Antibodies to ANNA-1, Amphiphysin, ANNA-2, CRMP-5, PCA-1, PCA-2, PCA-Tr, GM1, and GD1b were negative. On day 2 of hospitalization, he developed respiratory distress, tachycardia, and hypotension. He was intubated and placed on mechanical ventilation, and then started on plasma exchange (PLEX). During the hospitalization, there were wide fluctuations in heart rate and blood pressure, which were partly attributed to dysautonomia secondary to acute inflammatory demyelinating polyneuropathy (AIDP) because they were persistent between the sessions of PLEX and present after other potential causes such as possible sepsis and dehydration were appropriately treated. He was started on midodrine on day 5 of hospitalization, but on day 9 became severely hypotensive and bradycardic, requiring pressure support, and subsequently expired as the family withdrew life-sustaining therapies. His GBS disability score4 during the course of his disease starting with administration of influenza vaccine is demonstrated in Figure 2.
Immune checkpoint receptors cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) and PD-1 promote immune tolerance and prevent autoimmunity by a number of mechanisms that include inhibition of effector T (Teff) cells and increasing the number and activity of Foxp3+CD4+ regulatory T (Treg) cells.5 There is high expression of PD-1 on Treg cells and PD-1 signaling results in Treg proliferation and enhancement of their immunosuppressive activities.5 On the other hand, PD-1 signaling constitutes a major tumor resistance mechanism because different neoplasms express PD-1 ligands to evade the immune responses.5 Therefore, specific CPIs that are new immunotherapies for melanoma and other cancers heighten the immune response by increasing T-cell response against the tumoral tissues, through downregulation of Treg cells among other mechanisms.5,6 A recent study on mice with knock in human ctla-4, which were treated with ipilimumab, an anti-CTLA-4 monoclonal antibody, showed correlation between emergence of irAEs and systemic T-cell activation as indicated by low ratio of Treg/Teff cells.7 A previous study on experimental allergic neuritis, an animal model that mimics clinical, pathological, and electrophysiological features of GBS, suggests that upregulation of Treg cells likely has an important role in the recovery phase of the disease.8 On the other hand, peripheral blood Treg cells are lower in the in the acute stage and increase toward the level of normal controls in the recovery phase of the disease, and after IVIG treatment in patients with GBS.9,10 Furthermore, in a rat model for experimental allergic neuritis, administration of PD-1 ligand alleviated the disease course.11 In that study, PD-1 ligand treatment upregulated Treg and anti-inflammatory IL-4+CD4+ Th2 cells and decreased proinflammatory IFN-γ+CD4+ Th1 and IL-17+CD4+ Th17 cells.
Considering the fact that immunotherapy may result in exacerbation of autoimmunity, patients with baseline autoimmune disease were generally excluded from trials with CPIs. In a small, retrospective multicenter study on patients with advanced melanoma and preexisting autoimmune disease who received ipilimumab, 8 (27%) had exacerbation of their autoimmune disease (increasing joint pain in patients with arthritis and new plaques in patients with psoriasis), which were successfully managed with corticosteroids.12 In the same study, grade 3–5 (severe, life-threatening, or fatal) de novo irAEs, occurred in 10 (33%) of the patients, including fatal outcome in 2 patients. In another recent review,13 approximately 50% of 123 patients with history of underlying autoimmune disease who underwent treatment with CPIs developed exacerbation of underlying autoimmune disease, including deterioration in 2 of 6 patients with multiple sclerosis and 3 of 4 who had preexisting myasthenia gravis.13 In the aforementioned study, 1 patient with a history of GBS did not experience recurrence after CPI therapy. Among the patients with underlying autoimmune neurological disease who received CPI, relapse of myasthenia gravis has been reported in several cases previously14–16; the symptoms could generally be controlled with steroids, sometimes with IVIG.
The subacute course of the neuropathy in our patient and the timing of vaccination were consistent with a postinfluenza virus vaccination GBS. GBS occurs after seasonal flu vaccination in the North America with an estimated risk of 1 case per every 1 million vaccinations, with mean odds ratio of 1.7 (95% CI, 1.0–2.8; P = 0.04).17 Our patient had the demyelinating variant of GBS (AIDP) considering the results of the second EMG/nerve conduction study, despite the fact that first study did not meet the criteria for AIDP. Follow-up study is often needed to differentiate AIDP from axonal variants of GBS.18 Furthermore, although the normal CSF protein level in our patient is atypical for AIDP patients in general, normal CSF protein in the second week of the disease was encountered in about 25% of patients with postflu vaccination GBS in a previous study.19 Recurrence or relapse occurs in about 6%–10% of patients with GBS.20 The initial relapse of GBS in our patient, which occurred shortly after partial response to IVIG treatment, is consistent with a treatment-related fluctuation (TRF).20 TRFs are more frequent in patients treated with IVIG or PLEX early in the disease course and usually respond to additional treatment with IVIG or PLEX.20,21 TRFs occurred in 18.7% of patients in a cohort of 48 cases of postflu vaccination GBS, and only 1 patient (2.1%) had a fatal outcome.19 Most of the previously reported GBS or GBS-like patients associated with CPI therapy improved with steroid and IVIG treatment,1,13 although fatal outcome has been reported in at least 3 previous cases.22–24 Dysautonomia, which contributed to fatal outcome in our patient, was the initial manifestation of GBS secondary to CPI treatment in another report.25 Although it is likely that CPI treatment with nivolumab given during a recovery stage of AIDP resulted in disease exacerbation, the possibility of primary disease progression in our patient cannot be completely excluded.
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