Effectiveness of low-dose radiation therapy to improve mortality in coronavirus disease (COVID-19): A Systematic Review and Meta-Analysis

doi:10.21203/rs.3.rs-1988827/v1

Download PDF

Systematic Review

Effectiveness of low-dose radiation therapy to improve mortality in coronavirus disease (COVID-19): A Systematic Review and Meta-Analysis

https://doi.org/10.21203/rs.3.rs-1988827/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Background

Before antibiotics were available, X-ray therapy was used to treat pneumonia, but its effectiveness is unknown. It was not fully understood how low-dose radiation could reduce inflammation in early attempts to treat pneumonia with X-rays. Exposure to low-dose radiation therapy (LDRT) may activate anti-inflammatory molecules such as TGF-b1 and IL-10. This systematic review and meta-analysis aimed to determine whether LDRT effectively treats COVID-19-associated pneumonia.

Methods

This study followed the PRISMA guidelines (Principles for Reporting Systematic Reviews and Meta-Analyses). A search was conducted on Google Scholar and PubMed for articles published before June 12, 2022. The Newcastle–Ottawa Scale (NOS) was used to evaluate the included research quality.

Results

In these studies, patients were given lung radiation at doses ranging from 0.5 to 1.5 Gy. Except for one study, all clinical, radiological, and survival outcomes improved. The study showed that whole-lung radiation at doses of 0.5–1.5 Gy was beneficial to patients with COVID-19-associated pneumonia who were oxygen-dependent. In these studies, the reported SR was 59% (95% CI, 44–75%).

Conclusions

LDRT has the potential to be a viable therapy option, although large-scale randomized trials are necessary, particularly in the elderly, who are more at risk of mortality from COVID-19.

Radiation therapy

COVID-19

Pneumonia. Review

SARS-CoV-2 causes COVID-19 (Meziani et al.; Mortazavi et al. 2021). China's Wuhan, the capital of Hubei province, was initially affected by this illness in December 2019 (Moreno-Olmedo et al. 2021a; Mortazavi et al. 2021). Some symptoms are associated with COVID-19, including fever, cough, anosmia, and myalgia. Some people experience symptoms such as dyspnea, coughing, and high temperatures (Jackson et al.; Arenas et al. 2021). Before antibiotics were available, X-ray therapy was used to treat pneumonia, but its effectiveness is unknown. Calabrese and Dhavan (Calabrese and Dhawan 2013) reviewed 15 studies in 2013 that involved 863 cases of severe pneumonia caused by various pathogens. Two trials using low-dose kilovoltage X-rays showed excellent results, with reduced mortality (Calabrese and Dhawan 2013). A total of 56 patients with suspected viral pneumonia were treated with X-rays using 130–150 kVp in 1943(BAYLIN et al. 194). It was not fully understood how low-dose radiation could reduce inflammation in early attempts to treat pneumonia with X-rays (Moreno-Olmedo et al. 2021a; Mortazavi et al. 2021). UNSCEAR defines low-dose radiation as radiation below 100 mGy (Hess et al. 2020; Mortazavi et al. 2020; Ahmadikia et al. 2021). "Low-dose radiation" refers to the radiation used for medical purposes rather than protection. Dose and rate are important factors in the link between irradiation and inflammation. Exposure to low-dose radiation therapy (LDRT) may activate anti-inflammatory molecules such as TGF-b1 and IL-10 (Rödel et al. 2007; Rodel et al. 2012). LDRT has been used to reduce inflammation for decades (Glatzel et al. 2004; Ameri et al. 2021a; Lumniczky et al. 2021a; Hess et al. 2021).

The LDRT may also reduce oxidative stress, which is linked to thrombosis (Violi and Pignatelli 2012). An LDRT study reported that 1.0 Gy of radiation was most effective in mice with mild lung damage caused by bleomycin. LDRT has shown potential immunological benefits as a treatment for COVID-19-associated pneumonia (Jackson et al.). It has been reported that LDRT has decreased mortality in some cases but not in others, depending on the study (Jackson et al.; Ameri et al. 2020, 2021a; Ortiz et al. 2022). We cannot conclude that LDRT has a positive or negative effect based on the results of one study. This systematic review and meta-analysis aimed to determine the Effectiveness of low-dose radiation therapy to improve mortality in coronavirus disease (COVID-19).

Search strategy

This study followed the PRISMA guidelines (Principles for Reporting Systematic Reviews and Meta-Analyses) (Moher et al. 2015). A search was conducted on Google Scholar and PubMed for articles published on June 12, 2022. The search terms included (2019-nCoV OR Coronavirus OR COVID-19 OR SARS-CoV-2 OR 2019-nCoV OR Wuhan Coronavirus AND low dose radiation therapy OR LDRT OR whole lung irradiation OR lung irradiation OR radiotherapy). To identify additional studies, we manually searched relevant reviews and original papers. Two reviewers independently performed these steps.

Inclusion and exclusion criteria

Inclusion criteria for this research are: (1) All original publications on the therapeutic efficacy of LDRT for COVID-19. (2) in English; (3) between January 2020 and January 2022; and Criteria for exclusion: (1) Reviews, summaries of meetings, or debates; (2) Inadequate data information; (3) Duplicate publications.

Quality assessment and data extraction

Two investigators performed the data extraction and quality assessment independently, and disagreements were resolved through discussion or consultation with a third reviewer (Terrin et al. 2005; Peters et al. 2008; Sterne et al. 2016a, 2019a, b). The Newcastle–Ottawa Scale (NOS) was used to evaluate the included research quality. Three aspects of the NOS are selection, comparability, and exposure. Studies with a NOS score of 5 were considered suitable for publication. The greater the NOS score, the better the quality of the book; the following data were extracted: publication data, which included the first Authors, Year, Study type, Country of study, Control Group, Treatment group, Average Age (year), Follow-up time, Photon energy (MV), Absorb dose in PTV (Gy), CTV, Number of discharged patients, Number of dead patients, Median number of days in the hospital, Median time to LD-RT (day). Both univariate and multivariate analyses were available, so we chose the multivariate analysis. It was estimated using data from original publications in cases where the Event Rate was not immediately provided.

Statistical analysis

The meta-analysis was performed in Stata12.0 (Stata Corp, College Station, Texas). The Event Rate (ER) and 95 percent confidence interval (CI) were estimated for each included study. ER and 95 percent CI were calculated to assess the relationship between LDRT and COVID-19 pneumonitis decrease. Cochran Q and I2 statistics were used to determine heterogeneity. A random-effects model was used instead of fixed-effects models for moderate heterogeneity (I2 50%). Statistical significance was defined as a p-value less than 0.05. Egger linear regression was used to measure publication bias. P values less than .05 indicate publication bias (Terrin et al. 2005; Peters et al. 2008; Sterne et al. 2016b, a, 2019b).

Study selection

(Fig. 1) illustrates the search process and the final section of relevant studies. We found 3475 studies in PubMed and Google Scholar based on reference lists. The titles and abstracts of 1074 references were screened after duplicates were removed. Following the first screening based on abstracts or titles, 776 articles were excluded, leaving 298 for full-text review. In the current analysis, 9 articles were eligible for inclusion after 289 articles were excluded for violating inclusion criteria.

The meta-analysis flow diagram in PRISMA

There were three studies done in Spain, two in the United States, two in Iran, and one in Switzerland. Radiotherapy-related COVID-19 cases have been reported in studies. Additionally, patients with COVID-19 who recently underwent radiotherapy were also evaluated. In (Table 1), we summarize the characteristics of LDRTs. NOS scores for all articles are greater than 5.

Reported SR of Patients with Severe COVID-19 treated with LDRT

In nine studies (Ameri et al. 2020, 2021b; Khan et al. 2020; Hess et al. 2020; Moreno-Olmedo et al. 2021b; Papachristofilou et al. 2021; Sanmamed et al. 2021; Sharma et al. 2021; Arenas et al. 2021), LDRT and survival events in rats were evaluated. According to the included studies, 56 people died, and 74 survived. In all the studies, whole-lung LDRT was shown to prevent or delay invasive respiratory support. Except for one study (Papachristofilou et al. 2021), all survival rates and clinical findings of about 60% of patients improved. There is still a need for more preclinical research to determine whether LDRT can delay or prevent the need for invasive respiratory support. COVID-19 study conducted in Switzerland reported that LDRT did not improve clinical outcomes in critically ill patients with pneumonia requiring mechanical ventilation [25]. In these studies, the reported SR was 59% (95% CI, 44-75%). (Fig. 2) shows the Forest plot of the reported case survival rates.

Publication bias

There was no evidence of publication bias based on Classic fail-safe N, and visual inspection of the funnel plot. (Fig. 3)

We conducted a systematic review and meta-analysis to estimate the SR for COVID-19 patients treated with LDRT. Our opinion is that the lack of a good systematic review and meta-analysis has led to unjustified radiation exposure of COVID-19 patients worldwide.

LDRT for COVID-19 was supplemented with radiotherapy that is easily accessible worldwide (Sterne et al. 2011; Bhandari et al. 2020; Zhang et al. 2020; Papachristofilou et al. 2021; Ameri et al. 2021b). Several studies have shown that LDRT can control pneumonia (Ameri et al. 2020, 2021b; Khan et al. 2020; Hess et al. 2020; Moreno-Olmedo et al. 2021b; Papachristofilou et al. 2021; Sanmamed et al. 2021; Sharma et al. 2021; Arenas et al. 2021). At 0.5 and 1 Gy radiation doses, LDRT can significantly affect lung macrophages. The exposure of human lung macrophages to LDR can decrease IFNγ production and increase IL-10 secretion(Rödel et al. 2007). As a result of LDRT, human lung macrophages can produce more IL-10(Rödel et al. 2007). In contrast, LDRT decreases the percentage of human lung macrophages that produce IL-6. Regardless of sex and age, doses less than 1 Gy can provide an acceptable lifetime attributable risk (LAR) of radiation-induced cancer (Trott and Kamprad 2006; Shuryak et al. 2021).

According to a recent paper (Lumniczky et al. 2021b), doses up to 1 Gy have anti-inflammatory effects, while doses above 1 Gy cause pro-inflammatory effects.

LDRT with doses up to 250 mGy was first proposed by Ghadimi-Moghadam(Ghadimi-Moghadam et al. 2020) in March 2020. Eventually, researchers worldwide increased radiation doses in competition with one another. The Emory University Hospital (Hess et al. 2021) used 1.5 Gy, while Ameri et al. used 0.5 Gy and 1.0 Gy (Ameri et al. 2020, 2021a).

A recent randomized trial involving 22 elderly COVID-19 patients with pneumonia and mechanical ventilation showed that whole-lung LDRT was ineffective in improving clinical outcomes (Papachristofilou et al. 2021).

Consequently, the doses used in the clinical trials conducted by Emory University Hospital may have been unjustified (Hess et al. 2020). LDRT might not be effective in Switzerland because of the relatively high dose used (Papachristofilou et al. 2021). Furthermore, this point clarifies why Ameri et al. finally admitted that 0.5 Gy was more effective than 1.0 Gy in their trial.

The use of doses less than 0.5 Gy not only increases the therapeutic effects of LDRT and maintains the risks at an acceptable level but also decreases the cancer risk to a reasonable level. In their trials, Ameri et al., Papachristofilou et al., and Sanmamed et al. used doses of 1 Gy.

Except for one study, all clinical, radiological, and survival outcomes improved. The study showed that whole-lung radiation at doses of 0.5–1.5 Gy was beneficial to patients with COVID-19-associated pneumonia who were oxygen-dependent. The results of our study did not find any evidence of acute radiation toxicity.

Our meta-analysis found an association between LDRT and a higher chance of survival among COVID-19 patients. The calculated survival rate was 0.59 (95% CI, 0.44:0.75). Thus, we can demonstrate that LDRT significantly impacts the recovery of severe COVID-19 patients. Moreover, we found that a dose above 1 increases mortality risk.

This study has several limitations, which should be considered when interpreting its results. First, the study has a small sample size, which may result in underpowered results. Second, the interval delimitations are not precise and uniform due to a lack of information in the included study. Finally, the quality of different studies was different, which could cause bias.

LDRT has the potential to be a viable therapy option, although large-scale randomized trials are necessary, particularly in the elderly, who are more at risk of mortality from COVID-19. Researchers should focus on determining optimal radiation dosages and dose rates and ensuring staff and patient safety. The efficacy of this therapy strategy will be better assessed through long-term patient follow-up.

Conflicts of interest: The authors declare that they have no conflicts of interest.

Financial support: None

Author Contribution Statement S.S., Z.M., and S.B. contributed to the design and implementation of the research, to the analysis of the results and to the writing of the manuscript.

S.B, F.G.A, contributed in the conception of the work, and in the writing,

A.B, M.R. contributed in the writing

Ahmadikia K, Hashemi SJ, Khodavaisy S, et al (2021) The double-edged sword of systemic corticosteroid therapy in viral pneumonia: A case report and comparative review of influenza-associated mucormycosis versus COVID-19 associated mucormycosis. Mycoses 64:798–808
Ameri A, Ameri P, Rahnama N, et al (2021a) Low-dose whole-lung irradiation for COVID-19 pneumonia: Final results of a pilot study. International Journal of Radiation Oncology* Biology* Physics 109:859–866
Ameri A, Ameri P, Rahnama N, et al (2021b) Low-Dose Whole-Lung Irradiation for COVID-19 Pneumonia: Final Results of a Pilot Study. International Journal of Radiation Oncology Biology Physics 109:859–866. https://doi.org/10.1016/j.ijrobp.2020.11.065
Ameri A, Rahnama N, Bozorgmehr R, et al (2020) Low-dose whole-lung irradiation for COVID-19 pneumonia: short course results. International Journal of Radiation Oncology* Biology* Physics 108:1134–1139
Arenas M, Algara M, de Febrer G, et al (2021) Could pulmonary low-dose radiation therapy be an alternative treatment for patients with COVID-19 pneumonia? Preliminary results of a multicenter SEOR-GICOR nonrandomized prospective trial (IPACOVID trial). Strahlentherapie und Onkologie 197:1010–1020. https://doi.org/10.1007/s00066-021-01803-3
BAYLIN GJ, DUBIN IN, GOBBEL WG (1946) The effect of roentgen therapy on experimental virus pneumonia; on feline virus pneumonia. Am J Roentgenol Radium Ther 55:
Bhandari S, Rankawat G, Bagarhatta M, et al (2020) Clinico-Radiological Evaluation and Correlation of CT Chest Images with Progress of Disease in COVID-19 Patients. The journal of the association of physicians of india 68:34–42
Calabrese EJ, Dhawan G (2013) How radiotherapy was historically used to treat pneumonia: could it be useful today? Yale J Biol Med 86:555
Ghadimi-Moghadam A, Haghani M, Bevelacqua JJ, et al (2020) Covid-19 tragic pandemic: Concerns over unintentional “directed accelerated evolution” of novel coronavirus (sars-cov-2) and introducing a modified treatment method for ards. Journal of Biomedical Physics and Engineering 10:. https://doi.org/10.31661/jbpe.v0i0.2003-1085
Glatzel M, Frohlich D, Basecke S, Krauss A (2004) Analgesic radiotherapy for osteoarthrosis of digital joints and rhizarthrosis. In: Radiotherapy and Oncology. ELSEVIER SCI IRELAND LTD CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON …, pp S24–S25
Hess CB, Buchwald ZS, Stokes W, et al (2020) Low-dose whole-lung radiation for COVID-19 pneumonia: Planned day 7 interim analysis of a registered clinical trial. Cancer 126:5109–5113. https://doi.org/10.1002/cncr.33130
Hess CB, Eng TY, Nasti TH, et al (2021) Whole-lung low-dose radiation therapy (LD-RT) for non-intubated oxygen-dependent patients with COVID-19-related pneumonia receiving dexamethasone and/or remdesevir. Radiotherapy and Oncology 165:20–31. https://doi.org/10.1016/j.radonc.2021.10.003
Jackson MR, Stevenson K, Chahal SK, et al Low-dose lung radiotherapy for COVID-19 lung disease: a preclinical efficacy study in a bleomycin model of pneumonitis. https://doi.org/10.1101/2021.03.03.433704
Khan M, Hess CB, Buchwald ZS, et al (2020) Low-Dose Whole-Lung Radiation for COVID-19 Pneumonia. https://doi.org/10.1101/2020.07.11.20147793
Lumniczky K, Impens N, Armengol G, et al (2021a) Low dose ionizing radiation effects on the immune system. Environment International 149:106212. https://doi.org/https://doi.org/10.1016/j.envint.2020.106212
Lumniczky K, Impens N, Armengol G, et al (2021b) Low dose ionizing radiation effects on the immune system. Environment International 149:106212. https://doi.org/https://doi.org/10.1016/j.envint.2020.106212
Meziani L, Robert C, Classe M, et al Low doses of radiation increase the immunosuppressive profile of lung macrophages during viral infection and pneumonia. https://doi.org/10.1101/2020.05.11.077651
Moher D, Shamseer L, Clarke M, et al (2015) Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 4:1–9
Moreno-Olmedo E, Suárez-Gironzini V, Pérez M, et al (2021a) COVID-19 pneumonia treated with ultra-low doses of radiotherapy (ULTRA-COVID study): a single institution report of two cases. Strahlentherapie und Onkologie 197:429–437. https://doi.org/10.1007/s00066-020-01743-4
Moreno-Olmedo E, Suárez-Gironzini V, Pérez M, et al (2021b) COVID-19 pneumonia treated with ultra-low doses of radiotherapy (ULTRA-COVID study): a single institution report of two cases. Strahlentherapie und Onkologie 197:429–437. https://doi.org/10.1007/s00066-020-01743-4
Mortazavi A, Mortazavi SMJ, Sihver L (2020) Selective Pressure-Free Treatments for COVID-19. Radiation 1:18–32. https://doi.org/10.3390/radiation1010003
Mortazavi SMJ, Shams SF, Mohammadi S, et al (2021) Low-Dose Radiation Therapy for COVID-19: A Systematic Review. Radiation 1:234–249. https://doi.org/10.3390/radiation1030020
Ortiz CS, Hernández D, Trujillo C, et al (2022) The clinical efficacy of low-dose whole-lung irradiation in moderate-to-severe COVID-19 pneumonia: RTMX-20 trial. Radiotherapy and Oncology 166:133–136
Papachristofilou A, Finazzi T, Blum A, et al (2021) Low-dose radiation therapy for severe COVID-19 pneumonia: a randomized double-blind study. International Journal of Radiation Oncology* Biology* Physics 110:1274–1282
Peters JL, Sutton AJ, Jones DR, et al (2008) Contour-enhanced meta-analysis funnel plots help distinguish publication bias from other causes of asymmetry. J Clin Epidemiol 61:991–996
Rodel F, Frey B, Gaipl U, et al (2012) Modulation of Inflammatory Immune Reactions by Low-Dose Ionizing Radiation: Molecular Mechanisms and Clinical Application. Current Medicinal Chemistry 19:. https://doi.org/10.2174/092986712800099866
Rödel F, Keilholz L, Herrmann M, et al (2007) Radiobiological mechanisms in inflammatory diseases of low-dose radiation therapy. International Journal of Radiation Biology 83:. https://doi.org/10.1080/09553000701317358
Sanmamed N, Alcantara P, Cerezo E, et al (2021) Low-dose radiation therapy in the management of coronavirus disease 2019 (COVID-19) pneumonia (LOWRAD-Cov19): Preliminary report. International Journal of Radiation Oncology* Biology* Physics 109:880–885
Sharma DN, Guleria R, Wig N, et al (2021) Low-dose radiation therapy for COVID-19 pneumonia: a pilot study. The British Journal of Radiology 94:20210187
Shuryak I, Kachnic LA, Brenner DJ (2021) Lung cancer and heart disease risks associated with low-dose pulmonary radiotherapy to COVID-19 patients with different background risks. International Journal of Radiation Oncology* Biology* Physics 111:233–239
Sterne JAC, Hernán MA, Reeves BC, et al (2016a) ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. bmj 355:
Sterne JAC, Hernán MA, Reeves BC, et al (2016b) ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. bmj 355:
Sterne JAC, Savović J, Page MJ, et al (2019a) RoB 2: a revised tool for assessing risk of bias in randomised trials. bmj 366:
Sterne JAC, Savović J, Page MJ, et al (2019b) RoB 2: a revised tool for assessing risk of bias in randomised trials. bmj 366:
Sterne JAC, Sutton AJ, Ioannidis JPA, et al (2011) Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. Bmj 343:
Terrin N, Schmid CH, Lau J (2005) In an empirical evaluation of the funnel plot, researchers could not visually identify publication bias. J Clin Epidemiol 58:894–901
Trott K-R, Kamprad F (2006) Estimation of Cancer Risks from Radiotherapyof Benign Diseases. Strahlentherapie und Onkologie 182:431–436. https://doi.org/10.1007/s00066-006-1542-8
Violi F, Pignatelli P (2012) Platelet oxidative stress and thrombosis. Thrombosis Research 129
Zhang J, Meng G, Li W, et al (2020) Relationship of chest CT score with clinical characteristics of 108 patients hospitalized with COVID-19 in Wuhan, China. Respir Res 21:1–11

Table 1 is available in the Supplementary Files section.

No competing interests reported.

Download PDF

Version 1

posted

You are reading this latest preprint version

Effectiveness of low-dose radiation therapy to improve mortality in coronavirus disease (COVID-19): A Systematic Review and Meta-Analysis

Status:

Version 1

Abstract

Background

Methods

Results

Conclusions

Figures

Introduction

Methods

Results

Discussion

Conclusion

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1