Jialin Jin

Evaluation of the Diagnostic Potential of IP-10 and IL-2 as Biomarkers for the Diagnosis of Active and Latent Tuberculosis in a BCG-Vaccinated Population

Background The Mycobacterium tuberculosis (Mtb)-specific T-cell interferon gamma release assays (IGRAs) are useful in detecting Mtb infection but perform poorly at distinguishing active tuberculosis disease (ATB) and latent tuberculosis infection (LTBI). This study is aimed at evaluating additional cytokines as biomarkers besides interferon-gamma (IFN-γ) to improve the identification of ATB and LTBI. Methodology/Principal Findings Sixty-six patients with ATB, 73 household contacts (HHC) of ATB patients and 76 healthy controls (HC) were recruited to undergo QuantiFERON TB GOLD in-tube assay (QFT) and the enzyme-linked immunosorbent assay (ELISA) where the release of IFN-γ, IFN-γ inducible protein 10 (IP-10), Interleukin 2 (IL-2) and Tumor Necrosis Factor-α (TNF-α) was determined in the whole blood with or without antigen-stimulation. The positive rates of the QFT, IP-10 and IL-2 tests were 86.4%, 89.4% and 86.4% for the ATB group with no difference between them (p>0.05). However, QFT in combination with IP-10 and IL-2 significantly increased the detection rate to 95.5% in the ATB group (p = 0.03) and the indeterminate rate of all samples decreased from 2.3% (5/215) to 0.4% (1/215). The un-stimulated level of IP-10 was significantly higher in the HHC than the ATB and HC groups. The IP-10 responses were strongly associated with extended Mtb exposure time and the degree of smear-positivity of the index cases. The IL-2/IFN-γ ratio in the antigen-stimulated plasma could discriminate LTBI from ATB with a sensitivity of 77.2% and a specificity of 87.2%. Conclusion The increased Mtb-specific antigen-stimulated expression of IP-10 and IL-2 may be useful for detecting both ATB and LTBI. Combining the QFT with IP-10 and IL-2 could increase the detection accuracy of active TB over the QFT alone.

Interferon-Gamma Release Assay Performance in Pulmonary and Extrapulmonary Tuberculosis

Background The diagnosis of tuberculosis remains difficult. This study aimed to assess performance of interferon-gamma release assay (IGRA) in diagnosis of active tuberculosis (ATB) with pulmonary and extrapulmonary involvements, and to determine the diagnostic role of IGRA (T-SPOT.TB) and tuberculin skin test (TST) in BCG-vaccinated population. Methods and Findings Two hundred twenty-six ATB suspects were recruited and examined with T-SPOT.TB. Among them, fifty-two and seventy-six subjects were simultaneously tested by TST with 5TU or 1TU of purified protein derivative (PPD). The sensitivity of T-SPOT.TB was 94.7% (71/75), comparable in pulmonary and extrapulmonary disease groups (95.6% vs. 93.3%, P>0.05), while the specificity was 84.10% (90/107) but differed in two groups (69.2% vs. 88.9%, P = 0.02). Compared to T-SPOT.TB, TST with 5TU-PPD showed less sensitivity (92.3% vs. 56.4%) and specificity (84.6% vs. 61.5%) (both P<0.01); the sensitivity of TST with 1TU-PPD was 27.8%, and despite its specificity identical to T-SPOT.TB (both 82.8%) positive predictive value (PPV) was only 33.3%. By combining T-SPOT.TB with TST (1TU), the specificity rose to 95%, but the PPV stayed unchanged. Conclusions IGRA could function as a powerful immunodiagnostic test to explore pulmonary and extrapulmonary TB, while TST failed to play a reliable or auxiliary role in identifying TB disease and infection in the BCG-vaccinated population.

Avian Influenza A(H7N9) Virus Infections, Shanghai, China

To the Editor: On March 31, 2013, the National Health and Family Planning Commission of China notified the World Health Organization of 3 cases of human infections with avian influenza A(H7N9) virus. These cases were caused by a novel virus that was identified by laboratory testing at the China Centers for Disease Control and Prevention (CDC) on March 29 (1). As of April 19, 2013, a total of 91 laboratory-confirmed human cases (17 deaths) of infection with avian influenza A(H7N9) virus were reported in 4 provinces in China (2). We report clinical features of 2 infected adults who died, 2 critically ill infected adults who recovered, and 1 infected child who had a mild case during this outbreak in Shanghai, China. A 3.5-year-old boy had fever (39.5°C) for 3 days and mild rhinorrhea starting on March 31. He was admitted to a district pediatric outpatient clinic on April 1. At admission, the child was given oseltamivir for 5 days, even though signs and symptoms had resolved. Nasopharyngeal swab samples were positive by real-time PCR for avian influenza A(H7N9) virus. All symptoms resolved uneventfully by April 3, and CDC was notified that avian influenza A(H7N9) virus was identified in his respiratory sample. The patient was discharged on day 11 after illness onset. The 4 adult patients were given diagnoses of severe pneumonia with shortness of breath, dyspnea, and marked hypoxia (Table). Duration from disease onset to severe illness was 5–7 days. At admission, the 4 patients with severe cases had decreased peripheral blood leukocyte counts and increased levels of aspartate aminotransferase; 3 had increased levels of lactate dehydrogenase (Table). Table Characteristics for 4 patients infected with avian influenza A(H7N9) virus, Shanghai, China* All 4 adult patients had radiologically confirmed pneumonia and bilateral patchy alveolar opacities or diffused lobar consolidation with or without pleural effusion (Figure, Appendix). Findings on chest radiographs for severe cases requiring mechanical ventilation were consistent with those for acute respiratory distress syndrome. Figure Chest computed tomographic scans for 3 patients infected with avian influenza A(H7N9) virus, Shanghai, China. A) Patient 1, who died, showing extensive lung infiltrates at day 7 of illness onset. B) Patient 3, who had a severe case, showing partial rear ... Among the 4 severe cases in adults, a 52-year-old woman (patient 1) and a 49-year-old man (patient 2) died from acute respiratory distress syndrome and multiple organ failure on days 14 and 10, respectively, after disease onset and 1–2 days after progression to respiratory failure. Two other patients showed improvement and were virus negative 6 and 4 days after antiviral treatment. After 23–24 days of treatment in an intensive care unit, the 2 patients with severe cases recovered and were discharged (Table). The 2 patients who died were given methylprednisolone. Of the 2 patients who recovered, 1 was given a low dose of methylprednisolone for 1 week and the other was not given methylprednisolone. Although it is difficult to assess the role of glucocorticoids in treatment because of limited number of cases, caution is advised because of possible serious adverse events, including death, as reported for human infection with influenza A(H1N1) virus (4). One of the adult patients reported exposure to poultry. The family of the child patient raised chickens and ducks, but these animals had no apparent disease, and cloacal swab specimens were negative for avian influenza A(H7N9) virus. One patient who died (patient 2) had frequent occupational exposure to poultry. Sixteen contacts of the child and 45 contacts of the 4 adult patients were monitored, and routine virologic sampling was performed. One contact (husband of patient 1) of a patient who died (Table) became febrile and was positive for avian influenza A(H7N9) virus on April 12 (day 24 after disease onset for patient 1); as of the date of this report, he was receiving treatment in an intensive care unit. However, it is difficult to tell if this is a case of human-to-human transmission or if both persons were exposed to infectious poultry. All remaining contacts had no symptoms and were negative for virus by PCR. Several features of this avian influenza A(H7N9) outbreak are distinct from those of previous avian influenza outbreaks. Human infection with this virus showed a case-fatality rate of 18.7% (17/91), but this rate is not as high as that for avian influenza A(H5N1) virus (case-fatality rate 59%) (5). Avian influenza A(H7N9) virus infection seems to cause more severe human illness than do other subgroups of H7 influenza A viruses (subtypes H7N2, H7N3, and H7N7), which are usually associated with poultry outbreaks but cause mild disease in humans. However, infection with avian influenza A(H7N7) virus resulted in the death of a veterinarian during an outbreak in the Netherlands (6). In the 5 patients reported here, avian influenza A(H7N9) virus caused fatal disease in 2 adult patients 52 and 49 years of age, who had other medical conditions. Older age has been reported to confer higher risk for developing more severe influenza-associated outcomes (7). In conclusion, these cases indicated that avian influenza A(H7N9) virus might not be as virulent as avian influenza A(H5N1) virus in humans. Avian influenza A(H7N9) virus does not appear to cause obvious disease in poultry and causes mild disease in children. More severe disease in adults occurred among those had concurrent diseases or were immunodeficient.

Lactic acidosis during telbivudine treatment for HBV: A case report and literature review

All oral nucleoside analogues against hepatitis B virus, with an exception of telbivudine, have been reported causing lactic acidosis (LA). Here we report the first case of chronic hepatitis B developing severe refractory LA during telbivudine monotherapy. A 36-year-old man of Chinese origin received telbivudine antiviral treatment for chronic hepatitis B. After 11 mo of therapy, he developed anorexia, nausea, and vomiting with mild muscle weakness. The patient was found with elevated serum creatine phosphokinase up to 3683 U/L (upper limit of normal 170 U/L) and marked LA. LA did not resolve immediately following discontinuation of telbivudine. His condition began to improve after hemodialysis treatment for 16 times and usage of glucocorticosteroid. The patient fully recovered after 16 wk of treatment. This is the first documented case with severe LA caused by telbivudine monotherapy. Besides serum creatine phosphokinase, blood lactate level should also be closely monitored in patients receiving telbivudine.

Moxifloxacin and gatifloxacin for initial therapy of tuberculosis: a meta-analysis of randomized clinical trials

Moxifloxacin (MOX) and gatifloxacin (GAT) have exhibited promising mycobactericidal activity, and a number of clinical trials have been conducted in recent decades to compare the treatment efficacy of MOX-containing and/or GAT-containing regimens with the standard regimen. The aim of this meta-analysis for clinical trials of MOX- or GAT-containing regimens was to evaluate their treatment efficacy and safety in initial therapy for drug-sensitive tuberculosis (TB). Databases were searched for randomized controlled trials, and nine studies with 6980 patients were included. We found that fluoroquinolone substitution for isoniazid or ethambutol in short-course regimens might result in more frequent unfavorable treatment outcomes compared with the standard regimen—in particular, an increased incidence of relapse. In a per-protocol analysis, MOX-containing regimens had slightly higher rates of sputum culture conversion at two months than the standard regimen (RR 1.08, 95% CI 1.04–1.11, P <0.001); there was no significant difference in the rate of sputum conversion between the GAT-containing regimens and the standard regimen (RR 1.13, 95% CI 0.96–1.33, P = 0.13). There were no significant differences in the incidence of death from any cause, including TB, nor were there serious adverse events between the MOX- or GAT-containing regimens and the standard regimen. In conclusion, MOX or GAT might not have the ability to shorten treatment duration in the initial therapy for tuberculosis despite the non-inferiority or even slightly better efficacy in the early phase of treatment compared with the standard regimen. Furthermore, it is safe to include MOX or GAT in initial TB treatment.

Linezolid Manifests a Rapid and Dramatic Therapeutic Effect for Patients with Life-Threatening Tuberculous Meningitis

ABSTRACT We conducted a retrospective cohort study of patients with MRC grade II/III tuberculous meningitis (TBM) who accepted a background antitubercular regimen (BR) with or without linezolid (LZD). At the 4th week, the LZD-BR group achieved a faster and higher percentage of Glasgow coma scale recovery and temperature recovery, a higher cerebrospinal fluid (CSF)/blood glucose ratio, and lower CSF white blood cell counts than did the BR group. Short-term linezolid supplementation may be a more effective treatment for life-threatening TBM.

Mycobacterium tuberculosis Region of Difference (RD) 2 Antigen Rv1985c and RD11 Antigen Rv3425 Have the Promising Potential To Distinguish Patients with Active Tuberculosis from M. bovis BCG-Vaccinated Individuals

ABSTRACT Antigens encoded in the region of difference (RD) of Mycobacterium tuberculosis constitute a potential source of specific immunodiagnostic antigens for distinguishing tuberculosis (TB) infection from BCG vaccination. We evaluated the diagnostic potential of specific T-cell epitopes selected from two immunodominant antigens, Rv1985c and Rv3425, from RD2 and RD11, respectively, on the basis of epitope mapping, in TB patients and BCG-vaccinated healthy individuals. Using a whole-blood gamma interferon release assay, a wide array of epitopes was recognized on both Rv1985c and Rv3425 in TB patients. Those epitopes that could specifically discriminate TB infection from BCG vaccination were carefully selected, and the most promising peptide pools from Rv1985c showed a sensitivity of 53.9% and a specificity of 95.5%. When the novel specific peptides from Rv1985c joined the diagnostic antigens in the QuantiFERON-TB Gold In-Tube (QFT-IT) assay, the sensitivity was increased from 86.4% to 96.2%, with no drop in specificity. These results indicate that the peptide pools selected from Rv1985c and Rv3425 have the potential to diagnose TB infection by a method that may be routinely used in clinical laboratories.

Evolution and Transmission Patterns of Extensively Drug-Resistant Tuberculosis in China

ABSTRACT The emergence and transmission of extensively drug-resistant tuberculosis (XDR-TB) pose an increasing threat to global TB control. This study aimed to identify the patterns of evolution and transmission dynamics of XDR-TB in populations in a region of China where TB is highly endemic. We analyzed a total of 95 XDR-TB isolates collected from 2003 to 2009 in Chongqing, China. Eight drug resistance genes covering 7 drugs that define XDR-TB were amplified by PCR followed by DNA sequencing. Variable-number tandem repeat 16-locus (VNTR-16) genotyping and genotypic drug resistance profiles were used to determine the evolution or transmission patterns of XDR-TB strains. Our results indicated that the Beijing genotype was predominant (85/95 [89.5%]) in XDR-TB strains, and as many as 40.0% (38/95) of the isolates were distributed into 6 clusters based on VNTR-16 genotyping and drug resistance mutation profiles. All isolates of each cluster harbored as many as six identical resistance mutations in the drug resistance genes rpoB, katG, inhA promoter, embB, rpsL, and gidB. Among the nine cases with continuous isolates from multidrug-resistant (MDR) to XDR-TB, 4 cases represented acquired drug resistance, 4 cases were caused by transmission, and 1 case was due to exogenous superinfection. The XDR-TB epidemic in China is mainly caused by a high degree of clonal transmission, but evolution from MDR to XDR and even superinfection with a new XDR strain can also occur.

MTBDRplus results correlate with treatment outcome in previously treated tuberculosis patients.

BACKGROUND Although MTBDRplus is validated for the detection of multidrug-resistant tuberculosis (MDR-TB), its role in the assessment of treatment outcome is less clear. We evaluated the association of MTBDRplus results with treatment outcome in new and previously treated patients in an endemic setting in China and determined factors associated with poor treatment outcomes. METHODS We prospectively enrolled 298 smear-positive pulmonary TB patients who received the World Health Organization recommended initial treatment regimen or retreatment regimen. MTBDRplus was compared with conventional drug susceptibility testing and DNA sequencing for the detection of MDR-TB. Treatment responses were monitored using sputum smear, culture and chest radiography. RESULTS MTBDRplus successfully identified all MDR-TB and had good concordance with sequencing. MDR-TB rates were low among new patients (4/187, 2.1%), but high in previously treated patients (12/28, 42.9%); 65.2% (15/23) of previously treated cases and 17.1% (27/158) of new cases were unsuccessfully treated (P < 0.001). Seven of eight (87.5%) previously treated MDR-TB patients failed the retreatment regimen. In addition to drug resistance, sputum smear positivity at week 8 and cavitation are associated with treatment failure. CONCLUSION Not only did MTBDRplus correctly identify all MDR-TB cases, MTBDRplus results are also associated with treatment outcomes in previously treated patients. The retreatment regimen should no longer be used; treatment should be guided by molecular testing.

Erratum: A fatal case caused by novel H7N9 avian influenza A virus in China.

[This corrects the article DOI: 10.1038/emi.2013.22.].