The Diagnosis and Treatment of Tuberculosis

Background: Around 10 million people worldwide contract tuberculosis every year. According to the World Health Organization (WHO), approximately one-quarter of the worlds population is latently infected with Mycobacterium tuberculosis. In Germany, the incidence of tuberculosis was in decline over several decades but rose in 2015 to 7.3 new cases per 100 000 persons. In 2018, a total of 5429 new cases were documented, corresponding to 6.5 new cases per 100 000 persons. Methods: This article is based on literature retrieved by a selective search in PubMed and on the authors' clinical experience. Results: Tuberculosis involves the lungs in almost 75% of patients but can generally involve any organ. In Germany, the majority of patients come from high-incidence countries. If a patients differential diagnosis includes tuberculosis, the main tests for the detection of the pathogen in sputum and tissue samples are culture (the gold standard), microscopy, and nucleic acid amplification tests. Imaging studies are also used for diagnosis and follow-up. The standard treatment consists of a combination of isoniazid. rifampicin. ethambutol, and pyrazinamide, followed by a combination of isoniazid and rifampicin only. Liver damage is one of the more common adverse effects of this treatment, arising in 2.4% of patients. Multidrug-resistant tuberculosis, which is rare in Germany (around 100 cases per year), should be treated in specialized centers. Conclusion: Rapid diagnosis and targeted treatment are essential to prevent an unfavorable course of the disease as well as its transmission to other individuals. In patients presenting with unclear symptoms. tuberculosis should always be considered as a differential diagnosis. The diagnosis of latent tuberculosis and decision-making regarding its treatment are difficult because of the lack of specific biomarkers and of relevant data from clinical trials

Postoperative granulomatous peritonitis mimicking abdominal tuberculosis

Key Clinical Message Granulomatous peritonitis represents a rare postoperative complication that should be considered as important differential diagnosis in all patients who present to the hospital with abdominal pain, abdominal tenderness, and fever after abdominal surgery. Clinical distinction from abdominal tuberculosis remains a diagnostic challenge and requires thorough histopathological and microbiological examination

Characterization of the Peptide-Binding Specificity of Mamu-B*17 and Identification of Mamu-B*17-Restricted Epitopes Derived from Simian Immunodeficiency Virus Proteins

The SIV-infected rhesus macaque is an excellent model to examine candidate AIDS virus vaccines. These vaccines should elicit strong CD8(+) responses. Previous definition of the peptide-binding motif and optimal peptides for Mamu-A*01 has created a demand for Mamu-A*01-positive animals. We have now studied a second MHC class I molecule, Mamu-B*17, that is present in 12% of captive-bred Indian rhesus macaques. The peptide-binding specificity of the Mamu-B*17 molecule was characterized using single substitution analogs of two Mamu-B*17-binding peptides and libraries of naturally occurring sequences of viral or bacterial origin. Mamu-B*17 uses position 2 and the C terminus of its peptide ligands as dominant anchor residues. The C terminus was found to have a very narrow specificity for the bulky aromatic residue W, with other aromatic residues (F and Y) being only occasionally tolerated. Position 2 is associated with a broad chemical specificity, readily accommodating basic (H and R), bulky hydrophobic (F and M), and small aliphatic (A) residues. Using this motif, we identified 50 peptides derived from SIV(mac)239 that bound Mamu-B*17 with an affinity of 500 nM or better. ELISPOT and intracellular cytokine-staining assays showed that 16 of these peptides were antigenic. We have, therefore, doubled the number of MHC class I molecules for which SIV-derived binding peptides have been characterized. This allows for the quantitation of immune responses through tetramers and analysis of CD8(+) function by intracellular cytokine-staining assays and ELISPOT. Furthermore, it is an important step toward the design of a multiepitope vaccine for SIV and HIV

Resting-State Networks as Simultaneously Measured with Functional MRI and PET

Functional MRI (fMRI) studies reported disruption of resting-state networks (RSNs) in several neuropsychiatric disorders. PET with F-18-FDG captures neuronal activity that is in steady state at a longer time span and is less dependent on neurovascular coupling. Methods: In the present study, we aimed to identify RSNs in F-18-FDG PET data and compare their spatial pattern with those obtained from simultaneously acquired resting-state fMRI data in 22 middle-aged healthy subjects. Results: Thirteen and 17 meaningful RSNs could be identified in PET and fMRI data, respectively. Spatial overlap was fair tomoderate for the defaultmode, left central executive, primary and secondary visual, sensorimotor, cerebellar, and auditory networks. Despite recording different aspects of neural activity, similar RSNs were detected by both imaging modalities. Conclusion: The results argue for the common neural substrate of RSNs and encourage testing of the clinical utility of resting-state connectivity in PET data

Intensified adjunctive corticosteroid therapy for CNS tuberculomas

Introduction Central nervous system (CNS) tuberculomas are a challenging manifestation of extrapulmonary tuberculosis often leading to neurological complications and post-treatment sequelae. The role of adjunctive corticosteroid treatment is not fully understood. Most guidelines on management of tuberculosis do not distinguish between tuberculous meningitis and CNS tuberculomas in terms of corticosteroid therapy. Methods We describe five patients with CNS tuberculomas who required intensified dexamethasone treatment for several months, in two cases up to 18 months. Results These patients were initially treated with the standard four-drug tuberculosis regimen and adjuvant dexamethasone. Neurological symptoms improved rapidly. However, multiple attempts to reduce or discontinue corticosteroids according to guideline recommendations led to clinical deterioration with generalized seizures or new CNS lesions. Thus, duration of adjunctive corticosteroid therapy was extended eventually leading to clinical cure and resolution of lesions. Conclusion In contrast to tuberculous meningitis, the treatment for CNS tuberculomas appears to require a prolonged administration of corticosteroids. These findings need to be verified in controlled clinical studies

Diagnostic challenges in infective endocarditis: is PET/CT the solution?

PurposeDespite developments in both imaging and microbiological techniques, the final diagnosis of IE often remains challenging. In this single-center cohort study, we aimed to identify the specific indications for request of F-18-FDG-PET/CT in clinical practice and to evaluate the diagnostic benefit of this nuclear imaging technique.MethodsA total of 235 patients with possible (n=43) or definite (n=192) IE according to the revised Duke criteria were prospectively studied from July 2013 until December 2016. Echocardiography was generally used as the primary cardiac imaging technique. All patients were treated by a multidisciplinary Endocarditis Team. Diagnostics with F-18-FDG-PET/CT were undertaken on request by at least one member of the multidisciplinary team when overall diagnostics were inconclusive.ResultsIn 20 patients, F-18-FDG-PET/CT scan was performed for additional diagnostic evaluation. Hereof, 15 patients had a history of implanted cardiac prosthetic material. In six patients with definite IE, the use of F-18-FDG-PET/CT was helpful for further clarification of the diagnosis. In one patient with possible IE, the diagnosis could be reclassified to definite IE. In addition, one case of vertebral osteomyelitis as well as upper and lower leg abscesses and knee empyema were detectable as extracardiac foci. Furthermore, F-18-FDG-PET/CT leads to a modification of the management in five patients.ConclusionOur findings support the utility of F-18-FDG-PET/CT as an adjunctive diagnostic tool especially in the evaluation of prosthetic valve-/cardiac device-related IE and for the detection of extracardiac foci in some cases. However, due to remaining limitations also of this imaging technique, a multidisciplinary clinical evaluation still remains the essential basis for the diagnostic assessment

Severe disseminated tuberculosis in HIV-negative refugees

In high-income countries, the presentation of tuberculosis is changing, primarily because of migration, and understanding the specific health needs of susceptible populations is becoming increasingly important. Although disseminated tuberculosis is well documented in HIV-positive patients, the disease is poorly described and less expected in HIV-negative individuals. In this Grand Round, we report eight HIV-negative refugees, who presented with extensively disseminated tuberculosis. We discuss the multifactorial causes, such as deprivations during long journeys, precarious living conditions, and the experience of violence, which might add to nutritional factors and chronic disorders, eventually resulting in a state of predisposition to immune deficiency. We also show that disseminated tuberculosis is often difficult to diagnose when pulmonary symptoms are absent. Communication difficulties between refugees and health-care workers are another major hurdle, and every effort should be made to get a valid patient history. This medical history is crucial to guide imaging and other diagnostic procedures to establish a definite diagnosis, which should be confirmed by a positive tuberculosis culture. Because many of these patients are at risk for multidrug-resistant tuberculosis, drug susceptibility testing is imperative to guide therapy. In the absence of treatment guidelines for this entity, clinicians can determine treatment duration according to recommendations provided for extrapulmonary tuberculosis and affected organs. Paradoxical expansion of tuberculous lesions during therapy should be treated with corticosteroids. In many cases, treatment duration must be individualised and might even exceed 12 months

Consequences of Cytotoxic T-Lymphocyte Escape: Common Escape Mutations in Simian Immunodeficiency Virus Are Poorly Recognized in Naïve Hosts

Cytotoxic T lymphocytes (CTL) are associated with control of immunodeficiency virus infection but also select for variants that escape immune recognition. Declining frequencies of epitope-specific CTL frequencies have been correlated with viral escape in individual hosts. However, escape mutations may give rise to new epitopes that could be recognized by CTL expressing appropriate T-cell receptors and thus still be immunogenic when escape variants are passed to individuals expressing the appropriate major histocompatibility complex class I molecules. To determine whether peptide ligands that have been altered through escape can be immunogenic in new hosts, we challenged naïve, immunocompetent macaques with a molecularly cloned simian immunodeficiency virus (SIV) bearing common escape mutations in three immunodominant CTL epitopes. Responses to the altered peptides were barely detectable in fresh samples at any time after infection. Surprisingly, CTL specific for two of three escaped epitopes could be expanded by in vitro stimulation with synthetic peptides. Our results suggest that some escape variant epitopes evolving in infected individuals do not efficiently stimulate new populations of CTL, either in that individual or upon passage to new hosts. Nevertheless, escape variation may not completely abolish an epitope's immunogenicity. Moreover, since the mutant epitope sequences did not revert to wild type during the study period, it is possible that low-frequency CTL exerted enough selective pressure to preserve epitope mutations in viruses replicating in vivo

Cytotoxic T-Lymphocyte Escape Does Not Always Explain the Transient Control of Simian Immunodeficiency Virus SIVmac239 Viremia in Adenovirus-Boosted and DNA-Primed Mamu-A*01-Positive Rhesus Macaques

Adenovirus 5 (Ad5) vectors show promise as human immunodeficiency virus vaccine candidates. Indian rhesus macaques vaccinated with Ad5-gag controlled simian-human immunodeficiency virus SHIV89.6P viral replication in the absence of Env immunogens that might elicit humoral immunity. Here we immunized 15 macaques using either a homologous Ad5-gag/Ad5-gag (Ad5/Ad5) or a heterologous DNA-gag/Ad5-gag (DNA/Ad5) prime-boost regimen and challenged them with a high dose of simian immunodeficiency virus SIVmac239. Macaques vaccinated with the DNA/Ad5 regimen experienced a brief viral load nadir of less than 10,000 viral copies per ml blood plasma that was not seen in Mamu-A*01-negative DNA/Ad5 vaccinees, Mamu-A*01-positive Ad5/Ad5 vaccinees, or vaccine-naive controls. Interestingly, most of these animals were not durably protected from disease progression when challenged with SIVmac239. To investigate the reasons underlying this short-lived vaccine effect, we investigated breadth of the T-cell response, immunogenetic background, and viral escape from CD8(+) lymphocytes that recognize immunodominant T-cell epitopes. We show that these animals do not mount unusually broad cellular immune response, nor do they express unusual major histocompatibility complex class I alleles. Viral recrudescence occurred in four of the five Mamu-A*01-positive vaccinated macaques. However, only a single animal in this group demonstrated viral escape in the immunodominant Gag(181)(-)(189)CM9 response. These results suggest that viral “breakthrough” in vaccinated animals and viral escape are not inextricably linked and underscore the need for additional research into the mechanisms of vaccine failure

Dominance of CD8 Responses Specific for Epitopes Bound by a Single Major Histocompatibility Complex Class I Molecule during the Acute Phase of Viral Infection

Cytotoxic T-lymphocyte (CTL) responses are thought to control human immunodeficiency virus replication during the acute phase of infection. Understanding the CD8(+) T-cell immune responses early after infection may, therefore, be important to vaccine design. Analyzing these responses in humans is difficult since few patients are diagnosed during early infection. Additionally, patients are infected by a variety of viral subtypes, making it hard to design reagents to measure their acute-phase immune responses. Given the complexities in evaluating acute-phase CD8(+) responses in humans, we analyzed these important immune responses in rhesus macaques expressing a common rhesus macaque major histocompatibility complex class I molecule (Mamu-A*01) for which we had developed a variety of immunological assays. We infected eight Mamu-A*01-positive macaques and five Mamu-A*01-negative macaques with the molecularly cloned virus SIV(mac)239 and determined all of the simian immunodeficiency virus-specific CD8(+) T-cell responses against overlapping peptides spanning the entire virus. We also monitored the evolution of particular CD8(+) T-cell responses by tetramer staining of peripheral lymphocytes as well as lymph node cells in situ. In this first analysis of the entire CD8(+) immune response to autologous virus we show that between 2 and 12 responses are detected during the acute phase in each animal. CTL against the early proteins (Tat, Rev, and Nef) and against regulatory proteins Vif and Vpr dominated the acute phase. Interestingly, CD8(+) responses against Mamu-A*01-restricted epitopes Tat(28-35)SL8 and Gag(181-189)CM9 were immunodominant in the acute phase. After the acute phase, however, this pattern of reactivity changed, and the Mamu-A*01-restricted response against the Gag(181-189)CM9 epitope became dominant. In most of the Mamu-A*01-positive macaques tested, CTL responses against epitopes bound by Mamu-A*01 dominated the CD8(+) cellular immune response