Anatomy of a serial killer: differential diagnosis of tuberculosis based on rib lesions of adult individuals from the Coimbra Identified Skeletal Collection, Portugal

The role of new bone formation on visceral surfaces of ribs in the diagnosis of tuberculosis (TB) in past human populations has been explored by many researchers, using both skeletal remains with known causes of death and archaeological samples. This study focuses, firstly, on adult skeletons from the Coimbra Identified Skeletal Collection in Portugal and investigates the skeletal manifestations of individuals known to have died from TB; secondly, this study focuses on the role of rib lesions in the diagnostic criteria for TB. One hundred and fifty-seven males and 106 females aged between 22-87 years were examined; causes of death were assigned as pulmonary TB, extrapulmonary TB, and pulmonary non-TB; a control group, extrapulmonary non-TB, was selected from the remaining individuals. Of individuals with rib lesions, 85.7% (69/81) had pulmonary or extrapulmonary TB as an assigned cause of death, while 17.8% (16/90) of individuals with rib lesions had a non-TB cause of death. Rib lesions were significantly more common in individuals who had died from TB, although the lesions cannot be considered pathognomonic for TB. In individuals dying from pulmonary TB, ribs in the central part of the rib cage were most affected, at their vertebral ends. The lower part of the rib cage may be a marker for peritoneal TB, and "coral-like" new bone formation on ribs may be an indicator of neoplastic disease. Further work on rib involvement in TB in clinical contexts, and the study of further documented skeletal collections, are recommended.     

Rib lesions in a prehistoric Puebloan sample from southwestern Colorado

An unusually high frequency of periosteal lesions of visceral rib surfaces was observed in a small, prehistoric skeletal series from southwestern Colorado. Lesions of this type have been concordant with pulmonary tuberculosis in three studies of human skeletal collections with known cause of death, and in a recent clinical investigation of rib dimensions in living patients with lung disorders. Diseases such as pneumonia and actinomycosis have also been found to cause these lesions, but in much lower frequencies. Archaeological evidence suggests that Puebloan farmers of Sleeping Ute Mountain's southern piedmont, from which the sample is drawn, endured unusually harsh environmental conditions punctuated by severe drought and exacerbated by escalating warfare. It is argued here that these environmental stressors increased susceptibility to an opportunistic respiratory infection reminiscent of tuberculosis, and possibly also some form of pneumonia, resulting in high rates of active disease previously noted only in historic Puebloan peoples.     

Tuberculosis in the New World: a study of ribs from the Schild Mississippian population, West-Central Illinois

Vertebral lesions have been the main evidence for infection by the Mycobacterium tuberculosis complex (MTC) in paleopathology. Skeletal involvement is expected in a small percentage of infected individuals. Recently, several authors report a correlation between rib lesions and tuberculosis (TB) complex infection. This study tests the hypothesis that rib lesions can serve as a useful marker for MTC infection within the Mississippian Schild skeletal collection from West-Central Illinois. Ribs from 221 adults and juveniles were examined, and affected individuals were tested for TB complex infection. DNA from rib samples of affected individuals was amplified with primers targeting the IS6110 insertion element, which is common to all members of the TB complex. Although it cannot allow discrimination between different species of TB, IS6110 is present in many copies within their genomes, and its presence is thus an indication of MTC infection. The results support the use of rib lesions as a marker for TB infection. Additionally, we demonstrate that MTC DNA can be recovered from ribs that lack lesions in individuals who have lesions of other bones. We recommend that an examination of ribs be incorporated into investigations for TB.     

Chest radiography findings in primary pulmonary tuberculosis in children

Plain chest radiography plays a major role in the diagnosis and follow-up of pulmonary tuberculosis in childhood. The aim of our study was to investigate the distribution of characteristic chest radiographic findings at diagnosis in children with pulmonary tuberculosis. The age of the patients and the type and localization of radiographic changes at admission were retrospectively analyzed. We reviewed chest radiographs in 204 children admitted from January 1, 1991 until June 30, 1994 for newly diagnosed pulmonary tuberculosis. Mean age +/- SD was 6.4 +/- 4.2 years (range 0-14). The most common lesion was lymphadenopathy (found in 172 children, 84.3%). It was significantly more common in the youngest age group (0-4 years) and was more significantly present in the right hilo-mediastinal region. Parenchymal changes were found in 125 children (61.3%). They were also significantly more common in the young age group and in the right lung. Other less common lesions included pleuritis, atelectasis, destructive-cavitary lesions and miliary dissemination. In conclusion, the leading radiographic finding in pulmonary tuberculosis in childhood remains hilar lymphadenopathy, but parenchymal changes are clearly strongly present, and should be sought and appreciated in the diagnostic work-up for pulmonary tuberculosis in childhood.     

Development and characterization of a caprine aerosol infection model of melioidosis

Infection with Burkholderia pseudomallei causes the disease melioidosis, which often presents as a serious suppurative infection that is typically fatal without intensive treatment and is a significant emerging infectious disease in Southeast Asia. Despite intensive research there is still much that remains unknown about melioidosis pathogenesis. New animal models of melioidosis are needed to examine novel aspects of pathogenesis as well as for the evaluation of novel therapeutics. The objective of the work presented here was to develop a subacute to chronic caprine model of melioidosis and to characterize the progression of disease with respect to clinical presentation, hematology, clinical microbiology, thoracic radiography, and gross and microscopic pathology. Disease was produced in all animals following an intratracheal aerosol of 10(4) CFU delivered, with variable clinical manifestations indicative of subacute and chronic disease. Bronchointerstitial pneumonia was apparent microscopically by day 2 and radiographically and grossly apparent by day 7 post infection (PI). Early lesions of bronchopneumonia soon progressed to more severe bronchointerstitial pneumonia with pyogranuloma formation. Extrapulmonary dissemination appeared to be a function of pyogranuloma invasion of pulmonary vasculature, which peaked around day 7 PI. Histopathology indicated that leukocytoclastic vasculitis was the central step in dissemination of B. pseudomallei from the lungs as well as in the establishment of new lesions. While higher doses of organism in goats can produce acute fatal disease, the dose investigated and resulting disease had many similarities to human melioidosis and may warrant further development to provide a model for the study of both natural and bioterrorism associated disease.     

Comparative investigation of the pathogenicity of three Mycobacterium tuberculosis mutants defective in the synthesis of p-hydroxybenzoic acid derivatives

p-Hydroxybenzoic acid derivatives (p-HBADs) are glycoconjugates secreted by all Mycobacterium tuberculosis isolates whose contribution to pathogenicity remains to be determined. The pathogenicity of three transposon mutants of M. tuberculosis deficient in the biosynthesis of some or all forms of p-HBADs was studied. Whilst the mutants grew similarly to the wild-type strain in macrophages and C57BL/6 mice, two of the mutants induced a more severe and diffuse inflammation in the lungs. The lack of production of some or all forms of p-HBADs in these two mutants also correlated with an increased secretion of the pro-inflammatory cytokines tumour-necrosis factor alpha, interleukin 6 and interleukin 12 in vivo. We propose that the loss of production of p-HBADs by tubercle bacilli results in their diminished ability to suppress the pro-inflammatory response to infection and that this ultimately provokes extensive pulmonary lesions in the C57BL/6 model of tuberculosis infection.     

Investigation of the link between visceral surface rib lesions and tuberculosis in a Medieval skeletal series from England using ancient DNA

Seven human skeletons from a large assemblage from a rural English Medieval burial site show lesions, predominantly proliferative in nature, on the visceral surfaces of the ribs. In order to investigate whether these rib lesions were regularly associated with tuberculous infection, these individuals, together with a group of age- and sex-matched control skeletons without bony signs of infection, were subjected to polymerase chain reaction (PCR) assays aimed at detecting traces of DNA from infecting microorganisms of the Mycobacterium tuberculosis complex. The results provided no evidence for any regular association between visceral surface rib lesions and the presence of M. tuberculosis complex DNA in the study group. The significance of these findings for the paleopathological interpretation of visceral surface rib lesions is discussed.     

Rational antimicrobial pharmacotherapy of secondary infections in patients with pulmonary tuberculosis]

The results of 3-year (2002-2004) local microbiological monitoring of secondary infections due to opportunistic microflora that complicated the treatment of the main disease in patients of a regional (Moscow) tuberculosis hospital are presented. The monitoring revealed the leading microorganisms, the etiological agents of the secondary lower respiratory tract infection in the patients with pulmonary tuberculosis. The level of their resistance to the up-to-date antimicrobials was determined. Recommendations for optimization of antibacterial therapy of patients with pulmonary tuberculosis complicated by secondary lower respiratory tract infection due to opportunistic microorganisms were developed and validated.     

Gramnegative opportunistic microflora as etiological factor of secondary infection in patients with pulmonary tuberculosis]

The results of the laboratory diagnoses of respiratory tract secondary infections in patients with pulmonary tuberculosis within a period of 12 months in a tuberculosis clinic were generalized. The species composition of the causative agents of lower respiratory tract secondary infection and the frequency of their detection in various clinical speciments (sputum, bronchial washings) were determined. The data on resistance of the opportunistic gramnegative bacilli (enterobacteria, pseudomonads, Acinetobacter spp.) isolated from the patients with pulmonary tuberculosis to various groups of antibacterials are presented.     

Osteological and Biomolecular Evidence of a 7000-Year-Old Case of Hypertrophic Pulmonary Osteopathy Secondary to Tuberculosis from Neolithic Hungary

Seventy-one individuals from the late Neolithic population of the 7000-year-old site of Hódmezővásárhely-Gorzsa were examined for their skeletal palaeopathology. This revealed numerous cases of infections and non-specific stress indicators in juveniles and adults, metabolic diseases in juveniles, and evidence of trauma and mechanical changes in adults. Several cases showed potential signs of tuberculosis, particularly the remains of the individual HGO-53. This is an important finding that has significant implications for our understanding of this community. The aim of the present study was to seek biomolecular evidence to confirm this diagnosis. HGO-53 was a young male with a striking case of hypertrophic pulmonary osteopathy (HPO), revealing rib changes and cavitations in the vertebral bodies. The initial macroscopic diagnosis of HPO secondary to tuberculosis was confirmed by analysis of Mycobacterium tuberculosis complex specific cell wall lipid biomarkers and corroborated by ancient DNA (aDNA) analysis. This case is the earliest known classical case of HPO on an adult human skeleton and is one of the oldest palaeopathological and palaeomicrobiological tuberculosis cases to date.     

Chronic pulmonary histoplasmosis in the State of Rio de Janeiro,Brazil

Three cases of chronic pulmonary histoplasmosis affecting aged patients with chronic obstructive pulmonary disease are reported. They had a history of recurrent episodes of respiratory infection and presented radiological lung lesions inducing a misdiagnosis of chronic pulmonary tuberculosis of the adults. The diagnosis of histoplasmosis, suggested by the immunodiffusion test and the detection of yeastlike cells in smeared and stained sputum, was confirmed by the isolation and identification of Histoplasma capsulatum var. capsulatum in selective media. The treatment was carried out with amphothericin B and ketoconazole or itraconazole. Clinical, radiologic, mycologic and serologic improvement was obtained in all the patients. However, relapses occurred within a period of 1 to 18 months after the interruption of the treatment. Mycological diagnosis and the difficulties observed in the tretament were discussed. In addition data on the epidemiology of histoplasmosis in the state of Rio de Janeiro, Brazil, were presented. This revised version was published online in June 2006 with corrections to the Cover Date.     

Characteristics of the x-ray picture of pulmonary tuberculosis in alcoholics

Tuberculosis prevalence among alcoholics is high, and pathomorphological and clinical manifestations of the disease are marked. Altogether 84 chronic alcoholics with pulmonary tuberculosis (the 1st group) and 100 tuberculosis non-alcoholic patients (100 controls--the 2nd group) were investigated. X-ray signs of the disease progression, more prevalent changes and more frequent multiple disintegration cavity of larger size are noted in the 1st group. During x-ray investigation of such patients emphasis must be laid on a search for disintegration cavities and bronchogenic dissemination.     

7例影像学表现为弥漫肺间质性病变的肺结核报道及文献复习

目的:通过对7例高分辨CT(High Resolution Computed Tomography,HRCT)表现为弥漫肺间质性病变的肺结核患者的相关资料进行分析,结合相关文献,提高对该类肺结核的认识。方法:分析本院2012.2~2015.3确诊的7例HRCT表现为弥漫肺间质性病变的肺结核的临床症状、体征、影像学资料及痰抗酸杆菌、结核菌素纯蛋白衍生物(Purified Protein Derivative,PPD)试验、T细胞斑点试验(T-SPOT.TB)、抗结核抗体、血常规、血沉(Erythrocyte Sedimentation Rate,ESR)等实验室检查、病理检查等资料。结果:6例经2次以上痰涂片阳性确诊为肺结核,1例抗结核治疗有效诊断为肺结核;弥漫肺间质性病变的肺结核患者HRCT上间质性病变的范围与抗酸杆菌的检出及发热症状的出现有关联;与盗汗、乏力、咯血等结核中毒症状及PPD、结核抗体、ESR等指标无明显相关关系。结论:弥漫肺间质性病变也可为肺结核的一种特殊表现,极易误诊为其他间质病变。当患者临床表现及实验室检查无特殊发现时,需考虑肺结核的可能并进行结核病相关检查,尤其是抗酸杆菌及肺组织病理检查,以尽早明确诊断。     

Role of some representatives of opportunistic microflora in development of secondary infection in patients with pulmonary tuberculosis]

The results of the laboratory diagnosis of secondary (mixed) infection of the respiratory tracts in patients with respiratory tract tuberculosis were summarized. The study was performed for 12 months in a Tuberculosis Clinic. The species of the pathogens and the frequency of their detection in various clinical specimens from pulmonary tuberculosis patients were determined. The data on resistance of the strains of Streptococcus viridans group isolated from the pulmonary tuberculosis patients to various antimicrobials including new fluoroquinolones are presented.     

慢性阻塞性肺疾病患者继发肺部真菌感染的临床分析

目的探讨慢性阻塞性肺疾病(COPD)患者继发肺部真菌感染的临床特点。方法回顾性分析2008年1月到2010年12月安徽医科大学第一附属医院收治的COPD继发肺部真菌感染患者病例,并对其耐药情况进行比较。结果本组199例COPD患者检出白色念珠菌137例(68.84%),光滑念珠菌32例(16.08%),热带念珠菌17例(8.54%),克柔念珠菌9例(4.52%),毛霉菌3例(1.51%),清酒假丝酵母菌1例(0.50%);白色念珠菌检出率有下降趋势,热带念珠菌有上升趋势;196例真菌对伏立康唑、氟康唑、两性霉素B、伊曲康唑、氟胞嘧啶的耐药率分别为3.6%、5.1%、1.0%、8.7%和0;2008年至2010年白色念珠菌和光滑念珠菌耐药率变化差异无统计学意义。结论 COPD患者继发肺部真菌感染病原菌仍以白色念珠菌为主,其次为光滑念珠菌和热带念珠菌;白色念珠菌和光滑念珠菌耐药率无明显改变。     

On the trail of pulmonary tuberculosis based on rib lesions: results from the Human Identified Skeletal Collection from the Museu Bocage (Lisbon, Portugal)

In the last 20 years, studies on human identified skeletal collections have revealed a significant relationship between new bone formation on the visceral surface of ribs and pulmonary tuberculosis (TB). To improve methods of differential diagnosis of respiratory diseases in archaeological skeletons, an investigation was conducted on 197 individuals from the Human Identified Skeletal Collection of the Museu Bocage (Lisbon, Portugal). This sample included 109 males and 88 females who lived during the 19th-20th centuries, with ages at death ranging from 13-88 years. The skeletons were grouped according to cause of death: 1) pulmonary TB (N = 84); 2) pulmonary non-TB diseases (N = 49); and 3) a control group (N = 64) composed of individuals randomly selected among the extrapulmonary non-TB causes of death. The ribs, sterna, scapulae, and clavicles were macroscopically observed. New bone formation on the visceral surface of ribs was recorded in 90.5% (76/84) of individuals who died from pulmonary TB, in 36.7% (18/49) with a pulmonary non-TB disease as cause of death, and in 25.0% (16/64) of the control group. These differences were statistically significant (P < 0.001). Furthermore, in individuals with pulmonary TB, the bony lesions presented mainly as lamellar bone on the vertebral end of the upper and middle thoracic rib cage. Proliferative alterations also occurred on one sternum and in nine clavicles and eight scapulae. This work strongly supports the results of similar studies performed on other documented collections, suggesting that new bone formation on ribs, although not pathognomonic, is a useful criterion for the differential diagnosis of pulmonary TB.     

Transmembrane TNF is sufficient to initiate cell migration and granuloma formation and provide acute, but not long-term, control of Mycobacterium tuberculosis infection

TNF is critical for immunity against Mycobacterium tuberculosis infection; however, the relative contributions of the soluble and transmembrane forms of TNF in this immunity are unknown. Using memTNF mice, which express only the transmembrane form of TNF, we have addressed this question. Wild-type (WT), TNF-/-, and transmembrane TNF (memTNF) mice were infected with M. tuberculosis by aerosol. TNF-/- mice developed overwhelming infection with extensive pulmonary necrosis and died after only 33 days. memTNF mice, like WT mice, contained bacterial growth for over 16 wk, developed an Ag-specific T cell response, and initially displayed compact granulomas, comprised of both lymphocytes and macrophages. Expression of mRNA for the chemokines CXCL10, CCL3, CCL5, and CCL7 was comparable in both WT and memTNF mice. As the infection progressed, however, the pulmonary lesions in memTNF mice became larger and more diffuse, with increased neutrophil accumulation and necrosis. This was accompanied by increased influx of activated memory T cells into the lungs of memTNF mice. Eventually, these mice succumbed to infection with a mean time to death of 170 days. The expression of memTNF on T cells is functionally important because the transfer of T cells from memTNF, but not TNF-/- mice, into either RAG-/- or TNF-/- mice conferred the same survival advantage on the M. tuberculosis-infected recipient mice, as the transfer of WT T cells. Therefore, memTNF, in the absence of soluble TNF, is sufficient to control acute, but not chronic, M. tuberculosis infection, in part through its expression on T cells.     

Passive serum therapy with polyclonal antibodies against Mycobacterium tuberculosis protects against post-chemotherapy relapse of tuberculosis infection in SCID mice

We investigated the protective role of immune-sera against reactivation of Mycobacterium tuberculosis infection in SCID mice and found that passive immunization with sera obtained from mice treated with detoxified M. tuberculosis extracts (delivered in liposomes in a composition known as RUTI) exerted significant protection. Our SCID mouse model consisted of aerosol infection by M. tuberculosis, followed by 3 to 8weeks of chemotherapy with isoniazid+rifampicin (INH+RIF) (25 and 10mg/kg, respectively). After infection and antibiotic administration, two groups of mice were treated for up to 10weeks with intraperitoneal passive immunization using hyperimmune serum (HS) obtained from mice infected with M. tuberculosis, treated with chemotherapy (INH+RIF) for 8weeks and inoculated with RUTI (HS group) or with normal serum (CT group). Significant differences were found between HS and CT groups in the number of bacilli in the lungs (3.68+/-2.02 vs. 5.72+/-1.41log(10) c.f.u.), extent of pulmonary granulomatomous infiltration (10.33+/-0.67 vs. 31.2+/-1.77%), and percentage of animals without pulmonary abscesses (16.7% vs. 45.5%). These data strongly suggest a protective role of specific antibodies against lung dissemination of M. tuberculosis infection.     

Interleukin-1 contributes to an effective clearance of Mycobacterium kansasii from the respiratory tract

Mycobacterium kansasii is an emerging pathogen that is able to induce pulmonary disease resembling tuberculosis. To determine the role of interleukin (IL-)1 in lung infection caused by this atypical mycobacterium, IL-1 receptor type 1 knockout (IL-1R(1) KO) and normal wild type mice were intranasally infected with M. kansasii. IL-1R(1) KO mice demonstrated a reduced antibacterial response in the lungs and an increased dissemination to the liver, which was accompanied by an enhanced pulmonary inflammatory response. These data identify IL-1 as an important component of the innate immune response to lung infection by M. kansasii.