COVID-19 in a pediatric heart transplant recipient: Emergence of donor-specific antibodies

Early reports have suggested that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) associated coronavirus disease 2019 (COVID-19) generally causes mild disease in children.¹ Pediatric solid organ transplant recipients are generally more susceptible to viral respiratory infections and have increased morbidity and mortality.² There have been limited reports of COVID-19 disease in heart transplant recipients.³

A 3-year-old female child underwent orthotopic heart transplantation at 11 months of age for congenital dilated cardiomyopathy in late 2017. Her post-transplant course had been unremarkable, except for persistent Ebstein Barr virus (EBV) viremia, for which the intensity of immunosuppression had been reduced to tacrolimus monotherapy. In the first week of March 2020, the patient developed a productive cough with rhinorrhea and nasal congestion. She was afebrile with no symptoms of shortness of breath. One month before this illness, she was treated for febrile bronchiolitis as an outpatient. The potential for COVID-19 was considered, but community incidence was low at the time. The patient had no Centers for Disease Control risk factors for infection, and testing was not widely available. One week later, a follow-up telehealth visit was performed with improvement in the severity of cough, and she remained afebrile. Surveillance laboratory studies including complete blood count, EBV whole blood DNA, and anti-human leukocyte antigen antibody testing by Luminex assay happened to be performed at that time. The patient was noted to have baseline leukopenia of 4.73 × 10³/μl, stable tacrolimus trough of 4.9 ng/ml, and the following de novo Class II donor-specific antibodies: DQ4 (strong mean fluorescent intensity [MFI] 10110), DR8 (moderate MFI 3,389), and DQA1*04 (weak MFI 3,458). The patient was scheduled for admission to administer intravenous immunoglobulin one week after the laboratory studies were obtained. Because of the history of cough, our patient immediately underwent SARS-CoV-2 RNA nasal swab reverse transcriptase polymerase chain reaction testing and was placed under enhanced droplet precautions. Admission vitals were notable for axillary temperature of 36.4°C, heart rate of 123 beats per minute, respiratory rate of 24 breaths per minute, and systemic oxygen saturation of 96%. Examination was notable for intermittent wet cough but with no increased work of breathing and clear breath sounds on auscultation. Overnight, the patient tolerated administration of 0.5 g/kg of intravenous immunoglobulin (IVIG) without complication. The SARS-CoV-2 reverse transcriptase polymerase chain reaction test returned positive the following morning. The patient remained well, appearing without symptoms of respiratory distress, and vital signs remained unchanged. Given the history of symptoms beginning 2‒3 weeks before admission and clinical stability, further testing and evaluation were deferred, and the patient was eventually discharged. Repeat SARS-CoV-2 nasal polymerase chain reaction was planned for 2 weeks with repeat anti‒human leukocyte antibody testing, and IVIG administration was repeated every month for 2 more months.

Notably, this patient was receiving tacrolimus monotherapy at the time of infection because of persistent EBV viremia and, therefore, may have mounted a more efficient immune response than if she had additionally been receiving an anti-metabolite or corticosteroid. In vitro data suggest inhibition of viral replication of human coronaviruses by FK-506.⁴ Interestingly, de novo donor-specific Class II antibodies were also detected during the infection. Allosensitization after viral infections is described, and because of reduced immunosuppression, our patient may have been prone to this phenomenon.⁵ This patient tolerated IVIG administration with concurrent COVID-19 infection without any notable reaction. We would be hesitant to attempt more aggressive forms of desensitization with active infection until more clinical knowledge of COVID-19 infection is available. Although mechanisms and relationship between allosensitization and COVID-19 remain uncertain, we suggest that careful measurement of donor-specific antibodies be undertaken in heart transplant survivors of this infection.