Pulmonary Report 7.10.17
Thank you to Ugo for presenting the case of an elderly male with widely metastatic melanoma refractory to PD1 inhibitors presenting with 1-2 weeks of fatigue, FTT, DOE found to have PCP pneumonia!
- PD1 inhibitors are considered first-line therapy for metastatic melanoma.
- Common toxicities of immune check point inhibitors include immune-mediated inflammation of virtually any organ system. See below for more details on PD1 inhibitors.
- The risk for opportunistic infections w/ checkpoint inhibitors is related to the steroids that are generally given to treat the checkpoint inhibitor toxicities. A case report & paper (https://www.ncbi.nlm.nih.gov/pubmed/27501841) illustrating this risk.
- Remember! For patients on steroids if > 20 mg/day of prednisone for > 2 weeks –> give PCP prophylaxis. (per expert opinion -> the rule of Dr. Jen B!)
Which patient that are immunocompromised get PCP?
- HIV-positive patients (CD4 < 200)
- Cancer, solid organ transplant, BMT – related to type & chemo intensity
- Rheumatologic (GPA has intrinsic risk)
- Chronic steroids (see Jen rule above)
Steroids for Rx of PCP in HIV-Negative patients??
- Not well studied in HIV-negative patients, only a few retrospective studies
- No mortality benefit, but may expidite recovery
- Steroids are recommended in the AJT guidelines
- 40-60 mg Prednisone BID x 5-7 days with 7-14 day taper
Table Comparing PCP in HIV Positive and Negative Patients (thanks Jen!)
- See this paper Harry and Jen referred to on the risk of infection in patients on checkpoint inhibitors. https://www.ncbi.nlm.nih.gov/pubmed/27501841
PD-1 Inhibitors (blast from the past)
Emerging data show that 20% of patients with melanoma treated with ipilimumab achieve long-term survival! See this associated review.
PD-1 (programmed cell death 1) and its association with the ligand (PD-L1) is a necessary step in stimulating apoptosis of T-cells, serving as an immune checkpoint. PD-L1 is generally expressed by native cells, signaling to the T-cell “I’m one of you! Don’t hurt me”. Some tumors have been found to also express PD-L1, enabling them to evade destruction by T-cells. In order to treat these malignancies, PD-1 inhibitors (pembrolizumab, nivolumab) serve to block the interaction between PD-1 and PD-L1, enabling T-cells to stay “programmed on”, and thus enable immune-mediated destruction of tumor.
Because of this mechanism of action, a common consequence is the upregulation of cell-mediated immunity and, unfortunately, inhibition of native tissues to turn off T-cells. As a result, we commonly see autoimmune-mediated inflammation manifested as new rash, diabetes, thyroid disease, pneumonitis, hepatitis, colitis, etc.
Common Immune-Mediated Toxicities Seen with Check-point Inhibition:
|Skin & Mucosa||Pruritic rash (most common!)
Consider oral steroids
|GI Tract||Diarrhea/colitis – presents ~6wks into treatment||R/O infxn
Steroids if severe
|Liver||Hepatitis (rate <5%, severe toxicity very rare)||Stop therapy if moderate-severe.
Steroids + mycophenolate given rarely.
|Lung||Pneumonitis – (rate <5%, but occasionally fatal)||Steroids common. Infliximab, cyclophosphamide also used, though patients requiring therapy beyond steroids have nearly 100% mortality.|
Autoimmune thyroid disease
Adrenal Insufficiency T1 DM
Less commonly reported immune-mediated adverse events include the following: acute renal injury, pancreatitis, neurotoxicity (GBS, myasthenia gravis, PRES, aseptic meningitis, autoimmune encephalitis), cardiotoxicity (myocarditis), hematologic (cytopenias), and ocular inflammation.
Many of the adverse events described above can be managed with continued use of PD-1 inhibitors if mild. However, for severe adverse reactions, PD-1 inhibitors are withheld and potential discontinued permanently.