Thank you to Daniel Kwon for presenting a case of a older gentleman with ESRD, NAFL cirrhosis with HCC presenting with sepsis and RUQ pain 1 week after receiving nivolumab. On imaging he was found to have gas within the liver parenchyma in addition to gram positive rod bacteremia, inspiring HH to take to the board for an approach to GPR (more details below)!
- Nivolumab is an example of immune checkpoint blockade that acts by blocking a negative regulator (PD-1) of T-cell activation and response, thus allowing the immune system to attack the tumor.
- As the PD-1 inhibitors become more broadly used, we are seeing new immune-mediated complications of therapy.
- The differential for GPR bacteremia can be guided by the appearance of the rods – with a clear distinction between filamentous (long & sleek) and non-filamentous rods (short & stout). Call the lab to get a head-start on your diagnosis based on the appearance of the rods!
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.
Nivolumab – Drug Information
According to the FDA, Nivolumab is a human IgG4 anti-PD-1 monoclonal antibody. It is first line treatment for inoperable or metastatic melanoma, as a second-line treatment for squamous non-small cell lung cancer, and as a second-line treatment for renal cell carcinoma.
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.
A Simple Approach to Gram Positive Rods (courtesy of HH!)
(long & sleek)
(short & stout)
* Also stains Acid-Fast