Choices for Testing Latent TB

Motivation: You suspect latent TB in a high-risk patient.  Which test do you order: an expensive blood test or a cheaper skin test that needs to be read after two days?  Ever since the interferon-gamma release assay for latent TB testing has been available, I have noticed that we often use the blood test rather than PPD to screen for TB.  Is there a rational basis for this?  Are we driven by convenience or by sound science?

As way of background, there are two commercial interferon-gamma release assays (QuantiFERON and T-SPOT) available.  The assay depends on in-vitro production of interferon-gamma by patient's immune cells in response to M. tuberculosis specific antigens.  In contrast to the PPD testing which also cross-reacts with bacille Calmette-Guerin (BCG) vaccine and many nontuberculous mycobacteria (NTM), the interferon release assay is more specific for  tuberculosis though M. marinum and M. kansasei also cross-react in the interferon release assay.

Paper: Menzies, D., Pai, M., and Comstock, G. "Meta-analysis: New Tests for the Diagnosis of Latent Tuberculosis Infection: Areas of Uncertainty and Recommendations for Research" Ann Intern Med. (2007); 146: 340-354.

Methods: Meta-analysis of studies measuring sensitivity and specificity of interferon-gamma release assays and tuberculin skin testing.  For sensitivity, the study sample was counted positive if the person had active TB (therefore should also test positive for latent infection) or exposure to person with active TB.  For specificity, healthy life-long residents of low-incidence populations without high-risk exposure were counted as negative for TB.

Results: 
Tuberculin Skin Test: There were fourteen studies assessing sensitivity and eight studies measuring specificity.    For the skin test, the sensitivity depends on diameter of induration set as the threshold for positive testing.
Sensitivity:
- 5 mm cutoff, sensitivity of 74% (95% CI of 0.66-0.82)
- 10 mm cutoff, sensitivity of 72% (CI: 0.50-0.95)
- 15 mm cutoff, sensitivity of 40% (CI: 0.25-0.56)
- Pooled pediatric data, sensitivity of 55% (0.43-0.67)
Specificity: 
- All studies: 66% (CI: 0.46-0.86)
- Non-BCG vaccinated: 98% (0.96-1.0)
- BCG vaccinated: 0.56 (0.34-0.78)
- 10 mm cutoff: 58% (0.37-0.79)
- 15 mm cutoff: 87% (0.7-1.0)

QuantiFERON: Thirteen studies assessed sensitivity and nine studies measured specificity
Sensitivity: 
- All studies: 76% (CI: 0.7-0.83)
- Pediatric: 66% (CI: 0.5-0.83)
Specificity: 
- All studies: 97% (CI: 0.95-0.99)
- BCG vaccinated: 96% (CI: 0.93-0.99)
- Non-vaccinated: 100% (CI: 0.94-1.0)

T-SPOT: Twelve studies assessed sensitivity and four studies measured specificity.
Sensitivity:
- All studies: 88% (CI: 0.81-0.95)
- Pediatric: 62% (CI: 0.43-0.81)
Specificity:
- All studies: 92% (CI: 0.88-0.95)
No data available for assessing specificity based on BCG status.

Discussion: For patients at risk of latent tuberculosis, screening by tuberculin skin test or interferon release assay is acceptable.  Although the confidence intervals overlap, there is a trend for higher sensitivity for the T-spot assay compared to the tuberculin skin testing and QantiFERON assay.  This will need to be verified further in future studies.  The specificity of the tubeculin skin testing is affected primarily by BCG status.  For patients without BCG vaccine, specificity is quite high for skin testing as well.  Skin testing is additionally affected by multiple non-tuberculous mycobacteria (NTM) strains.  There was no data presented on results of interferon-release assay or skin testing on patients with confirmed NTM infections.  Another point of caution in the results is that testing data in adults do not necessarily translate to pediatrics, where the sensitivity of the assays could be lower.

One of the major problems with this field at large is that there is no gold standard for latent tuberculosis.  By definition, latent TB does not cause symptoms and is held in check.  So far, the only way to verify prior exposure is when patients develop active TB or have high exposure to active TB infection.  Of the estimated 2 billion people with TB, only a minority will ever develop active TB.  It is quite unclear what the sensitivity of these assays are in patients with well-controlled TB for years.  

Rasburicase in gout

Question: Rasburicase is an IV medication that is a recombinant urate oxidase found in many organisms but NOT humans. There is a clear role for rasburicase in tumor lysis syndrome especially in the setting of hematological malignancy/chemotherapy and urate nephropathy, but what is the role of rasburicase in an acute gout flare, which is also characterized by high serum uric acid levels? I found one study that dealt with this, as well as a few case reports that shared their experiences using rasburicase for severe gout flares.

Study:

Rasburicase for tophaceous gout not treatable with allopurinol: an exploratory study.

Richette P, Brière C, Hoenen-Clavert V, Loeuille D, Bardin T.

J Rheumatol. 2007 Oct;34(10):2093-8. 

Summary of results:  10 patients with gout that did not improve with allopurinol therapy were selected for this study. These patients received rasburicase 0.2 mg/kg 1) in 6 monthly infusions (Group 1, N=5) and 2) in 5 daily infusions (Group 2, N=5). It was reported that Group 1 had statistically significant lowered serum uric acid levels after 6 months. In Group 2, serum uric acid levels decreased in the acute setting of treatment, but were not significantly lowered from baseline at 1 or 2 months. Reportedly, 2/5 patients in Group 1 (versus 0/5 in Group two) also had decreased tophus sizes. However, 2/5 patients in Group 1 and 4/5 patients in Group 2 had gout flares, despite colchicine treatment. (Richette et al., 2007)

Other papers to note: On a case report level, rasburicase has been shown to be useful in cases of severe gout. This is NOT an exhaustive list, just a few examples from the literature:

1) Rasburicase treatment in severe tophaceous gout: a novel therapeutic option.

Moolenburgh JD, Reinders MK, Jansen TL.

Clin Rheumatol. 2006 Sep;25(5):749-52. 

• This case reports the use of rasburicase in a severe case of gout that persisted despite standard therapy. Rasburicase helped improve the burden of tophaceous gout in this patient.

2) Successful treatment with rasburicase of a tophaceous gout in a patient allergic to allopurinol.

Richette P, Bardin T.

Nat Clin Pract Rheumatol. 2006 Jun;2(6):338-42; quiz 343.

• This case reports the use of rasburicase in a severe of gout in a patient who could not tolerate allopurinol. This patient also had some renal insufficiency likely secondary to urate nephropathy. The rasburicase helped to lower uric acid levels in this patient. 

3) Urate oxidase (rasburicase) for treatment of severe tophaceous gout.

Vogt B.

Nephrol Dial Transplant. 2005 Feb;20(2):431-3

• This case reports the use of rasburicase in a patient with severe gout and allopurinol allergy. Use of rasburicase was reported to lower serum uric acid levels, improve gouty arthritis symptoms and decrease tophaceous burden.

Thoughts: The current data supporting use of rasburicase in gout remains on the case series or report level. Undoubtedly, rasburicase lowers uric acid levels and may thereby possibly help with gout symptoms in some patients as reported by multiple authors, but I have not been convinced by current data that rasburicase effectively and consistently treats gout flares. It makes sense to use rasburicase in a gout flare when there is concurrent urate nephropathy or TLS - but the main indication would be for urate nephropathy  or TLS, and not the gout per se.

Dissection and Looking for Zebras

Motivation: A cervical artery dissection is a frightening event.  I met a middle age woman last year, who described sitting in a bench listening to a street musician playing guitar then feeling a twinge in her neck and then not being able to move her left side.  She had a carotid dissection leading to a large stroke - chances are that she will never be able to move her left side.  For other patients with stroke, we often feel that perhaps if the patient had not smoked and snacked on hamburgers, we could have prevented the stroke.  With dissections, we do not know the cause most of the time.  One of the more common maneuvers in rounds though is to see if the patient is flexible and can bend her fingers backwards without breaking - attempts to infer underlying connective tissue disorders.  But, how commonly are connective tissue diseases associated with cervical artery dissection?

Paper: Brandt, T., Orberk, E., Weber, R. et. al. "Pathogenesis of cervical artery dissections: Association with connective tissue abnormlities." Neurology (2001); 57: 24

Methods: Prospective study of patients with non-traumatic spontaneous symptomatic cervical artery dissection.  Dissections were confirmed by MRI of neck, CTA, and angiography.  Patients also received thorough clinical evaluation and had skin biopsy.  Ten controls with strokes from other mechanisms were also evaluated and biopsied.

Results:
Cohort: Total of 65 patients with dissection were recruited into the study - 36 with single vessel dissection  (29 with internal carotid artery and 7 with vertebral arter), 22 with multi-vessel dissection, and 7 with recurrent dissection.  Of the 65 patients, 52 presented with cerebral ischemia while the remaining had neck and cranial nerve palsies.

Family Inheritance: Six patients (9%) had first degree relative with cervical artery dissection.

Connective Tissue Disease: Three patients (5%) had systemic signs of connective tissue disorder such as hyperextensible skin, marfanoid appearance, and hypertrophic pseudo-molluscoid scars.

Vascular Disease: In total, six patients (9%) had other vascular anomalies: 2 with intracranial aneurysm, 3 with aortic dissection, and 1 with renal artery dissection.

Biopsy: On electron microscopy, ultrastructural aberrations of the connective tissue disease was found in 36 patients (55%).    None of the controls had similar abnormalities.  These abnormalities were typically in the collagen fibrils and elastic fibers.

Discussion: This exploratory study demonstrates, I think, that there probably exists new classes of connective tissue disorders affecting vascular structures that we do not at present know.  Interestingly, only 5% had other clinical signs of connective tissue disease yet more than half had microscopic evidence.  One of the other cautionary points from this paper is that a significant percentage (9%) had concurrent vascular anomalies such as dissection or aneurysms.  When treating a patient with newly diagnosed dissection, we should probably be extra vigilant for other anomalies as well.  This study, of course, suffers from the small number of controls, and it is unclear how many apparently normal people in a larger study would have microscopic abnormalities without every having any clinical symptoms.