Challenges and the Way forward in Diagnosis and Treatment of Tuberculosis Infection.

Globally, it is estimated that one-quarter of the world's population is latently infected with Mycobacterium tuberculosis (Mtb), also known as latent tuberculosis infection (LTBI). Recently, this condition has been referred to as tuberculosis infection (TBI), considering the dynamic spectrum of the infection, as 5-10% of the latently infected population will develop active TB (ATB). The chances of TBI development increase due to close contact with index TB patients. The emergence of multidrug-resistant TB (MDR-TB) and the risk of development of latent MDR-TB has further complicated the situation. Detection of TBI is challenging as the infected individual does not present symptoms. Currently, there is no gold standard for TBI diagnosis, and the only screening tests are tuberculin skin test (TST) and interferon gamma release assays (IGRAs). However, these tests have several limitations, including the inability to differentiate between ATB and TBI, false-positive results in BCG-vaccinated individuals (only for TST), false-negative results in children, elderly, and immunocompromised patients, and the inability to predict the progression to ATB, among others. Thus, new host markers and Mtb-specific antigens are being tested to develop new diagnostic methods. Besides screening, TBI therapy is a key intervention for TB control. However, the long-course treatment and associated side effects result in non-adherence to the treatment. Additionally, the latent MDR strains are not susceptible to the current TBI treatments, which add an additional challenge. This review discusses the current situation of TBI, as well as the challenges and efforts involved in its control.

Mini Review: Risk Assessment, Clinical Manifestation, Prediction, and Prognosis of Mucormycosis: Implications for Pathogen- and Human-Derived Biomarkers.

Mucormycosis is a fungal disease caused by members of the fungal order Mucorales, which are abundantly found in terrestrial environments. The fungi propagate clonally via mitospores, which are transmitted to humans through the air and cause superficial or invasive infections. The disease has emerged in recent years and coincides generally with immunosuppression on the patient side. Mucormycosis is still rarely recognized in the clinical because of its unspecific symptoms which often triggers misdiagnosis with bacterial or viral infections leading to prolonged therapeutic cycles and loss of valuable time to manage mucormycosis properly. Infected patients develop various clinical forms, most notably ranging from rhinocerebral via pulmonary to gastrointestinal forms. Traditional diagnosis is based on culture and histopathologic examinations of the affected tissue. But, the achievement of a precise result is time-consuming, labor-intensive, requires mycological expertise and the finding appears often too late. A rapid and precise diagnosis is mandatory because symptoms are non-specific and the disease is rapidly progressing with often fatal outcome. Mucormycosis was increasingly associated with other infections and underlying conditions and risk factors causing comorbidities, which are difficult to successfully manage. This mini-review summarizes the current knowledge on the epidemiology and causative agents of mucormycosis, transmission, risk factors, clinical presentation, diagnosis, and highlights the lack of appropriate biomarkers on the pathogen and the host sides for rapid pathogen and host susceptibility detection, respectively. Fungal antigens and single nucleotide polymorphisms (SNPs) in human host genes are useful for the assessment of susceptibility. This mini-review addresses possibilities for early prediction of susceptibility to mucormycosis based on forecasting of the risk of infection with fungal pathogens other than Mucorales. The topic of early prediction and diagnosis of mucormycosis represents a current research gap and highlights the importance of potential future developments in the area of risk assessment, susceptibility prognosis in conjunction with early diagnosis to reduce mortality in patients suffering from mucormycosis.

Evaluation of cytokine responses against novel Mtb antigens as diagnostic markers for TB disease.

OBJECTIVE: We investigated the accuracy of host markers detected in Mtb antigen-stimulated whole blood culture supernatant in the diagnosis of TB. METHODS: Prospectively, blood from 322 individuals with presumed TB disease from six African sites was stimulated with four different Mtb antigens (Rv0081, Rv1284, ESAT-6/CFP-10, and Rv2034) in a 24 h whole blood stimulation assay (WBA). The concentrations of 42 host markers in the supernatants were measured using the Luminex multiplex platform. Diagnostic biosignatures were investigated through the use of multivariate analysis techniques. RESULTS: 17% of the participants were HIV infected, 106 had active TB disease and in 216 TB was excluded. Unstimulated concentrations of CRP, SAA, ferritin and IP-10 had better discriminating ability than markers from stimulated samples. Accuracy of marker combinations by general discriminant analysis (GDA) identified a six analyte model with 77% accuracy for TB cases and 84% for non TB cases, with a better performance in HIV uninfected patients. CONCLUSIONS: A biosignature of 6 cytokines obtained after stimulation with four Mtb antigens has moderate potential as a diagnostic tool for pulmonary TB disease individuals and stimulated marker expression had no added value to unstimulated marker performance.

Biomarkers of therapeutic responses in chronic Chagas disease: state of the art and future perspectives

The definition of a biomarker provided by the World Health Organization is any substance, structure, or process that can be measured in the body, or its products and influence, or predict the incidence or outcome of disease. Currently, the lack of prognosis and progression markers for chronic Chagas disease has posed limitations for testing new drugs to treat this neglected disease. Several molecules and techniques to detect biomarkers in Trypanosoma cruzi-infected patients have been proposed to assess whether specific treatment with benznidazole or nifurtimox is effective. Isolated proteins or protein groups from different T. cruzi stages and parasite-derived glycoproteins and synthetic neoglycoconjugates have been demonstrated to be useful for this purpose, as have nucleic acid amplification techniques. The amplification of T. cruzi DNA using the real-time polymerase chain reaction method is the leading test for assessing responses to treatment in a short period of time. Biochemical biomarkers have been tested early after specific treatment. Cytokines and surface markers represent promising molecules for the characterisation of host cellular responses, but need to be further assessed.