Discussion
Pediatric cases represent 1-5% of COVID-19 cases worldwide and there is a paucity of data on COVID-19 impact on bone marrow transplant patients. Children are less infected perhaps due to the lower expression level of angiotensin-converting enzyme 2 in their nasal mucosa.3 Bone marrow recipients are suspected to be more prone to COVID-19 as they have immunosuppressive therapy or delayed immune reconstitution after transplantation. Reports describing the COVID infections so far in bone marrow transplant recipients always have pointed these two situations. Most of the COVID cases in these reports were on immunosuppressive treatments or there was a history of high dose steroid use due to GVHD. In our case, the immunosuppression treatment was discontinued approximately one month before the diagnosis of COVID-19 and there was no sign of GVHD, both in the early post-transplant period and the time around the COVID-19 diagnosis. We know that, in most recipients, the first clinical manifestation of acute GVHD usually occurs at or near the time of the white blood cell engraftment, not at around day 100. In our opinion, COVID-19 infection was the factor that triggered GVHD findings after the COVID infection had transmitted from his mother.
Pathologically, acute GVHD is apparent as an inflammatory T cell infiltrate with associated tissue destruction and apoptosis. Many factors contribute to the pathophysiology of acute GVHD.4,5 In acute GVHD, a trigger initiates inflammation mediated by the innate immune system in cooperation with T and B lymphocytes of the adaptive immune system.6Macrophages, neutrophils, and dendritic cells mediate this response through Toll-like receptors (TLRs), which are involved in pathogen recognition.7-9 And in the end, TLR pathway activation induces transcriptional activation of interferon (IFN) alpha and induces tumor necrosis factor (TNF) and interleukin (IL)-6.10-12 IFN alpha drives Th1 commitment and results in IFN gamma production and, together, IFN alpha and IFN gamma induce chemokines that recruit Th1 cells to sites of inflammation and enhance processing and presentation of host antigens.6,13 These interactions shows that TLRs are important contributing factors to the pathogenesis of acute GVHD.
Several clinical variables are associated with the development of GVHD such as donor type, source, sex-mismatch and infection history (eg, CMV, EBV).6 Like EBV and CMV, COVID-19 which is a powerful trigger for immune response may have a potential to trigger viral-mediated TLR4 activation.
From the studies referring the pathophysiology of COVID, we have learned that TLRs play a significant role between COVID and exacerbated immunological host response leading a cytokine storm. Overexpression of pro-inflammatory cytokines such as IL-6 and TNF alpha, which are products of the TLR4 pathway, may play a critical role as a trigger for acute GVHD as SARSCoV-2 spike protein has strong interaction with TLRs. This may be the link between the unbalanced immune response in COVID-19 and GVHD.14
In conclusion, although the diagnosis of GVHD was not histologically proven in this patient, the patient’s clinic, the absence of any other condition to explain this clinical picture and the good response to GVHD treatment indicate that the triggering factor in the development of GVHD may be COVID-19 in the era of TLR, which plays a common role in the pathogenesis of both GVHD and COVID-19. So, it should be kept in mind that COVID-19 may not be so innocent as reported in children and especially in the patients with HSCT and may progress with manifestations other than classical findings in bone marrow transplant recipients.
* No conflict of interest