versus 19.7%), although the portion of solitary IgM phase II was equal for IFAT and for ELISA (18.2% and 16.7%, respectively). Twelve months after the diagnosis of acute Q fever, 83.5% and 62.2% of the sera were still positive for IgM phase II with IFAT and ELISA, respectively. At 12 months IFAT IgG phase II showed the slowest decline. Therefore, definitive serological evidence of acute Q fever cannot be based on a single serum sample in areas of epidemicity and should involve measurement of both IgM and IgG antibodies in paired serum. Based on IgG phase II antibody detection in paired samples (at 0 and 3 months) from 62 patients, IFAT confirmed more cases than ELISA and CFT, but the differences were not statically significant (100% for IFAT, 95.2% for ELISA, and 96.8% for CFT). This study demonstrated that the three serological tests are equally effective in diagnosing acute Q fever within 3 months of start of symptoms. In follow-up sera, more IgG antibodies were detected by IFAT than by ELISA or CFT, making IFAT more suitable for prevaccination screening programs.

Chronic Q fever: review of the literature and a proposal of new diagnostic criteria.

A review was performed to determine clinical aspects and diagnostic tools for chronic Q fever. We present a Dutch guideline based on literature and clinical experience with chronic Q fever patients in The Netherlands so far. In this guideline diagnosis is categorized as proven, possible or probable chronic infection based on serology, PCR, clinical symptoms, risk factors and diagnostic imaging.