Late Tuberculosis Reactivation After Severe Covid-19.

Background: Although there is no specific therapy for COVID-19, it is recommended that patients with severe SARS-CoV-2 infection are treated with corticosteroids and anti-IL-6 receptor monoclonal antibodies. Both COVID-19 itself and the treatment modalities mentioned above have suppressive effects on the immune system which may lead to an increased susceptibility to other infections. In patients with latent tuberculosis (TB) reactivation of TB infection after recovery from severe COVID-19 has been described. Most of these cases have occurred in parts of the world where tuberculosis is endemic. Case description: The patient is a female in her 70s who was born and raised in Southeast Asia and has lived in the Netherlands for more than 30 years. She was treated for a severe COVID-19 requiring mechanical ventilation for several weeks and pharmaceutical treatment with corticosteroids and anti-IL-6 receptor monoclonal antibodies (Sarilumab). She recovered well. Two years later she was readmitted with symptoms of a serious pulmonary infection and meningitis. Her condition deteriorated in a short time. An active TB infection was diagnosed. Despite adequate antibiotic treatment and supportive therapy her condition worsened and four days after admission to the ICU she deceased. Discussion: Reactivation of latent TB after recovery from a severe COVID-19 has been described several times and may occur several months after the SARS-CoV-2 infection. In this case the reactivation presented two years after COVID-19. This case illustrates that long-term follow-up of patients with latent TB that recover from a severe COVID-19 may be indicated. LEARNING POINTS: Reactivation of latent tuberculosis infection in patients treated for a severe COVID-19 may occur even two years after recovery from SARS-CoV-2 infection.Most cases of reactivation of tuberculosis after COVID-19 are described in regions where tuberculosis is endemic. However, it may also occur in countries with a relatively low prevalence of tuberculosis infection. The exact incidence of tuberculosis reactivation after COVID-19 is unknown and probably underestimated.A long-term follow-up of patients after severe COVID-19 treated with corticosteroids and/or anti-IL-6 receptor monoclonal antibodies with a history of tuberculosis or patients migrated from countries where tuberculosis is endemic seems to be important.

Use of an algorithm based on routine blood laboratory tests to exclude COVID-19 in a screening-setting of healthcare workers.

BACKGROUND: COVID-19 is an ongoing pandemic leading to exhaustion of the hospital care system. Our health care system has to deal with a high level of sick leave of health care workers (HCWs) with COVID-19 related complaints, in whom an infection with SARS-CoV-2 has to be ruled out before they can return back to work. The aim of the present study is to investigate if the recently described CoLab-algorithm can be used to exclude COVID-19 in a screening setting of HCWs. METHODS: In the period from January 2021 till March 2021, HCWs with COVID-19-related complaints were prospectively collected and included in this study. Next to the routinely performed SARS-CoV-2 RT-PCR, using a set of naso- and oropharyngeal swab samples, two blood tubes (one EDTA- and one heparin-tube) were drawn for analysing the 10 laboratory parameters required for running the CoLab-algorithm. RESULTS: In total, 726 HCWs with a complete CoLab-laboratory panel were included in this study. In this group, 684 HCWs were tested SARS-CoV-2 RT-PCR negative and 42 cases RT-PCR positive. ROC curve analysis showed an area under the curve (AUC) of 0.853 (95% CI: 0.801-0.904). At a safe cut-off value for excluding COVID-19 of -6.525, the sensitivity was 100% with a specificity of 34% (95% CI: 21 to 49%). No SARS-CoV-2 RT-PCR cases were missed with this cut-off and COVID-19 could be safely ruled out in more than one third of HCWs. CONCLUSION: The CoLab-score is an easy and reliable algorithm that can be used for screening HCWs with COVID-19 related complaints. A major advantage of this approach is that the results of the score are available within 1 hour after collecting the samples. This results in a faster return to labour process of a large part of the COVID-19 negative HCWs (34%), next to a reduction in RT-PCR tests (reagents and labour costs) that can be saved.

Retrieval and re-evaluation of previously diagnosed chronic hepatitis C infections lost to medical follow-up in the Netherlands.

OBJECTIVES: Many individuals previously diagnosed with chronic hepatitis C virus (HCV) infection are likely to be lost to medical follow-up and, therefore, remain untreated despite new highly effective drug treatment, direct acting antivirals. We aim to identify and retrieve these chronic HCV-infected individuals to re-evaluate them and offer treatment. METHODS: Possible chronic HCV infections were identified from test results of the medical microbiological laboratory, notifications to the public health service, and the hospital registries over the past 15 years were checked in South Limburg, the Netherlands. Individuals were contacted based on the physician-patient relationship of the gastroenterologist or microbiologist (retrieval). Individuals were informed about the new treatment options, offered an HCV-RNA test, and if still positive, referred to the gastroenterologist for treatment (re-evaluation). RESULTS: In total, 689 individuals with a positive anti-HCV test in the past were identified, 308 (45%) were eligible for retrieval, 90 (29%) of them were retrieved, 34 (38%) of those retrieved were re-evaluated, 19 (56%) of those tested were HCV-RNA positive, and 12 (63%) of these individuals were offered treatment. CONCLUSION: During every step of the retrieval chain, many patients were lost. Nevertheless, with substantial effort, we were able to identify, retrieve, and positively re-evaluate a limited number of individuals with a possible chronic HCV infection who were lost to medical follow-up (19 patients). With this case-finding approach, we were able to prevent potential severe complications in these patients and contribute to a small step in the eradication of HCV in the Netherlands.

Susceptibility of ESBL Escherichia coli and Klebsiella pneumoniae to fosfomycin in the Netherlands and comparison of several testing methods including Etest, MIC test strip, Vitek2, Phoenix and disc diffusion.

Objectives: Fosfomycin susceptibility testing is complicated and prone to error. Before using fosfomycin widely in patients with serious infections, acquisition of WT distribution data and reliable susceptibility testing methods are crucial. In this study, the performance of five methods for fosfomycin testing in the routine laboratory against the reference method was evaluated. Methods: Ten laboratories collected up to 100 ESBL-producing isolates each (80 Escherichia coli and 20 Klebsiella pneumoniae). Isolates were tested using Etest, MIC test strip (MTS), Vitek2, Phoenix and disc diffusion. Agar dilution was performed as the reference method in a central laboratory. Epidemiological cut-off values (ECOFFs) were determined for each species and susceptibility and error rates were calculated. Results: In total, 775 E. coli and 201 K. pneumoniae isolates were tested by agar dilution. The ECOFF was 2 mg/L for E. coli and 64 mg/L for K. pneumoniae. Susceptibility rates based on the EUCAST breakpoint of ≤32 mg/L were 95.9% for E. coli and 87.6% for K. pneumoniae. Despite high categorical agreement rates for all methods, notably in E. coli, none of the alternative antimicrobial susceptibility testing methods performed satisfactorily. Due to poor detection of resistant isolates, very high error rates of 23.3% (Etest), 18.5% (MTS), 18.8% (Vitek2), 12.5% (Phoenix) and 12.9% (disc diffusion) for E. coli and 22.7% (Etest and MTS), 16.0% (Vitek2) and 12% (Phoenix) for K. pneumoniae were found. None of the methods adequately differentiated between WT and non-WT populations. Conclusions: Overall, it was concluded that none of the test methods is suitable as an alternative to agar dilution in the routine laboratory.

Multiplex autoantibody detection for autoimmune liver diseases and autoimmune gastritis.

Autoantibody detection for autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and autoimmune gastritis (AIG) is traditionally performed by IIF on a combination of tissues. Multiplex line/dot blots (LIA/DIA) offer multiple advantages, i.e. automation, objective reading, no interfering reactivities, no coincidental findings. In the current study we evaluated automated DIA (D-Tek) for detecting autoantibodies related to autoimmune diseases of the gastrointestinal tract. We tested samples of the Dutch EQC program and compared the results with the consensus of the participating labs. For the autoimmune liver diseases and AIG, respectively, 64 and 36 samples were tested. For anti-mitochondrial and anti-smooth muscle antibodies a concordance rate of 97% and 88% was observed, respectively. The concordance rate for anti-parietal cell antibodies was 92% when samples without EQC consensus (n=15) were excluded. For antibodies against intrinsic factor a concordance of 96% was observed. For all these antibodies discrepancies were identified that relate to the different test characteristics and the preponderance of IIF utilizing labs in the EQC program. In conclusion, we observed good agreement of the tested DIA blots with the consensus results of the Dutch EQC program. Taken together with the logistic advantages these blots are a good alternative for autoantibody detection in the respective diseases. A large prospective multicenter study is warranted to position these novel tests further in the whole spectrum of assays for the detection of these antibodies in a routine autoimmune laboratory.

A comprehensive overview of urogenital, anorectal and oropharyngeal Neisseria gonorrhoeae testing and diagnoses among different STI care providers: a cross-sectional study.

BACKGROUND: Gonorrhoea, caused by Neisseria gonorrhoeae (NG), can cause reproductive morbidity, is increasingly becoming resistant to antibiotics and is frequently asymptomatic, which shows the essential role of NG test practice. In this study we wanted to compare NG diagnostic testing procedures between different STI care providers serving a defined geographic Dutch region (280,000 inhabitants). METHODS: Data on laboratory testing and diagnosis of urogenital and extragenital (i.e. anorectal and oropharyngeal) NG were retrieved from general practitioners (GPs), an STI clinic, and gynaecologists (2006-2010). Per provider, we assessed their contribution regarding the total number of tests performed and type of populations tested, the proportion of NG positives re-tested (3-12 months after treatment) and test-of-cure (TOC, within 3 months post treatment). RESULTS: Overall, 17,702 NG tests (48.7% STI clinic, 38.2% GPs, 13.1% gynaecologists) were performed during 15,458 patient visits. From this total number of tests, 2257 (12.7%) were extragenital, of which 99.4% were performed by the STI clinic. Men were mostly tested at the STI clinic (71%) and women by their GP (43%). NG positivity per visit was 1.6%; GP 1.9% (n = 111), STI clinic 1.7% (n = 131) and gynaecology 0.2% (n = 5). NG positivity was associated with Chlamydia trachomatis positivity (OR: 2.06, 95% confidence interval: 1.46-2.92). Per anatomical location, the proportion of NG positives re-tested were: urogenital 20.3% (n = 36), anorectal 43.6% (n = 17) and oropharyngeal 57.1% (n = 20). NG positivity among re-tests was 16.9%. Proportions of NG positives with TOC by anatomical location were: urogenital 10.2% (n = 18), anorectal 17.9% (n = 7) and oropharyngeal 17.1% (n = 6). CONCLUSIONS: To achieve best practice in relation to NG testing, we recommend that: 1) GPs test at extragenital sites, especially men who have sex with men (MSM), 2) all care providers consider re-testing 3 to 12 months after NG diagnosis and 3) TOC is performed following oropharyngeal NG diagnosis in settings which provide services to higher-risk men and women (such as STI clinics).

Chronic Q fever diagnosis­ consensus guideline versus expert opinion

Chronic Q fever, caused by Coxiella burnetii, has high mortality and morbidity rates if left untreated. Controversy about the diagnosis of this complex disease has emerged recently. We applied the guideline from the Dutch Q Fever Consensus Group and a set of diagnostic criteria proposed by Didier Raoult to all 284 chronic Q fever patients included in the Dutch National Chronic Q Fever Database during 2006­2012. Of the patients who had proven cases of chronic Q fever by the Dutch guideline, 46 (30.5%)would not have received a diagnosis by the alternative criteria designed by Raoult, and 14 (4.9%) would have been considered to have possible chronic Q fever. Six patients with proven chronic Q fever died of related causes. Until results from future studies are available, by which current guidelines can be modified, we believe that the Dutch literature-based consensus guideline is more sensitive and easier to use in clinical practice.

The added value of chlamydia screening between 2008-2010 in reaching young people in addition to chlamydia testing in regular care; an observational study.

BACKGROUND: Internet-based Chlamydia Screening Implementation (chlamydia screening programme) was introduced in the Netherlands in 2008-2010 to detect and treat asymptomatic infections and to limit ongoing transmission through annual testing and treatment of Chlamydia trachomatis in young people (16-29 years). This population-based screening may be less effective when addressing individuals who are already covered by regular care, instead of addressing a hidden key population without chlamydia testing experience in regular care. This study had two aims: (1) to assess the rate and determinants of newly reached (i.e. not previously tested in 2006-2010) participants in the chlamydia screening programme, and (2) to assess the chlamydia positivity in these newly reached participants. METHODS: This observational matching study included all chlamydia tests performed in subjects aged 16-29 years in eastern South Limburg in the Netherlands (population 16-29 years:41,000) between 2006-2010. Testing was conducted during the systematic chlamydia screening programme (2008-2010), at a sexually transmitted infections clinic (STI clinic), by general practitioners (GPs), and by medical specialists as reported by the medical laboratory serving the region. Data were matched between testing services on individual level. The study population included all participants who were tested at least once for chlamydia by the chlamydia screening programme. Participants were included at their first chlamydia screening participation. RESULTS: In the chlamydia screening programme, 80.7% (4298/5323) of participants were newly reached, others were previously tested by the STI clinic (5.7%, n=304), GPs (6.2%, n=328), medical specialists (3.5%, n=187) or a combination of providers (3.9%, n=206). Chlamydia prevalence was similar in newly reached participants (4.8%, 204/4298) and participants previously tested (4.5%, 46/1025, P=0.82). Independent determinants for being a newly reached participant were male gender (men OR 2.9; 95% CI 2.5-3.4) and young age <21 years (versus 25-29 years OR 1.8; 95% CI 1.5-2.2). CONCLUSIONS: The majority of the chlamydia screening programme participants have not been tested by regular care, and show similar chlamydia prevalence as those previously tested. Thereby population-based chlamydia screening adds to the existing regular care by testing young individuals hidden to current regular care.

Anti-nuclear antibodies in daily clinical practice: prevalence in primary, secondary, and tertiary care.

For the diagnosis of systemic autoimmune rheumatic diseases (SARD), patients are screened for anti-nuclear antibodies (ANA). ANA, as assessed by indirect immunofluorescence (IIF), have a poor specificity. This hampers interpretation of positive results in clinical settings with low pretest probability of SARD. We hypothesized that the utility of positive ANA IIF results increases from primary to tertiary care. We retrospectively determined ANA, anti-ENA, and anti-dsDNA antibody prevalence in patient cohorts from primary (n = 1453), secondary (n = 1621), and tertiary (n = 1168) care settings. Results reveal that from primary care to tertiary care, ANA prevalence increases (6.2, 10.8, and 16.0%, resp.). Moreover, in primary care low titres (70% versus 51% and 52% in secondary and tertiary care, resp.) are more frequent and anti-ENA/dsDNA reactivities are less prevalent (21% versus 39% in secondary care). Typically, in tertiary care the prevalence of anti-ENA/dsDNA reactivities (21%) is lower than expected. From this descriptive study we conclude that positive ANA IIF results are more prone to false interpretation in clinical settings with low pretest probabilities for SARD, as in primary care. Whether alternative approaches, that is, immunoadsorption of anti-DFS70 antibodies or implementation of anti-ENA screen assays, perform better, needs to be determined.

Identification of hidden key hepatitis C populations: an evaluation of screening practices using mixed epidemiological methods.

BACKGROUND: Hepatitis C virus (HCV) is a major cause of liver diseases worldwide. Due to its asymptomatic nature, screening is necessary for identification. Because screening of the total population is not cost effective, it is important to identify which risk factors for positivity characterize the key populations in which targeting of screening yields the highest numbers of HCV positives, and assess which of these key populations have remained hidden to current care. METHODS: Laboratory registry data (2002-2008) were retrieved for all HCV tests (23,800) in the south of the Netherlands (adult population 500,000). Screening trends were tested using Poisson regression and chi-square tests. Risk factors for HCV positivity were assessed using a logistic regression. The hidden HCV-positive population was estimated by a capture-recapture approach. RESULTS: The number of tests increased over time (2,388 to 4,149, p<.01). Nevertheless, the positivity rate among those screened decreased between 2002 and 2008 (6.3% to 2.1%, p<.01). The population prevalence was estimated to be 0.49% (95%CI 0.41-0.59). Of all HCV-positive patients, 66% were hidden to current screening practices. Risk factors associated with positivity were low socio-economic status, male sex, and age between 36-55. In future screening 48% (95%CI 37-63) of total patients and 47% (95%CI 32-70) of hidden patients can be identified by targeting 9% (men with low socio-economic status, between 36-55 years old) of the total population. CONCLUSIONS: Although the current HCV screening policy increasingly addresses high-risk populations, it only reaches one third of positive patients. This study shows that combining easily identifiable demographic risk factors can be used to identify key populations as a likely target for effective HCV screening. We recommend strengthening screening among middle-aged man, living in low socio-economic neighborhoods.

Cross-border dissemination of methicillin-resistant Staphylococcus aureus, Euregio Meuse-Rhin region.

Because the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) differs among the 3 countries forming the Euregio Meuse-Rhin (EMR) region (Belgium, Germany, and the Netherlands), cross-border healthcare requires information about the spread of MRSA in the EMR. We investigated the emergence, dissemination, and diversity of MRSA clones in the EMR by using several typing methods. MRSA associated with clonal complexes 5, 8, 30, and 45 was disseminated throughout the EMR. Dutch isolates, mainly associated with sequence types (ST) ST5-MRSA-II, ST5-MRSA-IV, ST8-MRSA-IV, and ST45-MSRA-IV had a more diverse genetic background than the isolates from Belgium and Germany, associated with ST45-MRSA-IV and ST5-MRSA-II, respectively. MRSA associated with pigs (ST398-MRSA-IV/V) was found in the Dutch area of the EMR. Five percent of the MRSA isolates harbored Panton-Valentine leukocidin and were classified as community-associated MRSA associated with ST1, 8, 30, 80, and 89.

Sensitivity and specificity of single IgA and IgG antibody concentrations for early diagnosis of pertussis in adults: an evaluation for outbreak management in public health practice.

BACKGROUND: An accurate, practical laboratory test is needed to confirm clinical diagnosis of pertussis in adults during the first 3 symptomatic weeks, when treatment is effective and transmission can be interrupted. METHODS: The sensitivity and specificity of single IgA and IgG levels were assessed in a cohort study of a pertussis epidemic in 99 adults in a closed community. Sensitivities were assessed in the sera of 46 laboratory confirmed clinical pertussis cases during the first 3 weeks. Specificities were calculated in sera of 35 asymptomatic controls without clinical symptoms or laboratory confirmed infections from the same community (internal controls). We compared these specificities with the specificities of single IgA and IgG levels in 4275 external controls from a cross-section of the general Dutch population aged 21-79 years who had not coughed for more than 2 weeks in the past year, and without pertussis diagnoses. The study was done in the Netherlands when whole-cell pertussis vaccine was used in the national vaccination programme. RESULTS: Levels of 24 U/ml for IgA and 27 U/ml for IgG gave sensitivities of 100% and 75%, respectively, in the first 2 weeks, 100% in the third week, and 97% after the fourth week. The levels were reached within 2 days after onset of increase, and remained above these levels for roughly 7.2 and 5.1 months, respectively. Specificity was 82% for IgA and 89% for IgG in the internal controls and 90% in the external controls, respectively. CONCLUSION: We suggest levels of 24 U/ml for IgA level and 27 U/ml (= 27 International Units (IU)/ml) for IgG as sensitive, specific, and practical for laboratory confirmation of clinical pertussis in adults in the first 3 weeks of outbreak management.