Extrapulmonary Infection Research Articles

Advances in Drug Discovery and Development for Pediatric Tuberculosis.

Pediatric tuberculosis is an underappreciated global epidemic estimated to afflict around half a million children worldwide. This problem has historically been overlooked, due in part to their low social status and the difficulty in diagnosis of tuberculosis in children. Children are more susceptible to tuberculosis infection and disease progression, including rapid dissemination into extrapulmonary infection sites. Treatment of pediatric tuberculosis infections has been traditionally built around agents used to treat the adult disease, but the disease pathology, drug pharmacokinetics and the safety window in children differs from the adult disease. This produces additional concerns for drug discovery and development of new agents. This review examines: (i) the safety concerns for current front and second line agents used to treat complex drug resistant infections and how this knowledge can be used to identify, prioritize and dose agents that may be better tolerated in pediatric populations; and (ii) the chemistry and suitability of new drugs in the clinical development pipeline for tuberculosis for the treatment of pediatric infections indicating several new agents may offer significant improvements for the treatment of multi-drug resistant tuberculosis in children.

To Determine the Role of Procalcitonin in Febrile Neutropenic Episodes of Children Undergoing Treatment for Childhood Cancers

Background: Infections are major cause of morbidity and mortality in children receiving cancer chemotherapy particularly when they are neutropenic, mainly due to immune deficiency. Between 48-60% neutropenic patients with fever have an underlying infection which can often be life threatening. Before putting the child on empiric antimicrobial regimes for FN, it is essential to know the spectrum of locally prevalent pathogens and their susceptibility patterns. Often these children don’t manifest fever even in presence of infection and fever may be present in neutropenic patients receiving chemotherapy even in the absence of infection. Present diagnostic tools available for diagnoses in FN are often not so robust and do not differentiate between various classes of organisms causing these infections. Procedure: Blood culture is time consuming and negative blood culture does not exclude bacteremia, which leads to the empirical use of broad-spectrum antibiotic treatment in pediatric patients with neutropenia, even where signs of infection are absent. We propose to evaluate the role of PCT, as a sensitive marker to evaluate pediatric oncology patients presenting with FN. Results: Blood-culture was positive in 18.05% of the patients, with majority of patients having gram-negative bacterial infections. On comparison with the focus of infection, high PCT and CRP values were obtained in patients with pulmonary infection than in extra-pulmonary infections. In our study the sensitivity of PCT was high upto 73.3% at a cut-off of ≥0.25 ng/ml for ruling out bacteremia, when compared to blood culture and CRP in our patients. Conclusion: The PCT value is certainly helpful in guiding the physicians in clinical decisions and thus the better approach towards the management of pediatrics oncology patients with FN.

Clinical, diagnostic and therapeutic management of patients with breast tuberculosis: Analysis of 46 Cases

Breast tuberculosis is a rare form of extrapulmonary tubercular infection. Our aim is to highlight the nonspecific clinical presentations, diagnostic difficulties and therapeutic approaches of mammarian tuberculosis. Forty-six patients diagnosed with breast tuberculosis between 2005 and 2015 were reviewed retrospectively. Clinical features, all diagnostic methods, and the outcomes of treatment were analysed. All cases were female with a mean age of 36.4 years. Breast mass and pain were the most common complaints. While 34.8% of the cases had a physical examination with suspicions for malignancy, 43.5% of the patients had Breast Imaging Reporting and Data System (BI-RADS) 4 or 5 lesions suggested malignancy radiologically. Definitive diagnosis was based on histopathologic examination through core needle biopsy (n = 29), excisional biopsy (n = 12), and open biopsy (n = 5) taken from the abscess wall during drainage. Standard antiTB therapy for 6 months was given to all cases. Thirty-three patients recovered with standard 6-month therapy while extended treatment for 9–12 months was needed in 13 (28.2%) cases. Surgery was carried out in 17 cases. Two patients developed recurrence. Breast tuberculosis can be easily confused with breast cancer, suppurative abscess, and other causes of granulomatous mastitis, both clinically and radiologically. A multidisciplinary approach is required to prevent diagnostic delays and unnecessary surgical interventions. Although antiTB therapy is the mainstay treatment of breast TB, surgery is usually indicated in patients refractory to medical treatment.

Computed Tomography Features of Septic Pulmonary Embolism Caused by Klebsiella pneumoniae Liver Abscess Associated With Extrapulmonary Metastatic Infection.

The aims of the study were to investigate the computed tomography (CT) features and clinical course of septic pulmonary embolism (SPE) caused by Klebsiella pneumoniae liver abscess (KPLA) and to explore the possible mechanism underlying the spread of infection. Twenty-one patients with KPLA-induced SPE admitted to our hospital between January 2010 and May 2015 were evaluated. According to the presence or absence of extrapulmonary metastatic infection (EMI), they were divided into EMI and non-EMI groups and clinical and CT features of the 2 groups were compared. Hepatic vein thrombophlebitis was evaluated on liver CT images. Chest CT features included nodules, wedge-shaped lesions, ground-glass opacity, consolidation, cavitation, feeding vessel sign, pleural effusion, and lymphadenopathy. All the vessels within the so-called feeding vessel sign were confirmed as pulmonary veins by multiplanar reconstruction, so we used an alternative name draining vessel sign (DVS) instead. Peripheral nodules, DVS, and consolidation were the main CT features of KPLA-induced SPE. Peripheral nodules and DVS were more frequently seen in the EMI group than in the non-EMI group (P = 0.019 and 0.008, respectively). Five of 8 patients with hepatic vein thrombophlebitis had lung consolidation, whereas only 3 of 13 patients without hepatic vein thrombophlebitis had lung consolidation, although the difference was not significant (P = 0.09). Multiple pulmonary nodules and DVS were associated with EMI. Hepatic and pulmonary vein invasion are possible causes underlying the metastatic spread of infection.

Accuracy of QuantiFERON-TB Gold Test for Tuberculosis Diagnosis in Children.

ObjectivesTo evaluate the accuracy of the QuantiFERON-TB Gold assay (QFT-IT) in children with suspected active or latent TB infection (LTBI).MethodsA retrospective study was conducted on 621 children (0–14 years old) evaluated for TB infection or disease. Following clinical assessment, children were tested with the QFT-IT assay.ResultsAmong the 140 active TB suspects, we identified 19 cases of active disease. The overall sensitivity for active TB was 87.5%, ranging from 62.5% in children 25–36 months old to 100% in children older than 49 months. The overall specificity for active TB was 93.6%. Among the 481 children tested for LTBI screening, 38 scored positive and all but 2 had at least one risk factor for TB infection. Among the 26 children with indeterminate results, bacterial, viral or fungal pneumonia were later diagnosed in 11 (42.3%) cases and non-TB related extra-pulmonary infections in 12 (46.1%).ConclusionsOur results indicate that the children's response to QFT-IT associates to active TB and risk factors for LTBI. Moreover, we show that mitogen response is also found in children of 1 year of age, providing support for QFT-IT use also in young children.

Atypical pneumonias caused by Legionella pneumophila, Chlamydophila pneumoniae and Mycoplasma pneumonia

Atypical pneumonias, a group of diseases relatively unfamiliar to most clinicians, are caused by bacteria not normally associated with pneumonia and usually occur in patients with some kind of comorbidity. They can present as extrapulmonary infections, and prognosis can differ from typical pneumonias. Many clinicians are unfamiliar with the diagnosis of these diseases, and they are often incorrectly treated. In this review, we describe the clinical manifestations of the most common forms of atypical pneumonia, and outline the diagnostic procedures and therapies used in each case. In this way, hope to give physicians and other healthcare professionals the knowledge and diagnostic tools they need to deal with cases in which atypical pneumonia is suspected.

Comparative genome analysis of Mycoplasma pneumoniae

BackgroundMycoplasma pneumoniae is a common pathogen that causes upper and lower respiratory tract infections in people of all ages, responsible for up to 40 % of community-acquired pneumonias. It also causes a wide array of extrapulmonary infections and autoimmune phenomena. Phylogenetic studies of the organism have been generally restricted to specific genes or regions of the genome, because whole genome sequencing has been completed for only 4 strains. To better understand the physiology and pathogenicity of this important human pathogen, we performed comparative genomic analysis of 15 strains of M. pneumoniae that were isolated between the 1940s to 2009 from respiratory specimens and cerebrospinal fluid originating from the USA, China and England.ResultsIllumina MiSeq whole genome sequencing was performed on the 15 strains and all genome sequences were completed. Results from the comparative genomic analysis indicate that although about 1500 SNP and indel variants exist between type1 and type 2 strains, there is an overall high degree of sequence similarity among the strains (>99 % identical to each other). Within the two subtypes, conservation of most genes, including the CARDS toxin gene and arginine deiminase genes, was observed. The major variation occurs in the P1 and ORF6 genes associated with the adhesin complex. Multiple hsdS genes (encodes S subunit of type I restriction enzyme) with variable tandem repeat copy numbers were found in all 15 genomes.ConclusionsThese data indicate that despite conclusions drawn from 16S rRNA sequences suggesting rapid evolution, the M. pneumoniae genome is extraordinarily stable over time and geographic distance across the globe with a striking lack of evidence of horizontal gene transfer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1801-0) contains supplementary material, which is available to authorized users.

Risk factors for delayed isolation of tuberculosis patients in a tertiary care hospital in a low-incidence country

Results In the three-year time period, 58 patients had a cultureproven tuberculosis infection in our hospital, 20 with an extrapulmonary infection only. For 41 patients (70.7%), isolation measures were not taken. Twelve of these were patients with extrapulmonary tuberculosis only, and in these cases isolation measures were forgotten with aerosol generating procedures. The median number of days of non-isolation was 4 (range 1-162). For the patients with pulmonary tuberculosis (38 patients, 25 (65.8%) not isolated) four factors were predictive for non-isolation: presence of the symptom “fatigue”, absence of hemoptysis, absence of tuberculosis in the differential diagnosis, absence of involvement of a pulmonologist or infectious diseases specialist on admission. Due to these non-isolated patients, 1115 heath care workers and 78 patients had to be screened for tuberculosis.

To Be or Not to Be a Pseudogene: A Molecular Epidemiological Approach to the mclx Genes and Its Impact in Tuberculosis.

Tuberculosis presents a myriad of symptoms, progression routes and propagation patterns not yet fully understood. Whereas for a long time research has focused solely on the patient immunity and overall susceptibility, it is nowadays widely accepted that the genetic diversity of its causative agent, Mycobacterium tuberculosis, plays a key role in this dynamic. This study focuses on a particular family of genes, the mclxs (Mycobacterium cyclase/LuxR-like genes), which codify for a particular and nearly mycobacterial-exclusive combination of protein domains. mclxs genes were found to be pseudogenized by frameshift-causing insertion(s)/deletion(s) in a considerable number of M. tuberculosis complex strains and clinical isolates. To discern the functional implications of the pseudogenization, we have analysed the pattern of frameshift-causing mutations in a group of M. tuberculosis isolates while taking into account their microbial-, patient- and disease-related traits. Our logistic regression-based analyses have revealed disparate effects associated with the transcriptional inactivation of two mclx genes. In fact, mclx2 (Rv1358) pseudogenization appears to be primarily driven by the microbial phylogenetic background, being mainly related to the Euro-American (EAm) lineage; on the other hand, mclx3 (Rv2488c) presents a higher tendency for pseudogenization among isolates from patients born on the Western Pacific area, and from isolates causing extra-pulmonary infections. These results contribute to the overall knowledge on the biology of M. tuberculosis infection, whereas at the same time launch the necessary basis for the functional assessment of these so far overlooked genes.

Diagnosis, treatment, and outcomes of coccidioidomycosis in allogeneic stem cell transplantation.

Allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients have multiple risk factors for coccidioidomycosis, and previous reports of coccidioidomycosis in this patient population describe severe infections with poor outcomes. We performed a retrospective chart review of allo-HSCT recipients with active coccidioidomycosis to characterize the utility of diagnostic tests for coccidioidomycosis and to determine treatment outcomes. Eleven of 426 (2.6%) allo-HSCT recipients experienced active coccidioidomycosis after transplantation. Of these 11 patients, 1 (9%) had extrapulmonary infection, 9 (82%) patients were hospitalized, and 5 (45%) died. Culture or histology was positive in 33% (3/9) of the patients tested. Most (64% [7/11]) had at least 1 positive serologic test result, and the enzyme immunoassay immunoglobulin G test was positive most often (overall 55% [6/11]). Chest radiographs and chest computed tomography scans showed miliary or multifocal nodular infiltrates or consolidations, consistent with coccidioidomycosis, in 80% (8/10) and 100% (9/9), respectively, of patients tested throughout the course of active illness. Rapid polymerase chain reaction testing was positive in 71% (5/7) of the patients tested. Peripheral eosinophilia was present in 18% (2/11) of patients. Coccidioidomycosis is associated with high morbidity and mortality in allo-HSCT recipients in an area endemic for Coccidioides. Diagnosis of this infection can be difficult and often requires multiple and frequently invasive tests. Antifungal prophylaxis should be considered for patients at highest risk.

Susceptibility to and transmission of H5N1 and H7N1 highly pathogenic avian influenza viruses in bank voles (Myodes glareolus).

The study of influenza type A (IA) infections in wild mammals populations is a critical gap in our knowledge of how IA viruses evolve in novel hosts that could be in close contact with avian reservoir species and other wild animals. The aim of this study was to evaluate the susceptibility to infection, the nasal shedding and the transmissibility of the H7N1 and H5N1 highly pathogenic avian influenza (HPAI) viruses in the bank vole (Myodes glareolus), a wild rodent common throughout Europe and Asia. Two out of 24 H5N1-infected voles displayed evident respiratory distress, while H7N1-infected voles remained asymptomatic. Viable virus was isolated from nasal washes collected from animals infected with both HPAI viruses, and extra-pulmonary infection was confirmed in both experimental groups. Histopathological lesions were evident in the respiratory tract of infected animals, although immunohistochemistry positivity was only detected in lungs and trachea of two H7N1-infected voles. Both HPAI viruses were transmitted by direct contact, and seroconversion was confirmed in 50% and 12.5% of the asymptomatic sentinels in the H7N1 and H5N1 groups, respectively. Interestingly, viable virus was isolated from lungs and nasal washes collected from contact sentinels of both groups. The present study demonstrated that two non-rodent adapted HPAI viruses caused asymptomatic infection in bank voles, which shed high amounts of the viruses and were able to infect contact voles. Further investigations are needed to determine whether bank voles could be involved as silent hosts in the transmission of HPAI viruses to other mammals and domestic poultry.

Comparison of diagnostic values of procalcitonin, C-reactive protein and blood neutrophil/lymphocyte ratio levels in predicting bacterial infection in hospitalized patients with acute exacerbations of COPD.

Viral or bacterial upper respiratory infections are the most common cause of acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Based on available data, no reliable parameter has been presented to distinguish between bacterial and nonbacterial exacerbations. Therefore, we compared the diagnostic value of procalcitonin (PCT) level, which is a newer marker for predicting bacterial infections in patients with AECOPD, to routine parameters such as C-reactive protein (CRP) levels and the neutrophil/lymphocyte (N/L) ratio. This study included all consecutive patients who were admitted for a diagnosis of AECOPD between January 1 and March 31, 2014. PCT, CRP, and the N/L ratio were assessed in addition to cultures from tracheal aspirates or sputum on the first day of admission. Patients with a pneumonic infiltration on chest radiographs, or an extrapulmonary infection focus, or whose blood samples were not obtained for PCT and/or CRP at the same time as sputum culture were excluded from the study. A total of 77 patients were included with a mean age of 71.7 ± 9.5 years. Bacteria were isolated in 37.4 % of the patients. Mean PCT levels were significantly higher in patients with positive sputum cultures than in patients with negative sputum cultures. The cut-off values for PCT, CRP, and the N/L ratio for predicting a bacterial infection were 0.40 ng/mL, 91.50 mg/L, and 11.5, respectively; sensitivity was 61, 54, and 61 % respectively; specificity was 67, 52, and 58 %, respectively; and the area under the curve (AUC) values were 0.64, 0.52, and 0.58, respectively. The AUC value of PCT was significantly better for predicting bacterial infection compared with the CRP level or the N/L ratio (p = 0.042). PCT was better than CRP and the N/L ratio for predicting a bacterial infection in hospitalized patients with AECOPD. However, we find PCT not so reliable in predicting bacterial infection in AECOPD due to sensitivity and specificity of less than 80 % and a low AUC value.

Mycobacterial Co-Infection in Retroviral Disease

Atypical mycobacteria are increasingly afflicting pulmonary and extra pulmonary systems. Disease caused by these organisms are less common compared with tuberculosis caused by human strain of mycobacteria, but there has been a significant increase in pulmonary and extra pulmonary infections due to atypical mycobacteria especially in retroviral disease in the last two decades. 75 HIV positive patients who had pulmonary and/or extrapulmonary manifestations suggestive of Tuberculosis were included in our study. Of these, 48 (64%) were males and 27(36%)were females. Majority of these patients were in economically productive and sexually active age group of 31-50 years. Of the 75 samples, 25 were culture positive for Acid Fast Bacilli whereas 50 samples showed no growth on culture at end of 8 weeks. Of the 25 who had positive cultures, 15 showed growth for Mycobacterium TB and 10 showed growth for Atypical mycobacteria. Of the 25 patients who were Culture positive, 16 i.e 64% had Sputum smears by Z-N stain positive for AFB, which was statistically significant. It was observed that Atypical mycobacterial infection was more common in CD4 count < 100 cells/cu mm. Infection with Mycobacterium TB was more common in CD4 count between 101-200 cells/cu mm.

Analysis of clinical and CT characteristics of patients with Klebsiella pneumoniae liver abscesses: an insight into risk factors of metastatic infection

PurposeTo compare the clinical and CT characteristics of patients with Klebsiella pneumoniae liver abscess (KPLA), with or without metastatic infection. Materials and MethodsClinical information (age, sex, clinical symptoms, underlying disease, hematological parameters, abscess-related mortality) and CT characteristics of abscesses were analyzed to investigate associations with metastatic infection. Metastatic infections were divided into septic pulmonary embolism (SPE) and extra-pulmonary metastatic infection (EMI). ResultsWe identified 66 consecutive patients with KPLA. Metastatic infection occurred in 22/66 patients (33.3%); 8/66 (12.1%) patients had SPE, 6/66 (9.09%) patients had EMI; and 8/66 (12.1%) patients had both SPE and EMI. Patients with SPE were younger than patients without SPE (47.7±13.7 y vs.55.6±12.0 y; p=0.03). Unilocular abscess was significantly more common in patients with SPE than the non-SPE group (43.75% vs 18.0%, p=0.036). The mean maximal diameter of EMI was 56.5±21.3mm and was significantly smaller than that of the non-EMI which was 79.9±31.4 (p=0.011). SPE was significantly associated with development of EMI (50% vs17.3%, p=0.011). ConclusionUnilocular liver abscess is associated with SPE, and SPE is strongly associated with EMI among patients with KPLA. A maximal diameter of KPLA<55mm can be used as a predictor of EMI.

Outbreak of extrapulmonary tuberculosis infection associated with acupuncture point injection

Mycobacterium tuberculosis infection is rarely reported to be associated with acupuncture practices. We performed a retrospective outbreak investigation of a unique outbreak of 33 extrapulmonary M. tuberculosis infections related to acupuncture point injection therapy (AIT) among clients who visited a private traditional Chinese medicine clinical centre in China. The lumps, abscesses and ulcers occurred mostly on the neck, shoulders, waist, knees and hips, localized at acupuncture point meridian sites. These symptoms appeared from January to November 2011, with a peak cluster of infections in September 2011 (nine cases). M. tuberculosis Beijing strain was isolated and confirmed by DNA sequencing. All diagnosed patients were treated empirically with appropriate antibiotic treatment, and their condition improved. Our study indicated that this outbreak was most likely resulted from contaminated AIT. Drafting standard guidelines for AIT is urgently needed, and routine medical supervision should be provided, including obligating health providers to perform routine physical examinations that include testing for infectious diseases.

Autoantibodies binding to ubiquitin-fold modifier-conjugating enzyme 1 (Ufc1) and pleckstrin homology domain containing, family G (with RhoGef domain) member 2 (Plekhg2) are associated with mycobacterial infections.

The diagnosis of extrapulmonary tuberculous infections and nontuberculous mycobacterial (NTM) infections is difficult because the symptoms are nonspecific and suitable specimens for bacterial culture are often not available. Recent publications reported the existence of autoantibodies in tuberculous infections. We screened for specific autoantibodies in mycobacterial infections. We screened four in 29 patients with active mycobacterial infections and different controls using protein array technology. We could identify autoantibodies against ubiquitin-fold modifier-conjugating enzyme 1 (Ufc1) and pleckstrin homology domain containing, family G (with RhoGef domain) member 2 (Plekhg2) in all four patients. Subsequently, we designed enzyme-linked immunosorbent assays (ELISAs) for the detection of autoantibodies binding to Ufc1 and Plekhg2. Autoantibodies binding to Ufc1 and Plekhg2 were found in 19 of 29 patients (66%) with active mycobacterial infections. In comparison, we found these autoantibodies in one of 31 patients (3%) with successfully treated mycobacterial infections, in three of 40 (8%) HIV-infected patients not receiving combination antiretorviral therapy (cART) and in six of 134 (5%) blood donors. Interestingly, six of eight (75%) patients with HIV-associated B-cell non-Hodgkin lymphoma (B-NHL) at the onset of disease had autoantibodies against Ufc1 and Plekhg2, but none of nine (0%) patients after treatment of HIV-associated B-NHL, none of seven patients with non-HIV-associated B-NHL and 11 of 115 (10%) patients with other malignant diseases had autoantibodies against both proteins. In view of the high frequency of these autoantibodies, we postulate that they might be of potential use for additional diagnostics for mycobacterial infections, and further studies may shed light on the pathomechanisms of these two autoantibodies.

Fine-needle aspiration in a low-resource setting.

Fine-needle aspiration in a low-resource setting.

Associations and Outcomes of Septic Pulmonary Embolism

Background: Septic pulmonary embolism is a serious but uncommon syndrome posing diagnostic challenges because of its broad range of clinical presentation and etiologies.Objective: To understand the clinical and radiographic associations of septic pulmonary embolism in patients presenting to an acute care safety net hospital. Methods: We conducted a retrospective analysis of imaging and electronic health records of all patients diagnosed with septic pulmonary embolism in our hospital between January 2000 and January 2013. Results: 41 episodes of septic pulmonary embolism were identified in 40 patients aged 17 to 71 years (median 46); 29 (72%) were men. Presenting symptoms included: febrile illness (85%); pulmonary complaints (66%) including pleuritic chest pain (22%), cough (19%) and dyspnea (15%); and those related to the peripheral foci of infection (24%) and shock (19%). Sources of infection included: skin and soft tissue (44%); infective endocarditis (27%); and infected peripheral deep venous thrombosis (17%). 35/41 (85%) were bacteremic with staphylococcus aureus. All patients had peripheral nodular lesions on chest CT scan. Treatment included intravenous antibiotics in all patients. Twenty six (63%) patients required pleural drainage and/or drainage of peripheral abscesses. Seven (17%) patients received systemic anticoagulants. Eight (20%) patients died due to various complications. Conclusion: The epidemiology of septic pulmonary embolism has broadened over the past decade with an increase in identified extrapulmonary, non-cardiac sources. In the context of an extrapulmonary infection, clinical features of persistent fever, bacteremia and pulmonary complaints should raise suspicion for this syndrome, and typical findings on the chest CT scans confirm the diagnosis. Antibiotics, local drainage procedures and increasingly, anticoagulation are keys to successful outcomes.

Extra-pulmonary Pneumocystis jiroveci infection: a case report

In physical examination abdominal tenderness, gate disturbance and penile herpetic lesions were detected. Decreased disc height at T11-T12 level was detected in chest X-ray. Abdominal sonography and CT scan revealed hypo dense lesions in Lt left Lobe of liver and multiple hypo dense splenic and pancreatic lesions, ascitis, Lt left sided pleural effusion, thickening of jejuneal mucosa and edema of bowel wall. Vertebral body lesion and paravertebral abscess, bony calvarial involvement and adjacent extra axial brain lesion were observed in imaging were other findings. RNA analysis for HIV was positive. Vertebral lesion biopsy and aspiration of splenic lesion were performed and pathology revealed Pneumocystis jirovecii suggestive of extra pulmonary Pneumocystis carinii infection.

THU0284 Poncet's Disease in Tuberculous Mastitis, A CASE Report

BackgroundPoncet's disease, named after a French surgeon, Antonin Poncet, is a rare form of polyarthritis occurring in patients with tuberculous infection. It is an immunological reaction to tuberculoprotein wherein CD4+...