Multiple Peaked Cytokine Storm: Is Multiple Exposures to the COVID-19 Virus a Possible Cause?

DISCUSSION

Pathogens usually make us sick by two ways. One is by the direct effects and another indirect effect. Indirect effect is caused by activation of our hyperactive immune responses to the pathogen by the release of IFNs, ILs, TNF-α, chemokines, and several other mediators. This indirect mechanism plays a major role in severe COVID-19 infections. The “cytokine storm” caused by SARS-CoV-2 has been found to be a major cause of mortality in COVID-19 patients. The production of excessive cytokines and inflammatory markers leads to acute respiratory distress syndrome (ARDS) aggravation, thrombosis, and tissue damage resulting in multi-organ failure and death.¹ This “cytokine storm” leads to sequestration of neutrophils, CD4 helper T cells, and CD8 cytotoxic T cells in the lung tissue. In the process of fighting off the virus, these cells cause inflammation and lung injury. The virus-laden pneumocytes then undergo apoptosis with the release of new viral particles, which then infect the adjacent type 2 alveolar epithelial cells and the vicious cycle continues. This leads to loss of both type 1 and type 2 pneumocytes resulting in diffuse alveolar damage eventually causing ARDS.^5,6

Huang et al. reported that severely infected patients show high levels of proinflammatory cytokines and chemokines.² The cytokine storm is readily followed by the immune system “attacking” the body, which in turn can cause ARDS, multiple organ failure, and finally death.⁶

Repeated exposure to the virus can lead to a dose-dependent immune response that may be associated with more disease severity and higher mortality.⁷ Enhanced immune responses and exhaustion of immune cells can be seen in these patients due to persistent and large-scale viral infection. We hypothesize that multiple surges in cytokines storm in some patients may be due to multiple exposures of the same patient within the incubation period, sepsis, or other inflammatory lesions inside the body. In our cases, sepsis as a cause of cytokine storm was ruled out by doing the procalcitonin test, which was within the normal limit.

In our cases, the condition of the patient improved initially followed by a sudden deterioration in the clinical condition. This deterioration was not explained by any other cause except for an increase in the inflammatory markers. In the course of ICU stay patient showed multiple surges of inflammatory markers with waxing and waning of symptoms of the patient. Sudden deterioration/ increased oxygen consumption after initial improvement may be due to multiple surges of cytokines storm within a short period and the possible cause may be due to multiple exposures within the incubation period. This can be correlated with different stages of infiltrative lesions of the lung. There is a possibility that patients get reinfected in the hospital before the formation of an adequate antibody. It has been observed that healthcare workers have a high mortality rate and this might be because of multiple exposures to the virus during their duty hours. We can suspect multiple exposures whenever there are multiple surges in cytokines at different intervals. To validate our hypothesis, serial CT scan analysis or lung biopsy at different time intervals is required.