Detection of a monoclonal component after pediatric liver transplantation: a case report

To the Editor,

Monoclonal gammopathies (MG) are a group of disorders ranging from monoclonal gammopathy of undetermined significance (MGUS) to malignant plasma cell dyscrasias, characterized by the presence of a monoclonal component (MC) at protein electrophoresis of serum or urine [1].

In the pediatric population, the presence of MG has been associated with a range of clinical diagnoses, many of which involving immunodeficiencies, autoimmune diseases, malignancies, or hematologic disorders. Malignant plasma cell disorders are extremely rare below age 18 years [2].

Patients that undergo organ transplant must follow immunosuppressive therapy. The penalty for the nonspecific nature of immunosuppression is the susceptibility of the recipient to the development of opportunistic infections, as well as an increased risk of developing malignancies. Post-transplant lymphoproliferative disease (PTLD) is the most common form of post-transplant malignancy in pediatric transplant recipients, because of the immunosuppressive state induced to avoid organ rejection or a reaction disease against the host [3]. The incidence is very variable and depends on age, transplanted organ, intensity of immunosuppression and viral status of the recipient before transplantation. PTLD is more common in pediatric recipients than in adults, with a prevalence above 10%.

The pathogenetic role of Epstein–Barr virus (EBV) in the onset of PTLD is widely documented in the literature; indeed, about 70% of patients test positive for infection within three months of transplantation [4, 5].

Therefore, the most significant risk factor for PTLD is the age at transplant because the state of seronegativity of pediatric patients at the time of transplant makes them susceptible to infection in the post-transplant period. In addition, the type of immunosuppression, the matching between an EBV- and an EBV + organ recipient and a concomitant cytomegalovirus (CMV) infection occurring when immunosuppression is maintained at high levels should also be considered [6].

In July 2019, a seven-month-old infant underwent hepatotransplantation for cirrhosis decompensated by biliary atresia; the patient had already been operated for portoenteroanastomosis according to Kasai at 41 days of life, with poor restoration of bile flow.

The post-transplant course was uneventful, except for a Human Herpes Virus 6 (HHV6) infection.

Immunosuppressive therapy administered immediately after transplantation included Basiliximab (BSX), Methylprednisolone, Tacrolimus and, one month after transplant, exclusively oral Tacrolimus at decreasing doses.

The functionality of the hepatic graft, the auxological parameters and the psychomotor development were normal.

From November 2019 to February 2020 (4–7 months post-transplant) the patient missed the follow-up for the laboratory tests required by the post-transplant protocol; therefore the immunosuppressive therapy remained the same.

In March 2020 (eight months post-transplant) the patient was again hospitalized for an acute respiratory infection at the Pediatric Department of Federico II University Hospital (Naples).

For the first time, a significant increase in IgG immunoglobulins was found at the hematochemical evaluation. Serum protein electrophoresis (SPE), performed using Capillarys 2 Flex-Piercing (Sebia, France), showed a monoclonal peak, characterized by immunosubtraction using Capillarys Immunotyping kit (Sebia, France) as IgG κ 8.3 g/L. This finding cannot be attributed to BSX therapy, since treatment had been withdrawn one month after the transplant, while MC onset occurred eight months later.

The serum free light chain (FLC) measurements, performed with the N-Latex reagent kit on BN Prospec system (Siemens, Germany) were normal, with a FLC κ/λ ratio of 1.3 (0.31–1.56).

The patient also presented an increase in lactate dehydrogenase levels equal to 458 U/L (192–321) and a decrease in hemoglobin levels to 93 g/L (110–160), while other biochemical parameters were within reference ranges.

The serological EBV-DNA and CMV-DNA tests performed gave negative results.

To assess the patient’s immune status and rule out an underlying hematological malignancy, we performed immunophenotyping of peripheral blood lymphocytes through flow cytometry, which resulted within the reference range. Moreover, imaging tests failed to find evidence of PTLD.

In April 2020 (nine months post-transplant), the patient tested positive for liver/kidney microsome type 1 (LKM1) antibodies (anti-LKM1=50 AU/mL; <15), in the absence of signs of autoimmune hepatitis on hepatic histological examination and of rejection. On the other hand, antinuclear antibodies were negative.

In the following three months (April–June 2020, 9–11 months post-transplant), the patient’s clinical conditions were good and stable, with no lymphadenomegaly or splenomegaly. Following the reduction of immunosuppressive therapy, MC decreased over time, as shown in Figure 1.

Figure 1:

Tacrolimus blood levels and MC.

The graph shows the correlation between the blood levels of tacrolimus and the reduction of MC in the post-transplant period (8–18 months). MC, monoclonal component.

In October 2020 (15 months post-transplant), EBV-DNA (982 IU/mL) was positive for the first time. In December 2020 (17 months post-transplant), CMV-DNA (1132 IU/mL) was positive and the patient tested positive for COVID-19 as well, with no relevant symptoms.

In the following months, the patient was in good clinical conditions; at the follow-up visit performed in September 2021 (26 months post-transplant) as well as at the subsequent evaluations, there was no evidence of MC at the serum protein electrophoresis.

Liver transplantation in pediatric patients has become increasingly more successful in recent decades, thanks to the benefits of immunosuppression, which has reduced the risk of rejection. However, this therapy exposes patients to quite serious consequences, such as recurrent infections and PTLD – a rare complication of solid organ transplantation. Early forms of PTLD sometimes escape diagnosis because they do not manifest with obvious signs or symptoms [7, 8].

The present case describes the course of transient MG in a pediatric hepatotransplanted patient.

Monoclonal or oligoclonal gammopathies can be part of a transient immune response. The etiopathology of these gammopathies in early childhood is possibly multifactorial, and viruses, as in this case, may be involved in the transient proliferation of monoclonal B-cell clones [9].

Although the onset of MG initially cast doubts on the possible development of a PTLD, in this case, it could be explained by the immunosuppressive therapy to which the infant was subjected and by the concomitant infection with HHV6 and later by EBV and CMV. In fact, the reduction of immunosuppressive therapy was sufficient to restore the patient’s immune system and induce complete MC remission over time.

In conclusion, although the SPE test is inappropriate in pediatric age, because MG is a rare finding, we believe that in transplanted pediatric patients, it could be useful to minimize the risk of misdiagnosing any underlying PTLD, especially for early forms that could clinically escape diagnosis. Further studies in this subpopulation are needed to confirm our hypothesis.