key: cord-0958076-n9m4ms9x
authors: huang, l.; li, q.; Sayed, S. Z. A.; Mohammad, N.; chen, b.; Iftikhar, M. A.; Xie, L.; Hu, J.; chen, h.
title: Ultra-short-wave diathermy shortens the course of moderate and severe COVID-19: a randomized controlled trial
date: 2021-02-01
journal: nan
DOI: 10.1101/2021.01.28.21250163
sha: 0e3d98e5786d3850df23f054395d1f8350f67ec4
doc_id: 958076
cord_uid: n9m4ms9x

Background COVID-19 patients have severe lung injury. The USWD could play a supportive role in relieving lung injury and enhance clinical recovery. Methods and findings The design was a single-center, evaluator blinded; 2-arm parallel design superiority randomized controlled clinical trial. Moderate and severe coronavirus-2 (SARS-CoV-2) positive patients with acute respiratory syndrome, Fifty patients were randomized (USWD, 25; control, 25) between February 18/2020 and April 20/2020. There were male 22 (44.0%) and female 28 (56.0%) with mean (SD) age 53(10.69). Time to clinical recovery (USWD 36.84 vs control 43.56, P = 0.03) was significantly shortened with a between-group difference of 6.72 days. The median SIRS score at day 28 was 0 (0-1) in the USWD group, while 0 (0-2) in the control group ( P = 0.011), and the seven-point scale at day 28 showed significant improvement in the USWD group (P = 0.003). While the rate of RNA negative conversion at day 7 (2/25 vs 7/25, p=0.054), day 14 (14/25 vs 18/25 p=0.239), day 21 (22/25 vs 18/25 p=0.279), and day 28 (25/25 vs 22/25 p=0.730) did not show statistical significance. Similarly, no significant differences were observed in the AI-assisted CT analysis. No treatment-associated adverse events or worsening of pulmonary fibrosis were found. Conclusions Among the 50 moderate and severe COVID-19 patients, the USWD as an adjunctive therapy to standard therapy could shorten the recovery course and enhance clinical improvement without aggravating pulmonary fibrosis. However, the study did not report statistical significance in the negative conversion rates of SARS-CoV-2 nucleic acid due to the small sample size and early termination, the findings of this study are limited.

The outbreak of the COVID-19 pandemic has prompted efforts to manage the threat to the wellbeing of populations worldwide. 1, 2, 3, 4 The second wave of the COVID-19 epidemic has emerged in some countries 5 , however to date, no effective treatment for COVID-19 has been confirmed.

In response to the critical demand for high-quality clinical guidance at the extreme point of the outbreak in China, guidelines have been published to clarify the role that physical therapy can play in managing COVID-19. 6, 7, 8, 9 Suggestions have also been made that supportive therapies such as ultra-short-wave diathermy (USWD) perform functions to boost the immune responses and inhibit inflammation. 10, 11, 12, 13 Although USWD has been used in the field of physical therapy and rehabilitation for many decades 14, 15, 16 , the evidence for its application as part of COVID-19 management is debatable. 10 During the outbreak of severe acute respiratory syndrome (SARS), USWD was employed widely by rehabilitation professionals in China, to reduce pneumonia inflammation. Zhang group evaluated the efficacy of both USWD and conventional therapy in 38 SARS patients, where USWD was used as an adjuvant treatment in addition to standard therapy. The study concluded that using USWD could accelerate recovery and reduced the lengths of hospital stay. 17 Although the pathogens of COVID-19 and SARS are both coronaviruses, the clinical manifestation, death rate, and pathological changes especially fibrosis are different. High-quality evidence to recommend the application of USWD in pulmonary conditions is still lacking, while there is a complete absence of evidence on the use of USWD in COVID-19 because of its novel nature. The scant evidence for the USWD safety and efficacy makes its application in clinical settings questionable. Herein we designed a randomized controlled trial to investigate the clinical efficacy and safety of USWD in managing COVID-2019.

This single-center, evaluator-blinded, 2-arm (1:1 ratio) parallel design superiority randomized (Figure 1 ). Participants were recruited from February 18/2020 through April 20/2020. Before randomization, written and verbal informed consent was taken from every patient and an informative essay that clearly shows the risks and the supposed benefits accompanying the participation was provided to each patient.

Patients of all genders with an age range from 18 to 65 diagnosed positive for SARS-CoV-2 by nasopharyngeal swabs were recruited from the Tongji Hospital of Huazhong University of Science and Technology (Wuhan, China). Patients meeting all of the following criteria were included: (1) those aged 18 to 65 years, (2) Positive SARS-CoV-2 nucleic acid test by nasopharyngeal swabs, (3) Chest CT showed multiple patchy ground-glass shadows or other A Priori sample size calculation was performed with GPower 3.1(software (Düsseldorf, Nordrhein-Westfalen, Germany) based on the mean values for our primary variable, length of recovery from symptoms, from a previously published SARS study. 17 We estimated that with an 80% power, 5% two-sided type I error rate, and an effect size of 0.72, the enrolment of 62 participants would be enough to detect a statistically significant between-group difference of 6.6 days in the length of recovery from symptom. Moreover, 4 participants were added to the total sample size to manage the expected 5% dropouts, making the total sample size 66 (each group 33 participants).

The experimental group (USWD group) received the nationally recommended standard medical treatment in addition to the USWD. The USWD was performed through the application of the ultra-short-wave therapy electrodes on the anterior and posterior parts of the trunk for 10 minutes, twice a day for 12 consecutive days. The Ultra short wave therapy machine specifications and details are as follows: ultrashort-wave electrizers (Dajia DL-C-C, factory no ： BE1003094, A.C.power 220V, 50Hz, 700VA, Shantou Medical Equipment Factory co., Ltd, China, Guangdong). We applied USWD in continuous mode with a frequency of 27.12MHz and power of 200w, with these parameters the patient would feel a mild or no heat. On the other hand, the control group only received the nationally recommended standard treatment. Moreover, the testing of USWD machine output, disinfection of the machine and electrodes, wearing masks, protective suit, and testing the patient's skin sensation before the intervention were done to ensure the treatment safety.

The primary outcome measures were the length of recovery from symptoms measured by 7category ordinal, and SIRS scale (Appendix in supplement 1), and a negative conversion rate of the SARS-CoV-2 nucleic acid test by RT-PCR. The secondary outcome measures included vital signs assessment, treatment adverse effects, Computed Tomography (CT) imaging and AIassisted analysis, the length of stay in the hospital, and blood test including Complete blood count (CBC), Creatine kinase (CK), Lactate dehydrogenase (LDH), serum glutamic pyruvic transaminase (SGPT), serum glutamic oxaloacetic transaminase (SGOT), and international normalized ratio (INR). The primary and secondary variables were measured at baseline, after 7 days, 14 days, 21 days, and 28 days of treatment. However, in this trial, we didn't perform CT scans very frequently due to radiation hazards.

The criteria of clinical recovery were (1) Temperature returned to normal for more than 3 days: (2) . Respiratory symptoms (such as cough, and breathing difficulty) improved significantly; (3).

Lung CT imaging showed a significant decrease in acute exudative lesions; (4). Two consecutive negative nucleic acid tests by nasopharyngeal swabs (the sampling interval was at least 24 hours).

The data collection forms developed for this trial were consisting of medical history forms for taking a relevant medical history, Case Report Form (CRF) to collect treatment-related data, adverse events form to collect data regarding any adverse event happening during the trial. All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted February 1, 2021. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

We planned to enroll 66 participants according to our protocol, however, due to the unavailability of COVID-19 patients later in our hospital, we had to close our study early on 50 patients. All the statistical analyses were carried out using SPSS (Statistical Package for social sciences, version 25.0) and Graphpad Prism 8. Intention to treat analysis was used. Data normality was assessed with the Kolmogorov Smirnov and Shapiro-Wilk tests. Continuous variables are presented as mean (SD) in case of the normal distribution of data or median (IQR) in case of non-normal distribution, while the categorical variables were presented as count (%).

Descriptive statistics (mean, frequencies, and percentages) were calculated for demographic variables, primary, and secondary variables of the study. Baseline and post-intervention comparison between the USWD and control group was performed using independent samples ttest and Mann-Whitney statistics based on normality results of the data. The proportions of categorical variables were compared using Fischer's exact test /chi-square tests. Chi-square test was used for the evaluation of the Seven-point scale, and Mann-Whitney test was used in the SIRS scale (treated as ordinal scales). A Difference-in-difference (D-in-D) analysis was used for analyzing the AI-assisted CT scans data. Patients who failed to reach the negative conversion of SARS-CoV-2 by the cut-off date of the analysis were considered as right-censored at the last visit date. All the patients were treated after completion of follow-up duration (28 days).

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The copyright holder for this preprint this version posted February 1, 2021. ; https://doi.org/10.1101/2021.01.28.21250163 doi: medRxiv preprint Among 50 enrolled participants, there were 22 (44.0%) male and 28 (56.0%) female participants.

The mean (SD) age was 53±10.69. Most of the participants were non-smokers (86.0%), and 34.0% were having comorbid conditions, with the most common coexisting diseases as diabetes (22%), hypertension (20%), cardiovascular diseases (8%). Fever (90%), breathing difficulty (56%), dry cough (50%), diarrhea (34%), and fatigue (24%) were the top 5 common symptoms reported on presentation. Moreover, it is worth noting that most patients were having a dry cough (50%), while very few were having productive cough (14% only). CT findings showed more severe patients in the USWD group (52%) than in the control group (28%) but the baseline difference was not significant (Table 1) .

The baseline clinical characteristics of all participants are given in Table 2 . Both of the groups were balanced at the baseline with significant differences in demographic data, clinical features, laboratory tests, and CT scan of the lung.

The time to clinical recovery (days) in the USWD group was significantly shortened than the control group (36.84±9.93 vs 43.56±12.15, P = 0.037). The SARS-CoV-2 nucleic acid test negative conversion rate showed no significant difference between the USWD and control group at day 7 (P = 0.054), day14 (P = 0.239), day 21 (P = 0.279), and day 28 (P = 0.730) ( Table 3) .

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The SIRS scores which reflect the patient's present clinical condition (including heart and respiratory rate, mean arterial pressure, SpO2 %, body temperature, white blood cells, and level of consciousness) showed a statistically significant difference between the two groups at day 7 (P = 0.030), day14 (P = 0.002), day 21 (P = 0.003), and day 28 (P = 0.011). Likewise, the sevenpoint scale after intervention at day 14, day 21, day 28 also showed significance (P = 0.046, 0.001, 0.003), however, the difference at day 7 was insignificant (P = 0.371). These findings reveal the therapeutic efficacy of USWD in COVID-19 patients (Table 3) .

The CT images in figures 2 and 3 depict the treatment progress of moderate and severe cases from both groups, through the entire interventional period. Artificial intelligence (AI) aided CT images (AI-aided CT) analysis system was adopted for quantitative analysis of the infected lung area proportion and volume before and after treatment. The mean values for different CT scan parameters for the total population before and after treatment are given in Table 4 . The lower lung had the worst infective conditions, on CT both groups improved in infected lung area proportion and volume. A comparison of AI-assisted quantitative analysis of CT scan images before and after treatment between the control and USWD group showed no significant differences (Table 5 and Figure 3 ). All rights reserved. No reuse allowed without permission.

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No serious AEs, deaths, permanent disability, neoplasia, or empyrosis cases were registered during the trial. In the USWD group 14/15 cases of pulmonary fibrosis recovered, one had no change in fibrosis, similarly in the control group 16/18 cases of fibrosis recovered, and two had no changes in fibrosis. No worsening of pulmonary fibrosis was observed in both groups. Out of 50, 22 in USWD and 22 in the control group were having complications such as abnormal liver function test (LFTs) (52% vs 48%, P = 0.777), electrolyte imbalance (32% vs 44%, P = 0.382), hyperfibrinogenemia (44% vs 48%, P =0.777), and mild anemia (32% vs 52%, P = 0.152). The blood routine investigation showed all parameters in almost equal and in the normal range in both groups. However, the WBCs were significantly low in the USWD group (USWD 5.51±1.38 vs control 6.56±1.97 ), on the other hand, the median monocyte count was significantly higher in USWD (USWD group 8.92 (2.20) vs control group 7.10 (1.15)), the difference was statistically significant but of uncertain clinical importance.

To our knowledge, this is the first randomized clinical trial investigating the USWD treatment of (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The USWD enhances fibroblast activity. 18 Fibroblasts are oxygen-sensitive 19 , and it is theorized that the synergistic activity of USWD and high oxygen environment in COVID-19 patients could cause or aggravate pulmonary fibrosis. Interestingly we did not observe any worsening of pulmonary fibrosis in this study. On the contrary, fibrosis was alleviated in 14 out of 15 patients in USWD and 16 out of 18 patients in the control group after treatment.

In this study, we didn't find that USWD enhances the SARS-CoV-2 negative conversion rate, suggesting that USWD exerts therapeutic function doesn't depend on the direct antivirus effect. On the other hand, although within the normal range, the USWD had raised the number of monocytes which is an important component of the body immune system, at the same time All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted February 1, 2021. Lung CT scan is providing supportive assistance in the early diagnosis and recovery monitoring of lung lesions in COVID-19. The AI-aided CT analysis could be used to identify the severity of patients and triage scientifically 25 , data has proven the reliability of artificial intelligence (AI) AI-aided CT quantification of lung lesion in COVID-19. 26 We attempted to do AI-aided CT analysis in order to compare the treatment effects on lung involvement between the two groups in our study. The CT quantitative analysis showed no significant differences in USWD and control group, however, in most of the patients, the fibrosis observed before treatment was recovered (USW=14/15 recovered, control group 16/18 recovered). The fibrosis recovery result could completely allay the concerns about the safety of USWD. These results show a promising improvement upon using USWD in COVID-19 patients who were hospitalized and needed supplemental oxygen therapy. However, due to the early termination of the study and the small sample size, the findings of this study could be limited.

The USWD as adjunctive therapy to standard therapy shortens the course of moderate and severe COVID-19 without aggravating pulmonary fibrosis. Based on the observed beneficial clinical All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted February 1, 2021. ; effects and no adverse effects of USWD, we recommend the use of USWD as an adjunct to standard therapies in COVID-19 patients. We suggest studies with a larger sample size to confirm our findings and explore the USWD benefits further.

This study had some strengths and limitations. It is the first randomized controlled trial addressing the safety and efficacy of USWD in COVID-19 patients conducted in Tongji Hospital, which is compliant with good clinical practices. However, this study had some limitations, including the early termination, small sample size, and single-center design.

•The USWD as adjunctive therapy shortened the recovery course and improved the clinical status of COVID-19 patients without obviously adverse events.

•Negative SARS-CoV-2 conversion rate didn't improve in the USWD group, suggesting USWD exert therapeutic effect doesn't depend on direct antivirus activity.

HC contributed to the conception, supervision, drafting, and finalizing of the study. LH and QL contributed to designing the CRF, medical history forms development, data collection, and interpretation. Authors SZASH and MN contributed to writing, designing, formatting the manuscript, and compiling and describing the results. Author IA, LX and JH contributed to data analysis. The trial data could be provided by a reasonable request to the corresponding authors (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted February 1, 2021. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted February 1, 2021. ; 

Randomized (n= 50)

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The copyright holder for this preprint this version posted February 1, 2021. ; Fig 2. the outcomes on days 7, 14, 21 and 28 by treatment group. (A) The SARS-CoV-2 nucleic acid negative conversion rate showed no significant difference between the USWD and control group at day 7 (P = 0.054), day14 (P = 0.239), day 21 (P = 0.279), and day 28 (P = 0.730). (B) The clinical condition on SIRS score showed no significant difference on study day 28(P = 0.011), but statistically significant difference on day 7 (P = 0.030), day14 (P = 0.002), day 21 (P = 0.003). C Time to clinical recovery in the USWD group was significantly shortened comparing with control group (P = 0.037). D Clinical status on 7-point ordinal scale on study days 14, 21 and 28 showed significance (P = 0.046, 0.001, 0.003), whereas the difference at day 7 was insignificant (P = 0.371).

:Multiple ground glass opacity(GGO) in both lower lungs, with local thickening and adhesion of bilateral pleura at baseline, whlie GGO significantly absorbed, streak shadows were also lighter, pleural thickening and adhesions were alleviated in week 4. Moderate cases in USWD group(e-h) : Bilateral scattered GGO in the lower lungs, with grid shadows and striae foci visible inside, obvious near the pleura, and local pleural adhesions were obsersed at baseline, while bilateral scattered GGO showed lightened with a significant decrease in week4. Bilateral local pleural slight adhesion. Severe cases in control group(i-l): Bilateral multiple GGO, accompanied by consolidation shadows and a few cord lesions, near the pleura. while GGO still existed with slight alleviation. No obvious changes in consolidation shadows, grid shadows, and cord lesions but some pulmonary fibrosis in week 4. severe cases in USWD group(m-p) Bilateral multiple GGO, and striped shadows, accompanied by bronchial inflation, and local thickening and adhesion of the pleuraat baseline, while obviously alleviated in week 4. Moreover, the bronchial inflation disappeared, along with slightly thickened and adherent pleura, and little pulmonary fibrosis and consolidation. 

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(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted February 1, 2021. ; 

Systemic Inflammatory Response scale (SIRS) is used for evaluation of clinical improvement based on heart rate, mean arterial pressure(MAP mmHg), respiratory rate/min, blood oxygen saturation (SpO2 %), body temperature (℃), white blood cells (WBC *10 9 /L), blood glucose (mmol/L) and level of consciousness (Aware/awake, Lethargy or irritability, shallow coma, coma, brain death). All these parameters, except" Level of consciousness" are assigned a score from 0 to 4 based on the actual values recorded from the patient corresponding to the range of values in the table below. For the level of consciousness: Aware/awake (0), Lethargy or irritability (1), Shallow coma (2), coma (3), brain death (4). The 7-category ordinal The 7-category or 7-point ordinal scale is consisting of seven separate categories. The categories range from 1-7, 7 corresponds to death; category 6 patients need ICU hospitalization, require ECMO and invasive mechanical ventilation; category 5 patients need ICU hospitalization but do not require ECMO and/or invasive mechanical ventilation; category 4 patients are non-ICU hospitalized patients, requiring supplemental oxygen; category 3 patients are also non-ICU hospitalized patients, but they do not require supplemental oxygen; category 2 patients are not hospitalized, but unable to resume normal activities; category 1, not hospitalized with the resumption of normal activities.

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