v
Search
Advanced Search

Publications > Journals > Journal of Clinical and Translational Hepatology > Article Full Text

  • Review Article
  • OPEN ACCESS

Special Considerations in the Management of Autoimmune Hepatitis in COVID-19 Hotspots: A Review

  • Deepak Madhu1,2 ,
  • Sanchit Sharma3 ,
  • Ashish Agarwal3,4  and
  • Anoop Saraya3,* 
 Author information  Cite
Journal of Clinical and Translational Hepatology   2021;9(4):568-575

doi: 10.14218/JCTH.2021.00001

Abstract

The ongoing coronavirus disease-2019 (COVID-19) pandemic has necessitated special considerations in the management of diseases. The way presence of pre-existing diseases or treatment for it predisposes to, alters course of, and changes the management of COVID-19, is of relevance and is being extensively studied. Autoimmune hepatitis (AIH) is unique in that it is an autoimmune disease mandating treatment with immunosuppressive drugs, as well as a liver disease with potential for varying degrees of underlying fibrosis. The use of immunosuppressive drugs could alter the risk of acquiring COVID-19, the clinical course and severity of COVID-19 and the degree of underlying liver fibrosis could alter the clinical outcomes of patients with COVID-19. In this review, we try to summarize key areas relevant in understanding and improving the clinical care of patients with AIH in the current pandemic. Special considerations required in the management of patients with AIH in COVID-19 hotspots have been outlined based on the current evidence.

Keywords

Hepatitis, Autoimmune, Liver cirrhosis, COVID-19, SARS-CoV-2 infection, Immunosuppressive agents

Introduction

First noticed as a cluster of viral pneumonia among people known to have visited a market in the Wuhan City of Hubei province in China,1 and later on investigated by the China Center for Disease Control and Prevention and found to be due to infection with a new beta coronavirus,2 the disease was later named Coronavirus disease-2019 (COVID-19),3 and the virus causing it was christened severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2).4 The disease spread throughout the world over a period of a few months, to be declared as a pandemic by the World Health Organization (WHO) on the 11th of March 2020.5 By the 30th of December 2020, it had infected over 80 million people and resulted in the death of over 1.7 million people.6 While predominantly a respiratory pathogen, SARS-CoV-2 has also been shown to cause significant neurologic, cardiac, gastrointestinal, hepatic, renal, hematologic, obstetric, gynecologic, and rheumatologic abnormalities as well.7

The focus of this review is on special considerations for the management of autoimmune hepatitis (AIH) in areas with widespread community transmission of COVID-19. Factors that need to be considered include the risk of acquiring COVID-19 and the risk of poor outcomes with COVID-19. Outcomes in patients with COVID-19 could be altered due to AIH itself, because of the immunosuppressive medicines used to treat AIH, or by virtue of liver impairment that AIH has caused. We will be discussing aspects that are of specific relevance to a practitioner caring for AIH in COVID-19 hotspots. Relevant aspects of COVID-19-induced liver injury, aspects of COVID-19 prevention (including vaccination), and special considerations required in the management of AIH have been discussed herein. We have also discussed possible approaches that a clinician can adopt in various case-scenarios that may be encountered.

Liver injury in COVID-19

Liver abnormalities noted to be present in patients having COVID-19 include transaminitis, hyperbilirubinemia and hypoalbuminemia.8–11 These abnormalities are thought to occur by one or more of the following several mechanisms (Fig. 1): direct cytopathy;12 immune-mediated;13 3. hypoxia-related;14 drug-induced;14 and, microvascular thrombosis.15,16 Patients with COVID-19 and liver injury,17 as well as those with prior hepatic comorbidities, have been shown to have poor outcomes with COVID-19.18 Patients with cirrhosis are thought to be at moderate risk, whereas patients with decompensated cirrhosis are at high risk of poor outcomes with COVID-19.

Pathogenesis of liver injury in COVID-19.
Fig. 1  Pathogenesis of liver injury in COVID-19.

Direct cytopathy

ACE2 receptors, which the SARS-CoV-2 virus utilizes for entering cells have been shown to be expressed in cholangiocytes19 and probably hepatocytes20 as well. It has also been shown that SARS-CoV-2 invades liver cells and causes cytopathy.12 This may, at least partially, be responsible for the hepatic dysfunction seen in COVID-19 patients.12

Immune-mediated

SARS-CoV-2 infection results in a disordered inflammatory response, i.e. the cytokine storm,21 with increase in pro-inflammatory cytokines. This has been shown to be responsible for severe pulmonary and extrapulmonary dysfunction, including liver injury. Liver dysfunction has been shown to be particularly more in patients with increased levels of inflammatory markers, such as CRP, TNF and IL-6.13

Hypoxic/ischemic

In severe COVID-19, multiorgan dysfunction can lead to hypoxia-related to acute-respiratory distress syndrome,22 hypotension,23 or congestive cardiac failure. All of these can result in liver dysfunction.24

Drug-induced liver injury (DILI)

In addition to supportive therapy, antivirals, immunomodulators and antithrombotic drugs are used in the management of COVID-19. Several of these drugs, including antivirals such as lopinavir-ritonavir, remdesivir, favipiravir etc., and immunomodulators such as tocilizumab, baricitinib, etc. may cause liver dysfunction.25,26

Microvascular thrombosis

Endothelial dysfunction along with inflammation in patients with COVID-19 produces vascular thrombosis in multiple organs.27 Elevated D-dimer levels were found to be independently associated with liver dysfunction in one study,15 which could point to an association of thrombosis with liver dysfunction. Studies of liver biopsies from patients with COVID-19 and liver dysfunction have shown significant microvascular thrombosis which could lead to liver dysfunction.16 This could point to a contribution by microvascular thrombosis to the liver dysfunction seen in patients with COVID-19.

Pre-existing liver diseases and COVID-19

Patients with AIH have varying degrees of underlying fibrosis and as much as 40% of these patients develop cirrhosis.28 The degree of underlying fibrosis in patients with AIH has the potential to have an effect on the risk of acquiring COVID-19, as well as on clinical outcomes in patients with COVID-19.

It can be assumed that, despite a reduction in the immunity of patients with cirrhosis, the risk of acquiring COVID-19 does not seem to be higher in patients with cirrhosis, as evidenced by the results of a meta-analysis which demonstrated that the prevalence of cirrhosis in patients with COVID-19 is similar to that in the COVID-19-negative population.18

There seems to be an upregulation of ACE2 receptors in the liver, which probably makes patients with cirrhosis more vulnerable to COVID-19-related liver injury.29 Patients with pre-existing liver disease have been shown to have increased mortality and morbidity, with COVID-19.18 Multiple studies have found deterioration of liver functions and decompensation in cirrhotic patients with COVID-19.30–32 Patients were found to have significantly higher risk of mortality with worsening Child-Pugh status.31,32 Cirrhosis was also found to be an independent predictor of severe COVID-19, in patients with AIH in recent multicenter studies.33,34 With such poor outcomes, it becomes pertinent that patients with cirrhosis be considered high risk.

Immunosuppressants and COVID-19

Patients on immunosuppressants have a complex interplay of factors in favor of and against SARS-CoV-2. On one hand, immunomodulators such as mycophenolate mofetil (MMF)35,36 and calcineurin inhibitors (CNIs) like tacrolimus37 and cyclosporine38,39 have been demonstrated to have antiviral activity against coronaviruses, and glucocorticoids administered for COVID-19 have been shown to prevent the disordered immune response that is responsible for poor outcomes in COVID-19.40 On the other hand, the immunosuppression attributable to these drugs may cause increased susceptibility to SARS-CoV-2 infection,41 secondary bacterial or fungal infections, and prolongation of viral clearance.42 There have been studies that demonstrated increased risk41 as well as others that demonstrated average risk43 of acquiring SARS-CoV-2 infection for patients on immunosuppressants, and the question largely remains unresolved to date. Retrospective studies have demonstrated a risk of bacterial superinfection44 or increased use of antibiotics45 in patients managed with steroids for COVID-19, whereas randomized controlled trials have negated this46–48 as an adverse event of steroids. The data on the effect of steroids on viral shedding is mixed; although, the wealth of evidence suggests that low-dose steroids are not associated with any increase in viral shedding.42 Studies have also been performed to assess how these seemingly opposing actions translate to clinical outcomes in COVID-19. The risk of acquiring SARS-CoV-2 infection seems to be higher in patients with autoimmune diseases on steroids49 and clinical outcomes seem to be worse in patients on steroids as well as in patients on immunomodulators, in patients with autoimmune diseases.49 Early data available specifically in the context of AIH seem to show that continued immunosuppression does not lead to poor outcomes with COVID-19.33,34

AIH and COVID-19

Two large multicenter studies have addressed the impact of COVID-19 in patients with AIH.33,34 In both the studies, the outcomes of patients with AIH were compared with a cohort of non-AIH patients with chronic liver disease. The consistent findings across both the studies was that there is no increase in severity of COVID-19 infection across patients with AIH compared to other etiologies of chronic liver disease.33,34 Presence of cirrhosis, particularly Child-C disease, was the most significant factor of poor outcomes in these patients.34 New-onset liver injury was seen in one-third of the patients with AIH after COVID-19 in one study.33 However, the use of immunosuppressants was not associated with poor outcomes in patients with AIH and COVID-19.33 In fact, one study showed that continuation of immunosuppression was associated with lower risk of new-onset liver injury.33 This suggests that immunosuppression needs to be continued in patients with AIH and COVID-19. Apart from these two studies, however, data on AIH and COVID-19 are limited to a few small case series (Table 1).50–53

Table 1

Published data of AIH patients with COVID

StudyRegionNumber of COVID-19-positive AIHCOVID-19 requiring hospitalizationSurvived
Verhelst 202150Flanders, Belgium1100% (1/1)100% (1/1)
Rigamonti 202051Northern Italy450% (2/4)100% (4/4)
Di Giorgio 202052Northern Italy450% (2/4)75% (3/4)
Gerussi 202053Italy1060% (6/10)90% (9/10)
Marjot 202134Multinational7076% (53/70)77% (54/70)
Efe 202133Multinational11046% (51/110)90% (99/110)

Diagnostic approach

The diagnostic approach for AIH in COVID-19 hotspots can be the same as elsewhere, broadly speaking. Selected patients who are asymptomatic and being evaluated for abnormal transaminases or only mildly symptomatic for AIH can be, in the initial part of the diagnostic workup, evaluated by a telemedicine-based approach. Liver biopsy is necessary for a diagnosis of AIH to be made, as per American Association for the Study of Liver Diseases (AASLD) guidelines54 and can be performed in a COVID-minimal pathway, safely, for COVID-19-negative patients. Liver biopsy in COVID-19-positive patients need to be decided on a case-by-case basis, depending on the urgency to treat AIH, the severity of COVID-19, and other factors like the presence of coagulopathy, sepsis, logistics, chance of cross-infection, etc. The Asia Pacific Association for Study of Liver (APASL) recommends liver biopsy in COVID-19-negative patients when autoimmune flare is suspected and advises against liver biopsy in COVID-19-positive patients.55

Prevention of COVID-19

General measures

Owing to the high risk of poor outcomes that can be expected with the degree of pre-existing liver dysfunction and immunosuppression, prevention of SARS-CoV-2 infection is extremely important in patients with AIH. The preventive strategy against COVID-19 should comprise general measures as well as vaccination. General measures should involve measures to be adopted by the patient,56 hospital-designed infrastructure measures,57 and hospital operational measures,57 which include a COVID-minimal pathway,58 as well as measures to be adopted by health-care personnel.59 Telemedicine becomes particularly relevant during the current COVID-19 epidemic as it has the potential to reduce the need for hospital visits, which in turn reduces the chance of crowding in hospital outpatient clinics, thereby reducing the risk of spreading SARS-CoV-2.60 Telemedicine has been evaluated specifically in the context of management of AIH during the COVID-19 pandemic and has been shown to improve patient adherence to therapy thereby minimizing the chances of relapse, as compared to the standard care group.60

Vaccination

As on December 23rd, 2020, there have been at least seven COVID-19 vaccines61 licensed in different parts of the world and over 200 vaccines in different stages of development.62 In the context of patients with AIH, four specific aspects need to be addressed; these include: 1) safety of the vaccine in patients on immunosuppressants; 2) safety of the vaccine in patients with liver diseases; 3) efficacy of the vaccine in patients on immunosuppressants; and, 4) efficacy of the vaccine in patients with liver diseases.

As far as the licensed vaccines are concerned, patients on immunosuppression were excluded from vaccine licensing trials. While some trials included a small number of patients with pre-existing liver diseases, patients with advanced liver diseases were still excluded and no subgroup analysis was performed to assess outcomes or adverse events specifically in patients with liver diseases.63 Thus, it is not clear at this moment how safe and effective these vaccines would be, in standard doses, for patients with AIH, especially while on immunosuppressive medications. Extrapolating from the experience with vaccination for other diseases in patients with liver diseases,64–66 in patients on immunosuppression,67 and specifically in AIH,68 the likely efficacy of the COVID-19 vaccine in this subgroup of patients is likely to be lower compared to the normal healthy adult.

Considering the high risk of poor outcomes due to COVID-19 infection in patients with liver diseases18 and patients with immunosuppression,69 the benefits of vaccination may outweigh the risks. COVID-19 vaccination is being suggested in patients with chronic liver disease and solid organ transplant recipients on immunosuppression by various international societies, including AASLD63 and European Association for Study of Liver (EASL).70 Till further data on safety and efficacy are available, COVID-19 vaccines need to be administered at standard doses, unless other contraindications are present. Due to the high risk of adverse events, live vaccines71 and replicating viral vector vaccines72 are best avoided in patients on immunosuppressive medications. Further, household members and care providers of these patients should also receive vaccination while continuing appropriate use of masks, sanitizers and social distancing — the keystone of protection against COVID-19. EASL and APASL recommend patients with AIH to be also vaccinated against influenza and Streptococcus pneumoniae.55,73 The formation of neutralizing antibodies in liver transplant recipients (especially those receiving immunosuppressants) have been suboptimal, as shown by a recent study.74 The clinical impact of this suboptimal response remains to be seen. However, this should not deter any clinician from prescribing the vaccine in these patients.

Treatment in COVID-19 negative patients

Principles of treatment

It is clear that the presence of pre-existing liver disease has a significant bearing on the outcomes of patients with COVID-19,18 and given the fact that the present pandemic has been ongoing for the past several months and will continue to do so for some time, it seems prudent that the patients not having active COVID-19 but requiring induction or maintenance therapy for AIH be given immunosuppression as required because withdrawing, delaying or denying it may result in worsening fibrosis or cirrhosis.75–77 Recommendations by APASL55 and the EASL73 seem to support the view that immunosuppression needs to be continued. Strategies for treatment and follow-up should incorporate aspects of prevention as elaborated, including general measures and vaccination. We have discussed special considerations required in the treatment of COVID-19-negative patients with AIH below, and summarized them in Table 2. Decisions for patients with active COVID-19 requiring immunosuppression for AIH induction or maintenance need to be considered on an individualized, case-by-case basis after assessing risks and benefits.

Table 2

Special considerations in the management of AIH in COVID-19 hotspots: A suggested approach

COVID-19 statusAIH statusSpecial considerations
COVID-19-negativeDiagnosis of AIHDiagnostic algorithm same as otherwise. Liver biopsy to be planned in COVID–minimal pathway
Newly diagnosed patients with activitySteroids and azathioprine can be given as indicated otherwise. Budesonide to be preferred over prednisolone in appropriate situations, in noncirrhotic patients, and in patients without acute severe AIH
Patients in remissionContinue immunosuppressant at lowest recommended dose required to maintain remission. Decision to stop immunosuppression to be made in patients who have had long-term remission, as per latest guidelines for AIH. Telemedicine-based follow-up in appropriate cases
Patients who require start of second-line agentCNIs (tacrolimus) may be preferred over mycophenolate in patients with no other contraindicationsa
Patients who require start of third-line agentInfliximab may be preferred over rituximab in patients with no other contraindicationsa
Decompensated cirrhosisTreatment algorithm same as otherwise. Living donor liver transplant to be considered for urgent/emergency indications only
Acute severe AIHDiagnostic and treatment algorithm same as otherwise
ALF due to AIHDiagnostic and treatment algorithm same as otherwise. May require urgent liver transplantation
COVID-19-positiveDiagnosis of AIHEvaluation by serology, imaging same as otherwise. Decisions regarding liver biopsy to be taken on case-by-case basis
Newly diagnosed patients with activity/patients in remission/patients who require start of second-line agents/patients who require start of third-line agents/patients with decompensated cirrhosisDecisions regarding management to be taken on an individualized, case-by-case basis. Patients with AIH in remission may continue immunosuppressants as before, unless other contraindications or considerations are present. Treatment decisions in patients requiring induction or escalation of therapy for AIH needs to be taken on a multidisciplinary, case-by-case basis
Acute severe AIHNeed for aggressive immunosuppression likely to override all other considerations, final decision to be taken on a multidisciplinary, case-by-case basis
ALF due to AIHDecision to be taken on a multidisciplinary, case-by-case basis

aWeak suggestion, based on data extrapolated from other conditions.

First-line agents

Patients on systemic steroids have been found to have poor COVID-19-related outcomes.49 Prednisolone/prednisone or budesonide in combination with azathioprine is used for first-line management of AIH.54 Owing to high first pass metabolism of budesonide, it is known to have less systemic toxicity and less chance of infections.78 It seems reasonable that patients with new diagnosis of AIH, no cirrhosis and no acute severe AIH be considered for budesonide over predniso(lo)ne especially, as it has been proven to have a higher efficacy,78 and it is biologically plausible that patients on budesonide may fare better than patients on predniso(lo)ne, if infected with SARS-CoV-2.

Data from inflammatory bowel diseases (IBD)79 show that thiopurine monotherapy is associated with poor COVID-19 outcomes. Data regarding the safety of azathioprine specifically in AIH in the context of COVID-19, however, is not available, even though two studies had shown that continuation of immunosuppressive medicines in AIH is not associated with poor outcomes with COVID-19.33,34 Azathioprine still remains the first-line agent of choice as an immunomodulator, till conclusive evidence regarding an alternate first-line agent with better overall outcomes is available.

Second-line agents

Second-line agents for the management of AIH include MMF as well as CNIs, such as tacrolimus and cyclosporine.54 As far as AIH-related outcomes are concerned, MMF and tacrolimus are equivalent.54 Although specific data on AIH patients treated with these medicines and COVID-19-related outcomes are not available, data of safety of these same drugs used in other diseases, in terms of COVID-19-related outcomes, may be cautiously extrapolated to AIH, till specific data are available. In solid organ transplant patients, treatment with mycophenolate has been shown to be risky in a dose-dependent manner,80 but that with CNIs appears to not be.80,81 It would therefore seem appropriate that tacrolimus should be preferred over MMF when no other contraindications are present.

Third-line/salvage agents

Salvage options or third-line agents described by the AASLD guideline for AIH include infliximab and rituximab.54 Being an anti-TNF agent, infliximab has a potential to mitigate the cytokine storm, which is a crucial part of the pathogenesis of COVID-19.82 Studies in IBD83 and in rheumatology84 have shown that anti-TNF drugs are not associated with worse outcomes in COVID-19. Concerns have been expressed regarding risk of poor outcomes for patients on rituximab,85 and early evidence suggests this as well.86 Till conclusive evidence that supports safety in this regard is available, it is better to consider other third-line/salvage agents, such as infliximab, over rituximab, whenever possible.

Overlap syndromes

In addition to the immunosuppressants described above, patients with overlap syndromes may also require ursodeoxycholic acid.54 There is no reason to have concerns regarding the use of this agent in the context of the current COVID-19 pandemic. In fact, ursodeoxycholic acid is an agent with potential to have benefits in the treatment of COVID-19 as well.87 Till evidence to the contrary is available, treatment with this agent can be initiated or continued as indicated.

Liver transplant

Liver transplant is indicated in patients with AIH who present with acute liver failure (commonly referred to as ALF) or as salvage in acute severe AIH or in cirrhosis with decompensation.54 In the presence of widespread community transmission of COVID-19, considerations for liver transplant should consider appropriate local guidelines which specifically discuss this aspect. In view of the risk to donors, living donor liver transplantation is best restricted to urgent indications.88

Management of AIH in COVID-19 patients

The management of AIH in COVID-19-positive patients would require decisions to be taken on a multidisciplinary, case-by-case basis. Decisions should be based on a multitude of factors, such as urgency to treat AIH, severity of COVID-19, presence of co-existing sepsis, requirement of drugs for COVID-19 that may have interactions with drugs given for AIH, etc. APASL recommends continuing immunosuppression in patients with mild COVID-19.55 Data from two multinational studies are available which show no benefit of withdrawing immunosuppression in patients with AIH and active COVID-19.33,34 One study even showed that continuation of immunosuppression lowered the risk of new-onset liver injury.33 The exact reasons for stopping immunosuppression in these studies are not known. The numbers of patients on high-dose steroids and MMF were low in these studies, for meaningful conclusions to be made. However, these studies do support the continuation of immunosuppression in patients with AIH and COVID-19. Some special considerations required while managing patients with AIH who also have COVID-19 are summarized in Table 2.

Drug interactions are particularly important while managing patients with COVID-19 and AIH. Management of COVID-19 is constantly being revised with a variety of drugs being tried for its treatment, with varying efficacy. New data are emerging every day and with the introduction of new drugs, one needs to be aware of the side effect profile of the drugs being used and their potential interaction with the concomitant medications being used for the management of comorbid conditions. Interactions between drugs used for immunosuppression, such as CNIs, may have significant drug interactions, which, if not paid attention to, can be deleterious.89 We have listed the interactions between the drugs used for the management of COVID-19 and the drugs used in AIH in the table below (Table 3). As to the optimal treatment and drugs for COVID-19, the data are still evolving; however, it is suggested to check the side effect profile and drug interactions of the drug being used. One such useful updated resource to check for drug interactions is https://www.covid19-druginteractions.org/checker .

Table 3

Drug interactions between immunosuppressants used for management of AIH and drugs used for management of COVID-19

Drug typeAzathioprineMMFTacrolimusCyclosporine
Interferons
  Interferon-alphaPotential additive hematological toxicityNo interactionNo interactionNo interaction
  Interferon0betaPotential additive hematological toxicityNo interactionNo interactionNo interaction
Antivirals
  FavipiravirNo interactionNo interactionNo interactionNo interaction
  Lopinavir-ritonavirNo interactionPotential altered drug levels of mycophenolate; Drug level monitoring recommendedIncreased levels of tacrolimus; Risk of QT prolongationIncreased plasma levels of cyclosporine; Drug monitoring recommended
  RemdesivirNo interactionNo interactionNo interactionNo interaction
  RibavirinPotential additive hematological toxicityNo interactionNo interactionNo interaction
  NitazoxanideNo interactionNo interactionNo interactionNo interaction
Antimalarials
  ChloroquinePotential additive hematological toxicityNo interactionIncreased levels of tacrolimus; Risk of QT prolongationIncreased plasma levels of cyclosporine; Drug monitoring recommended
  HydroxychloroquinePotential additive hematological toxicityNo interactionIncreased levels of tacrolimus; Risk of QT prolongationIncreased plasma levels of cyclosporine; Drug monitoring recommended
Monoclonal antibody
  TocilizumabPotential additive hematological toxicityNo interactionMonitoring of tacrolimus drug levels recommendedMonitoring of cyclosporine drug levels recommended
  BamlanivimabNo interactionNo interactionNo interactionNo interaction
  CanakinumabPotential additive hematological toxicityNo interactionMonitoring of tacrolimus drug levels recommendedMonitoring of cyclosporine drug levels recommended
  SarilumabPotential additive hematological toxicityNo interactionMonitoring of tacrolimus drug levels recommendedMonitoring of cyclosporine drug levels recommended

Conclusions

Management of auto-immune hepatitis in areas with widespread community transmission of COVID-19 needs special considerations in the diagnostic approach, preventive aspects and treatment. The management of immunosuppression is particularly complex in this set of patients and specific data in the context of AIH in COVID-19 are lacking. Management of immunosuppression in patients with AIH in COVID-19 hotspots requires a tailored approach based on data from relatively small observational studies and from data extrapolated from other auto-immune diseases till better evidence is available. The management of AIH in patients diagnosed with COVID-19 requires a multidisciplinary approach with decisions considered on a case-by-case basis.

Abbreviations

AASLD: 

American Association for the Study of Liver Diseases

ACLF: 

acute on chronic liver failure

AD: 

acute decompensation

AIH: 

autoimmune hepatitis

ALF: 

acute liver failure

APASL: 

Asia Pacific Association for Study of Liver

CNIs: 

calcineurin inhibitors

COVID-19: 

coronavirus disease-2019

DILI: 

drug-induced liver injury

EASL: 

European Association for Study of Liver

IBD: 

inflammatory bowel diseases

MMF: 

mycophenolate mofetil

SARS-CoV-2: 

severe acute respiratory syndrome-coronavirus-2

WHO: 

World Health Organization

Declarations

Acknowledgement

We would like to acknowledge the contribution of Madhu Mathew Vennikandam, Advanced Hepatology Fellow, Columbia University Irving Medical Center, New York, USA, in the initial process of the literature search. Figure 1 was created with BioRender.com.

Funding

None to declare.

Conflict of interest

The authors have no conflict of interests related to this publication.

Authors’ contributions

Study concept and design (DM, SS, AS), acquisition of data (DM, AA, SS), drafting of the manuscript (DM, SS, AA), critical revision of the manuscript for important intellectual content (DM, AA, SS, AS), administrative support, study supervision (AS).

References

  1. Lu H, Stratton CW, Tang YW. Outbreak of pneumonia of unknown etiology in Wuhan, China: The mystery and the miracle. J Med Virol 2020;92(4):401-402 View Article
  2. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020;382(8):727-733 View Article
  3. World Health Organization. Naming the coronavirus disease (COVID-19) and the virus that causes it. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance/naming-the-coronavirus-disease-(covid-2019)-and-the-virus-that-causes-it
  4. The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol 2020;5(4):536-544 View Article
  5. Cucinotta D, Vanelli M. WHO declares COVID-19 a pandemic. Acta Biomed 2020;91(1):157-160 View Article
  6. World Health Organization. WHO Coronavirus disease (COVID-19) dashboard. Available from: https://covid19.who.int/
  7. Kordzadeh-Kermani E, Khalili H, Karimzadeh I. Pathogenesis, clinical manifestations and complications of coronavirus disease 2019 (COVID-19). Future Microbiol 2020;15:1287-1305 View Article
  8. Abdulla S, Hussain A, Azim D, Abduallah EH, Elawamy H, Nasim S, et al. COVID-19-induced hepatic injury: A systematic review and meta-analysis. Cureus 2020;12(10):e10923 View Article
  9. Kovalic AJ, Huang G, Thuluvath PJ, Satapathy SK. Elevated liver biochemistries in hospitalized chinese patients with severe COVID-19: Systematic review and meta-analysis. Hepatology 2021;73(4):1521-1530 View Article
  10. Shokri Afra H, Amiri-Dashatan N, Ghorbani F, Maleki I, Rezaei-Tavirani M. Positive association between severity of COVID-19 infection and liver damage: a systematic review and meta-analysis. Gastroenterol Hepatol Bed Bench 2020;13(4):292-304
  11. Kulkarni AV, Kumar P, Tevethia HV, Premkumar M, Arab JP, Candia R, et al. Systematic review with meta-analysis: liver manifestations and outcomes in COVID-19. Aliment Pharmacol Ther 2020;52(4):584-599 View Article
  12. Wang Y, Liu S, Liu H, Li W, Lin F, Jiang L, et al. SARS-CoV-2 infection of the liver directly contributes to hepatic impairment in patients with COVID-19. J Hepatol 2020;73(4):807-816 View Article
  13. Amiri-Dashatan N, Koushki M, Ghorbani F, Naderi N. Increased inflammatory markers correlate with liver damage and predict severe COVID-19: a systematic review and meta-analysis. Gastroenterol Hepatol Bed Bench 2020;13(4):282-291
  14. Saviano A, Wrensch F, Ghany MG, Baumert TF. Liver disease and COVID-19: from Pathogenesis to Clinical Care. Hepatology 2020 View Article
  15. Tsutsumi T, Saito M, Nagai H, Yamamoto S, Ikeuchi K, Lim LA, et al. Association of coagulopathy with liver dysfunction in patients with COVID-19. Hepatol Res 2021;51(2):227-232 View Article
  16. Zhao CL, Rapkiewicz A, Maghsoodi-Deerwester M, Gupta M, Cao W, Palaia T, et al. Pathological findings in the postmortem liver of patients with coronavirus disease 2019 (COVID-19). Hum Pathol 2021;109:59-68 View Article
  17. Kumar-M P, Mishra S, Jha DK, Shukla J, Choudhury A, Mohindra R, et al. Coronavirus disease (COVID-19) and the liver: a comprehensive systematic review and meta-analysis. Hepatol Int 2020;14(5):711-722 View Article
  18. Kovalic AJ, Satapathy SK, Thuluvath PJ. Prevalence of chronic liver disease in patients with COVID-19 and their clinical outcomes: a systematic review and meta-analysis. Hepatol Int 2020;14(5):612-620 View Article
  19. Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol 2004;203(2):631-637 View Article
  20. Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Proteomics. Tissue-based map of the human proteome. Science 2015;347(6220):1260419 View Article
  21. Fajgenbaum DC, June CH. Cytokine storm. N Engl J Med 2020;383(23):2255-2273 View Article
  22. Gibson PG, Qin L, Puah SH. COVID-19 acute respiratory distress syndrome (ARDS): clinical features and differences from typical pre-COVID-19 ARDS. Med J Aust 2020;213(2):54-56.e1 View Article
  23. Hanidziar D, Bittner EA. Hypotension, systemic inflammatory response syndrome, and COVID-19: A clinical conundrum. Anesth Analg 2020;131(3):e175-e176 View Article
  24. Zhong P, Xu J, Yang D, Shen Y, Wang L, Feng Y, et al. COVID-19-associated gastrointestinal and liver injury: clinical features and potential mechanisms. Signal Transduct Target Ther 2020;5(1):256 View Article
  25. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases. LiverTox: Clinical and research information on drug-induced liver injury. Available from: https://www.ncbi.nlm.nih.gov/books/NBK548196/
  26. Olry A, Meunier L, Délire B, Larrey D, Horsmans Y, Le Louët H. Drug-induced liver injury and COVID-19 infection: The rules remain the same. Drug Saf 2020;43(7):615-617 View Article
  27. Ali MAM, Spinler SA. COVID-19 and thrombosis: From bench to bedside. Trends Cardiovasc Med 2021;31(3):143-160 View Article
  28. Czaja AJ. Review article: The prevention and reversal of hepatic fibrosis in autoimmune hepatitis. Aliment Pharmacol Ther 2014;39(4):385-406 View Article
  29. Grace JA, Casey S, Burrell LM, Angus PW. Proposed mechanism for increased COVID-19 mortality in patients with decompensated cirrhosis. Hepatol Int 2020;14(5):884-885 View Article
  30. Shalimar, Elhence A, Vaishnav M, Kumar R, Pathak P, Soni KD, et al. Poor outcomes in patients with cirrhosis and Corona Virus Disease-19. Indian J Gastroenterol 2020;39(3):285-291 View Article
  31. Sarin SK, Choudhury A, Lau GK, Zheng MH, Ji D, Abd-Elsalam S, et al. Pre-existing liver disease is associated with poor outcome in patients with SARS CoV2 infection; The APCOLIS Study (APASL COVID-19 Liver Injury Spectrum Study). Hepatol Int 2020;14(5):690-700 View Article
  32. Marjot T, Moon AM, Cook JA, Abd-Elsalam S, Aloman C, Armstrong MJ, et al. Outcomes following SARS-CoV-2 infection in patients with chronic liver disease: An international registry study. J Hepatol 2021;74(3):567-577 View Article
  33. Efe C, Dhanasekaran R, Lammert C, Ebi B, Higuera-de la Tijera F, Aloman C, et al. Outcome of COVID-19 in patients with autoimmune hepatitis: an international multi-centre study. Hepatology 2021 View Article
  34. Marjot T, Buescher G, Sebode M, Barnes E, Barritt AS4th, Armstrong MJ, et al. SARS-CoV-2 infection in patients with autoimmune hepatitis. J Hepatol 2021 View Article
  35. Schoot TS, Kerckhoffs APM, Hilbrands LB, van Marum RJ. Immunosuppressive drugs and COVID-19: A review. Front Pharmacol 2020;11:1333 View Article
  36. Lai Q, Spoletini G, Bianco G, Graceffa D, Agnes S, Rossi M, et al. SARS-CoV2 and immunosuppression: A double-edged sword. Transpl Infect Dis 2020;22(6):e13404 View Article
  37. Carbajo-Lozoya J, Müller MA, Kallies S, Thiel V, Drosten C, von Brunn A. Replication of human coronaviruses SARS-CoV, HCoV-NL63 and HCoV-229E is inhibited by the drug FK506. Virus Res 2012;165(1):112-117 View Article
  38. Tanaka Y, Sato Y, Sasaki T. Suppression of coronavirus replication by cyclophilin inhibitors. Viruses 2013;5(5):1250-1260 View Article
  39. Pfefferle S, Schöpf J, Kögl M, Friedel CC, Müller MA, Carbajo-Lozoya J, et al. The SARS-coronavirus-host interactome: identification of cyclophilins as target for pan-coronavirus inhibitors. PLoS Pathog 2011;7(10):e1002331 View Article
  40. Sterne JAC, Murthy S, Diaz JV, Slutsky AS, Villar J, Angus DC, et al. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: A meta-analysis. JAMA 2020;324(13):1330-1341 View Article
  41. Pablos JL, Abasolo L, Alvaro-Gracia JM, Blanco FJ, Blanco R, Castrejón I, et al. Prevalence of hospital PCR-confirmed COVID-19 cases in patients with chronic inflammatory and autoimmune rheumatic diseases. Ann Rheum Dis 2020;79(9):1170-1173 View Article
  42. van Paassen J, Vos JS, Hoekstra EM, Neumann KMI, Boot PC, Arbous SM. Corticosteroid use in COVID-19 patients: a systematic review and meta-analysis on clinical outcomes. Crit Care 2020;24(1):696 View Article
  43. Kovvuru S, Nalleballe K, Onteddu SR, Sharma R, Jasti M, Kapoor N, et al. Immunosuppression in chronic autoimmune neurological disorders during the COVID-19 pandemic. J Neurol Sci 2021;420:117230 View Article
  44. Giacobbe DR, Battaglini D, Ball L, Brunetti I, Bruzzone B, Codda G, et al. Bloodstream infections in critically ill patients with COVID-19. Eur J Clin Invest 2020;50(10):e13319 View Article
  45. Ma Y, Zeng H, Zhan Z, Lu H, Zeng Z, He C, et al. Corticosteroid use in the treatment of COVID-19: A multicenter retrospective study in Hunan, China. Front Pharmacol 2020;11:1198 View Article
  46. Dequin PF, Heming N, Meziani F, Plantefève G, Voiriot G, Badié J, et al. Effect of hydrocortisone on 21-day mortality or respiratory support among critically ill patients with COVID-19: A randomized clinical trial. JAMA 2020;324(13):1298-1306 View Article
  47. Jeronimo CMP, Farias MEL, Val FFA, Sampaio VS, Alexandre MAA, Melo GC, et al. Methylprednisolone as adjunctive therapy for patients hospitalized with coronavirus disease 2019 (COVID-19; Metcovid): A randomized, double-blind, phase iib, placebo-controlled trial. Clin Infect Dis 2021;72(9):e373-e381 View Article
  48. Tomazini BM, Maia IS, Cavalcanti AB, Berwanger O, Rosa RG, Veiga VC, et al. Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: The CoDEX randomized clinical trial. JAMA 2020;324(13):1307-1316 View Article
  49. Akiyama M, Sakatsume K, Sasaki K, Kawatsu S, Yoshioka I, Takahashi G, et al. The incidence, risk factors, and outcomes of gastrointestinal bleeding in patients with a left ventricular assist device: a Japanese single-center cohort study. J Artif Organs 2020;23(1):27-35 View Article
  50. Verhelst X, Somers N, Geerts A, Degroote H, Van Vlierberghe H. Health status of patients with autoimmune hepatitis is not affected by the SARS-CoV-2 outbreak in Flanders, Belgium. J Hepatol 2021;74(1):240-241 View Article
  51. Rigamonti C, Cittone MG, De Benedittis C, Rizzi E, Casciaro GF, Bellan M, et al. Rates of symptomatic SARS-CoV-2 infection in patients with autoimmune liver diseases in northern Italy: A telemedicine study. Clin Gastroenterol Hepatol 2020;18(10):2369-2371.e1 View Article
  52. Di Giorgio A, Nicastro E, Speziani C, De Giorgio M, Pasulo L, Magro B, et al. Health status of patients with autoimmune liver disease during SARS-CoV-2 outbreak in northern Italy. J Hepatol 2020;73(3):702-705 View Article
  53. Gerussi A, Rigamonti C, Elia C, Cazzagon N, Floreani A, Pozzi R, et al. Coronavirus Disease 2019 (COVID-19) in autoimmune hepatitis: a lesson from immunosuppressed patients. Hepatol Commun 2020;4(9):1257-1262 View Article
  54. Mack CL, Adams D, Assis DN, Kerkar N, Manns MP, Mayo MJ, et al. Diagnosis and management of autoimmune hepatitis in adults and children: 2019 practice guidance and guidelines from the American Association for the Study of Liver Diseases. Hepatology 2020;72(2):671-722 View Article
  55. Lau G, Sharma M. Clinical practice guidance for hepatology and liver transplant providers during the COVID-19 pandemic: APASL expert panel consensus recommendations. Hepatol Int 2020;14(4):415-428 View Article
  56. Güner R, Hasanoğlu I, Aktaş F. COVID-19: Prevention and control measures in community. Turk J Med Sci 2020;50(SI-1):571-577 View Article
  57. Capolongo S, Gola M, Brambilla A, Morganti A, Mosca EI, Barach P. COVID-19 and healthcare facilities: a decalogue of design strategies for resilient hospitals. Acta Biomed 2020;91(9-S):50-60 View Article
  58. Boffa DJ, Judson BL, Billingsley KG, Del Rossi E, Hindinger K, Walters S, et al. Results of COVID-minimal surgical pathway during surge-phase of COVID-19 pandemic. Ann Surg 2020;272(6):e316-e320 View Article
  59. Gan WH, Lim JW, Koh D. Preventing intra-hospital infection and transmission of coronavirus disease 2019 in health-care workers. Saf Health Work 2020;11(2):241-243 View Article
  60. Efe C, Simşek C, Batıbay E, Calışkan AR, Wahlin S. Feasibility of telehealth in the management of autoimmune hepatitis before and during the COVID-19 pandemic. Expert Rev Gastroenterol Hepatol 2020;14(12):1215-1219 View Article
  61. Craven J. COVID-19 vaccine tracker. Available from: https://www.raps.org/news-and-articles/news-articles/2020/3/covid-19-vaccine-tracker
  62. World Health Organization. Draft landscape of COVID-19 candidate vaccines. Available from: https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines
  63. Fix OK, Blumberg EA, Chang KM, Chu J, Chung RT, Goacher EK, et al. AASLD expert panel consensus statement: Vaccines to prevent COVID-19 infection in patients with liver disease. Hepatology 2021 View Article
  64. Gutierrez Domingo I, Pascasio Acevedo JM, Alcalde Vargas A, Ramos Cuadra A, Ferrer Ríos MT, Sousa Martin JM, et al. Response to vaccination against hepatitis B virus with a schedule of four 40-µg doses in cirrhotic patients evaluated for liver transplantation: factors associated with a response. Transplant Proc 2012;44(6):1499-1501 View Article
  65. Gaeta GB, Stornaiuolo G, Precone DF, Amendola A, Zanetti AR. Immunogenicity and safety of an adjuvanted influenza vaccine in patients with decompensated cirrhosis. Vaccine 2002;20(Suppl 5):B33-B35 View Article
  66. Arguedas MR, Johnson A, Eloubeidi MA, Fallon MB. Immunogenicity of hepatitis A vaccination in decompensated cirrhotic patients. Hepatology 2001;34(1):28-31 View Article
  67. Papp KA, Haraoui B, Kumar D, Marshall JK, Bissonnette R, Bitton A, et al. Vaccination guidelines for patients with immune-mediated disorders on immunosuppressive therapies. J Cutan Med Surg 2019;23(1):50-74 View Article
  68. Wörns MA, Teufel A, Kanzler S, Shrestha A, Victor A, Otto G, et al. Incidence of HAV and HBV infections and vaccination rates in patients with autoimmune liver diseases. Am J Gastroenterol 2008;103(1):138-146 View Article
  69. Akiyama S, Hamdeh S, Micic D, Sakuraba A. Prevalence and clinical outcomes of COVID-19 in patients with autoimmune diseases: a systematic review and meta-analysis. Ann Rheum Dis 2021;80(3):384-391 View Article
  70. Cornberg M, Buti M, Eberhardt CS, Grossi PA, Shouval D. EASL position paper on the use of COVID-19 vaccines in patients with chronic liver diseases, hepatobiliary cancer and liver transplant recipients. J Hepatol 2021;74(4):944-951 View Article
  71. Croce E, Hatz C, Jonker EF, Visser LG, Jaeger VK, Bühler S. Safety of live vaccinations on immunosuppressive therapy in patients with immune-mediated inflammatory diseases, solid organ transplantation or after bone-marrow transplantation - A systematic review of randomized trials, observational studies and case reports. Vaccine 2017;35(9):1216-1226 View Article
  72. Robert-Guroff M. Replicating and non-replicating viral vectors for vaccine development. Curr Opin Biotechnol 2007;18(6):546-556 View Article
  73. Boettler T, Marjot T, Newsome PN, Mondelli MU, Maticic M, Cordero E, et al. Impact of COVID-19 on the care of patients with liver disease: EASL-ESCMID position paper after 6 months of the pandemic. JHEP Rep 2020;2(5):100169 View Article
  74. Rabinowich L, Grupper A, Baruch R, Ben-Yehoyada M, Halperin T, Turner D, et al. Low immunogenicity to SARS-CoV-2 vaccination among liver transplant recipients. J Hepatol 2021 View Article
  75. Soloway RD, Summerskill WH, Baggenstoss AH, Geall MG, Gitnićk GL, Elveback IR, et al. Clinical, biochemical, and histological remission of severe chronic active liver disease: a controlled study of treatments and early prognosis. Gastroenterology 1972;63(5):820-833
  76. Murray-Lyon IM, Stern RB, Williams R. Controlled trial of prednisone and azathioprine in active chronic hepatitis. Lancet 1973;1(7806):735-737 View Article
  77. van Gerven NM, Verwer BJ, Witte BI, van Hoek B, Coenraad MJ, van Erpecum KJ, et al. Relapse is almost universal after withdrawal of immunosuppressive medication in patients with autoimmune hepatitis in remission. J Hepatol 2013;58(1):141-147 View Article
  78. Manns MP, Woynarowski M, Kreisel W, Lurie Y, Rust C, Zuckerman E, et al. Budesonide induces remission more effectively than prednisone in a controlled trial of patients with autoimmune hepatitis. Gastroenterology 2010;139(4):1198-206 View Article
  79. Ungaro RC, Brenner EJ, Gearry RB, Kaplan GG, Kissous-Hunt M, Lewis JD, et al. Effect of IBD medications on COVID-19 outcomes: results from an international registry. Gut 2021;70(4):725-732 View Article
  80. Colmenero J, Rodríguez-Perálvarez M, Salcedo M, Arias-Milla A, Muñoz-Serrano A, Graus J, et al. Epidemiological pattern, incidence, and outcomes of COVID-19 in liver transplant patients. J Hepatol 2021;74(1):148-155 View Article
  81. Cavagna L, Seminari E, Zanframundo G, Gregorini M, Di Matteo A, Rampino T, et al. Calcineurin inhibitor-based immunosuppression and COVID-19: Results from a multidisciplinary cohort of patients in northern Italy. Microorganisms 2020;8(7):977 View Article
  82. Robinson PC, Richards D, Tanner HL, Feldmann M. Accumulating evidence suggests anti-TNF therapy needs to be given trial priority in COVID-19 treatment. Lancet Rheumatol 2020;2(11):e653-e655 View Article
  83. Brenner EJ, Ungaro RC, Gearry RB, Kaplan GG, Kissous-Hunt M, Lewis JD, et al. Corticosteroids, but not TNF antagonists, are associated with adverse COVID-19 outcomes in patients with inflammatory bowel diseases: Results from an international registry. Gastroenterology 2020;159(2):481-491.e3 View Article
  84. Gianfrancesco M, Hyrich KL, Al-Adely S, Carmona L, Danila MI, Gossec L, et al. Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry. Ann Rheum Dis 2020;79(7):859-866 View Article
  85. Mehta P, Porter JC, Chambers RC, Isenberg DA, Reddy V. B-cell depletion with rituximab in the COVID-19 pandemic: where do we stand?. Lancet Rheumatol 2020;2(10):e589-e590 View Article
  86. Loarce-Martos J, García-Fernández A, López-Gutiérrez F, García-García V, Calvo-Sanz L, Del Bosque-Granero I, et al. High rates of severe disease and death due to SARS-CoV-2 infection in rheumatic disease patients treated with rituximab: a descriptive study. Rheumatol Int 2020;40(12):2015-2021 View Article
  87. Abdulrab S, Al-Maweri S, Halboub E. Ursodeoxycholic acid as a candidate therapeutic to alleviate and/or prevent COVID-19-associated cytokine storm. Med Hypotheses 2020;143:109897 View Article
  88. Saigal S, Gupta S, Sudhindran S, Goyal N, Rastogi A, Jacob M, et al. Liver transplantation and COVID-19 (Coronavirus) infection: guidelines of the liver transplant Society of India (LTSI). Hepatol Int 2020;14(4):429-431 View Article
  89. Zijp TR, Toren-Wielema ML, Nannan Panday PV, Kosterink JGW, Berger SP, Touw DJ. Important interactions of immunosuppressants with experimental therapies for novel coronavirus disease (COVID-19): How to act. Ther Drug Monit 2020;42(4):652-653 View Article
Copyright © 2021 Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 4.0 License (CC BY-NC 4.0), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
  • Journal of Clinical and Translational Hepatology
  • pISSN 2225-0719
  • eISSN 2310-8819

Article Options

Metrics

Cite this Article

  • © 2024 Xia & He Publishing Inc.
  • Total visits : 2645085
  • Visits today : 1034
Back to Top

Special Considerations in the Management of Autoimmune Hepatitis in COVID-19 Hotspots: A Review

Deepak Madhu, Sanchit Sharma, Ashish Agarwal, Anoop Saraya
  • Reset Zoom
  • Download TIFF