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Episode #3 – A Transplant Tale

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Summary

Listen as our guest, Dr. Nicole Theodoropoulos, breaks down the pre-transplant evaluation and a few obstacles in a transplant recipient's story

Credits

Host: Sara Dong

Guest: Nicole Theodoropoulos

Writing/Producing/Editing/Cover Art: Sara Dong

Infographics: Hawra Al Lawati, Sara Dong

Our Guests

Nicole Theodoropoulos, MD

Twitter

Dr. Theodoropoulous is an Associate Professor at the University of Massachusetts Medical School and the Director of Transplant Infectious Diseases at UMass Memorial Medical Center. She completed her fellowship in Infectious Diseases with a focus in Transplant ID at Northwestern University in 2012. She is currently the Chair of the American Society of Transplantation Infectious Diseases Community of Practice and her research interests focus on donor-derived infections and prevention on infections in organ transplant recipients.  You’ll find a few of her publications in the Consult Notes below.

Hawra Al-Lawati, MD

Twitter

Dr. Hawra Al-Lawati was born and raised in Muscat, Oman and went to medical school at Weill Cornell in Qatar. She then moved to Boston for my Internal Medicine residency at Massachusetts General Hospital.  She is now an infectious diseases fellow at Beth Israel Deaconess Medical Center (BIDMC) who loves everything ID & MedEd

Culture

This episode’s culture features true crime! Here are some recommendations to check out.  Caution!  Darkness ahead.

Nicole recommends these podcasts:  Bear Brook, In the Dark, Someone Knows Something

Sara recommends the documentary film Dear Zachary: A Letter to a Son About His Father.  I recommend not knowing too much going into your first time watching, but it deals with the death of a young physician.  It is thrilling, powerful, and unsettling.

Consult Notes

Consult Q

Referral for pre-transplant evaluation

One-liner

40 yo F with primary biliary cirrhosis who underwent deceased donor liver transplantation complicated by adenoviral gastroenteritis and hepatitis.

Key Points

Jump to:

Approach to the pre-transplant evaluation — This is an opportunity to assess risk and create preventative strategies.  The major goals for this visit include: 

  • Infection screening of the potential recipient:
    • Prior infections and colonization patterns: Review old flora that might help drive empiric and prophylactic antibiotic choices, such as multidrug resistant bacterial infections
    • Exposure history and serologic testing for distant exposures.  A comprehensive social history including:
      • Places of birth, residence, and travel (don’t forget military service)
      • Occupation and lifestyle
      • Exposure to animal and environmental pathogens
  • Vaccination
  • Address antibiotic allergies.  Remove intolerances or mislabeled allergies.  If there is concern for true penicillin allergy, then send for PCN skin testing prior to transplant.
  • Counseling for safe living after transplant (such as safe food handling, hobbies/pets/lifestyle, prophylaxis)

Safe living after transplant

One of the keys to the pre-transplant evaluation is anticipating infection risk and providing counseling about risks. The highest risk of infection is during the first 6 months after transplant.  Here are some references regarding this topic below, followed by notes on several strategies for disease prevention.

______________________________

Hand Hygiene

  • Practice before/after cooking, eating, touching mucous membranes or wounds
  • Ideally would have other household members complete higher risk activities (such as pet/animal care, diaper changes), but if unable, ensure use of gloves and handwashing 
  • Handwash with soap and water when hands are visibly soiled.   Handwashing is also more effective with Norovirus and C.difficile
  • Remember that sanitizing hands are also important in other household members such as caregivers, children living with SOT recipients

Respiratory infection hygiene

  • Wearing a mask if higher risk activity (e.g. gardening)
  • Avoid sick contacts and crowded areas as able (such as shopping malls, subways)
  • Avoid smoking
  • Caution with marijuana smoking or vaping given risk of Aspergillus (and potentially other fungi or gram negative bacteria). It is likely that oral ingestion or baked products have decreased level of risk
  • Avoid construction sites, home remodeling, excavations (Aspergillus, Histoplasma)

Yardwork/Gardening and Outdoor Exposures

  • Direct contact with soil may lead to risk of:
    • Invasive fungal infections: Sporothrix schenckii, Blastomyces, non-tuberculous mycobacteria, Pseudallescheria boydii
    • Helminth infection: Ascaris, Trichiura, Ancyclostoma
  • Manipulation of soil can also result in disease from aerosolization, in particular fungal conidia from Aspergillus and Blastomyces
  • Wear gloves, mask, footwear that completely covers foot
  • Take measures to avoid mosquito and tick bites (such as insect repellants, long sleeves/pants)

Water safety

  • Waterborne pathogens can be a risk via ingestion, inhalation, or direct inoculation of wounds.
  • Well water concerns: Coliform bacterial contamination (C.jejuni, E.coli, Shigella), Cryptosporidium parvum, Giardia lamblia, Hepatitis A, Norovirus, non-tuberculous mycobacteria
  • Ocean water / fresh water concerns: Vibrio spp., M.marinum, Aeromonas
  • Recreational water activities (swimming, diving, boating, etc) concerns: Cryptosporidium, Pseudomonas, Shigella, Legionella, Norovirus
  • Cryptosporidium is commonly responsible for illness, and transplant recipients are at risk of severe protracted diarrhea and extraintestinal disease.  Crypto is tolerant of chlorine and can survive for days in chlorinated swimming pools
  • Standing water in home or basement concerns: Mold, Legionella
  • Encourage bottled water for drinking.
    • If well water is used, should be tested yearly for microbial contamination (and would still consider boiling water)
  • Avoid inadvertent swallowing of water with recreational activities, showering

Food safety.  Here are some foods and common pathogens associated with them:

  • Unpasteurized products (milk or dairy, fruit, vegetable juice, cider): E.coli, Salmonella, Brucella, Listeria, Yersinia, Cryptosporidium, C.jejuni
  • Undercooked beef: E.coli, Salmonella, Toxoplasma gondii
  • Undercooked pork: Trichinella spiralis
  • Undercooked poultry: E.coli, Salmonella, Toxoplasma gondii
  • Undercooked fish/seafood/sushi/ceviche: Vibrio, Norovirus, Cryptosporidium, C.jejuni, Salmonella
  • Raw seeds/sprouts (alfalfa, mung beans, etc) and raw produce: Cyclospora, E.coli, Listeria, Salmonella
  • Deli cold cuts, hot dogs, meat spreads: Listeria monocytogenes
  • Undercooked/unpasteurized eggs (uncooked cake or cookie batter, some Caesar salad dressing, mayonnaise, hollandaise sauce): Salmonella
  • USDA website on Food Safety is a resource to review current outbreaks, recalls, safe cooking temperatures and other general recommendations

Pets and zoonotic disease

  • Recommend waiting to acquire new pets until after immunosuppressive regimens have stabilized (6-12 months post-transplant without recent suppression for graft rejection)
  • Ideally recipient would avoid cleaning bird cages, bird feeders, litter boxes, handling animal feces, aquariums
  • Can consult with veterinarian to help select pet that is best suited for household and to ensure proper vaccination.  If live attenuated vaccine for B.bronchiseptica (kennel cough) is given, advisable to not have transplant recipient hold dog during vaccination to avoid direct contact with vaccine 
  • Animal-specific:
    • Cats:
      • Contaminated feces: Toxoplasma, Cryptosporidium, Salmonella, Campylobacter
      • Fleas or scratches: Bartonella
      • Bites or licking wounds: Pasteurella, Capnocytophaga, Sporothrix schenckii
      • Litter box should be changed daily (Toxoplasma oocysts do not become infectious until 1-5 days after shed in feces) 
      • Avoid feeding cat raw or undercooked meat to decrease risk of shedding infectious organisms in stool
    • Birds 
      • Fungal: Cryptococcus, Histoplasma
      • Bird cage linings should be cleaned daily, preferably by individual other than SOT recipient
      • Don’t let birds fly around house
    • Reptiles and amphibians (snakes, iguanas, lizards, turtles); Chicks and ducklings: 
      • Would avoid these pets, carry high risk of Salmonella
    • Ensure free of raccoon latrines

Safe sex practices should be stressed and encouraged

Travel safety: advise patient to discuss with transplant team prior to travel in case additional precautions or medications are needed

Work/School: There are no specific recommendations to guide the decision on when exactly to return to school or work → must weigh age of patient, net state of immunosuppression, prevalence of respiratory infections in the community, type of occupation

We spoke briefly about indeterminate IGRA testing and tuberculosis in the setting of cirrhosis and transplant.

Donor-derived infections are a big topic, but we focused briefly on donor bacteremia.  A few quick notes when thinking about bacteremic donors

  • It is estimated that ~5% of organ donors have bacteremia at the time of organ procurement.  Transmission to recipient is possible, especially if not susceptible to perioperative antibiotics, and this can lead to graft loss, morbidity, and mortality.
  • Infected donors should generally receive targeted antibiotics for at least 24-48h, ideally with some clinical response, and also assessed for the site of infection.  Metastatic donor infection such as endocarditis and embolic infection of  graft may increase risk of infection transmission and warrant longer durations of therapy for recipient.  These details are found in discussion with the transplant team and through DonorNet/UNOS.
  • Gram positive bacteria often have low risk of transmission if relatively avirulent (such as coagulase negative Staph, Corynebacterium, Bacillus).  Approach similar to a normal host — if there are multiple positive blood cultures, then that is more concerning; If just one set from time of procurement, likely contaminant.
  • MRSA, VRE, resistant gram negative, and fungal organisms are the real concern
  • Recipients should be treated for most true bacteremias in the donor unless the donor was obviously treated prior to organ procurement.
  • Recipients would typically receive a 7-14 day course of antibiotics targeted to organism isolated.
    • S.aureus: consider 4 wks of treatment in recipient based on expert opinion
      • Undiagnosed endocarditis in donors with S.aureus is an issue, as you might have embolic infection in the transplant graft, which would require treating similar to an abscess in the organ
    • Candida and Pseudomonas likely warrant at least 2 wks of treatment in recipient
  • Check out the AST IDCOP guidelines on donor-derived infections here: Wolfe CR, Ison MG; AST Infectious Diseases Community of Practice. Donor-derived infections: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33(9):e13547. doi:10.1111/ctr.13547

Check out infographics on the timeline of infections post-SOT as well as the differential diagnosis of diarrhea in transplant recipient.  Sources:

“I hate adenovirus. I’m not a big fan of many viruses, but adeno is in the least favorite top 5…A lot of people blow adenovirus off because it is common but it can cause significant disease, especially in kids and even immunocompetent hosts…Can be nasty and can go anywhere and do anything”

  • Adenovirus is a dsDNA virus that was first isolated in 1950.  Initially detected in military recruits in setting of acute respiratory illness, but later found to have a broad disease spectrum.
    • There are 7 subgroups (A-G) and over 60 serotypes
    • Present worldwide, year-round, and infects most individuals by age 10
    • Spread via aerosol droplets, fecal-oral spread, by contact with contaminated fomites, thru cervical/perinatal transmission, SOT
  • No consensus on definition of the adenovirus infection and disease — but can use AST IDCOP Guideline for guidance in transplant patients
    • Asymptomatic adenovirus infection: detection of adenovirus in patients from stool, blood, urine, or upper airway in absence of signs and symptoms associated with adenovirus disease
    • Adenovirus disease: presence of attributable organ signs and symptoms combined with adenovirus detection in biopsy specimens (immunohistochemical stain) or from culture, antigen detection, or PCR, in absence of other diagnosis
    • Positive adenovirus PCR from tissue or fluid and a negative immunohistochemical stain is not consistent with invasive disease
    • Disseminated: 2 or more organs are involved, not including viremia
  • Clinical manifestations can range from asymptomatic to severe prolonged disseminated disease
    • In liver transplant recipients, it often manifests as hepatitis, but other presentations have been noted (stomatitis, enteritis, pneumonia)
    • In lung transplant recipients, can cause severe pulmonary disease such as diffuse alveolar hemorrhage and necrotizing pneumonia.
    • In kidney transplant recipients: hematuria, dysuria, fever, orchitis, and gastroenteritis has been seen. Hemorrhagic cystitis and graft dysfunction is more often described in adult patients compared to pediatrics.
  • Diagnosis is often via molecular methods. PCR is widely used and sensitive; can be used on blood, respiratory secretions, tissue specimens, and stool
    • Histopathology is gold standard.  Adenovirus infected cells, “smudge cells,” can sometimes be seen – large nuclei with basophilic inclusions and thin rim of cytoplasm. Presence of virus in tissue can be confirmed with immune-peroxidase and in situ hybridization staining.
      • Histologic manifestations can be confused with T-cell mediated rejection, especially in kidney transplant recipients
    • Isolation from urine, respiratory, or stool specimens by cx or PCR does not confirm dz since pts can asymptomatically shed for prolonged periods of time
    • All serotypes, with exception of 40/41, grow well in human epithelial cells and produce cytopathic effect after 2-28d, which can be followed by serotyping
    • Serial quantitative PCR can be useful regarding decision to initiate therapy and monitoring response to therapy if available, but this may not always be readily available.
  • Treatment options are limited.  Some considerations for management of adenovirus in SOT:
    • Supportive care
    • Reduction in immunosuppression can be helpful if possible, but requires a fine balance. There is no consensus on which one to reduce or discontinue or when to resume
    • Use of antiviral agents is not supported by prospective randomized controlled trials, and no antiviral agents are approved by FDA for treatment of adenovirus infections.
    • Cidofovir – data are limited and even dosing is questionable
      • Nucleotide analog of cytosine that inhibits viral DNA polymerase; has in vitro activity against all serotypes
      • Can be nasty drug with significant adverse effects: nephrotoxicity, neutropenia
      • Many transplant centers consider IV cidofovir as standard practice for severe, progressive, or disseminated adenovirus disease
      • Dosing regimens: 
        • 1 mg/kg 3x/wk or
        • 5 mg/kg/wk for 2 wks → 5 mg/kg every other week 
        • Adjust for renal function. Administer with probenecid and hydration
        • Former dosing might be less nephrotoxic but also may be associated with breakthrough CMV or HSV infections and antiviral resistance
    • Brincidofovir – lipid conjugate of cidofovir and oral formulation is in development and not widely available
      • Potential advantages to cidofovir: good oral bioavailability, less nephrotoxicity, higher intracellular levels
      • Adverse effects: gastrointestinal
    • Adenovirus specific cytotoxic T-lymphocytes
    • IVIg: might benefit those with severe hypogammaglobulinemia, main downside is likely cost

Other miscellaneous mentions and notes:

Episode Art & Infographics

Goal

Listeners will be able to assess a patient who presents for pre-transplant evaluation

Learning Objectives

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

  • List the goals of the pre-transplant ID evaluation
  • Discuss safe living after transplant, such as food and water safety
  • Interpret indeterminate interferon-gamma release assay at pre-transplant evaluation
  • List a differential diagnosis for infectious etiologies of diarrhea and fever in a transplant recipient
  • Describe treatment options for adenovirus infection in a liver transplant recipient

Disclosures

Our guest (Nicole Theodoropoulous) as well as the Febrile podcast and host report no relevant financial disclosures.

Citation

Theodoropoulous, N., Dong, S.  “#3: A Transplant Tale”. Febrile: A Cultured Podcast.  https://player.captivate.fm/episode/360c993b-2d39-4f12-b1a1-d73b4b3b0594

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