Pernille Ravn

Reactivation of tuberculosis during immunosuppressive treatment in a patient with a positive QuantiFERON-RD1 test

A patient with polymyositis developed tuberculosis during immunosuppressive treatment. Tuberculin Skin Test and chest X-ray failed to demonstrate latent tuberculosis, whereas a blood sample that was tested with a modified QuantiFERON®-TB-assay, using the recombinant ESAT-6 and CFP-10, was positive indicating that this patient was latently infected before immunosuppressive therapy. This case indicates the risk of progressing from latent to active tuberculosis given that the subject is RD1 responsive, and we believe that preventive anti-tuberculous treatment could have prevented this case of tuberculosis. We suggest that RD1 based tests are evaluated further in immunocompromised patients.

Evaluation of Mycobacterium tuberculosis-Specific Antibody Responses in Populations with Different Levels of Exposure from Tanzania, Ethiopia, Brazil, and Denmark

BACKGROUND New, simple, and better-performing diagnostic tools are needed for the diagnosis of tuberculosis (TB). Much effort has been invested in developing an antibody-based test for TB, but to date, no such test has performed with sufficient sensitivity and specificity. A key question remaining is the extent to which the disappointing performance of current tests is associated with a high background prevalence of latent TB. METHODS We compared Mycobacterium tuberculosis-specific ESAT-6 and CFP-10 antibody responses in a total of 565 human serum samples from M. tuberculosis-uninfected donors and donors with latent infection, as well as samples from patients with active TB. Our study included samples from 4 countries, representing environments with low, intermediate, and high TB incidences. RESULTS We demonstrated significant increases in antibody levels in latently infected contacts, compared with M. tuberculosis-uninfected individuals, and in patients with active TB disease, compared with latently infected contacts. Furthermore, we found a striking increase in the magnitude of the antibody responses in samples obtained from infected Ethiopian individuals (with and without disease), compared with Danish and Brazilian infected individuals; this was presumably the result of higher exposure levels. CONCLUSIONS Our study confirms the presence of ESAT-6 and CFP-10 antibodies in patients with TB, and we demonstrate that significant antibody responses are not restricted to active TB disease but can reflect latent infection, particularly in areas with high levels of exposure to M. tuberculosis. This finding is important for the understanding of the poor discriminatory power of current serodiagnostic tests in regions of endemicity, and it may have major implications on the future development of serologic tests.

Detecting a low prevalence of latent tuberculosis among health care workers in Denmark detected by M. tuberculosis specific IFN-γ whole-blood test

The study was designed to estimate prevalence of tuberculosis infection among health care workers, using the tuberculin skin test (TST) and the new M. tuberculosis specific diagnostic whole-blood test and to identify possible risk factors. Employees at 2 departments of infectious diseases in Copenhagen were invited to enter the study. All attendants completed a questionnaire, had a TST and blood drawn for detection of interferon-γ produced after stimulation with M. tuberculosis specific antigens ESAT-6 and CFP-10 (QuantiFERON-TB-Gold®, Cellestis). 47 of 139 (34%) participants had a positive TST whereas only 2 of 139 (1%) had a positive QuantiFERON TB-Gold test (QFT-TB). 42 of 106 (40%) BCG vaccinated had positive TST (≥12 mm) compared with 2 of 27 (7%) unvaccinated persons. Among 47 persons with positive TST, 42 (89%) were BCG- vaccinated. The 2 QFT-TB positive participants as well as the remaining 45 TST positive participants showed no sign of active tuberculous disease and were allocated to 6-month clinical follow-up, without medical therapy. Today, 1.5 y later, all remain healthy. The high rate of positive TST among health care workers was most probably due to BCG vaccination and not to infection with M. tuberculosis. The overall transmission rate determined by QFT-TB was found to be very low. The QFT-TB may be useful in distinguishing persons with latent TB infection from persons with positive TST due to BCG vaccination and its use may reduce anxiety.

Elevated levels of soluble urokinase receptor in serum from mycobacteria infected patients: Still looking for a marker of treatment efficacy

In search for a serological marker, which may be used to monitor treatment efficacy in patients with extra-pulmonary mycobacterial infections, serum samples were collected prospectively from patients during a 6-months treatment period. The levels of soluble urokinase-type plasminogen activator receptor (suPAR) and soluble tumour necrosis factor receptor II (sTNFrII) were measured and compared with erythrocyte sedimentation rate (SR) and C-reactive protein levels (CRP). sTNFrII levels were elevated at the time of diagnosis and declined in parallel with traditional inflammation markers (SR and CRP). suPAR levels were elevated to more than double (median 7.7ng/ml, range 5.6–25.8) compared to levels previously reported for patients with pulmonary tuberculosis. The serum suPAR levels however remained high during the entire treatment period. This may reflect that significant inflammatory activity is continuing for more than 6 months in patients with extrapulmonary mycobacterial infections, despite adequate anti-tuberculosis treatment.

Challenges of Loss to Follow-up in Tuberculosis Research.

Background In studies evaluating methods for diagnosing tuberculosis (TB), follow-up to verify the presence or absence of active TB is crucial and high dropout rates may significantly affect the validity of the results. In a study assessing the diagnostic performance of the QuantiFERON®-TB Gold In-Tube test in TB suspect children in Tanzania, factors influencing patient adherence to attend follow-up examinations and reasons for not attending were examined. Methods In 160 children who attended and 102 children who did not attend scheduled 2-month follow-up baseline health characteristics, demographic data and risk factors for not attending follow-up were determined. Qualitative interviews were used to understand patient and caretakers reasons for not returning for scheduled follow-up. Results Being treated for active TB in the DOTS program (OR: 4.14; 95% CI:1.99–8.62;p-value<0.001) and receiving money for the bus fare (OR:129; 95% CI 16->100;P-value<0.001) were positive predictors for attending follow-up at 2 months, and 21/85(25%) of children not attending scheduled follow-up had died. Interviews revealed that limited financial resources, i.e. lack of money for transportation and poor communication, were related to non-adherence. Conclusion Patients lost to follow-up is a potential problem for TB research. Receiving money for transportation to the hospital and communication is crucial for adherence to follow-up conducted at a study facility. Strategies to ensure follow-up should be part of any study protocol.

Undiagnosed Diabetes Mellitus in Community-Acquired Pneumonia: A Prospective Cohort Study

Background Diabetes mellitus is an important risk factor for community-acquired pneumonia, whereas the prevalence of undiagnosed diabetes mellitus and prediabetes in patients with community-acquired pneumonia is largely unknown. We aimed to determine the prevalence of prediabetes, undiagnosed diabetes mellitus, and risk factors associated with undiagnosed diabetes mellitus in a large European community-acquired pneumonia cohort. Methods This was a multicenter prospective cohort study of hospitals and private practices in Germany and Austria encompassing 1961 adults with community-acquired pneumonia included in the German Community-Acquired Pneumonia Competence Network (CAPNETZ) study between 2007 and 2014. The prevalence of undiagnosed diabetes mellitus and prediabetes was estimated based on hemoglobin A1c measurements. Logistic regression was used to assess risk factors for undiagnosed diabetes mellitus. Results Fifteen percent of patients had known diabetes mellitus. Among patients without known diabetes mellitus, 5.0% had undiagnosed diabetes mellitus and 37.5% had prediabetes. Male sex (odds ratio [OR], 2.45 [95% confidence interval {CI}, 1.35-4.45]), body mass index ≥25 kg/m2 (OR, 2.64 [95% CI, 1.48-4.72]), and hyperglycemia at admission (6-11 mM: OR, 2.93 [95% CI, 1.54-5.60] and ≥11 mM: OR, 44.76 [95% CI, 17.58-113.98]) were associated with undiagnosed diabetes mellitus. Patients with undiagnosed diabetes mellitus had a higher 180-day mortality rate compared to patients without diabetes mellitus (12.1% vs 3.8%, respectively; P = .001). Conclusions Undiagnosed diabetes mellitus was prevalent among community-acquired pneumonia. Male sex, overweight, and hyperglycemia at admission were associated with undiagnosed diabetes mellitus. The long-term mortality among patients with undiagnosed diabetes mellitus was high compared to patients without diabetes mellitus.