Acute cholangitis following mRNA COVID-19 vaccine booster in a patient receiving an anti-amyloid antibody for Alzheimer’s disease: A case report

Abstract

A 77-year-old woman had 2 weeks of fever and flu-like symptoms starting several hours after receiving an mRNA booster for SARS-CoV-2 and the influenza vaccine, in separate shots. Laboratory tests showed cholangitis. Medical history included APOE-ε4 carrier genotype, mild Alzheimer’s disease, participation in a clinical trial of aducanumab, and resolving polymyalgia rheumatica. The patient recovered with at-home supportive care. She had aducanumab-associated amyloid-related imaging abnormalities–edema (ARIA-E) both before and after the acute cholangitis. Two months following the vaccinations polymyalgia rheumatica recurred. This case raises questions about interactions among immune-mediated disease, complications of anti-amyloid monoclonal antibodies, and adverse events following SARS-CoV-2 mRNA vaccination.

Introduction

Adverse events associated with SARS-CoV-2 vaccines must be ascertained so that potential causal mechanisms and at-risk populations can be identified.^1,2 Thromboembolism has received the most attention but is very rare, especially after the mRNA vaccines. ³ Similarly, acute hepatitis with autoimmune features^4,5 and myocarditis/pericarditis ² following vaccination are very rare occurrences. Acute cholangitis has not, to our knowledge, been previously reported following SARS-Cov-2 vaccination of any type. The illness presented here occurred during a waning episode of polymyalgia rheumatica (PMR), which has been reported as emerging or reactivating following SARS-CoV-2 vaccination. ⁶ In addition, the patient was a participant in a clinical trial of aducanumab for mild Alzheimer’s disease, during which she had two episodes of amyloid-related imaging abnormalities–edema (ARIA-E). The therapeutic rationale for aducanumab and other anti-amyloid monoclonal antibodies is based on the amyloid-cascade hypothesis of Alzheimer’s pathogenesis, which is supported in part by rare cases of early-onset disease due to dominant mutations in genes encoding amyloid precursor protein (APP) or its processing enzymes. ⁷ While ARIA-E, an inflammatory response of the brain to an immune-mediated therapy, was common in trial participants administered aducanumab, especially in APOE-ε4 carriers, ⁸ much remains to be learned about risk factors or potentiators.

Case report

A woman in her seventies had a 2-week episode of flu-like symptoms with cholangitis starting several hours after receiving SARS-CoV-2 booster and influenza vaccines (detailed timeline, Figure 1). The patient has a history of PMR and was approaching the end of a 1-year tapering course of prednisone, receiving 1 mg/day at the time of the acute illness. Prednisone treatment had been well-tolerated. She had mild Alzheimer’s disease and a strong family history thereof with apparent autosomal dominant inheritance. She is an APOE-ε4 heterozygote and tested negative for other relevant genetic variants. She had been a participant in the placebo arm of a double-blind Phase-3 trial of aducanumab. She then enrolled in the “Phase-3b Open-Label, Multicenter, Safety Study of BIIB037 (Aducanumab) in Subjects with Alzheimer’s disease Who Had Previously Participated in the Aducanumab studies 221AD103, 221AD301, 221AD302, and 221AD205,” in which participants received 10 mg/kg infusions of aducanumab i.v. at ~28-day intervals for ⩾26 cycles (NCT04241068). After her 17th infusion, she had MRI-detected, asymptomatic ARIA-E, without microhemorrhages, which led to 1 dose being held.

Figure 1.

Timeline of events. Green bars represent time, moving left to right. Scale bar (“1 month”) refers to right-hand segment centered around the acute illness (“event,” pink highlighting); scale in left-hand time segments is compressed. Following diagnosis of mild Alzheimer’s disease, ~4 years prior to the event, the patient tested negative for variants in 27 genes (Adult Neurodegenerative Disease panel, Invitae), including APP, PSEN1, and PSEN2. At no time has she been treated with cholinesterase inhibitors or memantine. Participation in the open-label extension trial of aducanumab (NCT04241068) began about a year and half before the event; “infusion months” refer to that trial. Thirty days before the event, PCR-based test for SARS-CoV-2, obtained for international travel, was negative. A 2-week illness with very abrupt onset began 4 h following the vaccinations. The patient reported, “I lost 2 weeks of my life.” She has clear memory of the acute onset but little recollection of the first week of illness. Regarding the second week, she said “I was in a fog.” Prednisone, 1 mg/day, was continued throughout the 2-week episode and for several days thereafter, completing 1-year tapering course for PMR. Aducanumab was administered (infusion #20) on day 10 after acute onset, the same day that bloodwork showed elevated GGT and alkaline phosphatase. Brain MRI on this day showed no evidence of ARIA-E, but the next two infusions (#21, #22) were held because of ARIA-E. Shortly thereafter and more than a month following resolution of the post-vaccine acute illness, PMR recurred, less severe than the episode that started a year earlier.

Twenty days after aducanumab infusion at the 19th month of the study, she received the Pfizer BioNTech BNT162b2 SARS-CoV-2 vaccine booster, as well as the quadrivalent influenza vaccine. She had had Moderna mRNA-1273 vaccines 7 and 8 months earlier, with no notable side effects. Her booster type and the concurrent administration of the flu vaccine were in accordance with guidance from the Centers for Disease Control and Prevention. ⁸ She had no history of reaction to influenza vaccinations, which she had received annually for decades.

Four hours after the vaccinations, she had sudden onset of precipitous diarrhea and vomiting with fever to 39°C. This was followed by 6 days of flu-like symptoms, including generalized myalgias, chills, and daily fevers of ⩾39°C, then 8 days of somnolence with occasional low-grade fevers (38°C). Other vital signs remained stable. She had very little appetite, consumed mostly liquids, and lost 2 kg, 3.5% of her baseline weight. Based on temporal proximity to the vaccinations, this acute illness was a “suspected adverse reaction” (Food and Drug Administration 21CFR312.32).

Laboratory bloodwork 10 days after the vaccinations, by which time the patient had started to improve clinically, revealed gamma-glutamyl transferase (GGT) was 268 U/L (four times upper limit) and alkaline phosphatase was 368 U/L (three times upper limit), whereas bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), other serum chemistries, and complete blood count, including white blood cell count, were within normal limits. GGT is a marker of biliary epithelia and is increased along with alkaline phosphatase by biliary pathology, while ALT and AST rise with hepatocellular inflammation. Therefore, this biochemical profile indicates cholangitis rather than hepatitis. Specifically, the laboratory tests and clinical course indicated non-obstructive cholangitis without evidence of bacterial infection. There was no past history of gallstones or other hepatobiliary disease.

The patient was managed at home with ibuprofen and oral hydration. Prednisone was continued to complete the 1-year tapering course. Liver function tests gradually returned to normal during the ensuing month, along with her activity level and sense of well-being.

Aducanumab was infused on day 10 after the vaccinations, the day that bloodwork showed elevated GGT and alkaline phosphatase. This dose led to another bout of MRI-detected ARIA-E lasting 2 months, again without microhemorrhages, altered neurological exam, or seizures. About 2 months after the vaccinations, and overlapping with the resolution of the second ARIA-E episode, mild PMR symptoms re-appeared (proximal upper extremity pain and weakness, without fever), less severe than the episode that started a year earlier. Those symptoms resolved without corticosteroids over ~6 months. The subsequent aducanumab infusions did not cause ARIA-E and she resumed monthly dosing as per the clinical trial protocol. At the time of manuscript preparation, the patient was doing well.

Discussion

The patient experienced an acute, self-limited febrile illness with cholangitis following immune-system stimulation by two vaccines in the setting of two inflammatory processes, resolving PMR and recent ARIA-E following aducanumab infusion. This flu-like illness was a Grade-2 (moderate-severity) adverse event, tightly time-linked to the vaccinations. The patient had never received the Pfizer BioNTech BNT162b2 vaccine and had no prior history of reactions to influenza vaccination. Hence, the SARS-CoV-2 mRNA vaccine seems likely to have been the immediate trigger. Data are still being collected to understand the adverse-event profiles associated with mix-and-match strategies for SARS-CoV-2 vaccines. ² Moreover, the most common complications of influenza vaccination are mild, brief fever, headache, and nausea; rare associated serious adverse events do not include cholangitis. ⁹ Concurrent administration of multiple vaccines does not increase the risk of reactions. ¹⁰ Thus, involvement of the influenza vaccine seems less likely, although it may have contributed to additional immune stimulation.

Reaction to the SARS-CoV-2 vaccine could be against the mRNA or the lipid nanoparticles used for packaging. The patient’s immune system may have been primed for vaccine-related activation by her several inflammatory condition(s). First, aducanumab clears amyloid plaques by immune mechanisms involving microglia and phagocytosis. ¹¹ The biliary tree would be exposed to i.v. aducanumab and circulating inflammatory cells. b-amyloid deposition within bile-duct epithelial cells and lumen has been reported in primary biliary atresia of childhood. ¹² Moreover, both ARIA-E and PMR re-emerged during follow-up, supporting the plausibility of interaction between vaccine-triggered immune-system stimulation and the patient’s underlying vulnerability to other inflammatory processes. This scenario is consistent with reports of immune-mediated disease, including PMR, being triggered or re-activated following SARS-CoV-2 vaccination. ⁹

Reported serious adverse events associated with COVID-19 vaccination include acute hepatitis with autoimmune inflammatory features, but not cholangitis.^4,5 On the other hand, liver involvement in PMR usually manifests as biliary cholangitis, with anti-mitochondrial antibodies and Toll-like receptors (TLRs) as candidate mediators. ¹³ TLRs, components of innate immunity, are activated by SARS-CoV-2 vaccines. ⁶ Thus, it is plausible that the SARS-CoV-2 mRNA booster vaccination triggered the acute episode of biliary cholangitis in this case.

In the liver, membrane-bound and soluble APP are internalized by low-density lipoprotein receptor-related protein (LRP). ¹⁴ It has even been suggested that Alzheimer’s is a liver disease. ¹⁵ Alzheimer’s patients show elevated AST-to-ALT ratios at baseline. In clinical trials of aducanumab, infrequent, asymptomatic aminotransferase elevations were the only hepatic adverse events. ¹⁶ More data will be available from the Phase 3b safety trial in which this patient is enrolled. Perhaps patients with ARIA-E are at higher risk of hepatobiliary inflammation, especially after mRNA SARS-CoV-2 vaccination.

Conclusion

In the current case of acute cholangitis, it seems plausible that there was an interaction among (i) aducanumab toxicity (inflammation leading to ARIA-E); (ii) COVID-19 mRNA vaccine toxicity, perhaps exacerbated by the influenza vaccine; and (iii) PMR-associated autoantibodies and/or TLRs, resulting in biliary duct inflammation. Given that mRNA vaccines against SARS-CoV-2 continue to be recommended and given the Food and Drug Administration’s conditional approval of aducanumab and full approval of lecanemab, with other anti-amyloid monoclonals in the pipeline, analysis of clinical trials data should be alert to acute cholangitis after vaccination, especially in patients with a history of ARIA-E or PMR. It is hoped that this unusual clinical scenario will spur investigation of interactions among immune-mediated disease (e.g., PMR), immunotherapy with anti-amyloid antibodies, and acute cholangitis following SARS-CoV-2 mRNA vaccination.