Updates By Carol Kemper, MD, FACP

Recommendations for the Use of IGRAs

Source: Updated guidelines for using interferon gamma release assays to detect Mycobacterium tuberculosis infection — United States, 2010. MMWR. 2010;59:1-25.

Since the release of initial CDC guidelines in 2005 for using the Quanti-FERON-TB Gold test, two additional interferon gamma-release assays (IGRAs) have been approved by the FDA, bringing the number of tests for detecting tuberculosis (TB) infection used in the United States to four. Newer data examining the utility of these tests have since become available. The CDC, therefore, convened a group of experts that reviewed 96 published articles and reports providing data on the sensitivity, specificity, predictive value, and the agreement between these differing tests. A general summary of that review, and recommendations, are as follows.

The three IGRAs currently approved for use in the United States include the original QuantiFERON-TB Gold test (QFT), the QuantiFERON-TB Gold In-Tube test (QFT-GIT), which allows for broader field use of the assay in areas without direct access to trained laboratory technicians, and the T-Spot.TB test. These, and the standard TST, each measure different aspects of the immune-system response, they employ different antigens, the interpretative cut-offs for each test differ, and the interpretive cut-offs used in published studies often differ from those used by the FDA for approval. Thus, test results can differ for each of the assays from report to report. Most published studies focus on the sensitivity and specificity of the assays, often compared with TST, but seldom have head-to-head studies of the IGRAs been performed. The lack of a "gold standard" for confirming TB infection only further muddies the water, and much of the sensitivity/specificity data is generated in patients with active TB (with or without microbiological confirmation). Interpretation of tests results may not be comparable for persons with latent TB.

• It is acceptable medical- and public-health practice to use an IGRA instead of (not in addition to) standard TST testing in adults and children ≥ 5 years of age.

• IGRAs are the preferred testing method for previously BCG-vaccinated persons. According to the guidelines, "For persons who have received BCG and who are not at increased risk for a poor outcome if infected, TST reactions < 15 mm in size may reasonably be discounted as false-positives when an IGRA is clearly negative."

• The IGRAs may be especially useful in certain populations at low risk for compliance for return visits for TST testing (e.g., homeless, alcoholics);

• TST is still preferred for children < 5 years of age.

• For all practical purposes, the QFT-GIT and T-Spot assays are similarly sensitive to the TST (meaning a similar risk of false-negatives); pooled data from published reports find a sensitivity for the T-Spot of ~ 90%, compared with TST of 89%. In 11 studies comparing the QFT-GIT and TST in persons with active TB, six studies demonstrated no significant difference in the sensitivity of the two tests, three found the TST to be more sensitive, and two found the QFT-GIT was more sensitive. Similarly, in 12 published reports comparing the T-Spot and TST, nine demonstrated no statistically significant difference between the sensitivity of the two assays, and three found the T-Spot provided greater sensitivity.

• Because of the narrower antigen profile employed by the IGRAs, the QFT-GIT and T-Spot are expectedly more specific (meaning fewer false-positives) than the TST. Pooled data from published reports of persons with active TB suggest that specificity of the QFT-GIT vs. TST is 99% vs. 85%. Similar pooled data for the T-Spot and TST are 88% vs. 86%.

• Both IGRAs and TST are less sensitive in HIV+ and immunocompromised persons, and negative test results in persons at risk for TB should be interpreted with caution.

• IGRAs, similar to TST, should generally not be used for screening persons at low risk for TB exposure (prevalence of MTb infection is < 1%); in such circumstances, false-positives begin to outnumber true positives, even with the use of the newer, more specific assays. Furthermore, HCWs who previously tested negative using TST, who then subsequently test positive using an IGRA, may be erroneously classified as a "conversion." Such tests results in persons at low risk for TB exposure should be interpreted cautiously.

• The use of both tests in one individual is generally discouraged but may prove useful in certain situations when screening for LTBI: promoting greater acceptance and compliance with treatment for LTBI in foreign born persons who place less value in a positive TST result; and in healthy persons at low risk for TB exposure with a positive test result. In the latter case, a positive alternate test lends greater weight to diagnosis of LTBI, and a negative second test might lend weight to the assumption the first test is a false-positive and that treatment is not warranted. In persons with discordant test results, decisions about medical management should be individualized, based on risk assessment, the specific tests used, and the magnitude of the test result. To quote the MMWR "For healthy persons who have a low risk for both infection and progression, discounting an isolated positive result as a false-positive is reasonable."

• It is not unreasonable to use an alternate test for confirmation if an IGRA test result seems unusual.

• Observations of serial IGRA test results suggest that interferon-gamma responses may fluctuate frequently and widely with time, the significance of which is not known and may be sufficient to alter the test interpretation from negative to positive (conversion) or positive to negative (reversion); there is also some suggestion that IGRA test results may wane in persons treated for TB.

• Limited data suggest that IGRAs may be better than TST at identifying recent exposure; a correlation has been observed between the IGRA response and the degree of exposure.

• There is little data on the ability of the IGRAs to predict the lifetime risk of developing active TB (it is assumed the risk is similar to that for TST, which is about 5%-10%, but since the assays measure different aspects of the immune system response, this may not be the case).

Malignancies in HIV

Source: Prosperi MCF, et al. Incidence of malignancies in HIV-infected patients and prognostic role of current CD4 cell count: Evidence from a large Italian cohort study. Clin Infect Dis. 2010;50:1316-1321.

Having been confronted with three recent cases of metastatic lung cancer in as many years in my HIV+ patients, I have stepped up my smoking cessation efforts, with some success. Most recent longitudinal studies of survival in HIV infection demonstrate a decrease in AIDS-related malignancies with improved treatment strategies but, unfortunately, point to an increase in non-AIDS-related malignancies. Earlier initiation of HAART may provide a benefit. The D:A:D study found a strong association between CD4 count and non-fatal malignancy.

An Italian cohort of 6,695 HIV+ individuals was assessed for risk factors for AIDS-defining and non-AIDS -defining malignancy (ADM and non-ADM). The median year of the first positive HIV test was 1997; the median duration from first positive test result to enrollment in the longitudinal project was 19 months (IQR 1-86 months), and the median duration of follow-up on study was 58 months (IQR, 15-97 months). At the time of the final follow-up visit, 54% were receiving HAART, 30% were not receiving antiretroviral therapy, and 16% were receiving suboptimal therapy.

The probability of developing a malignancy within 10 years of follow-up by Kaplan-Meier estimates was 5%. Overall, 3.76% of patients developed a malignancy (two-thirds of which was AIDS-defining and one-third non-ADM). ADM included Kaposi sarcoma, non-Hodgkin lymphoma, and invasive cervical cancer. Non-ADM included hematologic malignancy (in 22 cases), urogenital malignancy (in 16 cases), liver cancer (in 14 cases), and lung cancer (in 9 cases). Independent risk factors for ADM included lower current CD4 count, older age, MSM (vs. IDU), and a history of treatment interruption.

In addition, there was a statisically significant increased risk of non-AMD for persons with either those with CD4 counts < 50 or those with 50-200 cells/mm3, irrespective of current antiretroviral use. Age also was a significant risk factor for non-ADM, although less so than CD4 count.

This observation supports the need for earlier identification of patients with HIV infection and the continued evaluation of the benefits of earlier initiation of HAART therapy.

Metallo-beta-lactamase in the United States

Source: CDC. Detection of enterobacteriaceae isolates carrying metallo-beta-lactamase – United States, 2010. MMWR. 2010;59:750.

Between january and june, 2010, a novel resistance mechanism, called the New Delhi metallo-beta-lactamase (NDM-1), has been identified in three Enterobacteriaceae isolates in the United States. The three isolates, including an E. coli, Klebsiella pneumoniae, and Enterobacter cloacae, all carried "blaNDM-1," which confers resistance to all beta-lactams and carbapenems, with the exception of aztreonam. These three isolates were, however, additionally resistant to aztreonam, presumably by an additional resistance mechanism. The organisms were isolated from three patients who received recent medical care in India.

Similar isolates have been reported with increasing frequency in the United Kingdom, generally in persons who have received recent medical care in India and Pakistan.

Resistance, including that for carbapenems, is detected by standard techniques, including disk diffusion and the modified Hodge test. The CDC suggests that the occurrence of carbapenem resistance in enterobacteriaceae should trigger inquiry as to whether the patient has traveled, and has requested that all such isolates in patients who have received medical care from India or Pakistan within the previous six months be forwarded through the state public laboratories to the CDC.

Strict infection-control measures with contact isolation should be employed for patients either colonized or infected with these isolates. The CDC also suggested in this report that pointprevalence surveys may be considered among high-risk patients.