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Episode #29 – Double Trouble

29 Cover Art OPT

Summary

Welcome to Season 2! Drs. Alejandra Mendoza and John Wilson discuss a complex case of co-infection in a patient who presented with altered mentation.

Credits

Host(s): Alejandra Mendoza, Sara Dong

Guest: John Wilson

Writing: Alejandra Mendoza, Sara Dong

Producing/Editing/Cover Art/Infographics: Sara Dong

Our Guests

Guest Consultant

John Wilson, MD

Dr. John Wilson is a Consultant and Professor of Medicine in the Division of Infectious Diseases, Department of Internal Medicine at Mayo Clinic in Rochester, Minnesota.  His current research and projects include: tuberculosis and non-tuberculous mycobacterial infection, TB drug pharmacokinetics in HIV co-infected patients, Pneumocystis PCR applications in immunocompromised hosts, HIV and TB health care in international resource impoverished areas among others.  He completed his residency in Internal Medicine as well as his fellowship in Infectious Disease at Mayo Clinic.

Guest Co-Host

Alejandra Mendoza, MD

Dr. Alejandra Mendoza is an ID fellows at Mayo Clinic in Rochester, Minneosta

Culture

Boys in the Boat – Daniel James Brown

Consult Notes

Consult Q

Altered mental status of unclear cause

Case Summary

34 yo male who presented with altered mental status, shortness of breath, and dry cough who was found to have newly diagnosed HIV and disseminated TB infection.

Key Points

Jump to:

Febrile Survey Link
TBM Resources
Intro to CNS TB
TBM Clinical features
TBM Diagnostics
TBM + HIV
TBM Management
TBM + Steroids
TBM + Outcomes

Survey Announcement

We are conducting a research survey to better understand listener utilization and satisfaction with the Febrile podcast and learning resource. We want to better understand how you use Febrile podcast to teach and learn, but also what we can do to improve for future episodes! The survey is open to anyone who has listened or viewed material from Febrile and is voluntary.  This survey takes 5-10 minutes to complete, and responses are completely anonymous.  If you have any questions about the survey, you can send me (Sara Dong) an email at swdong@bidmc.harvard.edu.  Thank you!

Survey Link: https://hms.az1.qualtrics.com/jfe/form/SV_6o2iYLc1Sq7PMQC

This episode covered miliary pulmonary infiltrates again!  Check out the prior graphic on this for a refresher and listen to the episode!  This was similar to episode 27: Millet Seeds of Destruction.  We’ll focus on TB and HIV for the remainder of the Consult Notes, but one quick reminder that came up: unlike cavitary disease, often miliary or extrapulmonary TB disease is more paucibacillary (and can lead to negative AFB smears)

A quick overview of CNS TB. We didn’t touch on all the forms of CNS infection due to M.tuberculosis, but as a quick reminder.  CNS infection due to MTB affects ~1-5% of patients with TB and includes:

  • Meningitis: we’ll talk more about this throughout the Consult Notes
  • Tuberculoma: granulomatous focus from coalescing tubercles acquired during disseminated bacillemia; usually in brain but can occur in spinal cord
  • Spinal arachnoiditis: breakdown of granulomatous foci in spinal cord or meninges and then tuberculous exudates encase spinal cord and spinal nerve roots with inflammatory reaction

In regions with high TB prevalence, all three forms are common among children and younger adults (given increased prevalence of postprimary dissemination).  In areas like North America, extrapulmonary TB tends to represent adults with reactivation disease where the predominant form of CNS disease is meningitis.  You can check out more about Reported TB in the US at CDC website here.

TB meningitis clinical features and complications

  • Typical presentation: stiff neck, headache, fever, vomiting (similar to bacterial meningitis)
  • Some features that might favor TB meningitis over bacterial meningitis include:
      • Subacute presentation
      • Presence of neurologic symptoms 
      • Presence of cranial nerve palsies (usually CN II, CN VI)
  • TBM is classically described as having 3 phases:
      • Early prodromal phase (1-3 wks): insidious malaise, headache, low grade fever, personality change
      • Meningitic phase: pronounced neuro features such as meningismus, vomiting, CN signs
      • Paralytic phase: confusion, stupor, coma, seizures, hemiparesis (death can ensue within 5-8 wks if untreated)
  • In children, headache is often less frequent but children are more likely to have seizures
  • Patients do not need to have pulmonary symptoms!!!  Among patients with HIV co-infection and TBM though, concurrent TB elsewhere and in lung is more common
  • Complications of TBM can include hydrocephalus, hyponatremia, and vision loss

TB meningitis diagnosis:  Need a clinical suspicion!  The diagnostics are challenging given their suboptimal sensitivity/specificity.  See more below on what you might see and other notes

  • CSF examination
      • Opening pressure: usually elevated
      • CSF fluid can have “ground-glass” appearance with delicate web-like clot at the top
      • Cell count/diff:
          • Often WBC ranges from 100-500 with lymphocyte predominance (up can be up to 1500 in 20% of cases)
          • Early in illness though, a lower cell count +/- neutrophilic predominance may be present (this can also be seen in setting of spinal block and/or paradoxical worsening)
      • CSF protein: elevated (usually 100-500 mg/dL)
          • Very high protein in range of 2-6 g/dl is generally indicative of subarachnoid block and carries poor prognosis
      • CSF glucose: typically low (<45 mg/dL)
      • CSF smear and culture
          • Sensitivity of AFB stain for TBM diagnosis: 30-60%
          • Sensitivity of AFB culture for TBM diagnosis: <50% although some studies report closer to 85%
              • Requires 3-6 wks for detectable growth
          • Diagnostic yield is likely increased with multiple CSF specimens from repeated LPs and increased volumes (>=5 mL)
          • Sensitivity of AFB smear/culture is maintained for a few days after starting treatment
      • CSF M.tuberculosis NAAT
          • Most important diagnostic tool!  Faster turnaround time, high specificity (see Promohammad paper here for meta-analysis or below)
          • Use in combination with AFB smear and culture
          • Sensitivity maintained up to one month after treatment
      • If available, urine-based detection of mycobacterial cell wall glycolipid lipoarabinomannan (urine LAM testing) has been recommended by WHO for TB dx in patients with HIV and can be used as CSF assay
      • CSF adenosine deaminase (ADA)
          • Can be a useful adjunct, but may be elevated with certain bacterial infections and neurobrucellosis (no threshold to differentiate between these)
      • Don’t forget:
          • CSF testing for other infections in differential, particularly CrAg 
  • Imaging with CT or MRI.  Neuroimaging prior to LP is important particularly in setting of papilledema or signs of increased intracranial pressure (ICP)
  • Don’t forget CXR and diagnostic evaluation of pulmonary TB as well as diagnostic evaluation for other sites of infection as necessary.  Depending on the case, can sometimes complement work-up with urine or stool samples for TB, which can be markers for disseminated TB disease

TBM Resource Central!!!  Here are some excellent resources for CNS TB

Available guidelines/guidance:

 

Reviews and other references:

CNS TB Treatment/Management

The first principle and key message: do NOT delay empiric therapy if suspect this diagnosis given high mortality and complication rate of untreated infection

  • There are no RCTs to establish the optimal drug combination, dose, or duration of treatment for TBM
      • The principles of treatment rely on pulmonary TB management
      • Traditionally will have initial intensive phase (4 drugs x 2 months), followed by continuation phase (usually 2 drugs for 7-10 months) → total duration 9-12 months
  • Treatment includes prompt TB therapy + glucocorticoids.  Some patients with severe hydrocephalus may also require surgical consultation
  • Current guidelines are largely based on pulmonary TB and may not take into account differential ability of TB drugs to penetrate the brain.  Some challenges include:
      • Anatomic distribution, quantity, and metabolic state of bacilli is poorly characterized
      • Integrity of the BBB (related to infection, inflammation, blood supply) likely changes over course of treatment as antibiotics and anti-inflammatories given (affecting drug penetration)
      • Not clear how mechanisms of bacterial killing influence host inflammatory response, vasculitis, strokes, risk of death
  • So possible strategies to overcome these challenges have included:
      • Prolonging treatment
      • Increasing drug exposure in CNS
      • Increasing dose of poorly penetrating drugs
      • Add or replace drugs with different characteristics

Here are some notes and descriptions of the drugs in the context of TBM below:

Check out this reference paper: Cresswell FV, Te Brake L, Atherton R, et al. Intensified antibiotic treatment of tuberculosis meningitis. Expert Rev Clin Pharmacol. 2019;12(3):267-288. doi:10.1080/17512433.2019.1552831

HIV + TBM

In patients with CNS or disseminated TB and HIV co-infection, the most important priority is to start a TB regimen.  Patient with HIV should use the same anti-TB agents as have been described with close attention to drug-drug interactions

For patients with CNS TB who are ART-naive, initiation of ART should be delayed due to concern for significant IRIS, which in the context of meningitis can increase risk of serious and fatal neurologic complications.  

Steroids

At the end of the episode, we also touched on how hepatic insufficiency impacts our TB drug selection and the complications you encounter when creating a liver sparing regimen.  A few points made by John:

  • INH, RIF, PZA all are metabolized by the liver 
  • RIF is probably the least of these offenders and remains the most important drug for TB → so we want to prioritize a rif-containing regimen
  • Sometimes you have to consider a liver biopsy to determine whether LFT elevation is related to TB infection or something else

TBM Outcomes

Episode Art & Infographics

Find all the Febrile infographics here!

Goal

Listeners will be able to create an initial evaluation and treatment regimen for a patient with HIV and TB meningitis co-infection

Learning Objectives

After listening to this episode, listeners will be able to:

  • Compare and contrast diagnostic tests available for TB meningitis
  • Describe the components of an initial treatment regimen for TB meningitis
  • Identify the appropriate time frames for initiation of HIV antiretrovirals in the setting of central nervous system TB disease

Disclosures

Our guest (John Wilson) as well as Febrile podcast and hosts report no relevant financial disclosures

Citation

Wilson, J., Mendoza, A., Dong, S. “#29: Double Trouble”. Febrile: A Cultured Podcast. https://player.captivate.fm/episode/704adbe3-b236-4f77-87ae-0e95f52f1432

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