Diagnosis Of Active Disease Research Articles

Assessment of tuberculosis disease activity in people infected with Mycobacterium tuberculosis and living with HIV: A longitudinal cohort study.

SummaryBackgroundEarly detection of asymptomatic incipient tuberculosis (TB) could improve clinical outcomes and reduce the spread of Mycobacterium tuberculosis (MTB) infection, particularly in HIV endemic settings. This study assessed TB disease activity over 5 years in people living with HIV co-infected with MTB using a surrogate biomarker.MethodsBetween Jan 1, 2013 and Aug 31, 2018, 2014 people living with HIV were screened annually for active TB using the Xpert MTB/RIF diagnostic assay in 11 clinics in Kenya, Tanzania, Uganda, and Nigeria. Longitudinal blood mononuclear cell samples from 46 selected patients with active and recurrent tuberculosis, latent infection, or incipient TB were further analysed for MTB-specific T-cell activation (defined by CD38 expression) as a well-defined surrogate marker for TB disease covering a total of 1758 person-months.FindingsMTB-specific CD4 T-cell activation differentiated active, Xpert MTB/RIF positive TB from latent TB with a sensitivity and specificity of 86% and was reduced upon TB treatment initiation. Activated MTB-specific T cells were present in 63% and 23% of incipient TB cases 6 and 12 months before diagnosis of active disease, respectively. Transient increases of MTB-specific T cell activation were also observed in individuals with latent infection, while persistent activation was a hallmark of recurrent TB after the end of treatment.InterpretationIn most cases, progression to active TB disease started 6–12 months before diagnosis by clinical symptoms and sputum occurrence of bacilli. Blood biomarkers could facilitate early detection of incipient TB, improve clinical outcomes, and reduce the transmission of MTB.FundingThis work was supported by the President's Emergency Plan for AIDS Relief via a cooperative agreement between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the U.S. Department of Defense [W81XWH-11-2-0174, W81XWH-18-2-0040] and by the Bundesministerium für Bildung und Forschung (BmBF) through funding of the Deutsches Zentrum für Infektionsforschung (DZIF, TTU-TB personalized medicine TTU 02_813).

Monitoring for neovascular age-related macular degeneration (AMD) reactivation at home: the MONARCH study

AimsThis study aims to quantify the diagnostic test-accuracy of three visual function self-monitoring tests for detection of active disease in patients with neovascular age-related macular degeneration (nAMD) when compared with usual care. An integrated qualitative study will investigate the acceptability of these home-based testing strategies.MethodsAll consenting participants are provided with an equipment pack containing an iPod touch with two vision test applications installed and a paper journal of reading tests. Participants self-monitor their vision at home each week with all three tests for 12–18 months. Usual care continues over this period. Key eligibility criteria are: age ≥50 years; at least one eye with AMD with ≥6–≤42 months since first AMD treatment; and vision not worse than Snellen 6/60, LogMAR 1.04 or 33 letters. The primary outcome, and reference standard, is diagnosis of active disease during usual care monitoring in the Hospital Eye Service. Secondary outcomes include duration of study participation, ability of participants to do the tests, adherence to weekly testing and acceptability of the tests to participants.ConclusionsRecruitment is in progress at five NHS centres. Challenges in procuring equipment, setting up the devices and transporting devices containing lithium batteries to participating sites delayed the start of recruitment. The study will describe the performance of the tests self-administered at home in detecting active disease compared to usual care monitoring. It will also describe the feasibility of the NHS implementing patient-administered electronic tests or similar applications at home for monitoring health.

Proteomics and Leishmaniasis: Potential Clinical Applications.

Leishmaniases are diseases caused by protozoan parasites of the genus Leishmania. They are endemic in 98 countries, affect around 12 million people worldwide and may present several distinct clinical forms. Unfortunately, there are only a few drugs available for treatment of leishmaniasis, which are toxic and not always effective. Different parasite species and different clinical forms require optimization of the treatment or more specific therapies, which are not available. The emergence of resistance is also a matter of concern. Besides, diagnosis can sometimes be complicated due to atypical manifestations and associations with other pathologies. In this review, proteomic data are presented and discussed in terms of their application in important issues in leishmaniasis such as parasite resistance to chemotherapy, diagnosis of active disease in patients and dogs, markers for different clinical forms, identification of virulence factors, and their potential use in vaccination. It is shown that proteomics has contributed to the discovery of potential biomarkers for prognosis, diagnosis, therapeutics, monitoring of disease progression, treatment follow-up and identification of vaccine candidates for specific diseases. However, the authors believe its capabilities have not yet been fully explored for routine clinical analysis for several reasons, which will be presented in this review.

PF484 MARKERS ASSOCIATED WITH SHORT SURVIVAL IN PATIENTS WITH WALDENSTRÖM MACROGLOBULINEMIA

Background:Waldenström Macroglobulinemia (WM) is a rare, indolent B‐cell lymphoplasmacytic malignancy. Patient outcomes are highly heterogeneous, with a proportion of patients surviving less than 5 years (short survivors) and another proportion that survive longer than 10 years. The laboratory parameters in the currently used International Prognostic Scoring System for WM (IPSSWM) include hemoglobin, serum IgM, platelet count, and serum β2‐microglobulin.Aims:We aim to identify unique patient characteristics and prognostic features associated with short survival in WM.Methods:The medical records of patients with active WM that were diagnosed at Mayo Clinic Rochester, Arizona, and Florida between January 1st, 1996 and December 31st, 2013 were reviewed. The patients with smoldering WM were excluded. Cohorts of patients who either survived ≤ 5 years (Short Survival Group) or those with an overall survival (OS) ≥ 10 years (Long Survival Group) from the diagnosis of active disease were compared. Survivors with a follow‐up of ≤ 5 years were not included in the analyses. Two‐sided Wilcoxon rank sum test and Chi square/Fisher's exact test were used to compare the continuous and categorical variables, respectively. The variables that were statistically significant on univariate analysis (P < 0.05) were included in a multivariate logisitic regression analysis.Results:Of 893 consecutively seen WM patients (median follow‐up of 9 years [95% CI 8.4–9.7]), we identified 387 patients who could be categorized into either the Short Survival Group (n = 171 patients, 44%) or the Long Survival Group (n = 216, 56%). The Short Survival Group had a median OS of 2.4 years (2.1–2.8) and median age at diagnosis of 73 years (42–93), while the Long Survival Group (n = 216, 56%) had a median OS of 18.9 years (16‐NR) and median age at diagnosis of 62 years (31–85). The baseline characteristics and significant findings between the two groups are listed in the Table. Parameters significant on univariate analysis included age >65 years, albumin < 3.5 g/dL, β2‐microglobulin >3 μg/ml, and LDH > upper limit of normal (ULN). On multivariate analysis, albumin <3.5 g/dL and LDH > ULN were independently associated with short survival. Among the Long Survivors, 60 (28%) patients survived 15 years or more.Summary/Conclusion:Lactate dehydrogenase above the ULN and serum albumin <3.5 g/dL are independent biomarkers of short survival in WM. The MYD88 L265P status and the size of serum IgM are not prognostic in WM. Our data suggest the need for simplification of the current staging system with the use of widely available markers: serum albumin and lactate dehydrogenase.image

Childhood TB: When to think of it and what to do when you do

Although childhood tuberculosis has declined dramatically in the UK over the last century, it is now increasing again and globally childhood tuberculosis still accounts for a significant proportion of the tuberculosis disease burden. Children may present with non-specific symptoms, and because of the paucibacillary nature of disease and the difficulty of producing sputum samples, tuberculosis in children is often difficult to diagnose. Apart from the traditional diagnostic methods, like chest X-ray, tuberculin skin testing and mycobacterial staining or culture, new diagnostic strategies have been developed. In particular, immune-based diagnostics, such as interferon-gamma release assays, have now been introduced for clinical use. However these tests do not offer substantial improvements in sensitivity over tuberculin skin testing for the diagnosis of active disease. Further research is needed to develop better diagnostic tests for tuberculosis in children.

The value of fecal calprotectin as a marker of intestinal inflammation in patients with ulcerative colitis

To assess intestinal inflammation, simple, inexpensive and objective tools are desirable in inflammatory bowel disease. This study aimed to evaluate fecal calprotectin as a marker of active disease in ulcerative colitis. Sixty patients with a diagnosis of ulcerative colitis and 20 controls were recruited into the study. The disease activity of ulcerative colitis was determined by modified Truelove-Witts criteria and Rachmilewitz endoscopic index. The enzyme-linked immunosorbent assay was used to measure the concentrations of fecal calprotectin. C-reactive protein, erythrocyte sedimentation rate and hemogram were also measured, and inflammatory markers were compared with fecal calprotectin in determining disease activity. Fecal calprotectin concentration in the patients with active ulcerative colitis (n=30) was significantly higher than that in the inactive ulcerative colitis group (n=30) and in the controls (n=20) (95% confidence interval: 232.5 (0.75-625) vs 11.7 (0.2-625), 7.5 (0.5-512) mg/L, p<0.001). There was no significant difference between the patients with inactive ulcerative colitis and controls (p>0.05). The calprotectin concentration was greater in the patients with a more severe clinical index, higher endoscopic activity (>4), elevated C-reactive protein, leukocytosis, and extensive colitis (p<0.05). The areas under the curve of the receiver operating characteristics were 0.817, 0.809, 0.532, and 0.507 for C-reactive protein, fecal calprotectin, leukocyte count, and erythrocyte sedimentation rate, respectively. There was a significant correlation between the fecal calprotectin concentration and the endoscopic activity in ulcerative colitis (r = 0.548, p<0.001). Fecal calprotectin is a useful marker in the diagnosis of active disease and evaluation of clinical and endoscopic activity in ulcerative colitis.

Tuberculosis Characterization in a Special Population of Kidney Transplant Recipients

Setting. Tuberculosis clinical presentation is not typical in kidney transplant recipients and the diagnosis of active disease is usually delayed. Objective. To characterize tuberculosis presentation in Brazilian's kidney transplant recipients. Study Design. We analyzed the clinical records of tuberculosis cases regarding sociodemographic data and health history. Results. Thirteen TB cases were identified among 843 transplant recipients. The average time for TB development after transplantation was 4 years. Eight subjects presented pulmonary disease, seven patients required hospitalization Alertness to the possibility of TB and the careful evaluation for possible TB of all kidney transplant recipients with unexplained is vital, as is the related work of transplant and TB control teams and four died as a consequence of TB. Conclusion. The severe consequences of TB in posttransplantation can become critical.

Positron Emission Tomography in the Diagnosis and Treatment Management of Tuberculosis

Early diagnosis of TB is essential for community health and infection control, as well as for starting appropriate therapy for patients. Early detection of MDR is essential for the same reasons, plus the fact that currently a very high percentage of MDR patients die, especially in developing countries. Both genotypic and phenotypic methods allowing assessment of MDR tuberculosis on the bacilli isolated from fluids of infected patients are available, but these tests are lengthy (6-16 weeks) and require infected body fluids, which are not always easily assessable. Patients presenting pulmonary TB can also be culture-negative. Diagnosis of active disease in a pulmonary tuberculoma has long been problematic because the non-specific character of the disease, its changing manifestations and the slow growth of the organisms make its isolation a long and time-consuming process. Determination of pulmonary tuberculoma activity may be mandatory for optimal treatment strategy, therefore imaging techniques may be helpful in early detection. The aim of this review is to assess the role of Positron Emission Tomography (PET) imaging in the diagnosis and therapy management of TB. Although studies and data on the potential role of FDG PET in the diagnosis of tuberculosis are limited, a literature search revealed some interesting studies on this subject. Most of the studies described indicate that PET imaging, especially FDG PET as diagnostic tool, could be a noninvasive method that gives additional information about the disease status, enabling improved therapeutic management of pulmonary mycobacterial infection. Furthermore, several studies provide evidence that PET imaging could be useful in tuberculostatic therapy evaluation.

WE-B-201B-04: Monitoring and Validating Metastatic Tumor Growth in Lung CT

Purpose: The advent of body SRT has lead to dramatically improved survival of patients with metastatic spread to the lung. In turn, there is a renewed interest in CT surveillance of at‐risk cancer survivors and for radiologist‐assist diagnosis tools for early‐stage metastatic disease. Accurate measurement of nodule growth is critical for diagnosis of active disease and quantification of treatment response, but validation of methods for measuring growth is impeded by the large variability in radiologists' estimates of nodule volume. Method and Materials: A simulated nodule growth CTdatabase is being created based on real nodule morphology and image features. The database's utility is demonstrated on an automated growth assessment approach and the same tool is then applied to a patient with multiple metastases to the lung followed over a two‐year duration. Results: An initial simulated nodule dataset was created incorporating juxta‐vascular, juxta‐pleural, and parenchymal nodules. The automated assessment tool identified correctly growth as small as 16%, with the largest errors in the juxta‐pleural dataset. In a patient with multiple (>15) bladder cancer metastases, nodule growth rates were found to vary among nodules, suggesting that regional heterogeneity in lung perfusion and/or oxygenation may affect growth rates of metastases. Conclusion: A realistic simulated 3‐D CTlung nodule dataset has been initiated with the capacity to accurately mimic small changes in volume. Simulated nodules reconstructed from real patient lung metastases were employed to evaluate the efficacy of a novel 3‐D growth assessment algorithm. The validation of volume change accuracy in this manner reduces a great deal of the ambiguity and subjectivity that is encountered when radiologist measurements are utilized as the gold standard for nodule size. Assessment of variable growth rates of multiple metastases in an example patient shows promise for improved selection of active disease and characterization of treatment response.

Management of tuberculosis in HIV infection: where T-cells matter

Even 127 years after Robert Koch's identification of Mycobacterium tuberculosis as the causative agent of tuberculosis (TB), the diagnosis of active disease still depends in many parts of the world on the same tools that Koch has used: specifically staining of the bacilli and visual observation by microscopy 1. Thirty years later, von Pirquet developed the tuberculin skin-test (TST), which, instead of observing the pathogenic microbe itself, measures the immunological response to it 2. We now know that the specific induration in the skin-test is mediated by specifically activated T-lymphocytes that elicit a delayed-type hypersensitivity (DTH) response via production of a variety of inflammatory cytokines. While both test systems are still widely used, their sensitivity is highly variable and ranges from 20 to 60% for microscopy 3, 4, and 67 to 80% for skin-testing 5, 6. In patients with HIV infection and other forms of immunosuppression, the sensitivity is even worse and far beyond being adequate for a modern diagnostic test 7, 8. In their recent manuscript, Leidl et al. 9 now compare the performance …

The tuberculin skin test: a hundred, not out?

In 1890, at a World Congress of Medicine in Berlin, Robert Koch announced a substance that he claimed would both cure and prevent tuberculosis. Although this substance, a glycerin extract...

Herpes Simplex Virus Type‐Specific Serology: Where Does it Fit in the Diagnostic Armamentarium?

Herpes Simplex Virus Type‐Specific Serology: Where Does it Fit in the Diagnostic Armamentarium?

New tools and emerging technologies for the diagnosis of tuberculosis: Part II. Active tuberculosis and drug resistance

Tuberculosis (TB) is one of the world’s most important infectious causes of morbidity and mortality among adults. Between 8 and 9 million develop TB disease, and approximately 2 million die from TB each year. Despite this enormous global burden, case detection rates are low, posing major hurdles for TB control. Conventional TB diagnosis continues to rely on smear microscopy, culture and chest radiography. These tests have known limitations. Conventional tests for detection of drug resistance are slow, tedious and difficult to perform in field conditions. This second half of a two-part review series on new tools for TB diagnosis describes recent advances and emerging technologies in the diagnosis of active disease, and detection of drug resistance. For diagnosis, new tools include newer versions of nucleic acid amplification tests, immune-based assays, skin patch test and rapid culture systems. For drug resistance, new tools include line-probe assays, bacteriophage-based assays, molecular beacons and microscopic observation drug susceptibility assay. Although the ideal test for TB is still not in sight, substantial progress has been made in the past decade. With the resurgence of interest in the development of new tools for TB control, it is likely that the next decade will see greater progress and tangible benefits. However, the challenge will be to ensure that new tools undergo rigorous evaluations in field conditions, and also to make sure that benefits of promising new tools actually reach the populations in developing countries that need them most. Latent TB is discussed in Part I; 413–422 of this issue.

Reduced level of serum thiols in patients with a diagnosis of active disease.

Oxidative stress, or the production of oxygen-centered free radicals, has been hypothesized as the major source of DNA damage that in turn can lead to altered genetic expression, disease, and aging of humans. Serum protein thiol levels in blood are a direct measure of the in vivo reduction/oxidation (redox) status in humans, because thiols react readily with oxygen-containing free radicals to form disulfides. Moreover, serum thiols also reflect DNA repair capacity and the possible eventual accumulation of genetic damage, since a key DNA repair enzyme, poly ADP-ribose polymerase (PARP), is thiol/disulfide redox regulated. This study tests the hypothesis that serum protein thiols can be used to estimate individual aging status by comparing the levels of apparently healthy subjects (n = 90) to those of individuals (n = 306) with an active disease diagnosis. Nine categories of human disorders all showed highly significant reductions in serum protein thiols from 46 to 91 nM cysteine/200 microL serum (mean +/- S.D. = 59 +/- 40) compared to a control mean of 128 +/- 39 nM cysteine/200 microL serum (p <.001). These data strongly confirm an important role of oxidative stress in human disease development, and identify serum thiol status as a potential biochemical endpoint useful in the assessment of aging.

Anti-leishmanial IgE antibodies: a marker of active disease in visceral leishmaniasis.

Visceral leishmaniasis (VL) is characterized by a depression of the T helper cell type 1 immune response. Although mRNA expression for interleukin-4 (IL-4) is observed, evidence of the role of this cytokine in the pathogenesis of VL has been lacking. Since IL-4 is involved in IgE synthesis, we measured the total IgE and Leishmania antigen-specific IgE antibody levels in sera from patients with VL. Specific IgE antibodies detected by an ELISA technique after absorbing the sera with purified sheep IgG anti-human IgG were found in all 23 patients with VL and were not detected in subjects with subclinical Leishmania chagasi infection (n = 10), Chagas' disease (n = 10), atopic patients (n = 10), and healthy controls (n = 10). Levels of Leishmania-specific IgE (optical density values) before and after treatment were 0.100 +/- 0.03 (mean +/- SD) and 0.028 +/- 0.002, respectively (P < 0.05). These results indicate that a specific IgE response is useful in the diagnosis of active disease and to evaluate response to treatment.

Transient vitreous inflammatory reactions associated with combination antiretroviral therapy in patients with AIDS and cytomegalovirus retinitis

To report the observation that a transient vitreous inflammatory reaction may develop in the eyes of patients with acquired immunodeficiency syndrome (AIDS), cytomegalovirus retinitis, and an increased CD4+ T-lymphocyte count during treatment with antiretroviral therapy including a protease inhibitor. We reviewed the medical records of eight patients with AIDS and cytomegalovirus retinitis who developed vitreous inflammatory reactions greater than those usually seen with this disease. Vitreous inflammatory reactions obscured the view of the posterior pole in all patients. No iris nodules, synechiae, glaucoma, or cystoid macular edema were observed. Six patients had unilateral cytomegalovirus retinitis, and, in each, the inflammation occurred only in the eye with cytomegalovirus retinitis. The vitreous inflammatory reactions were associated with clinically inactive cytomegalovirus retinitis in six patients, with disease reactivation in one patient, and were present at diagnosis of active disease in one patient. Cytomegalovirus retinitis has not recurred in any of these patients since their episodes of vitreous inflammation. Vitreous inflammation developed in all eight patients after a substantial increase in CD4+ T-lymphocyte counts caused by combination antiretroviral therapy. Five patients had CD4+ T-lymphocyte counts of greater than 100 cells per microl at the time the vitreous inflammatory reaction developed. No other causes of uveitis were found. Patients with AIDS and cytomegalovirus retinitis may develop transient intraocular inflammation associated with combination antiretroviral therapy. We believe that this inflammation reflects an improved immune response against cytomegalovirus.

Outpatient management of inflammatory bowel disease. Let's keep it as simple as possible.

Inflammatory bowel disease is a conglomeration of disorders of unclear etiology and pathogenesis. Confirming the diagnosis of active disease may be difficult but is critical to judicious therapy. Sulfasalazine (Azulfidine) and its newer derivatives mesalamine (Asacol, Rowasa) and olsalazine sodium (Dipentum) are used for treatment of mild disease and maintenance. Corticosteroid therapy controls moderate disease in most patients, but withdrawal may be difficult. Immunosuppression or surgery may be necessary in severe or refractory cases. The risk of cancer as a complication of inflammatory bowel disease is often exaggerated but cannot be ignored.

Juvenile Graves disease: Usefulness and limitations of thyrotropin receptor antibody determinations

Thyrotropin receptor antibodies (TRAb) were measured in serum from 49 patients with active and inactive juvenile Graves disease, and the results were compared with values from control subjects and patients with Hashimoto disease. With a thyrotropin binding inhibition immunoglobulin (TBII) assay, TRAb were found in serum from 25 (93%) of 27 patients with untreated, active Graves disease. The TRAb values remained positive in 20 (72%) of 29 patients during the first 6 months of antithyroid therapy and in 13 (54%) of 24 patients during the second 6 months. After discontinuation of antithyroid therapy, 15 patients experienced 18 episodes of relapse of thyrotoxicosis; during relapse TRAb values were positive in all but one patient. Among 19 patients who remained clinically and biochemically euthyroid after cessation of antithyroid therapy, TRAb were not detected in 28 (78%) of 36 serum specimens. Of the eight positive values from six patients, no antiidiotypic antibodies were found, and thyroid stimulating immunoglobulins (TSI) were not detected in four specimens. The TRAb determination correctly predicted the subsequent clinical course in 26 (72%) of 36 patients. Furthermore, TRAb values and results of triiodothyronine suppression tests were in agreement in 27 of 36 patients, or 75% of the time. TSI were present in serum from only 19 (73%) of 26 patients with active disease; however, TSI were negative in all patients with inactive Graves disease. During the management of Graves disease, TRAb measurements by TBII determinations are valuable in the diagnosis of active disease, assist in the decision to discontinue antithyroid drug therapy, and are useful as the T3 suppression test to predict the clinical course of the disease. The TSI measurement is most useful to determine the activity of the disease when TRAb values are positive in a euthyroid patient.

DIAGNOSTIC CRITERIA FOR HUMAN BRUCELLOSIS

Human brucellosis for the most part appears as a sporadic disease. For this reason, and also because the symptomatology simulates many other illnesses, a definite diagnosis of active disease can only be made with the aid of laboratory procedures. After careful evaluation of the problem of the diagnosis of human brucellosis, and after consultation with investigators in this field, this committee has attempted to crystallize the available information on the subject. This report has been prompted by the interest and misunderstanding manifested by the medical profession, and by the confusion that has been engendered by the current emphasis being placed on chronic brucellosis and the wide use of the intradermal test for diagnostic purposes. For the sake of brevity and clarity, no attempt has been made to document the statements made in this report. 1 Critical clinical information now available has been summarized in the following statement. ISOLATION OF BRUCELLA