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.
 

Your urine tox screen was positive for cocaine...

Motivation: Awkwardness arises when a patient with bacterial endocarditis denies use of IV drugs, but his or her urine tox screen comes back positive for cocaine. Urine tox screens come with the disclaimer from the lab that these tests are not definitive, and further confirmatory testing is required. When a urine tox screen comes back positive for cocaine, how accurate is this result? Surprisingly, few studies have investigated this common issue, and it is difficult to compare study results to the exact test used in the hospital, as there are many different urine tox screen assays...but I did manage to find one article that dealt with this question:

Study: Linder MW, Bosse GM, Henderson MT, Midkiff G, Valdes R. Detection of cocaine metabolite in serum and urine: frequency and correlation with medical diagnosis. Clin Chim Acta. 2000 May;295(1-2):179-85.

Study design and results: A retrospective chart review was performed at a level 1 trauma center. 500 sequential subjects with urine tox screens in the ED were included. Urine specimens positive for the cocaine metabolite (benzoylecgonine-BE) were confirmed with GC/MS technique. 54 patients were positive for BE in the urine; of these patients, 10 had a medical diagnosis of acute cocaine intoxication. 25% of these 54 patients reported using cocaine in the past, and 1 reported use of cocaine on day of testing. Based on their chart review, the authors estimated sensitivity of 100%, specificity of 90.6%, NPV of 100%, but a PPV of only 18.5% for identifying acute cocaine intoxication in the urine test. (Linder et al., 2000)

Thoughts: This study addresses the relationship between cocaine positivity in the urine test and acute cocaine intoxication. I would have been interested in the relationship between cocaine positivity in the urine test and recent cocaine intake in general-but this is difficult because it would rely on actually knowing whether or not a patient took cocaine (which could be practically impossible to know with 100% certainty) or comparing to a gold standard (which is possible, but once again, no test is perfect). From this study, I take home the point that a negative result is useful, but a positive result may not be accurate and requires further testing. This is a key point to remember in keeping the trust in a therapeutic patient-physician relationship, when a patient lets a physician know in good faith that he or she has not taken cocaine, but a positive cocaine test results. One should then verify with further tests if a true positive result would change medical management.

Lyme cardiomyopathy

Question: Can Lyme disease be associated with cardiomyopathy?
Motivation: A patient presents with new onset cardiomyopathy and heart failure. She lives in a Lyme endemic area. EKG does not show any conduction abnormalities - which is the more common manifestation of Lyme disease in cardiac disease - but ECHO shows dramatically decreased LVEF. This study examines the evidence for Lyme cardiomyopathy from a pathological perspective.

Study: Kubánek M, Šramko M, Berenová D, Hulínská D, Hrbáčková H, Malušková J, Lodererová A, Málek I, Kautzner J. Detection of Borrelia burgdorferi sensu lato in endomyocardial biopsy specimens in individuals with recent-onset dilated cardiomyopathy. Eur J Heart Fail. 2012 Jun;14(6):588-96. doi: 10.1093/eurjhf/hfs027.

Design and results: This study was a pathological/molecular analysis of endomyocardial biopsy (EMB) specimens for the Borrelia (Borrelia burgdorferi sensu lato) genome in cases of dilated cardiomyopathy (DCM). The authors compared EMB of patients with new-onset DCM and of patients with CAD (as controls). Specimens were analyzed by PCR and EM. There was a higher frequency of Borrelia burgdorferi sensu lato in the DCM (24%) versus the control group (0%) (p=0.035), while CMV and parvovirus B19 were similar in both groups. (Kubanek et al., 2012)

Thought: The presence of the Borrelia genome in EMB specimens of DCM does not PROVE causation - it does not necessarily prove that Lyme disease causes DCM. Lyme disease may be incidentally found in DCM, and/or related to another etiological factor for DCM. It is also important to ensure in these cases of DCM that there does not exist a more obvious etiology for cardiomyopathy. Nevertheless, I find these data supportive of the hypothesis that Lyme disease can be an underlying pathological etiology for cardiomyopathy. I will be sending off Lyme serologies for patients from endemic areas who present with new cardiomyopathy, especially if it is DCM.

Restricting the transfusion threshold in acute UGIB

Question: When to transfuse in acute upper GI bleed (UGIB)?

Motivation: A common presentation in medicine, and unclear guidelines for when to transfuse. 

Study: Villanueva C, Colomo A, Bosch A, Concepción M, Hernandez-Gea V, Aracil C, Graupera I, Poca M, Alvarez-Urturi C, Gordillo J, Guarner-Argente C, Santaló M, Muñiz E, Guarner C. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med. 2013 Jan 3;368(1):11-21. doi: 10.1056/NEJMoa1211801.

Study design: This study randomized patients with severe UGIB (and hence high rebleed risk) to transfusion when Hb < 7 g/dL (restrictive) and Hb < 9 g/dL (liberal). The study took place in a hospital in Barcelona (so this was not a multi-center study). Patients were transfused 1 u pRBC until they met their transfusion thresholds, and were also followed up with further treatment (endoscopic therapy, PPI, and/or treatment of portal HTN or esophageal varices when indicated). Deviations for clinically appropriate transfusions (such as symptoms, active bleeding, surgical intervention) were also allowed. Primary outcome was rate of death, while secondary outcomes included any further bleeding or complications. Both groups had similar baseline characteristics (including baseline Hb), and were analyzed with intention-to-treat design. (Villanueva et al, 2003)

Results: Rate of mortality at 45 days was lower in the restrictive group (5%) versus the liberal group (9%) with p = 0.02. Subgroup analysis showed that this difference was more dramatic among patients with cirrhosis and Child-Pugh class A or B. Rate of continued bleeding was lower in the restrictive group (10%) versus the liberal group (16%) (p=0.01). Length of stay in the hospital and rate of complications (especially transfusion reactions and pulmonary edema) were also statistically significantly lower in the restrictive versus the liberal group. Note that deviations from transfusion threshold did occur more in the restrictive group, but in <10% of cases. (Villanueva et al, 2003)

Take home point: For patients who present with acute UGIB, setting a restrictive transfusion threshold of Hb < 7 is appropriate. It will, of course, continue to be important to transfuse (as with some of the patients in this study) when otherwise clinically appropriate (i.e. if necessary for surgical/procedural intervention, symptomatic, or severe active bleeding), but trying to use a lower transfusion threshold is a decision that is justified by the evidence presented in this study.

Is the 2012 Flu Vaccine Useful?

Motivation: The flu is rampant.  Emergency rooms are full.  And, what about the vaccine?  Did the vaccine miss the important strains or did most patients avoid the vaccine?  Speculation on this topic is common, and the answer is important for public health preparation for the year ahead.

As way of background, this year's vaccine consists of three strains:

• H1N1 virus: Type A influenza (A/California/7/2009)
• H3N2 virus: Type A influenza (A/Victoria/361/2011)
• Type B influenza strain: B/Wisconsin/1/2010 from B/Yamagata strain of viruses

Methods: Weekly Influenza Surveillance Report by CDC available at http://www.cdc.gov/flu/weekly.

Results:

Flu Positive Tests: In the week from December 30 to January 5, 12,876 samples were tested by collaborating laboratories, and 4,222 (32.8%) tested positive for influenza. 

Influenza Strains:  Between December 10 to January 5, the distribution of viral strains as tested in laboratories is as follows:

- 7340 samples (49.77%) of H3 strains of Influenza A

- 4328 samples (29.35%) of Influenza A (subtyping not performed)

- 2959 samples (20.07%) of Influenza B

- 120 samples (0.81%) of H1N1 strain of Influenza A

Detailed Antigenic Subtyping: Since October 2012, 521 influenza viruses have been characterized:

- 17 strains of 2009 H1N1 (included in vaccine)

- Of 327 strains of H3N2, 325 strains (99.4%) were A/Victoria subtype included in vaccine.  2 strains were of different subtype.

- Of 177 Influenza B subtypes tested, 118 strains (66.7%) were of the B/Wisconsin type included in vaccine.  59 additional strains (33.3%) were not included in the vaccine.

Neuraminidase Inhibitor Resistance: All tested strains in the US were susceptible to oseltamivir and zanamivir.  

Discussion: So far this season, the majority of virus strains are of the Influenza type A variety.  At least with the limited strain subtyping, most of the strains that are circulating were included in the year's vaccine.  From the surveillance data, the cause for this year's widespread flu infections is either lack of adequate vaccination or lack of efficacy of the vaccine.  Alternatively, the explanation could be a mix of the two.  In randomized trials, the efficacy of vaccines is about 50-70% with lower efficacy in people with high-risk medical comorbidities.  With a large unvaccinated pool and many elderly people, the disease could be propagated by both the unvaccinated and the elderly with failed efficacy.  In the next year, focus should be on higher levels of vaccination within the population.