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.

Lupus, TB, and IgG4

Motivation: Recently, I have heard increasing whispers about IgG4 related disease.  In the  list of diseases that are hard to diagnose with widely varying symptoms, long time residents like TB and lupus are being joined by IgG4.  Of course, I have yet to see a single patient with IgG4 related disease personally.  But, when mentioned, I do not know how to fend off the possibility.  So, how do patients with IgG4 typically present?

As way of background, IgG4 related disease has become the topic of much discussion only since 2001, when autoimmune pancreatitis related to IgG4 was first described.  Pathologically, IgG4 related disease is characterized by extensive IgG4+ plasma cell infiltration.

Paper: Zen, Y and Nakanuma, Y. "IgG4-Related Disease: A Cross-Sectional Study of 114 Cases" Am J. Surg. Pathol. (2010); 34: 1812.

Methods: Between 1990 and 2009, pathological samples with diffuse IgG4 plasma cell infiltration were retrieved from case files at Kanazawa University Hospital and affiliated hospitals in Japan.  Clinical features of patients meeting criteria were retrospectively reviewed from medical records.

Results: 
Location: Total of 114 patients with IgG4 related disorder were identified.  Location of disease is as follows:

• 23 patients (20.1%) with head and neck lesions - primarily salivary gland and lacrimal gland
• 16 patients (14.0%) with thoracic lesions found in lung, pleura, and breast
• 27 patients (23.6%) with hepatobiliary lesions in pancreas, bile duct, gallbladder, and liver
• 13 patients (11.4%) with retroperitoneal disease presenting with retroperitoneal fibrosis and aortitis
• 35 patients (30.7%) with diffuse systemic manifestations

Demographics: Median age of presentation is 64 with youngest aged 42.  Male and females were almost evenly distributed for the head and neck group.  On the other hand, >70% of the patients were male with thoracic lesions and >80% were male with hepatobiliary, retroperitoneal, and systemic presentations.

Associated Autoimmune Diseases: In the cohort, 22 patients had history of allergy while only 2 had a clinical history of autoimmune disease - one with sarcoidosis and one with rheumatoid arthritis.  Enlarged lymph nodes were found in 47 patients (41%) by physical and radiologic examination.

Serum Concentration of IgG4: IgG subset information was available in 58 patients.  Serum IgG4 was elevated in 50 of 58 patients (86%).  Serum levels of IgG4 were highest in patients with systemic and head & neck disease.

Lesion Features: Of the biopsied lesions, all except one lesion was macroscopic - could be identified by physical exam or by radiology.  When IgG4 related disease affected a solid organ, the pattern of infiltration was either diffuse or as mass-like lesion.

Malignancy: Of 114 patients, 3 patients in the systemic group presented with malignancy during follow-up: small cell carcinoma (1 year after IgG4 diagnosis), adenocarcinoma (2 years later), and B cell lymphoma (4 years later).

Discussion: What I take away from this cross-sectional description is that this oft invoked but little understood disease is very different from traditional auto-immune diseases.  IgG4 related disease can occur in just about any part of the body, but the likely presentation is a macroscopically visible diffusely infiltrative or mass-like lesion.  Besides testing for IgG subsets, there is little to distinguish it (at least in this survey) at first glance from neoplastic disease.  Importantly, the disease does not appear correlated with other auto-immune phenomenon such as lupus or rheumatoid arthritis or paraneoplastic disease.  I think that in the future, we will learn more about historical features, but for now, IgG4 related disease remains hard to diagnose with protean manifestations - just like lupus and TB.

MRI for C-spine

Motivation: An elderly man trips on ice and falls.  He complains of neck pain in the ED.  He gets a cervical spine CT, which is normal. He still complains of neck pain.  What do you do now?  I think that many doctors would follow different strategies.  Some would take off the cervical collar and provide ibuprofen.  Others would continue imaging with MRI.  What is the right approach?

As way of background, for cervical spine injury, potentially dangerous ligamentous injuries remain on the differential even after a negative CT.  What is less clear is the incidence of these injuries and the clinical significance of these findings.

Paper: Schoenfeld, A.J., Bono, C.M., McGuire, K.J. et. al. "Computed Tomography Alone versus Computed Tomography and Magnetic Resonance Imaging in the Identification of Occult Injuries to the Cervical Spine: A Meta-Analysis" J. Trauma. (2010); 68(1): 109.

Methods: Meta-analysis of prospective and retrospective studies of MRI after negative CT.  True positive MRI was defined as change in clinical management per clinician judgement.

Results:
Studies: Eleven studies were identified evaluating 1,550 blunt trauma patients evaluated initially by CT and then by MRI.  None of the trials were randomized controlled trials.

Abnormalities: Of the entire cohort, 194 MRI abnormalities were detected in 182 patients (12% of cohort) with negative CT scans.  Of these abnormalities, majority (86, 47% of abnormalities) were ligamentous injuries.  Other significant injuries detected were: degenerative changes (47, 24% of abnormalities),  cord contusion (16, 8.2% of changes), fracture (3, 1.5% of changes), and cord contusions (16, 8.2% of changes).

Clinical Outcomes: As a result of MRI, 84 patients (5% of cohort) required prolonged use of collar, and 12 patients (1% of cohort) required cervical stabilization.  In 86 patients (5.5% of patients), MRI findings were judged clinically insignificant.  For MRI, the pooled sensitivity was 100%, and the pooled specificity was 94%.

Discussion: This paper surprised me with the number of clinically significant injuries missed on CT scanning. About 1% of patients required operative intervention after an apparently normal CT scan.  Similarly, about 1% of patients had cervical cord contusions despite a negative CT scan.  What is not apparent from this paper though are the factors predictive of positive MRI findings with a negative CT scan.  In the absence of clear prospective data, I would think that persistent neck pain or any neurological findings calls for an MRI scan despite a negative CT scan.  So, in summary, if an elderly man continues to complain of neck pain even with a negative CT, I would recommend a cervical MRI.

Back Brace

Motivation: I have never worn body armor, but a thoracolumbar brace looks close to it.  I often see the full body brace clipped onto elderly women after a compression fracture of the spine from a fall, and I wonder if it actually does anything besides making for a closeted experience.  Although there are many practices in surgery without evidence, turns out that this idea has actually been tested in a single randomized trial.

Paper: Stadhouder, A., Buskens, E., Vergroeen, DA, et. al. "Nonoperative treatment of thoracic and lumba spine fractures: a prospective randomized study of different treatment options." J Orthop. Trauma (2009); 23: 588.

Methods: Randomized trial carried out in Amsterdam.  Patients younger than 80 with traumatic thoracic or lumbar compresssion fractures ( less than 50% disc height loss or 30% spinal canal stenosis) without neurological impairment were randomized to (1) physical therapy for 6 weeks, (2) removable brace for 6 weeks, or (3) plaster of paris cast for 6 or 12 weeks.  No single primary outcome pre-specified.  Parameters followed included radiographic improvement, pain measure, and disability index meaurd at 6 weeks, 12 weeks, 6 months, and 12 months.

Results:
Cohort: Total of 108 patient were randomized with 54.1% women with mean age of 45.  Baseline measurements such as gender distribution, age, and admission time were similar among groups.  Majority of patients had high-energy trauma.

Tolerability: For compression fractures, physical therapy was better tolerated than plaster of paris but not significantly different than brace therapy.  Brace therapy was also better tolerated than plaster of paris therapy.

Residual Pain: At long term follow-up (1 year later), visual analogue scale residual pain was significantly less for brace compared to plaster of paris therapy for 12 weeks (mean difference 19.0, CI: 1.87-36.2).  There was no difference between physical therapy and brace therapy or between brace therapy and cast for 6 weeks.

Disability Index: At long term follow-up, measure by Owestry Disability Index, brace therapy for 6 weeks was superior to physical therapy (mean difference 14.9, CI: 2.7-27.1) and cast for 12 weeks (mean difference 10.1, CI: 0.25-25.0) or 6 weeks.

Discussion: I think that this paper represents one of the many cases in medicine where an exploratory trial of limited power has been generalized to a wide population.  The patients in the trial were primarily in their 40s presenting after a high-impact accident.  These patients are clearly different than the elderly patients with osteoporotic compression fractures encountered in clinical practice.  Moreover, the trial itself suffers from several notable flaws with perhaps the lack of a pre-specified primary outcome being the most significant one.  Even for the significant outcomes, the confidence intervals are very wide.  While a brace makes pathophyiological sense for treating fractures, the treatment choice for compression fractures remains an area of uncertainty.

CNS Tuberculosis

Motivation: As one of my attendings put it after morning rounds filled with arcane diagnoses, "By the time you end up at MGH, you the definition of atypical."  One of the atypical diagnoses we often consider is central nervous system tuberculosis - entering into the differential for both persistent meningitis and brain masses.  Every time you mention CNS TB, some smirk while others edge towards a face mask.  I am torn between the two largely because I do not know what the typical presentation is or even how to diagnose it prior to a culture that takes weeks to mature.  So, how do you diagnose CNS TB?

As way of background, central nervous system tuberculosis is thought to occur from hematogenous spread of TB from a primary pulmonary focus.  There is TB deposition and formation of subpial and subependymal foci - called Rich foci.  If these foci rupture, TB meningitis results.  Otherwise, growth of these foci results in tuberculomas.

Paper: Systematic review of diagnoses of CNS TB by British Infectious Society. "British Infectious Society guidelines for the diagnosis and treatement of tuberculosis of the central nervous system in adults and children" Journal of Infection (2009); 59: 167-187.

Methods: Systematic clinical evidence review of papers published in Medline and Pubmed between 1966 and 2008 dealing with CNS TB.  The working group consisted of an interdisciplinary group of specialists.

Results:
Basic Clinical and Laboratory Features of CNS TB:
TB Meningitis: The top three clinical features were fever (60-95%), headache (50-80%), and anorexia/weight loss (60-80%).  Top three clinical signs were neck stiffness (40-80%), focal cranial nerve palsy (30-50%), and coma (30-60%).  On CSF examination, majority have clear appearance (80-90%) with 50% having opening pressure > 25 cm H2O.  CSF glucose:blood glucose ratio was < 0.5 in 95% of patients with TB meningitis.  The leucocyte count varies between 5-1000 cells with variable neutrophilic and lymphocytic predominance.  Protein was also variable ranging from 45 to 300 mg/dL.
CNS Tuberculoma: Few large case series but most common presenting feature is seizure with complaints of headache, fever, and weight loss.  CSF pleocytosis of 10-100 cells is present in only 50%.

Microbiology:
TB Meningitis: Sensitivity of AFB smear up to 80% provided that multiple large volume (>6 mL) taps are submitted for analysis.  Culture media usually takes > 2 weeks to be positive and not helpful with decision making.
Tuberculoma: CSF AFB smear usually not positive and require stereotactic biopsy, which is diagnostic in about 94% of patients.

Nucleic Acid Amplification:
TB Meningitis: Currently available nuceic acid amplification tests about 56% sensitive (95% CI 46-66%) and 98% specific (95% CI 97-99%).  After start of anti-TB treatment, PCR test may retain sensitivity even when AFB smear turns negative.  PCR methods of CSF have not been well studies with tuberculomas.

PPD: Rates of positive PPD with CNS TB vary widely with reported ranges around 10-50%.
CSF adenosine deaminase activity: Unclear sensitivity (estimated around 57%) with CNS TB but lack of specificity with false positives from lymphoma, malaria, crytococcoal meningitis, and other etiologies.

Interferon-gamma release assay: Estimated sensitivity of about 50% since CSF lymphocytes may die more rapidly than peripheral lymphocytes.

Discussion: Analysis of the literature supports why TB occupies such a murky place in the differential for brain masses or meningitis.  There are no very sensitive ways to prove TB meningitis.  In some sense, the history of subacute onset of symptoms with a suggestive CSF profile is the best clue for TB meningitis.  The rest of diagnostic tests are not sensitive enough to rule out TB meningitis over clinical suspicion alone.  One point that I was especially surprised to learn is that although TB is acquired via pulmonary source and spread hematogenously, the PPD is positive in only 50%.  Other assays like CSF adenosine deaminase or even interferon-gamma release assay are relatively insensitive.  So, one has to be careful to over-rule clinical suspicion!