Episode #53 – Take My Breath Away

September 12, 2022

Summary

Drs. Pratik “Tik” Patel and Joshua Wolf discuss a case of an immunocompromised teenager with hypoxia.

Credits

Hosts: Pratik Patel, Sara Dong

Guest: Joshua Wolf

Writing: Pratik Patel

Producing/Editing/Cover Art: Sara Dong

Our Guests

Guest Consultant

Joshua Wolf, MBBS, PhD, FPIDS, FRACP

Josh is a pediatric infectious diseases physician at St. Jude Children’s Research Hospital, where he is the Division Director for Hematology and Oncology Infectious Diseases and Medical Director of Antimicrobial Stewardship. He is an Associate Professor at the University of Tennessee Health Science Center. He trained at the Royal Children’s Hospital and Peter MacCallum Cancer Center in Melbourne, Australia and St. Jude and Le Bonheur Children’s Hospital in Memphis, TN. His research focus is on novel approaches to prediction, prevention, and amelioration of life-threatening infections in children with cancer.

Guest Co-Host

Pratik “Tik” Patel, MD

Tik is a second year pediatric ID fellow at Emory University and Children’s Healthcare of Atlanta. He also completed a pediatric hematology/oncology fellowship at Emory. He wishes to leverage his training in both fields to advance the infectious disease care of immunocompromised children with a focus on those undergoing treatment of cancer and hematopoietic stem cell transplant. He has a burgeoning research interest in introduction and implementation of novel diagnostics for improved stewardship and clinical care.

Culture

Tik shared his love of travel hacking, while Josh has enjoyed sharing the book “That’s Not My Squirrel” with his daughter

Consult Notes

Consult Q

Teenage boy undergoing treatment for cancer with respiratory distress, admitted to the ICU overnight, please assist with evaluation and antibiotics

Case Summary

17 year old male with relapsed/refractory brain tumor who was found to have Pneumocytis pneumonia in setting of missed prophylaxis doses.

Key Points

Pneumocystis jirovecii basics and epidemiology

P.jirovecii, formerly P.carinii, is an opportunistic organism. It shares some features of protozoa but molecular studies have shown greater genetic similarities to fungi >> now recognized as ascomycetous fungi
- - Pneumocystis organisms have a high degree of host-species specificity: so P.jirovecii specifically infects humans
  - As discussed on the show, the abbreviation of “PCP” can still be used to refer to the clinical entity of “Pneumocystic pneumonia” even with the change in name
Worldwide distribution
PCP rarely occurs in patients without apparent immunodeficiency. Those at risk for Pneumocystis pneumonia:
- - Highest risk: patients with HIV and low CD4 count
  - In patients without HIV infection, highest risk: glucocorticoid use and defects in cell mediated immunity
    - - Hematopoietic cell and solid organ transplant recipients
      - Those with malignancy, especially hematologic
      - Those receiving steroids, chemotherapy, or other immunosuppression (such as TNF-alpha inhibitors)
      - Those with primary immunodeficiencies
      - Severe protein malnutrition
Acquisition: transmitted by airborne route and can likely occur by person to person spread (immunocompetent individuals may serve as reservoir with asymptomatic lung colonization >> that spread to Pneumocystis in immunocompromised host)
Just some references on PJP risk groups:

A quick note PJP history and Walter Hughes

Walter Hughes, MD [Read more here]
- Joined St. Jude in 1969, one of first physicians to specialize in pediatric ID
- Helped establish the hospital’s Department of ID and served as department chair
- Co-founder and first elected president of PIDS
- Led work that identified PCP as life-threatening infections: Used animal model and published clinical trial in NEJM

Clinical manifestations of Pneumocystis pneumonia

There have been two clinical patterns observed:
- - The endemic infantile form was observed first (interstitial plasma cell pneumonitis) among premature and malnourished infants ~4-6 mo old with bronchiolitis like illness by Jirovec and Vanek. This was a little after World War II
  - In older children and adults with underlying immunodeficiency, patients would develop abrupt onset of fever, tachypnea, and cough
    - - This increased dramatically in the setting of treatment for hematologic malignancies in 1960s/1970s and HIV in 1980s
Traditionally, PCP in patients without HIV infection was described by fulminant hypoxic respiratory failure with fever and cough >> but it is possible to see mild to moderate presentations that are more indolent
- - Almost all patients with PCP will have hypoxemia at rest or with exertion though
The classic radiographic features of PCP include diffuse bilateral interstitial infiltrates, but other patterns have been reported

Diagnosis of PCP pneumonia

Definitive diagnosis would be identification of the organism by staining or PCR-based assays of respiratory specimens

Notes on type of specimen
- - Can use induced sputum (induced by hypertonic saline inhalation)
  - If unable to diagnose based on induced sputum, bronchoscopy with BAL should be performed
  - Lung biopsy with tissue stains and PCR has good sensitivity but is rarely necessary (generally reserved for those with very high suspicion of PCP with negative BAL testing…or those who might have another reason to move to lung biopsy for diagnosis of pulmonary process)
Microscopy of sputum or BAL fluid
- - Direct fluorescent antibody (DFA) staining using fluorescein-conjugated monoclonal antibody can visualize trophic forms and cysts
  - Other dye based stains can be used, such as Gram-Weigert, modified Papanicolaou, Wright-Giemsa, GMS
  - *Pneumocystis cannot be cultured
PCR assays are available for induced sputum or BAL fluid, blood, or nasopharyngeal aspirates

An important learning point: The number of PCP organisms is significantly lower in patients with patients without HIV infection vs those with HIV

Diagnostic yield of microscopy with staining of induced sputum ~50-90% in patients with HIV+PCP, but likely less in those without HIV
For BAL, the yield is >90% in patients with HIV but likely lower in those without HIV
Limper AH, Offord KP, Smith TF, Martin WJ 2nd. Pneumocystis carinii pneumonia. Differences in lung parasite number and inflammation in patients with and without AIDS. Am Rev Respir Dis. 1989;140(5):1204-1209. doi:10.1164/ajrccm/140.5.1204
Pagano L, Fianchi L, Mele L, et al. Pneumocystis carinii pneumonia in patients with malignant haematological diseases: 10 years’ experience of infection in GIMEMA centres. Br J Haematol. 2002;117(2):379-386. doi:10.1046/j.1365-2141.2002.03419.x
Jacobs JA, Dieleman MM, Cornelissen EI, Groen EA, Wagenaar SS, Drent M. Bronchoalveolar lavage fluid cytology in patients with Pneumocystis carinii pneumonia. Acta Cytol. 2001;45(3):317-326. doi:10.1159/000327625
Thomas CF Jr, Limper AH. Pneumocystis pneumonia: clinical presentation and diagnosis in patients with and without acquired immune deficiency syndrome. Semin Respir Infect. 1998;13(4):289-295.

Other labs:

Elevated LDH can be seen (but in patients with underlying hematologic malignancy, it may be of limited use if already elevated)
Beta-D-glucan is a cell wall component of Pneumocystis, so this can be elevated in setting of PCP (as well as other fungal infections)

Presumptive diagnosis can be made based on clinical and radiographic findings highly suggestive of PCP in a patient with risk factors (sometimes the low burden or organisms and/or inability to obtain a sample may limit getting a definitive diagnosis)

Although empiric treatment based on presumptive diagnosis can be started, we discussed on the show the importance of obtaining a diagnosis if at all possible to do safely.
- - This may allow us to stop therapy, which can have many toxicities, if the right pathogen is not diagnosed. High dose TMP-SMX is tough to take

Treatment of Pneumocystis pneumonia

Trimethoprim-sulfamethoxazole (TMP-SMX) is the treatment of choice for any severity!!
- - Dosing is typically 15-20 mg/kg (TMP component) in 3-4 divided doses (assuming normal renal function)
  - Most will use IV therapy until patient is clinically stable
Alternative agents
- - If there is allergy to TMP-SMX, should ideally perform desensitization because it is the best and most effective regimen! But those with severe allergy such as Stevens-Johnson syndrome cannot undergo desensitization
  - For severe disease, would likely use: Clindamycin + Primaquine – or – IV pentamidine
  - Other options for mild-moderate disease: Trimethoprim + Dapsone – or – Atovaquone
How long do we treat?
- - The duration of therapy for PCP treatment in patients without HIV is not well studied
  - Most will treat for 21 days, which has been extrapolated from recommended duration in pts with HIV (who had greater risk of relapse with 14 vs 21 days of therapy but also who had greater organism burden and slower response)
  - Generally should start to see improvement by 7th day of treatment >> if not improving, would consider as treatment failure and manage similarly to patients with HIV who fail initial therapy
What about adjunctive steroids?
- - In patients with HIV and moderate-to-severe PCP, experts recommend adjunctive glucocorticoids (as improves clinical outcomes and mortality without increasing risk of other opportunistic infections)
  - Generally, experts recommend using steroid therapy in pts with PCP who have partial pressure of oxygen <70 mmHg or Aa oxygen gradient >=35 mmHg or pulse ox <92% while on room air
  - The data on efficacy of steroids in patients with PCP without HIV co-infection is mixed, and the role of steroids in this population is really poorly understood
    - - Limited data available do not support routine use of adjunctive steroids in mild/moderate PCP without HIV
        Wieruszewski PM, Barreto JN, Frazee E, et al. Early Corticosteroids for Pneumocystis Pneumonia in Adults Without HIV Are Not Associated With Better Outcome. Chest. 2018;154(3):636-644. doi:10.1016/j.chest.2018.04.026
        Delclaux C, Zahar JR, Amraoui G, et al. Corticosteroids as adjunctive therapy for severe Pneumocystis carinii pneumonia in non-human immunodeficiency virus-infected patients: retrospective study of 31 patients. Clin Infect Dis. 1999;29(3):670-672. doi:10.1086/598651
      - It seems to be more beneficial for severe disease though
        Ding L, Huang H, Wang H, He H. Adjunctive corticosteroids may be associated with better outcome for non-HIV Pneumocystis pneumonia with respiratory failure: a systemic review and meta-analysis of observational studies. Ann Intensive Care. 2020;10(1):34. Published 2020 Mar 20. doi:10.1186/s13613-020-00649-9
        Pareja JG, Garland R, Koziel H. Use of adjunctive corticosteroids in severe adult non-HIV Pneumocystis carinii pneumonia. Chest. 1998;113(5):1215-1224. doi:10.1378/chest.113.5.1215
Tik asked a question about the possible role of echinocandins since the cyst wall of PJP contains BDG – the role of these in human disease is not well established but there are a few reports of use
- - Tian Q, Si J, Jiang F, et al. Caspofungin combined with TMP/SMZ as a first-line therapy for moderate-to-severe PCP in patients with human immunodeficiency virus infection. HIV Med. 2021;22(4):307-313. doi:10.1111/hiv.13013
Is there PJP resistance to therapy?
- - There is not really any strong data on TMP-SMX resistance in Pneumocystis. Mutations have been noted but hasn’t translated in clinical failure
  - If there was no response in therapy after 7 days, Josh discussed how he might consider switching therapy or reconsidering the diagnosis!
Some references for TMP-SMX treatment (in patients without HIV):

PCP Prophylaxis Regimens

TMP-SMX is first line based on proven efficacy
- - May be given as 1 DS tablet daily or three times per week or 1 SS tablet daily
  - The randomized controlled evidence best support 3 consecutive days per week over daily as providing a balance between extremely high efficacy and low toxicity
  - Other regimens though, such as once or twice weekly or 3 non-consecutive days, are all supported by observational studies
  - Josh discussed that he’ll recommend 3 consecutive days, which allows for some non-adherence, is well-tolerated, very effective
Alternative agents **all are inferior protection against Pneumocystis*
- - Dapsone
  - Atovaquone
  - Combination of dapsone, pyrimethamine, leucovorin
  - Aerosolized pentamidine, less effective, requires special equipment, associated with transmission of MTB
As Josh mentioned, often the contraindications to TMP-SMX may be overcalled. Marrow suppression from 3x/week TMP-SMX is overdiagnosed and the drug should be retrialled if that is a possibility
Another note from Josh, a break from prophylaxis for up to 14 days is safe, so its ok to stop the TMP-SMX and not start an alternative agent for a few weeks while you sort out whether to rechallenge.
Here are some guidelines regarding PCP prophylaxis (in non-HIV)

Other miscellaneous mentions and notes:

Like textbook references?
- Mandell, Principles and Practice of ID, 8th Ed., 9th Ed.: Chapter 271 Pneumocystis species
- Long, Principles and Practice of Pediatric ID, 5th Ed.: Chapter 251 Pneumocystis jirovecii
- Comprehensive Review of Infectious Diseases
- AAP Red Book

Episode Art & Infographics

Infographics

Find all the Febrile infographics here!

Goal

Listeners will be able to diagnose and manage Pneumocystis pneumonia in a non-HIV immunocompromised host

Learning Objectives

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

Describe the typical clinical presentation of Pneumocystis pneumonia
Compare and contrast the efficacy and adverse effects of Pneumocystis treatment and prophylaxis regimens

Disclosures

Our guest, Joshua Wolf, receives in kind support for research from Karius Inc, which produces a test for metagenomic sequencing from blood for infectious diseases (relevant to comment in podcast about NGS for PJP). He also participated in industry-sponsored research with Merck Inc and Astellas Inc, and is Co-PI on a research grant from Pfizer Inc.

Febrile podcast and hosts report no relevant financial disclosures

Citation

Wolf, J., Patel, P., Dong, S. “#53: Take My Breath Away”. Febrile: A Cultured Podcast. https://player.captivate.fm/episode/284e730a-c019-4359-a6bb-16a39c05b064

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