Outcomes of Severe Seronegative Hepatitis-associated Aplastic Anemia: A Pediatric Case Series

Abstract

Objectives: Hepatitis-associated aplastic anemia (HAAA) is a potentially life-threatening diagnosis without clear treatment guidelines. The goal of the study was to characterize the presentation, evaluation, histopathology, and outcomes of therapy in children with HAAA to guide future research and to develop standardized care guidelines for this rare disease.

Methods: Retrospective chart review of 4 patients with HAAA who presented to Children's Hospital Colorado between 2016 and 2019 was conducted. Patient presentation, evaluation, bone marrow and liver pathology, interventions, and clinical course were collected. Immunohistochemistry of liver biopsies was performed.

Results: We treated 4 patients with HAAA without liver failure. All had evidence of systemic hyperinflammation and CD8+ T cell predominant liver tissue infiltration. One had a genetic mutation predisposing him to immune-mediated disease, but all other genetic testing was negative. In 3 of the 4 patients, hepatitis was poorly responsive to standard therapy with steroids, azathioprine, or tacrolimus; however, sustained biochemical remission of hepatitis was induced after more aggressive immunosuppressive therapies including Anti-Thymocyte Globulin (ATG) at standard immunosuppressive therapy (IST) dosing for severe Aplastic Anemia (sAA). Two patients underwent hematopoietic stem cell transplant (HSCT); 1 as first line therapy and 1 for refractory sAA.

Conclusions: We found that ATG-based IST induced remission of hepatitis in patients with steroid-refractory HAAA. This is also an appropriate initial treatment for severe Aplastic Anemia, though may not prevent the need for HSCT. We propose that equine ATG based IST at standard dosing regimen for sAA is a therapy that in select cases can be considered early on in the treatment course and could lead to a sustained remission of both hepatitis and sAA. This should be considered in collaboration with a pediatric hematologist.

Figure 1:. Aminotransferase and CBC Changes with Therapy:

Shown are laboratory results over time for Patients A-D. For each patient (A.-D.) the top graph shows aminotransferase levels and the lower graph shows the WBC, absolute lymphocyte count (ALC) (left axis) and platelet count (right axis). The time frame of administration of various therapies is shown with arrows. *Patient B had HSCT preparative regimen of equine ATG, cyclophosphamide, and methylprednisolone. *Patient C had HSCT preparative regimen of rabbit ATG, fludarabine, cyclophosphamide, and total body irradiation. Steroids= oral and IV formulations; Tacro= Tacrolimus; ATG = Anti-Thymocyte Immune Globulin 40 mg/kg; AZA= Azathioprine; HSCT = Hematopoietic Stem Cell Transplant; CsA = Cyclosporine A; ETOP = Etoposide 150 mg/m²; MMF = Mycophenolate Mofetil

Figure 1:. Aminotransferase and CBC Changes with Therapy:

Shown are laboratory results over time for Patients A-D. For each patient (A.-D.) the top graph shows aminotransferase levels and the lower graph shows the WBC, absolute lymphocyte count (ALC) (left axis) and platelet count (right axis). The time frame of administration of various therapies is shown with arrows. *Patient B had HSCT preparative regimen of equine ATG, cyclophosphamide, and methylprednisolone. *Patient C had HSCT preparative regimen of rabbit ATG, fludarabine, cyclophosphamide, and total body irradiation. Steroids= oral and IV formulations; Tacro= Tacrolimus; ATG = Anti-Thymocyte Immune Globulin 40 mg/kg; AZA= Azathioprine; HSCT = Hematopoietic Stem Cell Transplant; CsA = Cyclosporine A; ETOP = Etoposide 150 mg/m²; MMF = Mycophenolate Mofetil

Figure 1:. Aminotransferase and CBC Changes with Therapy:

Shown are laboratory results over time for Patients A-D. For each patient (A.-D.) the top graph shows aminotransferase levels and the lower graph shows the WBC, absolute lymphocyte count (ALC) (left axis) and platelet count (right axis). The time frame of administration of various therapies is shown with arrows. *Patient B had HSCT preparative regimen of equine ATG, cyclophosphamide, and methylprednisolone. *Patient C had HSCT preparative regimen of rabbit ATG, fludarabine, cyclophosphamide, and total body irradiation. Steroids= oral and IV formulations; Tacro= Tacrolimus; ATG = Anti-Thymocyte Immune Globulin 40 mg/kg; AZA= Azathioprine; HSCT = Hematopoietic Stem Cell Transplant; CsA = Cyclosporine A; ETOP = Etoposide 150 mg/m²; MMF = Mycophenolate Mofetil

Figure 1:. Aminotransferase and CBC Changes with Therapy:

Shown are laboratory results over time for Patients A-D. For each patient (A.-D.) the top graph shows aminotransferase levels and the lower graph shows the WBC, absolute lymphocyte count (ALC) (left axis) and platelet count (right axis). The time frame of administration of various therapies is shown with arrows. *Patient B had HSCT preparative regimen of equine ATG, cyclophosphamide, and methylprednisolone. *Patient C had HSCT preparative regimen of rabbit ATG, fludarabine, cyclophosphamide, and total body irradiation. Steroids= oral and IV formulations; Tacro= Tacrolimus; ATG = Anti-Thymocyte Immune Globulin 40 mg/kg; AZA= Azathioprine; HSCT = Hematopoietic Stem Cell Transplant; CsA = Cyclosporine A; ETOP = Etoposide 150 mg/m²; MMF = Mycophenolate Mofetil

Figure 2:. Immunohistochemistry of liver tissue at 200x magnification.

1A – 1E represent immunohistochemistry of normal liver tissue. 1A: hematoxylin and eosin stained normal liver tissue. 1B: CD4⁺ immunostain. 1C: CD8⁺ immunostain. 1D: CD20⁺ immunostain. 1E: CD56⁺ immunostain. 2A – 2E represent immunohistochemistry of liver tissue for Patient A. 2A: hematoxylin and eosin stained liver tissue. 2B: CD4⁺ immunostain. 2C: CD8⁺ immunostain. 2D: CD20⁺ immunostain. 2E: CD56⁺ immunostain.