Nationwide, multicenter survey on the efficacy and safety of piperacillin for adult community-acquired pneumonia in Japan.

A survey on adult community-acquired pneumonia was conducted jointly by multiple centers nationwide to verify the Japanese Respiratory Society Guidelines for the Management of Community-Acquired Pneumonia in Adults (JRS2005). The efficacy and safety of piperacillin (PIPC) were investigated at the same time. PIPC is recommended as the initial treatment for patients with suspected bacterial pneumonia and pneumococcal pneumonia in JRS2005. Overall, 552 and 333 patients were registered for safety and efficacy analysis in this study, respectively. The majority of the cases in which PIPC was used had moderate disease (63.7 %), and the most common daily dosage was 4 g (73.6 %). The efficacy rate was 83.5 % overall, 81.1 % in patients with suspected bacterial pneumonia, and 92.8 % in patients with pneumococcal pneumonia. The efficacy rate with a daily dosage of 4 g was 84.9 %, and the efficacy rates achieved with a daily dosage of 4 g in patients who had mild and moderate suspected bacterial pneumonia were 90.0 and 82.6 %, respectively. The most commonly isolated causative organisms were Streptococcus pneumoniae (S. pneumoniae) and Haemophilus influenzae (H. influenzae), and the bacterial eradication rates were high (97.2 and 100 %, respectively). The incidence of adverse drug reactions was 5.62 %, among which the main events were hepatic dysfunction and decreased white blood cell count. In conclusion, this study showed that PIPC is safe and effective at 4 g/day for mild-to-moderate adult community-acquired pneumonia.

Nationwide survey on the 2005 Guidelines for the Management of Community-Acquired Adult Pneumonia: validation of severity assessment.

INTRODUCTION: The Japanese Respiratory Society Guidelines for the Management of Community-Acquired Pneumonia (CAP) in Adults (JRS 2005) were published to revise the Basic Concept for the Management of CAP in Adults (JRS 2000). Revisions in JRS 2005 mainly focused on the criteria for the assessment of pneumonia severity and the differentiation between bacterial pneumonia and atypical pneumonia. To evaluate the JRS 2005 criteria for the assessment of pneumonia severity, we conducted a prospective survey. SUBJECTS AND METHODS: The survey was conducted from July 2006 to March 2007 as a nationwide joint study by 200 institutions. The study subjects included patients aged ≥16 years of age who had CAP. The severity at initial consultation was determined using the criteria established by JRS 2005, JRS 2000, and Infectious Diseases Society of America Guidelines (IDSA-GLs). The survival outcome 30 days after the start of the initial antimicrobial agent treatment was confirmed. RESULTS: A total of 1875 patients were analyzed. The numbers of cases of pneumonia assessed as being moderate and severe were significantly lower when the JRS 2005 criteria were used than when the JRS 2000 criteria were used. Thus, the severity of pneumonia could be determined more appropriately using the JRS 2005 criteria. Furthermore, the severity-dependent prediction of fatal outcomes or mortality according to these criteria was similar to that determined using the IDSA-GLs. CONCLUSIONS: Determining severity on the basis of JRS 2005 can resolve nearly all the problems encountered with JRS 2000; these criteria were found to be useful and rapidly and easily applicable in clinical practice.

Nationwide survey on the 2005 Guidelines for the Management of Community-Acquired Adult Pneumonia: validation of differentiation between bacterial pneumonia and atypical pneumonia.

INTRODUCTION: The Japanese Respiratory Society Guidelines for the Management of Community-Acquired Pneumonia (CAP) in Adults (JRS 2005) was published as a revision of the Basic Concept for the Management of CAP in Adults (JRS 2000). To evaluate the JRS 2005 criteria for differentiating between disease types and assessing the status of antimicrobial agent use in initial treatment, we conducted a prospective survey. SUBJECTS AND METHODS: The survey was conducted from July 2006 to March 2007 as a nationwide joint study by 200 institutions. The study subjects included patients aged ≥16 years of age who had CAP, and patients who met the inclusion criteria were consecutively enrolled. Disease type differentiation based on JRS 2005 and JRS 2000 was conducted. Disease type diagnosis was also performed based on test results. The sensitivity and specificity of disease type differentiation were calculated. The antimicrobial agents used in the initial treatment were classified as recommended or non-recommended based on JRS 2005. The validity of non-recommended antimicrobial agent use was investigated. RESULTS: A total of 1875 patients were analyzed. Differentiation of atypical pneumonia using the JRS 2005 criteria had higher sensitivity and lower specificity than differentiation using the JRS 2000 criteria. The antimicrobial agents recommended by JRS 2005 were used as initial treatment in a low number of cases. The efficacy of the recommended antimicrobial agents was similar to that of the non-recommended agents. CONCLUSIONS: JRS 2005 is advantageous in terms of reducing the number of items used in disease type differentiation. The recommended antimicrobial agents used for the initial treatment are believed to be appropriate.

GM3 synthase gene is a novel biomarker for histological classification and drug sensitivity against epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer.

Expression of gangliosides and alterations in their composition have been observed during cell proliferation and differentiation and in certain cell cycle phases, brain development and cancer malignancy. To investigate the characteristics of GM3 synthase, SAT-I mRNA and ganglioside GM3 expression levels in lung cancer, we examined the expression levels of SAT-I mRNA as well as GM3 in 40 tumor tissues surgically removed from non-small cell lung cancer patients. Adenocarcinoma tissues expressed SAT-I mRNA levels that were significantly higher than those of squamous and other carcinomas (P < 0.0001). Moreover, the SAT-I mRNA levels were high in the bronchioalveolar carcinoma subtype and low in the solid and mucin subtypes of adenocarcinomas (P = 0.049, 0.049 and 0.013, respectively). To clarify the relationship between SAT-I mRNA and epidermal growth factor receptor (EGFR)-tyrosine kinase (TK) inhibitor sensitivity, we carried out drug sensitivity tests for the EGFR-TK inhibitors gefitinib and AG1478 using eight adenocarcinoma cell lines expressing no EGFR mutations. The IC(50) values for gefitinib and AG1478 decreased dramatically with increasing SAT-I mRNA levels (R(2) = 0.81 and 0.59, respectively), representing a wide range of drug sensitivities among adenocarcinoma cell lines. To explore a possible mechanism of how GM3 could enhance the sensitivity to EGFR-TK inhibitors, the SAT-I gene was introduced stably into a GM3-negative clone of murine 3LL lung cancer cells to produce GM3-reconstituted clones. We found an increase in EGFR protein levels and gefitinib sensitivity in GM3-reconstituted cells, suggesting the involvement of GM3 in the turnover of EGFR protein. Therefore, it is highly expected that, by measuring the expression levels of SAT-I mRNA in lung biopsy samples from non-small cell lung cancer patients, enhanced pathological identification and individualized chemotherapeutic strategies can be established for the appropriate use of EGFR-TK inhibitors.

Mutations in the SLC34A2 gene are associated with pulmonary alveolar microlithiasis.

RATIONALE: Pulmonary alveolar microlithiasis is an autosomal recessive disorder in which microliths are formed in the alveolar space. OBJECTIVES: To identify the responsible gene that causes pulmonary alveolar microlithiasis. METHODS: By means of a genomewide single-nucleotide polymorphism analysis using DNA from three patients, we have narrowed the region in which the candidate gene is located. From this region, we have identified a gene that has mutations in all patients with pulmonary alveolar microlithiasis. MEASUREMENTS AND MAIN RESULTS: We identified a candidate gene, SLC34A2, that encodes a type IIb sodium phosphate cotransporter and that is mutated in six of six patients investigated. SLC34A2 is specifically expressed in type II alveolar cells, and the mutations abolished the normal gene function. CONCLUSION: Mutations in the SLC34A2 gene that abolish normal gene function cause pulmonary alveolar microlithiasis.

Elevated serum surfactant protein A and D in pulmonary alveolar microlithiasis.

Pulmonary alveolar microlithiasis (PAM) is a rare disease characterized by widespread localization of calcispherites in the alveolar spaces. The authors report two cases of PAM, with markedly elevated sera concentrations of surfactant protein-A and surfactant protein-D, which showed a tendency to increase as the disease progressed. Therefore, surfactant protein-A and surfactant protein-D may function as serum markers to monitor the disease activity and progression of PAM.

Gefitinib-induced interstitial lung disease showing improvement after cessation: disassociation of serum markers.

Gefitinib (ZD1839), a small-molecule epidermal growth factor receptor tyrosine kinase inhibitor, is an anticancer agent for patients with non-small cell lung carcinoma. Recently, however, as a result of accumulating evidence, it has been recognized that gefitinib can give rise to lethal lung toxicity. The authors report a case of interstitial lung disease (ILD) induced by gefitinib, which improved promptly following cessation of the administration of the agent. Clinical signs suggesting a good prognosis were noted, namely, findings similar to acute eosinophilic pneumonia on CT and a disassociation in the elevation of specific serum markers of ILD. At the time of onset of ILD, serum concentrations of surfactant protein (SP)-A and SP-D were significantly increased, whereas that of KL-6 was not increased. A previous study of three cases of lethal lung toxicity resulting from gefitinib administration revealed a significant and almost equal increase in KL-6, SP-A and SP-D. These results suggest that SP-A and SP-D may be indicators of gefitinib-induced ILD and that KL-6 is a predictor of outcome. Using a combination of these markers may help to establish a differential prognosis in patients with gefitinib-induced ILD.

Monitoring markers of disease activity for interstitial lung diseases with serum surfactant proteins A and D.

OBJECTIVES: Surfactant protein (SP) A and D are specific serum markers for interstitial lung diseases including idiopathic pulmonary fibrosis (IPF). The authors evaluated the critical roles of these markers on the prognoses of patients with IPF and the mechanisms of their elevation in sera. METHODOLOGY: The authors evaluated the relationship between prognosis and the serum markers in 82 IPF patients. The protein content and mRNA expression of the markers were evaluated using rats with interstitial pneumonia induced by bleomycin administration. RESULTS: Higher levels of serum SP-D at the time of the initial visit to the Sapporo Medical University Hospital were associated with poorer prognoses, while SP-A showed no significant affect on survival. Causes of the elevation in sera were due to the acceleration of, not only production in the lungs, leakage into the circulation. The elevation was associated with alveolitis but not fibrosis. CONCLUSIONS: SP-D is a good predictor of the prognosis in patients with IPF.

[A case of severe airflow limitation markedly improved by inhalation therapy in non-smoking woman with chronic obstructive pulmonary disease].

A 67-year old woman who had never smoked presented with dyspnea on effort and general fatigue, which had first appeared 4 years ago. She had lived for 35 years with her husband who was a heavy smoker. Chest roentgenogram showed pulmonary over-inflation, but chest CT scans didn't demonstrate emphysematous changes. Neutrophil-dominant sputum cytology, a PaO2 of 69.5 Torr, and combined ventilatory impairment on respiratory function test were revealed. FEV1.0 improved 80 ml after beta2-agonist inhalation. Although the respiratory symptoms were improved by inhaled anti-cholinergic drug, residual volume increased minimally. After the use of inhaled steroid drug (HFA-BDP) and salmeterol, the symptoms and residual volume were markedly improved. One year later, FEV1.0 increased by 450 ml. The low attenuation area detected by CT scans decreased, mainly in the lower lung field. Passive smoking might have contributed to her airflow limitation.

Napsin A is useful to distinguish primary lung adenocarcinoma from adenocarcinomas of other organs.

The aim of the present study was to compare the usefulness of the peripheral airway cell markers, naspin A and surfactant protein A (SP-A), for distinguishing primary lung adenocarcinoma from adenocarcinomas of other organs in various clinical conditions. Immunohistochemical expression of napsin A and SP-A was analyzed at primary sites of 120 lung carcinomas and 40 adenocarcinomas of other organs, at lung metastatic sites of 32 adenocarcinomas of other organs, and in metastatic lymph nodes of 21 lung adenocarcinomas and 45 adenocarcinomas of other organs. Napsin A and SP-A expressions were compared between primary and recurrent sites in 8 lung adenocarcinomas. Napsin A and SP-A expressions were noted in 84.3% and 53.0% of primary sites of 83 lung adenocarcinomas, respectively, but neither napsin A nor SP-A was expressed at primary sites of other histological types of lung carcinomas or at primary or metastatic sites of adenocarcinomas of other organs. In lung adenocarcinomas, napsin A and SP-A were expressed in metastatic lymph nodes in 81.0% and 19.0%, respectively, and at recurrent sites in 87.5% and 37.5%, respectively. Napsin A is superior to SP-A for distinguishing primary lung adenocarcinoma from adenocarcinomas of other organs at primary, metastatic, and recurrent sites.

Interferon-gamma up-regulates expression of cysteinyl leukotriene type 2 receptors on eosinophils in asthmatic patients.

STUDY OBJECTIVES: Cysteinyl leukotrienes (cysLTs) are strong bronchoconstrictive mediators that play a key role in asthma inflammation. They act through specific receptors including cysLT type 1 receptor (CysLT1R) and cysLT type 2 receptor (CysLT2R). Although these two receptors are co-expressed on inflammatory cells, little is known about CysLT2R in patients with asthma. The aims of this study were to investigate the changes in cysLT receptors (CysLTRs) during asthma exacerbations and to determine which cytokine modulates CysLTR expression on eosinophils. METHODS: We assessed protein expression and messenger RNA of CysLT1R and CysLT2R in peripheral blood eosinophils and measured urinary leukotriene E(4) levels in 36 patients with stable asthma, 23 subjects with asthma exacerbation, and 15 healthy subjects. We also evaluated the modulation of these receptors by interleukin (IL)-1beta, IL-4, IL-5, IL-13, interferon (IFN)-gamma and tumor necrosis factor-alpha in cultured eosinophils. RESULTS: Expression of both CysLT1R and CysLT2R on eosinophils during asthma exacerbations was significantly higher (p < 0.05) than in stable asthma and healthy subjects. A greater expression of CysLT2R in exacerbation was found in nonatopic asthmatics. Only IFN-gamma up-regulated cell-surface expression of CysLT2R in a dose-dependent manner and enhanced messenger RNA levels. No cytokine affected CysLT1R expression or messenger RNA level. CONCLUSIONS: CysLT2R expression on eosinophils was increased in patients, especially in nonatopic subjects, during asthma exacerbation, and was up-regulated by IFN-gamma; therefore we speculate that a pathway through CysLT2R might modulate exacerbations of asthma.

Prostaglandin E2 receptor selective agonists E-prostanoid 2 and E-prostanoid 4 may have therapeutic effects on ovalbumin-induced bronchoconstriction.

BACKGROUND: The pharmacologic actions of prostaglandin E(2) (PGE(2)) are mediated through specific E-prostanoid (EP)-1, EP-2, EP-3, and EP-4 receptors. In this study, we determined which PGE(2) receptor subtype(s) contribute to the prevention of allergen-induced bronchoconstriction. METHODS: We assessed the effects of these receptor agonists in ovalbumin (OA)-sensitized guinea pigs. The prostaglandin E receptor-subtype agonists tested were ONO-DI-004 (EP-1), ONO-AE1-259 (EP-2), ONO-AE-248 (EP-3), ONO-AE1-329 (EP-4), and sulprostone (EP-1 and EP-3) [Ono Pharmaceutical Company; Osaka, Japan]. We treated the animals with either PGE(2) or these agonists 15 min before OA challenge and measured respiratory resistance at 15 min, 1 h, and 3 h. RESULTS: Allergen-induced bronchoconstriction was significantly (p < 0.01) suppressed at doses > 85 nmol/kg of PGE(2). The respiratory resistance elevations 15 min after OA challenge were significantly (p < 0.01) suppressed by preadministration of EP-2 and EP-4 agonists, but airway responsiveness to inhaled methacholine did not improve. EP-1, EP-3, or EP-1/EP-3 agonists had no effect on any parameter. CONCLUSIONS: These results suggest that inhibition of OA-induced bronchoconstriction by PGE(2) acts through EP-2 and EP-4 receptors.

Cytokines involved in CNS manifestations caused by Mycoplasma pneumoniae.

Mycoplasma pneumoniae sometimes causes central nervous system manifestations, which may involve the host immune response, as the organism does not directly damage neural cells, or release toxins. Therefore we measured the levels of interleukin-6, interleukin-8, interleukin-18, interferon-gamma, tumor necrosis factor-alpha, and transforming growth factor-beta1 in serum and cerebrospinal fluid samples from patients who manifested central nervous system manifestations during acute M. pneumoniae infection. The subjects were nine patients with early-onset encephalitis (central nervous system disease onset within 7 days from the onset of fever), four with late-onset encephalitis (onset at 8 days or later), three with encephalitis but without fever, and three with aseptic meningitis. Intrathecal elevations of interleukin-6 and interleukin-8 in all four types of central nervous system manifestations, and of interleukin-18 in late-onset encephalitis were observed. None of the cerebrospinal fluid samples contained detectable levels of interferon-gamma, tumor necrosis factor-alpha, or transforming growth factor-beta1. In conclusion, interleukin-6, interleukin-8, and interleukin-18 might be involved in the inflammatory process leading to the central nervous system manifestations caused by M. pneumoniae.

Subepithelial microvasculature in large airways observed by high-magnification bronchovideoscope.

BACKGROUND: The bronchial vasculature serves important functions and is modified in a variety of pulmonary and airway diseases. The remarkable ability of the bronchial vasculature to undergo remodeling has implications for disease pathogenesis. However, there is very little information on normal bronchial circulation. OBJECTIVES: The aim of this study was to obtain information on bronchial microvessels in large airways using a high-magnification bronchovideoscope. METHODS AND PATIENTS: Recently, we developed a high-magnification bronchovideoscope (XBF-200HM3 [side-viewing type]) in cooperation with Olympus Medical Systems. This bronchovideoscope can provide information on the bronchial mucosa with a maximum magnification of 110 times. Between August 2000 and July 2004, 26 patients without abnormalities in the large airways were enrolled into this study. Patients underwent conventional bronchoscopy and subsequent bronchoscopy with the high-magnification bronchovideoscope. After the bronchoscopic examination, we calculated the vessel area ratios and hemoglobin indexes of images made with the high-magnification bronchovideoscope by using appropriate software. In addition, we compared the findings obtained with the high-magnification bronchovideoscope of the 26 subjects with microscopic findings of autopsied tracheas of two patients without abnormalities. RESULTS: Many ramifying subepithelial microvessels of large airways were mainly observed in intercartilage and membranous portions, whereas only a few microvessels were seen in cartilage portions. Histologically, these subepithelial microvessels were thought to be distributed within approximately 800 and 500 microm beneath the surface of the intercartilage portions and membranous portions, respectively. Vessel area ratios of the intercartilage portions were significantly higher than those of the cartilage and membranous portions. The hemoglobin indexes of the intercartilage portions were significantly higher than those of the cartilage and membranous portions, and these indexes were also significantly higher in the membranous portion than in the cartilage portion. CONCLUSIONS: A dense concentration of subepithelial microvessels was mainly observed in the intercartilage portion, indicating an increase in submucosal circulation. This high-magnification bronchovideoscope is a useful tool for observing and evaluating the subepithelial microvessels in large airways.

Surfactant protein gene expressions for detection of lung carcinoma cells in peripheral blood.

BACKGROUND: Inflow of tumor cells to circulation is an essential step for metastasis of primary tumors. To know its state may contribute to therapeutic strategy. However, methodology to detect lung carcinoma cells floating in peripheral blood has not been established. Pulmonary surfactant protein (SP)-A, SP-C and Clara cells-10 kd protein (CC10) are specific to the lung and often expressed in primary lung carcinomas. We evaluated the worth of these gene expressions for the detection of carcinoma cells in peripheral blood. METHODS: The expressions in 5 ml of venous blood were tested by RT-PCR. Ninety-nine patients with non-small cell lung carcinoma (NSCLC) and 17 with small cell lung carcinoma (SCLC) were compared to 13 with secondary lung tumor, 48 with non-malignant respiratory diseases and 19 healthy volunteers. RESULTS: The mRNA expressions of SP-A and SP-C were completely specific to NSCLC when compared to SCLC and secondary lung tumors. All of the healthy volunteers and patients with non-malignant respiratory diseases showed negative for these mRNA expressions, except for one sample. The positive rate of SP-A, SP-C and CC10 mRNA in patients with NSCLC was 33.3%, 14.1%, 3.3%, respectively. The rates of SP-A and SP-C mRNA were higher than that (11.1%) in CEA mRNA. The increased positive rate of mRNA of SP-A and SP-C was significantly dependent on the clinical stage and the existence of distant metastasis. CONCLUSION: These results demonstrate that the detection of mRNA of SP-A and SP-C would give clinicians valuable information suggesting the presence of blood-floating carcinoma cells as a step toward metastasis.

Clinical significance of vascular endothelial growth factor-C and vascular endothelial growth factor receptor 3 in patients with T1 lung adenocarcinoma.

BACKGROUND: Vascular endothelial growth factor-C (VEGF-C) plays an important role in lymphangiogenesis and activates VEGF receptor-3 (VEGFR-3). Lymphatic spread is an important prognostic factor in patients with lung adenocarcinoma. The aim of the current study was to determine whether the expression of VEGF-C and VEGFR-3 correlates with clinicopathologic factors and prognosis in patients with TNM classification T1 lung adenocarcinoma. METHODS: The authors conducted a retrospective review of 129 consecutive patients who underwent complete resection for T1 lung adenocarcinoma. Immunohistochemical staining for VEGF-C, VEGF, VEGFR-3, CD34 (microvessels), tryptase (mast cells), and CD68 (macrophages) was performed to statistically analyze clinicopathologic implications of VEGF-C and VEGFR-3 status. RESULTS: Of 129 patients with T1 lung adenocarcinoma, 56 (43.3%) patients were positive for tumor-cell VEGF-C and 73 (56.6%) and 69 (53.5%) patients were positive for tumor-cell and endothelial-cell VEGFR-3, respectively. Patients with positive staining for tumor-cell VEGF-C showed significantly less favorable survival rates than patients with negative staining (P = 0.031). The survival rates of patients with positive staining for tumor-cell and endothelial-cell VEGFR-3 were significantly lower than those with negative staining (P = 0.0034 and P = 0.0020, respectively). Patients with positive staining for both tumor-cell VEGF-C and endothelial-cell VEGFR-3 exhibited the most unfavorable prognoses. Multivariate analysis demonstrated that coexpression of tumor-cell VEGF-C and endothelial-cell VEGFR-3 was an independent negative prognostic factor (P = 0.0129) as well as N factor (P = 0.0020). CONCLUSIONS: VEGF-C and VEGFR-3 status may be indicative of survival rates for patients with T1 lung adenocarcinoma.

Cytological characteristics of pulmonary large cell neuroendocrine carcinoma.

To establish cytological features of pulmonary large cell neuroendocrine carcinoma (LCNEC), we evaluated the cytological characteristics of LCNEC. Samples from 25 histologically confirmed LCNECs (14 touch imprint (TI) and 11 curettage) were analyzed. The findings were compared with those for seven small cell lung carcinomas. Cytological findings of TIs were as follows: Tumor cells were medium- to large-sized, round or polygonal, and nuclear polymorphism was observed. Some of the tumor cells had clearly identified cytoplasms, but naked nuclei were frequently observed. Nuclei were round, oval, or polygonal, and possessed thin and smooth nuclear membranes. The nuclear chromatin pattern was finely or coarsely granular. One or two nucleoli were observed in the nuclei, but were inconspicuous in some cases. Tumor cells appeared in clusters, and rosette formation was observed, but single cells were frequently observed also. Necrotic background and nuclear streaking were frequently observed. In brush or curettage specimens, the number of cells observed on a glass was small, but the findings were almost the same as those for the TI samples. TI samples have characteristic features, such as a neuroendocrine morphologic pattern, large cell size, abundant cytoplasm, finely or coarsely granular chromatin of the nucleus, and prominent nucleoli, and the diagnosis of LCNEC is possible. In brush or curettage specimen, the LCNEC diagnosis may be possible if a sufficient number of tumor cells are obtained.

Circulating interleukin-18 and osteopontin are useful to evaluate disease activity in patients with tuberculosis.

BACKGROUND: T helper type 1 (Th1) responses have been implicated in the protective immunity, pathophysiology and development of tuberculosis. However, it is still unclear which molecule(s) reflect disease activity in patients with tuberculosis. METHODS: By specific enzyme immunoassays, circulating interferon-gamma. (IFN-gamma), interleukin-12 (IL-12), IL-18 and osteopontin (OPN) were measured in 47 patients with pulmonary tuberculosis and 7 patients with miliary tuberculosis before anti-tuberculosis therapy, and also measured in 19 patients with tuberculosis before and after anti-tuberculosis therapy. RESULTS: Circulating IFN-gamma, IL-18 and OPN levels were significantly higher in patients with pulmonary tuberculosis than in healthy controls, while there was no significant difference in levels of circulating IL-12 between tuberculosis patients and controls. Circulating IFN-gamma, IL-12, IL-18 and OPN paralleled the extent of lung lesions, and circulating IFN-gamma, IL-18 and OPN paralleled the magnitude of fever in patients with pulmonary tuberculosis. Patients with miliary tuberculosis had extremely high levels of circulating OPN, IFN-gamma and IL-18. Circulating IL-18 and OPN were significantly decreased with anti-tuberculosis therapy, whereas circulating IL-12 and IFN-gamma were not. CONCLUSIONS: Among Th1 response associated molecules, circulating levels of IL-18 and OPN, but not IFN-gamma or IL-12, reflect disease activity in patients with tuberculosis.