A 15-year-old Chinese girl suffering from fatigue, dizziness, and nausea was presented with severe bone marrow pancytopenia in October 2019. Acute jaundice hepatitis of unknown cause had been diagnosed 1 month before admission to our hospital. Complete blood count (CBC) showed that white blood cell counts were 0.19 x 109/L, absolute neutrophil count (ANC) was 0.11 x 109/L, hemoglobin level was 76 g/L, and platelet count was 12 x 109/L. Blood exams showed that the transaminase and bilirubin were 20 times higher than the normal range (total bilirubin (TBIL) 251.7 mumol/L, direct bilirubin (DBIL) 179.3 mumol/L, indirect bilirubin (IBIL) 72.4 mumol/L, aspartate aminotransferase (AST) 1420 IU/L, alanine aminotransferase (ALT) 1757 IU/L). T-cell subsets of peripheral blood detected by flow cytometry showed that CD4+ was 9.11%, CD8+ was 69.83%, and CD4/CD8 rate was 0.14, which the ratio of CD4+/CD8+ reduced significantly. Bone marrow biopsy showed extremely hypocellular bone marrow (5%), reduced granulocytes and erythrocytes, hyperplasia of adipose components, no megakaryocytes, and an increased number of lymphocytes, plasma cells, and histiocytes. A cytogenetic study showed a normal karyotype. Serological tests for hepatitis (A, B, C), Epstein-Barr virus, cytomegalovirus (CMV), parvovirus B19, herpes, and HIV were negative. No positive genetic and molecular tests were found for congenital bone marrow failure diseases such as Fanconi anemia, Shwachman-Diamond, and dyskeratosis congenita. Paroxysmal nocturnal hemoglobinuria (PNH) diagnosis also was excluded. HAAA with negative viral serology was finally diagnosed.
Treatments with liver protection, nutrition support, and immunosuppressive therapy (IST) with prednisone, cyclosporine (CsA), and hematopoiesis stimulation (granulocyte colony-stimulating factor (G-CSF), thrombopoietin receptor agonist (TPORA), and danazol) were started after admission. At the beginning of hospitalization, the patient refused antithymocyte globulin (ATG) or HSCT treatment due to the family's financial distress. Due to pulmonary infection from agranulocytosis, beta-lactamase inhibitors tazobactam (piperacillin-tazobactam, cefoperazone-sulbactam) and fluoroquinolones (levofloxacin) were used, successively. The patient's liver function improved, and transaminases were back to normal after 1 month of liver protection treatment. However, the pancytopenia treatment showed no significant response. The patient remained platelet and red blood cell transfusion-dependent. Without effective infection control, the patient developed an oral fungal infection (Figure 1A) and pulmonary infections with MDR to bacteria and fungus due to long-term neutropenia and antibiotic use. An aspergilloma and a large number of pleural effusions were found by CT scanning (Figure 2A). Laboratory tests repeatedly showed sputum culture with Pseudomonas aeruginosa resistance to multidrug in December 2019. Serum (1,3)-beta-D glucan (G-test) was negative, while galactomannan (GM-test) was positive. The bronchoalveolar lavage was rejected by the patient, and multiple fungal cultures from the sputum showed negative results. A conventional microdilution assay (CLSI methodology) showed the minimum inhibitory concentration values of imipenem and meropenem of 8 and >16, respectively. Empirical antibiotics Fosfomycin, Polymyxin, Meropenem, Voriconazole, and Micafungin could not control the patient's infections. The patient's symptom of fever, cough, and shortness of breath continued. Oral ulceration with fungal infection aggravated, and multidrug-resistant infection progressed to life-threatening sepsis. At the same time, the patient presented with vomiting blood and developed hemorrhagic shock. After effective antishock treatment, the patient's condition was under control. With uncontrolled infections after multiple antibiotic treatments, the patient was given Ceftazidime Avibactam Sodium (2.5 g/kg i.v. q8h) and Fosfomycin (4 g b.i.d., i.v.) with a continuous infusion of Voriconazole and liposomal amphotericin B. At the same time, continuous drainage of the pleural fluid was performed. The patient's status gradually improved, although the size of the fungus ball in the right upper lung showed no obvious shrinkage. The level of inflammatory markers of C-reactive protein (CRP) decreased from 175 to 68 mg/L, procalcitonin (PCT) from 3.5 to 0.1 ng/ml, and IL-6 from 1200 to 126 pg/ml (Figure 3). CT scan showed the bilateral pleural effusion was reduced significantly. The patient recovered from the hemorrhagic shock from gastrointestinal bleeding.
As the patient's health improved, we urgently considered hematopoietic stem cell transplantation with salvage therapy. When the patient family's financial situation improved, peripheral blood stem cells from her HLA-matched sister were transplanted. The conditioning regimen of peripheral blood stem cell transplantation was 2.5 mg/kg rabbit ATG (on day -5 to day -2) and 50 mg/kg/day cyclophosphamide (on days -5 to -2) from December 25 to 29 2019. Peripheral blood stem cells (CD34+ 10.15 x 106/kg) were infused on day 0 (December 302019). CsA with the goal serum level in the range of 200-300 ng/ml was started on day -1. In total, 15 mg/m2/day MTX (day +1), 10 mg/m2/day MTX (+3, +6), Mycophenolate (day +7 to +45), and ruxolitinib (5 mg, bid) were administrated for graft versus host disease (GVHD) prophylaxis after neutrophil engraftment. MTX on day +11 was discontinued to reduce the risk of hematological toxicity. On day +15 post-transplantation, the patient's ANC was 0.5 x 109/L and it continued to increase. G-CSF was discontinued 3 days after ANC reached >1 x 109/L. Platelet engraftment occurred on day +35. Then, the antibiotics were switched to antibacterial (cefoperazone/sulbactam, linezolid) and antifungal (caspofungin, liposomal amphotericin B) therapies. The patient's temperature was returned to normal since day +18. The CT scan showed aspergilloma in the right upper lung with bilateral pleural effusion and left atelectasis on day +22, which seemed more serious than before HSCT. That might be because the patient suffered prolonged neutropenia before granulocyte engraftment (Figure 2B). With the patient's health conditions improving rapidly, atelectasis and bilateral pleural effusion gradually disappeared. Shrank aspergilloma was seen on day +59 (Figure 2C). The patient's CBC returned to a nearly normal range (WBC of 6.5 x 109/L, Hb of 100 g/L, and platelets (PLT) of 104 x 109/L) on day +72 with normal liver and kidney function (May 1 2020). Oral fungal infection was cured (Figure 1C).
After allo-HSCT, the patient's condition continued to keep stable. Donor chimerism of 100% was achieved. Slightly chronic skin GVHD was observed and was well controlled with methylprednisolone. Following-up 26 months after transplantation, the patient was still in complete remission with a high-quality life. She was back to school after 1 year of allo-HSC transplantation.