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Episode #12 – Who Framed the Rabbit

12 Cover Art

Summary

Drs. Frances Ue and Lou Ann Bruno-Murtha solve a mystery case of persistent fever.

Credits

Hosts: Frances Ue, Sara Dong

Guest: Lou Ann Bruno-Murtha

Writing: Frances Ue, Sara Dong

Producing/Editing/Cover Art: Sara Dong

Infographics: Marcela Santana, Sara Dong

Our Guests

Lou Ann Bruno-Murtha, DO

Dr. Lou Ann Bruno Murtha is the Division Chief of Infectious Diseases, Medical Director of Infection Prevention at Cambridge Health Alliance (CHA), and Assistant Professor at Harvard Medical School.  She received a DO in Medicine at the University of Medicine and Dentistry in New Jersey – School of Osteopathic Medicine, and completed Internal Medicine residency at St. Vincent’s Hospitalist and Medical Center in New York and Infectious Diseases fellowship at Boston University Medical Center. She joined the Department of Medicine faculty at CHA in 1991 and has since focused on hospital epidemiology, infection prevention, antimicrobial stewardship, and quality improvement. Dr. Bruno-Murtha is a sought after educator and provides teaching to medical students, pharmacy residents, and internal medicine residents. She has provided mentorship to quite a few residents who have gone on to careers in infectious diseases, including 2 that have returned as faculty. She is the consummate physician leader with her work showcased in various news and academic publications, including this case that was featured in Boston Magazine.

Frances Ue, MD, MPH

Dr. Frances Ue is an experienced clinician educator, researcher, and leader with a background in public health and advocacy. Her passion for working with diverse, underserved communities and advancing social justice, has culminated in a career as an Internal Medicine attending physician and core teaching faculty at Cambridge Health Alliance (CHA) in Cambridge, Massachusetts. She completed Internal Medicine training at CHA, and also served as Chief Resident, above all during the COVID-19 pandemic. She has developed countless curricula for medical students and residents, and is a sought after educator. She completed the Harvard Macy post-graduate clinician educators course , and returned as junior faculty this past year. She notably led an innovative curriculum utilizing unscripted cases for clinical reasoning called ‘CHAse files,’ and is currently evaluating its impact on learners and faculty. Her research is mainly in the areas of medical education and infectious diseases. Her writing can be found in STAT Opinion  and the New England Journal of Medicine – Insights in Residency Training blog . She holds an Honors Bachelor of Science from Queen’s University in Canada, Master’s of Public Health from Columbia University in New York, and Doctorate of Medicine from Saint Louis University School of Medicine.

Marcela Araújo de Oliveira Santana

I am a medical student at Federal University of Uberlândia, completing my final year (6th year). I was born and raised in a small village in Minas Gerais, Brazil. I am hoping to be an internal medicine resident soon with the intent of specializing in infectious diseases! My interests are medical education, infectious diseases (especially tropical diseases), and rural health! I love reading (I am a big fan of dystopias), cooking, and playing board games with my friends.

Culture

Lou Ann is working on mastering the game of golf and her short game!

Consult Notes

Consult Q

Assistance with work-up of unremitting fever

One-liner

Elderly male who presented with fever, myalgias, and weakness and was found to have severe leptospirosis (L.interrogans, icterohemorrhagiae (serogroup).  His case was consistent with Weil’s disease given hyperbilirubinemia and acute renal failure!

Key Points

Jump to Leptospirosis topics:

Before we get to leptospirosis, a few quick links on tularemia.  Tularemia is often on the differential diagnosis, especially when considering animal contact

Introduction and Microbiology

Leptospirosis is caused by infection with pathogenic spirochetes of genus Leptospira

  • 22 leptospiral species have been described, and 11 are known to be pathogenic
      • Leptospira interrogans, L.kirschneri, L.noguchii are a few of the pathogenic ones
      • Isolates are identified by both species and serovar (eg, L.interrogans, icterohemorrhagiae (serogroup), serovar RGA)
  • Spiral-shaped highly motile spirochetes with 18+ coils
      • Known for a characteristic hook or ‘question mark’ shape at the end of the bacterium

Epidemiology and Transmission

Clinical Presentations

  • Broad range of manifestations
      • ~90% of cases are subclinical or mild self-limited disease >> indistinguishable from other febrile illness
      • Others present with severe multiorgan disease
  • Typical incubation period = 10 days (range 5-14d)
  • Severe disease can lead to variable manifestations.  Leptospirosis is often described as a biphasic disease with initial septicemic phase, followed by reduction in symptoms, then immune phase with potentially critical illness (more on this below). 
  • *Many severe cases though can progress directly to fulminant disease*

Acute septicemic stage

High fevers and rigors, headache, anorexia, nausea/vomiting, cough and pharyngitis

Characteristic symptoms:

  • *Conjunctival suffusion: extreme conjunctival redness without exudate. Classically described in older literature but only present in ~¼ patients in large series
  • *Myalgias/muscle tenderness: severe muscle pain and often prominent in calf and lumbar regions

Lasts about one week and leptospires can be found in blood + CSF

Immune phase

Disappearance of leptospires from blood and CSF coincides with appearance of IgM antibodies

Typical features:

  • Acute liver dysfunction with hyperbilirubinemia and jaundice (out of proportion to transaminase elevation)
  • Renal failure:
      • *Hallmark: nonoliguric hypokalemic renal insufficiency with impaired sodium reabsorption (appears to be due to selective loss of ENaC sodium channel in proximal tubular epithelium)
      • Renal biopsy: acute interstitial or immune complex glomerulonephritis
  • *Aseptic meningitis in up to 80% patients: intense headache, lymphocytic CSF pleocytosis
  • Other CNS manifestations or uveitis are possible
  • Pulmonary symptoms: spectrum of pulmonary involvement is broad, but can be serious with diffuse alveolar hemorrhage and acute respiratory distress syndrome

Lasts up to 30 days and leptospires can be detected in urine and other organs

The cardinal features of severe leptospirosis (nonoliguric renal failure, hepatic dysfunction, thrombocytopenia +/- pulmonary involvement) are known by eponym Weil’s disease — which only occurs in about 10% of patients but has high mortality rate

The image below from Mandell gives an overview of leptospirosis as well

Diagnosis is challenging and requires a high index of suspicion based on patient history and epidemiologic exposure!

  • Lou Ann mentioned some of the nonspecific but helpful labs you might encounter
      • CBC: thrombocytopenia and potentially pancytopenia
      • Renal failure with hyponatremia and hypokalemia
      • Elevated bilirubin (typically more so than elevated transaminases)
      • UA with proteinuria and hematuria
  • Leptospires in blood or urine can be directly visualized by dark field microscopy >> but low sensitivity/specificity
  • In some rare cases, may grow in culture from blood or urine in special labs – but typically would take 1-2 weeks or longer to grow even with special media
  • PCR-based testing of blood, urine, or CSF can be used in acute stage of disease >> but this is often not widely available
  • Diagnosis is typically made via serology:
      • Not atypical to have negative testing early in course of disease
      • Microagglutination test (MAT) is the gold standard or reference assay (should detect agglutinating Ab starting at about 5d after onset)
          • Requires live organisms, expertise
          • Confirmed case: Most specific if fourfold or greater rise in titer (between acute and convalescent serum)
          • Typically single titer of >1:800 is also thought to be suggestive of recent or acute leptospira infection
          • Looks at different responses to different serovars
          • Not readily available in most places and needs to be sent to CDC
      • Other serology testing
          • Macroscopic agglutination
          • Indirect hemagglutination
          • ELISA (in-house often available, but not necessarily validated)
  • Notes of caution: 

Management

Prevention

  • Avoidance potential sources of infection
      • Magnitude of risk depends on local prevalence of leptospiral carriage and degree/frequency of exposure
      • Reduce 
          • Direct contact with potentially infected animals 
          • Indirect contact with urine-contaminated soil and water (e.g. stagnant water, animal farm run-off)
      • Protection of food from animal contamination
      • Protective measures such as boots, goggles, rubber gloves
  • Administration of chemoprophylaxis for individuals with high exposure risk
      • Chemoprophylaxis with doxycycline 200mg once a week can be used for individuals who will be unavoidably exposed to endemic environments
  • Vaccination
      • Animal vaccination can provide some protection >> but immunized animals can become infected and still excrete leptospires in urine
      • Human vaccines have been developed for certain circumstances but are not widely available

Episode Art & Infographics

Goal

Listeners will be able to describe the clinical presentation, diagnosis, and management of leptospirosis

Learning Objectives

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

  • Recognize leptospirosis as a zoonotic infection that is endemic worldwide and key routes of transmission
  • Identify the characteristic symptoms of severe leptospirosis (and Weil’s syndrome)
  • Discuss the available diagnostic testing for leptospirosis
  • Recommend antimicrobial management for leptospirosis
  • Education patients about the prevention strategies for leptospirosis

Disclosures

Our guests (Frances Ue and Lou Ann Bruno-Murtha) as well as Febrile podcast and hosts report no relevant financial disclosures

Citation

Bruno-Murtha, L.A., Ue, F., Dong, S. “#12: Who Framed the Rabbit”. Febrile: A Cultured Podcast. https://player.captivate.fm/episode/527865cc-bb85-464d-861a-37f00cecff83

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