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Episode #2 – Brains and lungs and eyes, OH MY!

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Summary

What infections tie together brain and lung lesions? Follow our guest, Dr. Gerome Escota, as he travels the winding road through this complicated case.

Credits

Host: Sara Dong

Guest: Gerome Escota

Writing/Producing/Editing/Cover Art/Infographics: Sara Dong

Our Guest

Gerome Escota, MD

Twitter

Dr. Escota is the co-Program Director of the Infectious Diseases Fellowship and the Medicine Clerkship Director at Washington University in St. Louis. He is a member of the executive committee of the IDSA Medical Education Community of Practice and chairs its Teaching and Learning Resources Workgroup. Gerome is originally from the Philippines and has a long list of teachers that have inspired him to be an ID educator. More recently, he has expanded this role on social media by creating @WuidQ, the first Twitter resource that provides a platform for ID teaching and learning via board-style questions and case discussions. He is a dutiful son, a caring brother, a trusted friend, an approachable teacher, a lifelong learner, and always a wide-eyed camper.

Also check out Comprehensive Review of Infectious Diseases, 1st edition, a must-have book for ID fellows!!

Culture

Gerome’s recommendation was enjoying anything related to food!  Check out some recommended recipes from Gerome and Sara below:

Consult Notes

Consult Q

Patient with brain and lung lesions who presented with fatigue. Please assist with work-up

One-liner

70 yo F with history of a cavitary pulmonary nodule and parietal brain lesions who presented with fatigue and anorexia.  She was ultimately found to have disseminated Aspergillus fumigatus infection with endocarditis, bilateral endophthalmitis, pulmonary, and CNS disease.

Key Points

Tips on how to approach a complicated patient

  • “It is not uncommon for one to get overwhelmed when hearing about a complicated case and when you start actually digging into the file and assembling relevant information about consult.”
  • Summarize the case
    • Look at your patient and host factors — what are the important risk factors that might predispose to certain infections?  These could include age, immunosuppression, steroid use, prior splenectomy, etc
    • Look at the signs, symptoms – try to come up with a grouping of symptoms into a recognizable clinical syndrome
      • Here you can weave in the tempo of illness – is it chronic? Gradual onset or sudden evolution?
      • Take into account labs and imaging to help align with possible syndromes
  • Combining your summary of the patient and the summary of the syndrome = your problem representation

A common clinical syndrome for ID consults is the co-occurence of brain and lung lesions.  Keep these infections on your differential diagnosis!

  • Nocardia spp.
  • Fungal infections: 
    • Endemic fungi, depending on epidemiology(Dr. Escota abbreviated as ‘HBC’ = Histoplasma, Blastomycoses, Coccidiomycoses)
    • Yeast (Cryptococcus)
    • Mold (Aspergillus, Mucor)
  • Embolic disease: 
    • Cardiac is prototypical: look for infective endocarditis (Staph, Strep – but also other less common organisms that might cause endocarditis)
    • Non-cardiac embolizing disease can include Lemierre’s disease (often Fusobacterium), infectious aortitis, infected cardiac thrombus
  • Organisms predisposed to dissemination: hypervirulent Klebsiella pneumoniae
  • Mycobacterial disease: M.tuberculosis, non-tuberculous mycobacteria 
  • Check out these organisms on one of the episode infographics!

In this episode, we discussed the ID approach when you have a patient with ongoing disease while on therapy.  Here are some considerations in that setting:

  • Source control is key!  Must ensure that failure or progression while on therapy is not related to lack of source control.
  • Wrong bug?
    • Do you have the right causative organism identified?
    • Is there co-infection?
    • Is there an additional non-infectious process going on?
  • Wrong drug?
    • Do you have the right drug at the right dose?
      • In this case, we considered whether voriconazole could be subtherapeutic. Therapeutic drug monitoring is used, but voriconazole has non-linear kinetics — meaning increases or decreases in the dose do not directly predict what the drug level will do
    • Is the patient taking the medication?  Is there an absorption issue?
    • Are there drug interactions or toxicities? 
    • Does the drug penetrate the area of concern? This is typically going to be more of a question with a few specific locations: brain, eyes, testes/prostate.
  • Do you not have an expected response to therapy because there is misunderstanding about the host’s immune response?

“When there is a cat in the history, it is always to blame” — Classic cat-associated infections

“My cat loves PPeanut BBuTTTer”

  • PP = plague (Yersinia pestis), Pasteurella
  • B = Bartonella, Bordetella bronchiseptica
  • TTT = Tularemia, Toxoplasma, Toxocara cati

Want a more comprehensive resource for locating information on infections associated with different activities or animal exposures?  Here is a look at Infections of Leisure, Fifth Edition by David Schlossberg in Emerging Infectious Diseases.

A quick summary of definitions in endophthalmitis given this episode’s patient case

  • Endophthalmitis indicates an infection within the eye and usually implies infection of vitreous and/or aqueous (within the globe)
    • Endogenous endophthalmitis results from hematogenous seeding of pathogen into the eye
    • Exogenous endophthalmitis is due to infection introduced from “outside,” such as surgery, trauma, or extension from cornea (aka keratitis)

Beta-D-Glucan (BDG) / Aspergillus Galactomannan (GM)

    • Beta-D-glucan has been shown to be clinically useful in diagnosis of invasive fungal infection, especially if levels are significantly and repeatedly high — but it cannot be interpreted on it’s own.  The results must be synthesized in light of the clinical presentation and with consideration for possible causes of false BDG elevation. Keep the chart below for reference when you think about beta-D-glucan and Aspergillus galactomannan
    • The IDSA guidelines for aspergillosis recommend use of serum and BAL GM as well as BDG for diagnosing IA in high-risk patients (hematologic malignancy, allogeneic HSCT) in particular.  
    • Serum GM is not recommended for screening in SOT recipients, patients with chronic granulomatous disease (CGD), or those on mold-active antifungal therapy or prophylaxis (but potentially can be used in bronchoscopy)

Using histopathology from tissues to diagnose fungal infection can be tough.  Here is a great resource to keep for reference when you are trying to use morphology in tissue.  I’ve converted the major charts from this paper in the graphics following the link!

“When I hear fungal endocarditis, I cringe because I know the increased morbidity and mortality.”  Let’s briefly think about fungal endocarditis (FE) here.

  • Most common cause of FE is C.albicans, followed by: non-albicans Candida, Aspergillus, Histoplasma, others.
  • The most common risk factors typically identified historically included prior valve surgery, rheumatic heart disease, vascular lines, and host factors.  More recently, there seems to be a shift more towards invasive lines, noncardiac surgery, immunocompromised hosts, and IV drug use.
  • FE has a very high mortality.  In one study, there was a 55% mortality with combined medical/surgical treatment vs 36% with antifungal alone.  The major caveat here is that the majority of patients were treated with Amphotericin B.
  • FE has a high risk of embolization
  • Diagnosis is also difficult as blood cultures are negative in the vast majority of cases.
  • Take a closer look here, this is a review of FE cases over a 30 year window.  Ellis ME, Al-Abdely H, Sandridge A, Greer W, Ventura W. Fungal endocarditis: evidence in the world literature, 1965-1995. Clin Infect Dis. 2001;32(1):50-62. doi:10.1086/317550

In this following section, we’ll cover a few points about Aspergillus.

IDSA Guidelines for Aspergillus are available here, last updated in 2016: 

Key classic risk factors for Aspergillus infection:

  • Severe and prolonged neutropenia
  • Corticosteroid use (typically high doses +/- prolonged duration)
  • Chronically impaired cellular immune responses or severe immunosuppression (e.g. allogeneic HSCT, SOT, advanced HIV/AIDS, CGD or other immunodeficiency)

How long to treat?

  • Treatment durations for the various Aspergillus syndromes are outlined in Table 1 of the IDSA guidelines
  • Generally antifungals are continued until signs and symptoms of infection and immune dysfunction are resolved. For most immunosuppressed patients, antifungal therapy will be continued for months or even years. The total duration of therapy is dependent on:
    • Degree and duration of immunosuppression
    • Site of disease
    • Evidence of disease improvement (such as radiographic abnormalities)/ Response to therapy
  • Invasive pulmonary aspergillosis is treated for a minimum of 6-12 weeks, but typically much longer in patients who are immunosuppressed.  For those with endocarditis or other severe forms of infection (such as brain abscess), many would give lifelong suppressive antifungal therapy with oral triazole.

What about the use of combination antifungal therapy for invasive aspergillosis (IA)?

  • First off is ensuring that you have gone through the exercise of examining the current plan. Think about the antifungal therapy: is the antifungal choice, dose, penetration, etc. appropriate? is the med correct? What about the infection: is there a co-pathogen? And so on.  
  • Combination antifungal therapy has been evaluated both as initial therapy and salvage therapy for IA. Currently, the IDSA guidelines mention possible use of combination therapy with voriconazole and an echinocandin in select patients for salvage therapy (weak recommendation, moderate-quality evidence).  Combo antifungals for primary invasive pulmonary aspergillosis is not routinely recommended, but recommended to consider echinocandin with voriconazole for primary therapy in setting of severe disease (particularly if hematologic malignancy or profound/persistent neutropenia)

So you decide to consider combination therapy for your patient, what information is out there on efficacy and safety of antifungal combination therapy for invasive aspergillosis?

So the question of combination antifungal therapy in IA is not easy, as there is no data demonstrating clear superiority of it’s use.  Although only some of the studies addressed toxicity of the combination regimens, it does seem that azole-echinocandin regimens are tolerated fairly well.  Like everything else in medicine, it requires balancing the risks and benefits of dual drugs — weighing toxicity, severity of disease, degree of immunosuppression, risk of death, cost, patient factors (such as ability to use IV medication if needed).

Check out these references:

Other miscellaneous mentions and notes:

Episode Art & Infographics

Goal

Listeners will be able to evaluate a patient who presents with concurrent brain and lung lesions.

Learning Objectives

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

  • List a comprehensive differential diagnosis for infectious etiologies of concurrent brain and lung lesions, including bacterial, mycobacterial, parasitic, and fungal causes
  • Implement approach to identify possible causes of poor response to antimicrobial treatment
  • Interpret clinical use of beta-D-glucan testing for invasive fungal infection
  • Describe the evidence for use of combination antifungal therapy in invasive aspergillosis

Disclosures

Our guest (Gerome Escota) as well as the Febrile podcast and host (Sara Dong) report no relevant financial disclosures.

Citation

Escota, G., Dong, S.  “#2: Brains and lungs and eyes, oh my!”. Febrile: A Cultured Podcast. https://player.captivate.fm/episode/8af81a5a-0ce5-40e3-a35d-2e8d43fec71a

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