A 14-year-old boy without burdened family, pregnancy and perinatal history. At 3 months of age, he was diagnosed with cytomegalovirus (CMV) and EBV infection with severe hepatitis, which was confirmed by PCR. The boy did not meet diagnostic criteria for HLH. The parameters of humoral and cellular immunity assessed at that time were normal. At the age of 5, he had an episode of diarrhea, followed by pneumonia complicated by a pleural empyema, which required decortication of the left lung. The patient was also highly hypersensitive to insect bites [Figure 1A]. In repeated immunology tests at the age of 5, agammaglobulinemia was observed (IgG 0.5 g/l; IgA <0.06 g/l; IgM 0.12 g/l), the percentage and absolute number of CD19+ cells were normal for the primary lymphocyte subpopulations, the CD3+CD4+/CD3+CD8+ ratio was inverted. In our case NK studies were not performed. In addition, a decreased percentage of memory switched B cells was demonstrated. Genetic tests using the next-generation sequencing method (NGS) were carried out at the age of 13. A mutation in the TNFRSF13B gene was detected, which resulted in defective production of the TACI protein. Thus, the diagnosis of the heterozygous variant of CVID was confirmed and a heterozygous variant in the STX11 gene was also demonstrated.
At the age of 5, substitution therapy with intravenous human immunoglobulin was implemented. After one year, subcutaneous infusions were introduced and carried out for 7 consecutive years, without complications. EBV and CMV viremia was not determined at that time.
At the age of 13, an erythematous papular rash occurred on lower limbs and then papulopustular skin lesions were observed, which receded leaving deep scars. Moreover, periorbital edema was also periodically observed. A relapse of new skin lesions was accompanied by high fever. Laboratory tests revealed thrombocytopenia, neutropenia and hypertransaminasemia. After three months, serous-filled vesicles began to appear around the papular erythematous changes [Figures 1B, C]. The skin lesions occurred with periods of exacerbation and remission [Figure 1D]. HHV6, Adenovirus, Parvovirus B 19, VZV, HSV 1, HSV 2, HIV, Aspergillus spp, influenza A, influenza B, RSV, SARS-Cov-2, as well as tuberculosis and other mycobacteriosis were excluded. Staphylococcus epidermidis was cultured from swabs of the vesicles on the scalp. Targeted treatment was applied but with no improvement. At the same time, a rapid increase in EBV viremia (>5X106 IU/ml) was observed. In therapy, 4 doses of anti-CD 20 monoclonal antibodies (rituximab) were used. Rituximab was used before the final diagnosis of T-cell involvement was obtained. A transient reduction in EBV viremia was achieved, but with no clinical improvement. The treatment was followed by a complete depletion of B cells. Additionally, a significantly increased percentage and absolute number of CD3+CD8+ cells (cytotoxic T cells) were noticed. A skin biopsy was performed, and histopathological examination showed features of vasculitis. Therefore, prednisone 1 mg/kg body weight was used in the treatment, however with no clinical improvement. Due to the above, histopathological examination of skin tissue samples was performed in a reference center. The consulting pathologist recognized EBER+ CD8. The images of the histopathology results and their description are presented in Figure 2 [Figure 2]. The child was assessed for T-cell receptor (TCR) clonality in peripheral blood T lymphocytes. The result was normal. PET-CT scanning showed features of scalp involvement, with no changes in the lymph nodes, liver and spleen [Figure 3]. Based on the above clinical presentation and hystopatologic findings the systemic form of HV-LPD from mature cytotoxic T cells infected with EBV was diagnosed. According to the WHO classification fulfilled criteria were presence of general symptoms, hypersensitivity to insect bites [Figure 1A] and no signs of organ involvement (besides skin). The literature analysis showed that the best treatment effects of systemic forms of HV-LPD were achieved in patients in whom the EBV load in peripheral blood was reduced to <200 IU/ml, and then allogeneic hematopoietic cells were transplanted. Based on individual reports, different therapeutic regimens were used in the treatment preparing for HCT, as shown in Figure 4. None of them resulted in the expected decrease in viral load. Additionally, the disqualification of an unrelated donor made it necessary to postpone the planned HCT for another month. For this reason, it was decided to conduct an experimental cell therapy with the use of T cells sensitized by EBV. Before HCT, the boy underwent 2 cycles of immunotherapy with Tabelecleucel (TabCel) (i.v. 2x106/Kg, partially HLA matched) by Atara Biotherapeutics Inc. (Thousand Oaks, CA, USA). TabCel was administered three times in each cycle: on days 1, 8 and 15. The patient tolerated the treatment well, fever appeared on the 6th day after the first administration of the drug. Massive inflammation occurred on the scalp (erythema with subcutaneous swelling, petechiae and dark scabs), which disappeared after one day. Papular eruptions healed quickly with no tendency to deep scar [Figures 1E, F]. These changes were treated as the effect of immunotherapy. No such reactions were observed after subsequent intravenous administrations of the TabCel. Periodically, new HV skin lesions appeared that healed quickly leaving scars, but the general symptoms (fever, swelling) subsided. The EBV viremia did not decrease to the expected value of <200 IU/ml. In the first cycle of immunotherapy, the patient was infected with SARS-CoV-2, which was associated with a short-term fever, cough and increased fatigue that lasted for about 4 weeks. Pneumonia with the involvement of about 10% of the lung parenchyma was diagnosed. The treatment included remdesivir, convalescent plasma and empirical antibiotic therapy, which resulted in stabilization of lung lesions. Complications of COVID-19 were mild myocarditis and arterial hypertension. It was necessary to implement dual antihypertensive therapy (enarenal and metoprolol). COVID-19 and its treatment did not interfere with the implementation of specific immunotherapy. In the 8th week after the end of the 2nd cycle of HV-LPD therapy, conditioning according to Sawada was started and then allogeneic hematopoietic cell transplantation was performed from a 10/10 HLA matched unrelated donor, ABO and Rh incompatible with the recipient. Cyclosporine and methotrexate were used to prevent graft-versus-host disease (GvHD). On the +5 th day after allo-HCT, a single dose of anti-CD20 antibodies was administered. Due to the positive CMV infection status in the recipient and negative in the donor (high risk of CMV reactivation), letermovir was administered prophylactically. Engraftment was achieved on day +24. The early post-transplant period was complicated by gastrointestinal mucositis. No new skin lesions were formed since HCT. In addition, CMV infection was not reactivated and there were no reports of other infections or fever. Since the administration of the conditioning regimen, a gradual decrease in EBV viremia was observed until undetectable levels on day +17. Due to viremia (103 IU/ml) on day +24, it was decided to administer monoclonal anti-CD20 antibodies single dose as pre-emptive therapy. Symptoms of GvHD were not observed. From day +31, 2 consecutive cycles of EBV immunotherapy with specific cytotoxic T cells were administered on days 1, 8 and 15 of each cycle. Immunosuppressive treatment was completed on day + 134 after allo-HCT.
From day +38 to day +300, no reactivation of EBV and CMV was observed. At the time of preparing the paper (approx. +300 after HCT) the patient's condition was good. No clinical signs of HV-LPD recurrence occured but there still were elevated levels of transaminases and gamma-glutamyl transferase (GGT). Hematological parameters were normal, except for a slightly reduced number of platelets (in the range of 70-150 K/microl). The boy required systematic human immunoglobulin supplementation, which was carried out from day +180 by the subcutaneous route. In cyclic determinations of immunoglobulin levels around day +280, an increase in IgM concentration was observed, which may be an indication of reconstruction of humoral immunity. There was also an improvement in the analyzed lymphocyte subpopulations. The percentage of CD19+ cells decreased (3.4%), but their absolute number increased to normal (224/microl).