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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 17  |  Issue : 2  |  Page : 295-302

Low-dose radiotherapy for COVID 19: A radioimmunological perspective


1 Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi; Department of Radiation Oncology, National Cancer Institute, All India Institute of Medical Sciences, Jhajjar, Haryana, India

Date of Submission31-Jul-2020
Date of Decision06-Sep-2020
Date of Acceptance16-Dec-2020
Date of Web Publication11-Jun-2021

Correspondence Address:
Rishabh Kumar
Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi - 110 029
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_1045_20

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 > Abstract 


The world is fighting the onslaught of COVID 19 for the last 10 months, ever since the first case was reported in December 2019 in Wuhan, China. Now, it has spread to over 200 countries. COVID 19-associated respiratory syndrome is causing a lot of mortality and morbidity. There are reports suggesting that the complications and ARDS associated with COVID 19 is an immune response reaction. The cytokine storm associated with severe cases of COVID 19 acts as a cause of death in many sick patients. It has been shown that COVID 19 is associated with a peculiar immune profile: Decrease in CD3, CD4, CD8, natural killer cell and B-cells; Rise in interleukin (IL)-4, IL-6 and tumor necrosis factor (TNF) alpha; Decrease in IL-10; Decrease in interferon-gamma. Low-dose radiotherapy (LDRT) immunosuppressive features resulting from M2 macrophage phenotype activation, increase in IL-10, transforming growth factor beta, a decrease in IL-6, TNF alpha and an increase in CD3, CD4, and CD8 T cell counts may negate the harmful effects of cytokine release syndrome. Literature review shows that radiation was previously used to treat viral pneumonia with a good success rate. This practice was discontinued in view of the availability of effective antibiotics and antivirals. As there are no scientifically proven treatment for severe COVID 19-associated respiratory distress today, it is prudent that we understand the benefits of LDRT at this critical juncture and take rational decisions to treat the same. This article provides an radioimmunological rationale for the treatment of immune crisis mediated complications in severe cases of COVID 19.

Keywords: COVID 19, cytokine storm, immunology, low-dose radiotherapy, pneumonia, SARS-CoV-2


How to cite this article:
Kumar R, Haresh KP, Sharma DN, Gupta A, Gupta S, Vellaiyan S, Rath GK. Low-dose radiotherapy for COVID 19: A radioimmunological perspective. J Can Res Ther 2021;17:295-302

How to cite this URL:
Kumar R, Haresh KP, Sharma DN, Gupta A, Gupta S, Vellaiyan S, Rath GK. Low-dose radiotherapy for COVID 19: A radioimmunological perspective. J Can Res Ther [serial online] 2021 [cited 2021 Sep 23];17:295-302. Available from: https://www.cancerjournal.net/text.asp?2021/17/2/295/318105




 > Introduction Top


The first case of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was reported in early December of 2019[1] in Wuhan, China. Since then, COVID-19-associated respiratory syndrome has now become a global pandemic. As of September 8, 2020, there are 28 million cases globally in more than 200 countries, and it has resulted in 896,867 deaths worldwide. A variable mortality rate of 0.5%–11% has been reported in various studies, with an intensive care unit (ICU) mortality rate as high as 26% in Italy.[2],[3] Initial genomic sequencing classified it as a beta coronavirus, similar to Middle eastern respiratory syndrome (MERS) virus and the SARS virus.[4] There is 88% similarity to the sequence of two bat-derived SARS-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21, and about 50% identity to the MERS-CoV when compared to the novel beta-CoV.[4] As SARS-CoV-2 is similar to other beta-corona viruses, it requires the angiotensin-converting enzyme 2 (ACE2) as a receptor to enter the cells.[5] Expression of ACE 2 inhibitors is seen in vascular endothelial cells, the renal tubular epithelium, Leydig cells in the testes, lung, gastrointestinal tract, and heart. SARS-CoV-2 most commonly affects the lungs, and in the majority of the cases, the disease is self-limiting. Still, in 20% of the cases, this disease becomes severe and results in acute respiratory distress syndrome or sepsis due to a cytokine storm.[6] This pathophysiology is similar to what happens in the severe cases of SARS-CoV and MERS-CoV infection.[7] Currently, there is no substantial or definitive evidence from randomized clinical trials (RCTs) that any treatment improves outcomes in patients with confirmed SARS-CoV-2.[8] More than 500 active clinical treatment trials are underway, and currently more than 10 clinical trials are ongoing, that are using low-dose radiotherapy (LDRT) for COVID 19. Only one of them is taking place in India NCT04394793.[9] This review provides a radioimmunological rationale for the use of low-dose radiation (LDR) as a potential treatment for severe cases infected with SARS-CoV-2.


 > Immunopathogenesis of Severe Acute Respiratory Syndrome Coronavirus 2 Top


SARS-CoV-2 might elicit a biphasic immune response.[10] The initial phase is the milder one where the body elicits an adaptive immune response to clear the infection. Once this primary resistance fails, the virus spreads by destroying the affected tissue, especially in the organs with high ACE2 expression, namely, intestine and kidneys.[10] The immune effector cells are the main cells mediating the pathway of innate inflammation, in the damaged cells of the lungs. Their uncontrolled activation leads to a cytokine storm, which results in ARDS, multi-organ failure, and death similar to what is observed in severe cases SARS and MERS infection.[11],[12],[13],[14],[15] One of the primary mechanism of cytokine release syndrome (CRS) is an unrestrained systemic inflammatory response, arising from the release of copious amounts of pro-inflammatory cytokines (interleukin [IL]-6, interferon [IFN]-g, IL-1b, IL-12, IFN-a, IL-18, transforming growth factor [TGF]-b, IL-33, tumor necrosis factor [TNF]-a, etc.,) and chemokines (CCL3, CCL5, CCL2 CXCL8, CXCL10, CXCL9).[13] The same has recently been validated by a couple of clinical studies. The first study by Chen et al.[16] studied various immune parameters in the blood of severe and moderate cases of SARS-CoV-2. All the tests were done as a baseline investigation, and a correlation with the prognosis was made. As SARS-CoV-2 infection tends to primarily affect the CD8, CD4, and CD3 T cells, there is a decrease in their counts. Furthermore, there is a significant increase in macrophage-related M1 phenotype induced proinflammatory cytokines, particularly IL-6, and TNF-α, in the majority of severe cases. IL-6 levels are increased in both moderate and severe cases. The CD4+ and CD8+ T cells were found to be below the lower limit of normal in the majority of the patients, but the number was lesser in severe cases and this change was statistically significant. Interestingly the proportion of B cells was significantly higher in severe cases. In another study by He et al.,[17] dynamic testing of the immune status was done for 204 patients. It was observed that lymphocyte subsets count, CD3+ T cell, CD4+ T cell, CD8+ T cell, B cell (CD19+) and natural killer (NK) cell (CD16 + 56+), were significantly lower in severe group as compared to the nonsevere group (P < 0.001). The level of the T lymphocytes changes from baseline to recovery or death. T lymphocytes kept reducing from baseline in the severe group, and this was statistically significant. However, in the group that recovered, T lymphocyte levels began to increase after about 15-days of treatment and finally returned to the normal level after 25-days. It was also found that the value of T lymphocytes in the deceased subgroup of severe patients continued to fall until death. In this study the B cell and NK cell number were not significantly different between improved and deceased subgroup of severe cases. For the humoral immune function, levels of immunoglobulin G and complement C3 were statistically higher in the severe group and so were IL-4 and TNF alpha. The elevation of pro inflammatory cytokines indicate that SARS-CoV-2 stimulate the T helper type 1 (Th)-1 response.[18] All these changes might happen without the presence of a significant viral load in the patient. But this hypothesis remains controversial as a retrospective study, found an association between persistence of the virus and disease outcome.[19]

In short SARS-CoV-2 affects the immune system and results in a decrease in CD3, CD4 and CD8 T cells. It also increases the proinflammatory cytokine levels mainly IL-4, TNF alpha and IL 6 and it is this dysregulation of proinflammatory cytokines and inactivation of T cells that leads to ARDS, sepsis and death. Similar results have also been published by Chen et al.[20] and Wang et al.[21] where ICU patients had higher plasma levels of cytokines including IL-6, IL-2, IL-7, granulocyte-colony stimulating factor (G-CSF), IFN-γ-inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1 alpha, and TNF-α. This increase in inflammatory cytokines implies an occurrence of CRS. A summary of the immune changes is summarized in [Table 1]. It is this uncontrolled immune response that results in the damage of various organs ultimately leading to death.
Table 1: Immune changes in severe COVID 19 patients

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Hyaluronic acid (HA) is a jelly-like substance that is known to be associated with ARDS.[27] It is accumulation in the lung has also been seen in severe infections of SARS and MERS. A similar jelly-like substance has also been seen in the lung autopsy specimens of COVID 19 patients, although its exact nature is yet to be verified. It's been postulated that the accumulation of HA in the alveolar-capillary membrane prevents normal oxygen transfer and results in hypoxemia.


 > Role of Low-Dose Radiation in Viral or Atypical Pneumonia Top


Historically, LDR has been used for treating both complicated and uncomplicated pneumonia since 1905. Musser and Edsall published the first use of radiation in the treatment of pneumonia.[28] A remarkably favorable influence of a small dose of X-rays was found in four cases of delayed resolution of lobar pneumonia. Similar observations were made by Quimby.[29] Impressed by the rapid response of these patients to irradiation in 10 cases, they even testified that “no pathologic process in the body responds quicker to an X-ray exposure than the nonresolution following pneumonia.” A few review articles provide a detail account of the use of radiation in pneumonia and in other inflammatory conditions.[30],[31],[32] A summary of studies extracted from the reviews is shown in [Table 2]. Most of the older studies used resolution of the symptoms as an end point and considered that as a cure, few utilized resolutions of the chest X-ray opacity. With this definition, radiation achieved a cure rate of approximately 80%–85%[33] in 863 treated cases. However, this includes a mixture of pneumococcal and mixed pneumonia. Few studies have documented the use of LDRT for viral pneumonia; most of the cases in these studies failed from sulpha drug treatment or serum therapy and were then referred for radiation therapy. Even then, 315 cases out of the 352 were cured of the disease. This amounts to a success rate of close to 90%. At that time, the clinicians were unable to find the reason behind such an excellent clinical response of viral pneumonia to LDR and had then postulated a possible role of the immune system.[34] Even though radiation achieved good clinical results, it slowly fell out of favour after the arrival of penicillin. Due to lack of administrative support in the medical community or widespread scientific standing, X-ray therapy could not become a part of system wide public health measures to treat pneumonia.[35] A major draw back in these old studies is that all the patients were treated with a Kilovoltage unit with only a single field. This would result in an inferior dose distribution when compared to the current megavoltage units. Unavailability of sophisticated dosimetry and treatment planning systems in the past would certainly cast a doubt on the actual dose received by the patient. These technical uncertainties can be very well addressed by the modern technology of the current era.
Table 2: Historical treatment of atypical or viral pneumonia with low dose radiotherapy

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 > Radioimmunology of Low-Dose Radiotherapy Top


Effect of low-dose radiotherapy on cytokines and chemokines

A detailed account of radiobiological mechanisms of LDR is provided by Rödel et al.[36],[37] Briefly, LDR has an anti-inflammatory effect, which is mediated by the suppression of IL-6, IL-4, and induction of IL-10. Arenas et al.[38] showed that LDRT results in an increase in the levels of TGF-Beta1 and decreases leukocyte adhesion in intestinal venules. Cytokines such as IL-1 and TNF alpha are pro-inflammatory in nature and are involved in CRS. These cytokines are also elevated in severe cases of COVID 19, as mentioned above. TGF beta1 inhibits the action of TNF alpha and IL-1 and may prove to be protective in the event of a CRS. Schaue et al. experiments showed that LDRT results in a decrease of iNOS expression and an increase in HSP-70 and HO-1 expression. There is a reduction by 25%–40% in adhesion of the PBMC to the endothelial cells from the baseline to 4 and 24 h after. Interestingly, a decrease in adhesion is not observed 12 h after LDRT. This indicates a two-phase kinetics of adhesion.[39] LDRT also induces apoptosis, down-regulation of proinflammatory cytokines (TNF-a and IL-1) and up-regulation of the anti-inflammatory cytokine IL10. These apoptotic cells trigger an immunosuppressive pathway, mediated by the thrombospondin receptor (CD36), which is believed to be in the anti-inflammatory effect of LDRT. Kern et al. described that PBMC treated with LDRT shows a discontinuous dose dependence of apoptosis induction with a plateau or peak between 0.3 and 0.7 Gy.[40] Chemokines have a major role in the continuation of the inflammatory state by making the pathogen “tasty,” This results in the diapedesis of polymorphonuclear leukocytes to the inflammatory locus. Rödel et al. showed that LDRT reduces the expression of chemokine CCL20 and this is another mechanism by which LDRT exerts its anti inflammatory benefit.

Effect of low-dose radiotherapy on natural killer cells

In vitro and in vivo studies indicate that LDRT may enhance the activity of NK cells by stimulating cell proliferation and promoting their cytotoxic function, thereby enhancing the cytotoxicity of those cells which have earlier been exposed to cytokines.[41],[42],[43] This effect may increase the anti viral immune response of the body.[44]

Effect of low-dose radiotherapy on macrophages

Macrophages are polarized into two phenotypes, M1 (pro inflammatory) and M2 (anti-inflammatory).[45] Several studies have shown that a particular radiation dose can polarize macrophages to either M1 or M2 phenotype.[46],[47] A dose of <1 Gy creates an anti-inflammatory state due to polarization of the M2 macrophages and a dose >1 Gy results in an M1 polarization creating a pro-inflammatory microenvironment.[48] Irradiation of LPS/IFNg – first, activates M2 macrophages with 0.3–1.25 Gy thereby decreasing NO-production and iNOS protein expression without affecting iNOS mRNA expression or TNF-a synthesis.[49] Second, LDRT (0.3–0.6 Gy) significantly reduces oxidative burst activity (release reactive oxygen species or ROS) and superoxide production of the M1 macrophages. Schaue et al., therefore, concluded that a diminished release of ROS might also contribute to the local therapeutic effect of LDRT.[50]

The effect of low-dose radiotherapy on T and B cells

Multiple experiments have shown that LDRT could increase the subpopulations and enhance the cytotoxic activity of CD4+ and CD8+ T cells.[51],[52],[53],[54],[55] LDRT also has the potential to proliferate B lymphoblasts by increasing the levels of cyclin E and cyclin-dependent kinase 2, as well as elevation of the phosphorylation level of Ikaros protein, a member of the zinc finger-containing transcription factor family.[56] LDRT unlike other immunosuppressive agents, promotes the activity of T cells and while reducing the levels of pro inflammatory cytokines. It is also believed that LDRT can lead to a polarization from a Th1 to Th2 response which is in turn leads to the production of anti-inflammatory cytokines.[57]

Effect of low-dose radiotherapy on hyaluronic acid

HA has shown to be degraded by ultraviolet light and fast electrons. A significant drop in intrinsic viscosity of HA of large molecular weight can be observed with 50cGy.[58],[59] This effect of gamma radiation may possibly reduce the viscosity of HA which gets accumulated in the alveolar capillary membrane and improve oxygenation.

To summarize, LDRTs effect on the immune system is complex and is modulatory in nature. On the one hand, LDRT could enhance the cytotoxicity of NK cells, promote the differentiation into M1 macrophages (M1phenotype), and activate Th1 cells and B cells. This leads to the enhancement of the immune response, which can be applied in the treatment of malignant tumours. On the other hand, LDRT exerts an anti-inflammatory response by promoting the transformation of macrophages into a M2 phenotype, decreasing the expression of L selectin, and decreasing IL-4, IL-6, TNF alpha and increasing IL-10 levels. By promoting the activity of cytotoxic T cells which shows that LRT is immunomodulatory, and this action might be beneficial in the treatment of COVID related cytokine storm and may enhance viral clearance.[60],[61] [Table 3] provides a summary of the radiobiological and radioimmunological mechanisms of the anti-inflammatory effects of LDRT.[62],[63] [Table 4] provides a list of in vitro LDRT studies (Requested from Arenas M with permission).
Table 3: Summary of radioimmunological immune mechanism of low dose radiotherapy (adapted from the work of Arenas M)

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Table 4: Summary of in vitro low dose radiotherapy studies (requested from Arenas M with permission)

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 > Possible Complications of Low-Dose Radiotherapy Top


The dose in LDRT, which might be used in the treatment of SARS-CoV-2 will be between 0.3 and 0.7 Gy. At this dosage, acute symptomatic radiation reactions for various organs have not been reported. In the Chernobyl report 1995, it was observed that no deaths occurred during the 1st week of exposure, when the dose received was <2 Gy. The major risk with any radiation, is the development of secondary cancers. It has been well-reviewed and reported that the incidence of secondary cancers mostly leukemia was 0.5%, as found among the high radiation zone of Hiroshima atomic bomb survivors.[64] The dose threshold for leukemia in the UNSCEAR report (1958) for the same was found to be 500 mSv.[65] In the survivors of Hodgkin lymphomas, the long term incidence of second neoplasms was 7% at 15 years after the initial diagnosis.[66] For the childhood cancer survivor group, the cumulative incidence of second neoplasms was 7.9% at 30 years from primary cancer diagnosis.[67] This demonstrates a significant secondary malignancy risk for this population. Kirsch et al.[68] in their review have pointed that the risks of radiation-induced lung and breast cancer for a 25-year-old woman exposed to 1 Gy of whole thorax radiation may be as high as 5.9% and 5.5%, respectively and for a 25-year-old man, the risk of a radiation-induced esophageal cancer may be as high as 0.32%. This risk declines steeply with age.

Luckily, Severe COVID 19 affects mainly the older population rather than children and the risk of second cancers due to radiation, in old adults or older patients is not well established. In another hypothesis, genomic animal and human data has shown that LDRT, upto 0.3 Gy, stimulates each component of the protective systems of antioxidant prevention, enzymatic repair, and immunologic and apoptotic removal of DNA alterations. Its been postulated that LDR upto 0.2 Gy, might be protective for cancer as it activates the immune system, so that the free radical damage can be repaired.[33] To summarize, there is a dose threshold of 1.1 Gy for the development of leukemia, which results in an incidence of 0.5%. The dose used for LDRT to treat COVID 19 cases will be much lower.

The radiation community is currently divided in the possible use of LDRT for COVID 19. Schaue et al.[69] believe that there is a slim chance that LDRT can ameliorate the effects of the cytokine storm in COVID 19. Kefayat and Ghahremani[70] believe that the timing of LDRT is important. LDRT given during a wrong time can result in immunosuppression causing a possible delayed viral clearance. They also believe that LDRT is a good anti inflammatory remedy but whether it can supress the cytokine storm in doubtful. Another possible point to consider is the high mutation rate of RNA in the SARS CoV 2 virus, which might be increased with double-strand breaks induced by LDRT.[71],[72],[73]

Even after these reservations, the preliminary results of an ongoing trial of LDRT for COVID 19 were recently published. It was found that, with a response rate of 80%, whole-lung irradiation in a single fraction of 0.5 Gy had encouraging results in oxygen-dependent patients with COVID-19 pneumonia.[74]


 > Current Available Treatment for Severe Acute Respiratory Syndrome Coronavirus 2 Top


Chloroquine and hydroxychloroquine appear to block viral entry into cells by inhibiting glycosylation of host receptors, proteolytic processing, and endosomal acidification. These agents also have immunomodulatory effects through attenuation of cytokine production and inhibition of autophagy and lysosomal activity in host cells.[75] Currently, there are several RCTs of both chloroquine and hydroxychloroquine examining their role in COVID-19 treatment.

Lopinavir/Ritonavir in vitro activity against other novel coronaviruses via inhibition of 3-chymotrypsin-like protease was seen[76] and as a result it was used for the treatment of SARS and MERS. Clinical studies in SARS were associated with reduced mortality and intubation rates, but their retrospective, observational nature tprevents definitive conclusions.[77] An open label randomized trial conducted by Cao et al.[78] to trea COVID 19 has just been published but has not shown promising results. Although additional RCTs of lopinavir/ritonavir are ongoing, the current data suggest a limited role for lopinavir/ritonavir in COVID-19 treatment.

Oseltamivir has also been used[79] but currently it has no role in the management of COVID-19 once influenza has been excluded. Remdesivir is also a promising therapy and trials are underway to evaluate its efficacy in the setting of COVID 19. It has a broad spectrum of activity with promising EC50 and EC90[8],[80],[81],[82] NCT04292899, NCT04292730, NCT04257656, NCT04252664, NCT04280705 Corticosteroids are used by many centres to manage CRS in sick COVID 19 patients but they can suppress cell-mediated immunity, promote the decrease of T lymphocyte and delay the virus clearance,[83] therefore, the use of glucocorticoid should be used cautiously in severe patients with COVID-19 pneumonia. Toclizumab an IL-6 monoclonal antibody has shown some positive results in the treatment of COVID-19 cases in the setting of CRS[84] where 91% of patients reported improvement in symptoms. [Table 5] provides a list of immune changes in severe COVID-19 patients along with possible remedies.
Table 5: Treatment strategies that target and can possibly target the immune changes of COVID 19

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 > Timing of Low-Dose Radiotherapy in COVID 19 Top


Even though theoretically, LDRT appears to be promising in the management of cytokine storm in COVID 19, a question regarding the timing of Radiotherapy (RT) still exists. Pathogenesis of COVID 19 is marked by four phases, incubation, symptomatic, early pulmonary and late pulmonary phase. In general, the incubation period can last to a maximum of 14 days beyond which the symptomatic phase starts which can last about 5–7 days. The early pulmonary phase generally starts from day 11 and can continue till day 14.[26],[85] This phase is marked by reduced viral replication and an increase in the bodys immune response and thrombophilia. Patients start having shortness of breath and mild hypoxia during this stage. This stage in non survivors is also associated with an increase in D Dimer levels.[19] After day 14 from the infection, the late pulmonary phase starts which is marked clinically by progressive hypoxia, CRS and immune dysregulation. We believe that the anti inflammatory effect of LDRT might be useful in the early and late pulmonary phases of COVID-19 and the maximum therapeutic ratio might be there in the early pulmonary phase. Future studies with LDRT should incorporate the use of immune markers, cytokine levels and D Dimer levels for patient selection for LDRT.


 > Conclusion Top


To summarize, multiple drugs are being tested to treat SARS-CoV-2 but till now we have no conclusive evidence for any drug which can successfully treat severe cases of COVID 19. Many of these drugs are being given Food and Drug Administration clearances for compassionate use, some of them do not have in vitro activity against SARS-CoV-2, yet clinical trials are taking place to treat this menace. LDR to the lungs has historically demonstrated robust activity against viral pneumonia with a high cure rate. Immunologically also LDRT is able to induce IL-10 and TGF beta to enhance the immunosuppressive effects and is also able to increase the CD4 and CD8 count. Hypothetically LDRT appears to negate the effects of CRS through immunomodulation. It appears that LDRT can be beneficial in the management of COVID-19 cases, but the risk of secondary neoplasms exist. Therefore, clinical trials investigating the efficacy of whole lung LDRT in older patients would pose minimal risk in the development of secondary cancers while possibly alleviating the ill effects of COVID-19 pneumonia. This in turn could reduce COVID-19-related strains on the health-care systems.[86]

Acknowledgment

I would like to thank Dr. Kritika Chopra for her help to edit this article.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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