During the early stages of COVID-19 pandemic, the European Association for the Study of the Liver (EASL) and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) published a position paper to provide guidance for physicians involved in the case of patients with chronic liver diseases ^[1]. Specific recommendations were given to patients with autoimmune liver diseases in advising against reducing immunosuppressive therapy to prevent SARS-CoV-2 infections.

In this contest, unravelling the relationship between COVID-19 and patients with autoimmune liver diseases is crucial since these patients are generally characterized by an increased risk of infections due to the iatrogenic effect of immunosuppressive agents and the pathogenic mechanism of the disease itself. 

2. SARS-CoV-2-Induced Autoimmunity

It has been hypothesized that SARS-Co2 may trigger autoimmune mechanisms in genetically predisposed subjects ^[2]. In particular, an increase in several inflammatory cytokines including tumor necrosis factor (TNF)α, interleukin (IL)-1, and IL-6 has been demonstrated in patients with COVID-19 ^[3]. A recent review focused on the SARS-CoV-2 as an instrumental trigger of autoimmunity ^[4]. In general, three primary groups of factors (i.e., the ability of this virus to overstimulate the immune system, the formation of excessive neutrophil extracellular traps with related inflammatory responses, and the molecular resemblance between self-components of the host and the virus) can lead to hyper-stimulation of the immune system when varying from their physiological effect. These factors may contribute to the development of autoantibodies and autoimmune diseases. COVID-19 can activate a hyperstimulation of the immune system or, through the exposure to foreign peptides homologous to human peptides (molecular mimicry), contribute to the development of autoantibodies and autoimmune liver diseases. A list of numerous autoantibodies has been detected in patients with SARS-CoV-2 infection, including ANA (anti-nuclear antibody), ANCA (anti-neutrophil cytoplasmic antibodies), LAC (anti-phospholipid antibodies), etc. These autoantibodies have been generally shown in randomly chosen severely ill COVID-19 patients with no history of autoimmunity. As regard the autoimmune conditions linked to COVID-19 infection, besides the olfactory manifestations, several autoimmune diseases including SLE (systemic lupus erythematosus), myasthenia gravis, and systemic sclerosis have been described ^[4]. The exact mechanism by which SARS-CoV-2 leads to hyposmia/anosmia has not been elucidated so far. One hypothesis is a damage caused by the virus to the olfactory pathways ^[5]. Furthermore, olfactory manifestations have already been described in autoimmune diseases, including SLE, myasthenia gravis, and systemic sclerosis ^[6]. Interestingly, ANA, LAC, and ANCAs have been tested in 33 consecutive patients with COVID-19, 94% of whom had interstitial pneumonia ^[7]. Fifteen patients tested positive for at least one antibody (45%); four out of eleven tested positive for ANA had nucleolar staining, a reactivity that usually is present in diffuse systemic sclerosis. Of note, the presence of these subtype of ANA was associated with a bad prognosis ^[7]. However, the current literature on COVID-19 has focused mainly the development of autoimmune rheumatologic diseases ^[8]. Histopathological signs of autoimmune reactions have been observed analyzing autopsies from patients deceased from COVID-19 ^[9]. Diffuse infiltration of the lung, along with focal infiltration of the kidney, liver, intestine, adrenals, pancreas, and pericardium have been described. The infiltrate was dominated by T lymphocytes (CD3⁺ and CD8⁺ suppressors), suggesting that an autoimmune process might play a role in tissue damage. Regarding liver diseases, a case of a female patient who developed primary biliary cholangitis (PBC) concomitant with Guillain-Barrè syndrome during severe acute respiratory SARS-CoV-2 infection has been reported ^[10]. PBC developed in a 44-year-old obese and hypertensive woman who was already suffering from Hashimoto’s thyroiditis. She had a severe course from a bilateral interstitial pneumonia and was treated in the intensive care unit. During her hospitalization, she developed an important increase in the cholestatic enzymes and was tested positive for ANA 1:160 and anti-mitochondrial antibodies (AMA) 1:640. Her histology was compatible with early PBC. Furthermore, a case of autoimmune hepatitis (AIH)/PBC overlap syndrome has been reported in a 57-year-old man with a medical history of hypertension, pre-diabetes, and beta-thalassemia minor who suffered from COVID-19 infection with moderate respiratory symptoms in April 2020 ^[11]. This patient suffered from fatigue and arthralgias and was diagnosed with AIH/PBC overlap syndrome based on elevated liver enzymes, hyperbilirubinemia, SMA (smooth muscle antibodies), AMA positivity and anti-double-stranded DNA antibodies (anti-ds DNA). Anti-ds DNA positivity was reported in 38-60% of patients with AIH/PBC overlap syndrome [12,13,14]^[12][13][14]. Interestingly, the concomitant positivity for anti-ds DNA and AMA seems highly specific (98%) for the diagnosis of PBC-AIH OS ^[13].

3. Is the Risk of SARS-CoV-2 Infection Increased in Autoimmune Liver Disease Patients?

The relationship between autoimmune diseases and SARS-CoV-2 is very complex and only partially understood. An interesting study evaluating the association between autoimmune diseases and risk of COVID-19 has been performed in the population of Milan, an area particularly damaged by the virus, which includes the municipality of Codogno, where the Italian outbreak started ^[15]. A total of 20,364 test-positive and 34,697 test-negative subjects were analyzed. The adjusted odds ratio (OR) of having an autoimmune disease in COVID-19 positive-subjects compared to negative-subjects was 0.86 (95% CI 0.76–0.96). Comparing COVID-19 positive-subjects to a random sample of controls from the general population the adjusted OR of having an autoimmune disease was 0.98 (95% CI 0.90–1.08). In other words, patients with autoimmune diseases did not carry a specific risk for developing SARS-CoV-2 infection. Moreover, data regarding the clinical presentation and outcome of COVID-19 in patients with autoimmune liver disease are limited to international registry studies and to retrospective case studies. During the first outbreak of COVID-19, a phone-based survey using a 26-query questionnaire to explore the clinical features of SARS-CoV-2 infection in patients with autoimmune liver disease under immunosuppression has been performed in Northern Italy ^[16]. Of the 148 eligible patients, 47 (32%) were children diagnosed with AIH or autoimmune sclerosing cholangitis; 101 (68%) were adults diagnosed with AIH (n = 97), primary sclerosing cholangitis/AIH overlap syndrome (n = 2) and PBC (n = 2). Thirty-nine patients (26%) with fever or respiratory symptoms were suspected COVID-19 cases. None required admission to hospital, and none discontinued immunosuppression. Four patients had confirmed COVID-19 cases (all had AIH under immunosuppression). One of them (a 23-year-old female with Trisomy 21) died from septic shock unrelated to COVID-19. The same incidence of COVID-19 in autoimmune liver disease patients was observed in the general population. Since the outcome was favorable in most cases, the authors suggested that tapering or withdrawing immunosuppressive treatment is not required. Furthermore, another study conducted on telemedicine in Northern Italy during the COVID-19 pandemic in patients with autoimmune liver disease showed quite low rates of symptomatic SARS CoV-2 infection, with overall favorable outcomes ^[17]. Likewise, patients with scleroderma, evaluated with a phone-based survey, seemed not have an increased risk for developing severe COVID-19 ^[18]. Interestingly, the first case series of 10 Italian patients with AIH under immunosuppressive therapy has been described during the first outbreak of SARS-CoV-2 infection ^[19]. Eight patients were on biochemical remission. All patients had a respiratory syndrome; in 7 patients the dosage of immunosuppressive medication was reduced. In general, the clinical outcome was comparable to the reported cases occurring in non-immunosuppressed subjects. Another retrospective international study analyzed the outcome of 110 patients with AIH from 34 centers in Europe and America ^[20]. Use of antivirals was associated with liver injury (p = 0.041), while continued immunosuppression during COVID-19 was associated with a lower rate of liver injury (p = 009). Cirrhosis was an independent predictor of severe COVID-19 in patients with AIH (p = 0.001). However, patients with AIH were not at risk for worse outcomes with COVID-19 than other causes of chronic liver disease. Finally, data for patients with AIH and SARS-CoV-2 infection were combined from three international reporting registries and compared to those in patients with chronic liver diseases of different etiologies and to patients without liver disease ^[21]. The group with AIH included 70 patients, 83% of whom were taking immunosuppressive therapy. There were no differences in rates of major outcomes between patients with AIH and non AIH. Factors associated with death within the AIH cohort included age and advanced liver disease (Child B and C) but not immunosuppression.