Ailko W. J. Bossink

Prediction of Microbial Infection and Mortality in Medical Patients with Fever: Plasma Procalcitonin, Neutrophilic Elastase-α1-Antitrypsin, and Lactoferrin Compared with Clinical Variables

Fever suggests the likelihood of severe microbial infection. Abnormal temperature, tachycardia, tachypnea, and abnormal white blood cell counts define the systemic inflammatory response syndrome (SIRS). In 300 hospitalized medical patients with fever, we determined clinical variables and procalcitonin, elastase-alpha1-antitrypsin, and lactoferrin levels in plasma. Of the patients, 71% had clinical infection (by clinical judgment) and 44% had microbial infection (by microbiological testing). SIRS occurred in 95%, and the 28-day mortality rate was 9%. The sensitivity for predicting microbial infection, bacteremia, and mortality was less but the specificity was greater for supranormal procalcitonin, elastase-alpha1-antitrypsin, and lactoferrin levels than for SIRS. The area under the receiver operating characteristic curve (AUC) for microbial infection was higher for procalcitonin and elastase-alpha1-antitrypsin levels than for clinical variables and lactoferrin level. The AUC for bacteremia was also higher for inflammatory factors (>0.70; P < .001) than for clinical variables. The AUC for mortality (P < .05) was 0.79 for the respiratory rate, 0.69 for elastase-alpha1-antitrypsin level, 0.65 for heart rate, 0.61 for procalcitonin level, and 0.60 for white blood cell count. In febrile medical patients, plasma procalcitonin and elastase-alpha1-antitrypsin levels may predict microbial infection and bacteremia better than (and mortality as well as) do clinical symptoms.

Effect of tuberculin skin testing on a Mycobacterium tuberculosis-specific interferon-γ assay

Recently, interferon-γ release assays (IGRA) for specific diagnosis of Mycobacterium tuberculosis infection have become available. In recent UK tuberculosis (TB) guidelines, it has been advised to screen for latent M. tuberculosis infection using the tuberculin skin test (TST), followed by IGRA if the TST is positive. Since TST can boost immune responses to tuberculin, the present authors evaluated whether TST administration affects the result of QuantiFERON®-TB Gold in-tube (QFT-GIT), a whole blood-based IGRA. QFT-GIT was performed on the day of TST administration and the day of reading in 15 TST-negative subjects, 46 TST-positive subjects with recent or remote exposure to M. tuberculosis and five cured TB patients. No systematic boosting of QFT-GIT responses from negative to positive was observed. Only in a few TST-positive persons did TST enhance pre-existing QFT-GIT responses. Screening for latent Mycobacterium tuberculosis infection using tuberculin skin testing followed by interferon-γ release assays on the day of reading is a reliable approach, as the specificity of QuantiFERON®-TB Gold in-tube is not affected by prior tuberculin skin test administration.

Circulating inflammatory mediators predict shock and mortality in febrile patients with microbial infection.

The host response to microbial infection is associated with the release of inflammatory mediators. We hypothesized that the type and degree of the systemic response as reflected by levels of circulating mediators predict morbidity and mortality, according to the invasiveness of microbial infection. We prospectively studied 133 medical patients with fever and culture-proven microbial infection. For 3 days after inclusion, the circulating levels of activated complement C3a, interleukin (IL)-6, and secretory phospholipase A2 (sPLA2) were determined daily. Based on results of microbiological studies performed for up to 7 days, patients were classified as having local infections (Group 1, n = 80 positive local cultures or specific stains for fungal or tuberculous infections) or bacteremia (Group 2, n = 52 plus 1 patient with malaria parasitemia). Outcome was assessed as the development of septic shock and as mortality up to 28 days after inclusion. Fifteen patients (11%) developed septic shock and overall mortality was 18% (n = 24). Bacteremia was associated with shock and shock predisposed to death. Circulating mediator levels were generally higher in Group 2 than in Group 1. Circulating levels of IL-6 and sPLA2 were higher in patients developing septic shock and in nonsurvivors, particularly in Group 1. High C3a was particularly associated with nonsurvival in Group 2. In Group 1, the area under the curve (AUC) of the receiver operating characteristic (ROC) curve for the peak sPLA2 for shock development was 0.79 (P < 0.05). The AUC of the ROC curve of the peak IL-6 and sPLA2 for mortality was 0.69 and 0.68 (P < 0.05), respectively. In Group 2, the AUC of the ROC for peak C3a predicting mortality was 0.73 (P < 0.05). In conclusion, in medical patients with fever and microbial infection, the systemic inflammatory host response predicts shock and death, at an early stage, dependent on the invasiveness of microbial infection. The results suggest a differential pathogenetic role of complement activation on the one hand and release of cytokine and lipid mediators on the other in bacteremic and local microbial infections, respectively. They may partly explain the failure of strategies blocking proinflammatory cytokines or sPLA2 in human sepsis and may extend the basis for attempts to inhibit complement activation at an early stage in patients at risk of dying from invasive microbial infections.

Circulating Inflammatory Mediators in Patients with Fever: Predicting Bloodstream Infection

ABSTRACT The systemic host response to microbial infection involves clinical signs and symptoms of infection, including fever and elevated white blood cell (WBC) counts. In addition, inflammatory mediators are released, including activated complement product C3a, interleukin 6 (IL-6), and the acute-phase reactant secretory phospholipase A2 (sPLA2). To compare the value of the latter with the former in predicting (the degree of) microbial infection at the bedside, we determined clinical variables and took blood samples daily for 3 consecutive days in 300 patients with a new fever (>38.0°C rectally or >38.3°C axillary). Microbiological culture results for 7 days after inclusion were collected. Patients were divided into clinical and microbial categories: those without and with a clinical focus of infection and those with negative cultures, with positive local cultures or specific stains for fungal (n = 13) or tuberculous infections (n = 1), and with positive blood cultures, including one patient with malaria parasitemia. The area under the curve (AUC) of the receiver operating characteristic (ROC) for prediction of positive cultures was 0.60 (P < 0.005) for peak temperature and 0.59 (P < 0.01) for peak WBC count, 0.60 (P < 0.005) for peak C3a, 0.63 (P < 0.001) for peak IL-6, and 0.61 (P < 0.001) for peak sPLA2. The AUC under the ROC curve for prediction of positive blood cultures was 0.68 (P < 0.001) for peak temperature and 0.56 for peak WBC count (P < 0.05). The AUC for peak C3a was 0.69, that for peak IL-6 was 0.70, and that for sPLA2 was 0.67 (for all, P < 0.001). The degree of microbial invasion is thus a major determinant of the clinical and inflammatory host response in patients with fever. Moreover, circulating inflammatory mediators such as C3a and IL-6 may help to predict positive blood cultures, together with clinical signs and symptoms of the host response to microbial infection, even before culture results are available. This may help in the designing of entry criteria for therapeutic intervention studies.

Follow-Up Study of Tuberculosis-Exposed Supermarket Customers with Negative Tuberculin Skin Test Results in Association with Positive Gamma Interferon Release Assay Results

ABSTRACT We report a follow-up study of 29 subjects with negative tuberculin skin test (TST) results in association with positive gamma interferon release assay (IGRA) results, mainly due to responses to CFP-10 in the T-SPOT.TB assay, during a contact investigation. One year later, 12/29 subjects (41%) had converted to positive TST results in association with negative IGRA results.

Tuberculosis during TNF-α inhibitor therapy, despite screening

As part of a prospective study on the safety of TNF-α inhibitor therapy after screening for and treatment of latent tuberculosis infection (LTBI), we report two patients who developed active tuberculosis (TB) infection during TNF-α inhibitor therapy, despite negative screening for LTBI. The clinical history is suggestive of a primary infection acquired during travelling to TB-endemic countries. In this lesson of the month we would like to highlight the risk of travelling to TB-endemic areas in patients treated with TNF-α inhibitor therapy. Screening for latent tuberculosis infection is not enough to prevent tuberculosis in patients treated with TNF-α inhibitor therapy

Added value of use of a purified protein derivative-based enzyme-linked immunosorbent spot assay for patients with Mycobacterium bovis BCG infection after intravesical BCG instillations.

ABSTRACT In this case series, we describe four cases in which the use of gamma interferon release assays with purified protein derivative (PPD) as a stimulating antigen was able to demonstrate PPD-specific immune activation. This may help to improve the adequate diagnosis of (systemic) Mycobacterium bovis BCG infections after intravesical BCG instillations for bladder carcinoma.

Interferon gamma release assays for diagnosing active and latent tuberculosis

BACKGROUND In view of the continuing global epidemic of tuberculosis (TB), adequate diagnosis is crucial for controlling this disease. Two commercial interferon gamma release assays (IGRA) have become available: the QuantiFERON-TB (QFT) and the T-SPOT.TB (TSPOT). They offer an important new tool for detecting both latent and active TB. In particular, the increased specificity as compared with the tuberculin skin test (TST) has resulted in many now (considering) replacing TST with IGRA. OBJECTIVE This review tries to offer the reader more insight from a clinical perspective into the applicability of IGRA for both latent and active TB. CONCLUSION Although both IGRA are based on the same principle, they have marked different performance characteristics and it seems likely that both assays will establish their own niche. The increased specificity and sensitivity of IGRA in various settings as compared with TST show us that IGRA are here to stay. QFT might be the preferred tool for large-scale contact tracing, but in most clinical settings TSPOT has to be preferred. Much knowledge on IGRA has already been obtained in a short time; however, many questions remain unresolved, such as likelihood for developing active TB in individuals with a negative IGRA in contact tracing in various subgroups and the applicability of IGRA for detecting active TB.

Borderline QuantiFERON results and the distinction between specific responses and test variability

BACKGROUND QuantiFERON (QFT) results near the cut-off are subject to debate. We aimed to investigate which borderline QFT results were due to Mycobacterium tuberculosis (Mtb)-specific responses or to test variability. METHODS In a contact investigation, tuberculin skin test (TST), QFT and T-SPOT.TB (T-SPOT) were performed in 785 BCG-unvaccinated contacts. Contacts with a low-negative (<0.15), borderline (0.15-0.35), low-positive (0.35-0.70) or high-positive QFT (≥0.70 IU/mL) were compared with respect to exposure, TST and T-SPOT results. Development of active tuberculosis was assessed. RESULTS Borderline QFT results occurred in threefold excess over test variability (p = 0.0027). In contacts with low-negative, borderline or positive QFT results, a positive TST occurred in 24.9%, 62.1% and 91.4% (p < 0.0001) and a positive T-SPOT result in 6.3%, 41.3% and 86.4%, respectively (p < 0.0001). Two-third (20/29) of contacts with a borderline and 14/16 (88%) with a low-positive QFT had a positive TST and/or T-SPOT, indicating probable Mtb-infection. During 12 years of follow-up, seven patients were diagnosed with active tuberculosis, two of whom after a low-positive QFT. CONCLUSIONS In this study, most borderline and low-positive QFT results were Mtb-specific, showing the biological significance of a borderline QFT. The clinical relevance, however, will be most distinct in patients who are or will be immunocompromised.