key: cord-0720606-empw65zr
authors: Kirchner, Theresa; Jaeckel, Elmar; Falk, Christine S.; Eiz-Vesper, Britta; Taubert, Richard
title: SARS-CoV-2-specific immunity in immunosuppressed COVID-19 convalescents with autoimmune hepatitis
date: 2021-07-17
journal: J Hepatol
DOI: 10.1016/j.jhep.2021.07.012
sha: 571c6129fb03f9ee7ac07a1661736b40791f4a69
doc_id: 720606
cord_uid: empw65zr

nan

We read with interest the article "SARS-CoV-2 infection in patients with autoimmune Hepatitis" by Marjot et al. [1] recently published in the Journal of hepatology. While immunosuppressive therapy for autoimmune hepatitis (AIH) had no negative impact on the immediate outcome of COVID-19 [1] [2] [3] , the question remained, whether COVID-19 convalescents immunosuppressed for AIH (AIH-Con) are protected from a SARS-CoV-2 reinfection as nonimmunosuppressed convalescents (non-IS-Con).

To address this question, we prospectively quantified anti-SARS-CoV-2 antibodies against various SARS-CoV-2 antigens (Antigen Panel 1 IgG, IgM, IgA assays Millipore HC19SERM1-85K-04, HC19SERA1-85K-04, HC19SERG1-85K-04) and interferon-γ response to anti-SARS-CoV-2 antigen pools as previously described [4] in AIH patients at their first appointment at our center following SARS-CoV-2 infection. We recruited six AIH convalescents with ongoing immunosuppression (prednisolone 5-80 mg/day 4/6 pts.; mycophenolate 1000mg/day 2/6 pts.;

azathioprine 50 and 75 mg in 2/6 pts.). AIH-Con were compared to a matched cohort of 24 non-IS-Con (AIH-Con vs. non-IS-Con (Table S1) mild-moderate; 9% severe-critical (p=1.0)). Two of the AIH-Con had concomitant primary sclerosing cholangitis, 3/6 had liver cirrhosis, 1/6 AIH-Con acquired COVID-19 during the diagnosis work-up of AIH and COVID-19 was diagnosed in one AIH patient four days after the first mRNA vaccination.

Quantification of anti-SARS-CoV-2 antibodies was available in 4/6 AIH-Con and in two of these AIH patients even in cryo-conserved pre-pandemic samples from our biorepository.

Quantification of cellular immune response was available in 5/6 AIH-Con.

Apart from lower frequencies of IgA against spike S1 peptides and IgG against the nucleocapsid, presence of all other anti-SARS-CoV-2 IgA, IgG and IgM specificities was J o u r n a l P r e -p r o o f comparable in AIH-Con and non-IS-Con ( Figure 1A ). The actual antibody concentrations, quantified by the mean fluorescence intensity (MFI) in the assays, were not significantly different between AIH-Con and non-IS-Con ( Figure 1B) . IgA cross-reacting with nucleocapsid peptides (1/2 pts.), IgA and IgM cross-reacting with the receptor binding domain (RBD) of the spike protein (2/2 and 1/2 pts.) and IgA against spike S1 peptides (1/2 pts.) were found in two AIH-Con in pre-pandemic samples. However, the concentration of anti-SARS-CoV-2 antibodies relevantly increased during COVID-19 in AIH-Con irrespective if preformed crossreactive antibodies were present or not ( Figure 1C ). AIH-Con produced similar amounts of interferon-γ normalized to numbers of peripheral blood mononuclear cells (PBMCs) and T cells like non-IS-Con ( Figure 1D ). Similarly, interferon-γ response against other respiratory viruses (endemic corona viruses (HCoV-OC43; HCoV.229E), RSV, influenza) were not different between AIH-Con and non-IS-Con ( Figure S1 ).

With all the limitations of the statistical analysis of such a small study we found no evidence for a relevantly reduced humoral and cellular immunity against SARS-CoV-2 in AIH-Con in comparison to matched non-IS-Con. Although the frequency of some antibody specificities (anti-spike S1 IgA; anti-nucleocapsid IgG) was significantly lower in AIH-Con, the actual antibody concentrations were not different between AIH-Con and non-IS-Con. Similar findings of a slightly reduced humoral but otherwise robust cellular immunity against SARS-CoV-2 have been reported for liver transplant recipients (LTR), who usually had a much stronger immunosuppression [5] [6] [7] . LTR did not have increased COVID-19 mortality similar to AIH patients [1-3, 8, 9] , while association of COVID-19 disease course with intake of mycophenolate and tacrolimus was ambiguous in two LTR studies [8, 9] . In the light of these recent studies from more immunosuppressed LTR a comparable immunity against SARS-CoV-2 in AIH-Con is not surprising but reassuring. However, the development of an immunity against SARS-CoV-2 as strong as in non-IS-Con is remarkable especially with respect to the high cirrhosis rate of 50% of AIH-Con. Similar to LTR AIH-Con developed a robust immunity J o u r n a l P r e -p r o o f developed even after mild COVID-19 [6, 7] . Unfortunately, the AIH-Con cohort is too small for the subgroup analysis, e.g. strength of immunosuppression or COVID-19 severity.

This study has many limitations beyond the small sample number. The cross-sectional approach at a single time point cannot describe longitudinal changes over time like declining anti-SARS-CoV-2 antibody in LTR within 3-6 months after COVID-19 [10] . Furthermore, we cannot exclude a bias towards false high IgG antibody concentrations in AIH-Con with persistent hypergammaglobulinemia (Table S1 ). However, the parallel quantification of IgA antibodies, that are usually not elevated in AIH and which confer mucosal immunity, did not suggest a relevant bias by a hypergammaglobulinemia in AIH-Con. Fortunately, the success of the vaccination programs prevented a further recruitment of non-immunized AIH patients, because nearly all patients with ongoing immunosuppression and/or advanced liver disease are already vaccinated at our center.

In summary, AIH patients develop an immunity against SARS-CoV-2 as robust as in matched non-IS-Con despite ongoing immunosuppression. This finding might explain in part the missing negative impact of immunosuppression on COVID-19 outcome in AIH patients. 

CoV-2 infection in patients with autoimmune hepatitis

COVID-19 immune signatures reveal stable antiviral T cell function despite declining humoral responses

CoV-2-specific serological and functional T cell immune responses during acute and early COVID-19 convalescence in solid organ transplant patients

T cell-mediated response to SARS-CoV-2 in liver transplant recipients with prior COVID-19. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

SARS-CoV-2-specific cellular and humoral immunity in COVID-19 convalescence after liver transplantation

Protective Role of

Deleterious Role of Age and Comorbidities in Liver Transplant Recipients With Covid-19: Results From the ELITA/ELTR Multi-center European Study

Epidemiological pattern, incidence, and outcomes of COVID-19 in liver transplant patients