Study design
This study is a prospective RCT that will recruit participants with a diagnosis of viral pneumonia from Shanghai Sixth People’s Hospital. This manuscript is written according to the Standard Protocol Items for Randomized Trials (SPIRIT) guidelines18. Ethics committee of Shanghai Sixth People’s Hospital has approved this study (approval number 2022-005-(1)).
Patient and public involvement
The study was done without participant involvement. Participants were not invited to comment on the protocol, consulted to select patient-relevant outcomes, or invited to participate in writing or editing this manuscript for readability or accuracy. The final findings will be disseminated to the public via mass media. Participants as a whole will be acknowledged at the end of our publications and presentations.
Participant recruitment
Figure 1 shows the participant flow chart throughout the study. Participants will be recruited from our hospital within 12 months. In addition, recruitment can also be done through other physicians and healthcare professionals. Interested participants can contact the research assistant, who will provide more information about the purpose and protocol of the study, and will conduct an initial eligibility screening by phone or email.
Medical evaluation and enrolment procedure
Eligible participants will undergo laboratory and imaging examinations to confirm the diagnosis of viral pneumonia and to assess eligibility to participate in the study.
Inclusion criteria
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Age 30–80 years old;
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Hospitalized patients had pneumonia-related symptoms, computed tomography (CT) examination met the diagnostic criteria of pneumonia, and the etiology examination suggested a viral origin.
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Patients who can cooperate with various examinations during clinical research;
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The patient participates voluntarily, and he/she or his/her family agrees and signs the informed consent.
Exclusion criteria
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Other types of pneumonia, such as bacterial pneumonia, mycoplasma pneumonia, falling accumulation pneumonia, etc.;
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Patients with bronchiectasis or lung malignancies;
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Patients with chest skin injury who cannot wear the LIPUS device;
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Pregnant and breastfeeding women;
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Contraindications to the therapeutic ultrasonography (US), including dermatological conditions, local abnormal sensations in the chest or back, epilepsy, etc;
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Patients with mental illness or unable to communicate normally with staff.
Following the medical evaluation, the research assistant will meet with the eligible participants and sign a written informed consent. Investigators will collect demographic variables for all patients prior to treatment, including age, gender, height, weight, chest circumference, lifestyle (smoking and drinking), and medical history. Participants will also be asked questions about when the disease was diagnosed, how long symptoms lasted, and what treatments they had received. Other information such as occupation, work environment, and physical activity habits (hours of exercise per week, intensity of exercise) will also be collected.
Randomization and blinding
Participants will be randomized into three groups (LIPUS group; external control group; self-control group) in a ratio of 1:1:1 using a computer-generated randomization sequence. Research assistants not involved in clinical care or outcome assessment will prepare sequentially numbered, opaque, sealed envelopes based on the randomization list and ensure the confidentiality and independence of the allocation data. When appropriate, the assistant will open envelopes and ensure the coordination of therapeutic interventions.
Two members of the research team were responsible for recruiting and registering subgroup information. The clinician (W.L.) who performed LIPUS therapy was not blinded to the grouping results and the course of treatment. Clinicians, Y.Z., and W.B., have access to the final trial dataset. Patients and researchers who performed the image processing and statistics were masked to the grouping result.
Intervention
All participants will participate in a health education of approximately 20 minutes led by the research assistant prior to intervention treatment. The content of the education includes the transmission route of viruses, preventive measures, clinical manifestations, general treatment measures, etc. It is recommended that patients maintain hygiene, exercise moderately, drink an appropriate amount of water and have a light diet.
Participants in the test group will be treated with LIPUS (Shanghai, China) for 7 days at a frequency of 700 kHz and an intensity of 500 mW/cm2. 30 minutes each time at 8:00 am and 2:00 pm, with a single stimulation duration of 15 ms and an interval of 5 ms. The irradiation site of LIPUS will be located according to the site of inflammatory exudation on CT images. Operators will fix the wearable LIPUS therapeutic apparatus on the chest and back of the patient and fix the two movable ultrasound probes vertically on the body surface for irradiation therapy.
Participants in the external control group will be given a “null stimulus”, that is, the LIPUS therapeutic apparatus will be worn but the irradiation treatment will not be started. These patients will be treated at the same time of day as the patients in the control group, but neither the patients nor the operators of the LIPUS equipment are aware of the grouping.
Participants in the self-control group will be compared the LIPUS-treated area with the non-treated area in the lungs. First, a CT examination is performed to locate the body surface of the inflammatory exudative area. If the patient has bilateral pulmonary exudative inflammation, LIPUS treatment will be performed on one side of the lung. If the patient has unilateral pulmonary exudative inflammation, the inflammatory area will be divided into the upper and lower areas, and a single-area stimulus will be performed. Then the operator places the ultrasonic probe in a plane where the sound beams are perpendicular to each other, and the frequency and intensity of the probe and irradiation time are the same as above.
All participants will be given routine nutritional support care and symptomatic treatment. We discourage additional treatments to that assigned (that is, not per protocol) during the intervention period. Participants will report all not-per-protocol treatments, such as adding antiviral agents.
Data management
Investigators will collect data on participants' baseline status and daily after randomization. Registered participants will be withdrawn from the study if (1) the participant withdraws his/her consent, and (2) the exclusion criteria is discovered after registration. The date and reason of the suspension will be recorded. Consent to the use of data collected prior to the participant's opt-out will be included in the consent form.
Primary outcome measure
The primary outcome measure will be the difference in the extent of absorption and dissipation of lung inflammation on CT and US images. Results comparisons will be made between the experimental group and the control group, and between the LIPUS-treated and non-treated areas within the self-control group.
Pulmonary inflammation on CT images will be assessed by an expert chest radiologist before and 7 days after treatment to compare the area and volume of inflammation in the target area of the lung, as well as the area absorption rate (AAR) or volume absorption rate (VAR). A Pair software will be used to mark and 3D reconstruct the target area of CT images and record the data of pulmonary inflammation changes. AAR is defined as [(target site inflammation area before treatment - target site inflammation area after treatment)/ target site inflammation area before treatment] × 100 (%). VAR is defined as [(target site inflammation volume before treatment - target site inflammation volume after treatment)/ target site inflammation volume before treatment] × 100 (%).
US will be performed before and 7 days after treatment by sonographers with certified competency in thoracic US, blind to CT findings. Chest scans are performed using the convex 3.5–5 MHz and linear 4–8 MHz probes of the US equipment, with the patient in the sitting position. According to previous studies19, each hemithorax was divided into 4 regions: anterior-lateral sector, posterior sector, upper halve of the third intercostal space, and lower half of the third intercostal space. The evaluation criteria for pulmonary severity classification will be based on the scoring system proposed by Soldati et al20 (0 = regular pleural line, A-lines present; 1 = indented pleural line, focal B lines; 2 = broken pleural line, subpleural consolidations; and 3 = white lung with or without consolidations).
Secondary outcome
Secondary outcome measures will be differences in pulmonary function, blood gas analysis, fingertip arterial oxygen saturation (SaO2) monitoring, serum inflammatory factor levels, the sputum excretion volume, time to the disappearance of pulmonary rales, pneumonia status score, and course of pneumonia.
Pulmonary function Pulmonary function tester will detect vital capacity (VC), forced vital capacity (FVC), forced expiratory volume in one second (FEV1), peak expiratory flow (PEF), and maximal mid-expiratory flow (MMEF) before and 7 days after treatment.
Blood gas analysis and fingertip SaO 2 monitoring The blood gas analyzer will detect the arterial blood partial pressure of oxygen (PaO2), arterial blood carbon dioxide partial pressure (PaCO2), SaO2 and the pH value before and 7 days after treatment. The fingertip photoelectric sensor will also be used to measure the SaO2, and the nursing staff will record the data before treatment, 2 hours after daily treatment, and after the total course of treatment.
Serum inflammatory factor levels Before and 7 days after treatment, nurses will draw 5 ml of fasting venous blood from patients in the morning, and detect the proportion of inflammatory cells and the levels of inflammatory factors such as C-reactive protein (CRP), tumor necrosis factor (TNF)- α、 Interleukin (IL)-1, IL-2, IL-6, IL-8 and procalcitonin (PCT) in peripheral blood.
The sputum excretion volume For patients who can cough spontaneously, nurses will collect and record the amount of sputum that can be excreted in 24 hours, and those with negative pressure suction will use a disposable sputum suction device to record the amount of sputum excreted after each treatment. Collection by trained nurses takes place daily at 8:00 am and ends at 8:00 am the next day. Less than 10ml/24h is a small amount of sputum, 10-150ml/24h is a moderate amount of sputum, and more than 150ml/24h is a large amount of sputum. The color and consistency of the sputum will also be recorded.
Time to the disappearance of pulmonary rales Auscultation of pulmonary rales will be performed by an experienced respiratory physician before the treatment, 2 hours after the daily treatment period, and at the end of the treatment without using auxiliary expectoration equipment.
Pneumonia status score The pneumonia severity index (PSI)21 grading and clinical pulmonary infection score (CPIS)22 will be used for evaluation before treatment and after 7 days of treatment, and the worst value within 24 hours was calculated on the 7th day. The PSI risk level is reduced by two levels to be markedly effective, reduced by one level is effective, and the level is not reduced or increased is invalid. The clinical therapeutic effects of the test group and the control group will be compared by (markedly effective + effective) / total number of cases ×100%.
The course of pneumonia The hospitalization time and the time from the first symptom to discharge of the patients in each group will be counted. The discharge criteria for confirmed patients are: 1) body temperature returned to normal for more than 3 days; 2) respiratory symptoms improved significantly; 3) pulmonary imaging showed significant improvement in acute exudative lesions; 4) two consecutive viral antigen or nucleic acid tests were negative.
Adverse events
All adverse events, which refer to any negative or undesired reaction to the intervention, will be recorded through the patient-reported symptoms and observations by the researcher at each visit. Lung injury and hemorrhage, possibly caused by the US, have been reported in the past with acoustic pressure levels of at least 1 MPa, much higher than the LIPUS parameters proposed here. And to date, no adverse events have been reported with the low-power LIPUS regimen in soft tissue. Potential mild adverse reactions such as mild local swelling, spotting bleeding, enhanced local pain response, and local hyperesthesia or decrease. In case of corresponding symptoms, appropriate symptomatic treatment shall be carried out.
Sample size calculation
Sample size and power calculation are based on the primary outcomes. All sample size calculations assume two-sided analysis with a power of 90% (1-β = 0.90) at a significant level of α = 0.05. The use of therapeutic LIPUS in viral pneumonia has not yet been reported. Based on the time span of this clinical trial and the number of patients expected to meet the inclusion criteria in our hospital, it is estimated that a total of 60 participants will be required. Allowing for an up to 10% dropout rate, we aim to enroll at least 18 participants in each group to complete the study.
Analysis plan
Analysis of baseline characteristics of the three groups will be summarized by appropriate descriptive statistics. Analysis of both the primary and secondary outcomes will be performed blinded to treatment assignment and analyzed on the intention-to-treat approach23, with all randomized participants retaining their original randomization group. If these missing data are judged to be random, multiple imputations of the chained equation will be used to address missing data caused by lost access and non-response.
The primary comparisons for the AAR and VAR on CT images will be performed using Wilcoxon test, and the scores of the degree of absorption on US images will be performed using linear regression. In secondary analyses, repeated measures mixed model24 will also be used to examine the associations between treatments and repeated outcome measures, with treatment term, time, and corresponding baseline values as covariates (age, gender, height, weight, chest circumference, etc). Linear regression will be used for numerical results and logistic/ordinal regression for any categorical outcomes.
Quality assurance/monitoring/management
To standardize staff training and learning procedures such as participant recruitment, result collection, data import, data management, and analysis, a procedural manual, and case report form will be developed according to the protocol to further ensure information protection, data integrity, and consistency for participants. Researchers, physicians, research assistants, outcome assessors, and statisticians are a diverse group of people who are all trained in good clinical practice. Trained project leaders will regularly monitor protocol implementation and data collection to ensure data quality and compliance with the trial protocol.
All data obtained will be stored electronically in a securely accessible database and kept strictly confidential. The data transfer process will encrypt and any personally identifiable information will be deleted. De-identification of the data for analysis was allowed only during the final phase of this trial.