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