Treatment with a JAK inhibitor has been indicated, but it has not yet been possible to start it.
Figure 2
In April 2020, the child was once again admitted to hospital, complaining of dyspnea and chest pain for three days. His mother and sister had fever and anosmia for a week, with positive RT-PCR for SARS-CoV-2. He had no fever, cough or other respiratory symptoms. Laboratory results showed leukopenia (3.280/µL) and positive RT-PCR for SARS-CoV-2.
He was treated with inhaled salbutamol 800mcg/day, oral prednisolone 1mg/Kg/day, oral azithromycin 250mg/day and oral levofloxacin 250mg/day. Oxygen saturation was above 95% throughout the hospital stay, and glycemic level was satisfactory with human insulin and strict monitoring of a pediatric endocrinologist. Intraconazole prophylaxis was maintained. After ten days of hospitalization, white blood cell count went up to 9.710/uL. In addition, he presented D-dimer and interleukin 6 in the normal range (this last was 2.5, reference value less than 3.4 pg/mL). Chest CT did not show ground-glass opacities. Viral RNA load determined by cell culture was present on the seventh day of symptoms. At that same period, IgM against the novel virus was identified.
His nasopharyngeal swab for SARS-CoV-2 was still positive on the 13th day of symptoms and became negative on the 16th day, when antibodies that potentially neutralize SARS-CoV-2 were identified. During all this period, he remained hospitalized, afebrile, with no complaints and without supplemental oxygen.
SARS-CoV-2 is part of a large family of enveloped, single positive-strand RNA viruses2. When it enters the cell, its RNA is recognized by the Toll-like-receptors (TLRs): 7/8 and 9 TLR. The result is the activation of different signaling pathways and transcription factors, resulting in the expression of genes, which products are essential for antiviral and inflammatory responses. The 7/8 and 9 TLRs engage the MyD88 adapter leading to activation of the transcription factor NFkB, which induces inflammatory responses. They also signal via the TRIF adapter (TIR domain-containing adapter inducing IFN-β), that activates the interferon regulatory factor, which promotes the production of type 1 interferons (IFN-α / β), important for innate antiviral immune responses4.
Signal transducers and activators of transcription (STATs) are proteins present in different cell types, involved in multiple functions of the immune system 4,5. Mutations that lead to the gain of function in STAT1 (STAT1-GOF) increase the uncontrolled phosphorylation of this protein by impairing nuclear dephosphorylation. Thus, there is greater production of STAT-dependent cytokines, such as type 1 interferon (IFN-α / β) and interferon γ (IFN-γ). As already mentioned, the first one has the role in virus defense, and the second helps to fight mycobacteria. In addition, there is greater inhibitory effect on the IL17 pathway4.
Therefore, we have the hypothesis that despite the genetic dysregulation, this patient may present some degree of protection against a more severe form of COVID-19. Nonetheless, so far, there are no reports of patients with STAT1-GOF infected with the novel coronavirus in the world, which emphasizes the importance of continuing research on this inflammatory syndrome, as well as on SARS-CoV-2 infection. The patient and his legal responsible consented to the case report.
References
  1. Shaker M, Oppenheimer J, Grayson M et al. COVID-19: Pandemic Contingency Planning for the Allergy and Immunology Clinic. The Journal of Allergy and Clinical Immunology: In Practice . 2020;8(5):1477-1488.e5. doi:10.1016/j.jaip.2020.03.012
  2. Raoult D, Zumla A, Locatelli F, Ippolito G, Kroemer G. Coronavirus infections: Epidemiological, clinical and immunological features and hypotheses. Cell Stress . 2020;4(4):66-75. doi:10.15698/cst2020.04.216
  3. Reference G. STAT1 gene. Genetics Home Reference. https://ghr.nlm.nih.gov/gene/STAT1. Published 2020. Accessed September 7, 2020.
  4. Gaffen S. Structure and signalling in the IL-17 receptor family. Nature Reviews Immunology . 2009;9(8):556-567. doi:10.1038/nri2586
  5. Hwa V. STAT5B deficiency: Impacts on human growth and immunity. Growth Hormone & IGF Research . 2016;28:16-20. doi:10.1016/j.ghir.2015.12.006
  6. Shi Y, Wang Y, Shao C et al. COVID-19 infection: the perspectives on immune responses. Cell Death & Differentiation . 2020;27(5):1451-1454. doi:10.1038/s41418-020-0530-3