A pilot phase Ib/II study of whole-lung low dose radiation therapy (LDRT) for the treatment of severe COVID-19 pneumonia: First experience from Africa.

BACKGROUND: Low dose radiation therapy (LDRT) has been used for non-malignant conditions since early 1900s based on the ability of single fractions between 50-150 cGy to inhibit cellular proliferation. Given scarcity of resources, poor access to vaccines and medical therapies within low and middle income countries, there is an urgent need to identify other cost-effective alternatives in management of COVID-19 pneumonia. We conducted a pilot phase Ib/II investigator-initiated clinical trial to assess the safety, feasibility, and toxicity of LDRT in patients with severe COVID-19 pneumonia at the Aga Khan University Hospital in Nairobi, Kenya. Additionally, we also assessed clinical benefit in terms of improvement in oxygenation at day 3 following LDRT and the ability to avoid mechanical ventilation at day 7 post LDRT.
METHODS: Patients with both polymerase chain reaction (PCR) and high-resolution computer tomogram (HRCT) confirmed severe COVID-19 pneumonia, not improving on conventional therapy including Dexamethasone and with increasing oxygen requirement were enrolled in the study. Patients on mechanical ventilation were excluded. Eligible patients received a single 100cGy fraction to the whole lung. In the absence of any dose limiting toxicity the study proposed to treat a total of 10 patients. The primary endpoints were to assess the safety/feasibility, and toxicity within the first 24 hours post LDRT. The secondary endpoints were to assess efficacy of LDRT at Day 3, 7, 14 and 28 post LDRT.
RESULTS: Ten patients were treated with LDRT. All (100%) of patients were able to complete LDRT without treatment related SAE within the first 24 hours post treatment. None of the patients treated with LDRT experienced any acute toxicity as defined by change in clinical and respiratory status at 24hr following LDRT. Majority (90%) of patients avoided mechanical ventilation within 7 days of LDRT. Four patients (40%) demonstrated at least 25% improvement in oxygen requirements within 3 days. Six patients (60%) were discharged and remained off oxygen, whereas four progressed and died (1 due to sepsis and 3 in cytokine storm). Median time to discharge (n = 6) was 16.5 days and median time to death (n = 4) was 11.0 days. Patients who ultimately died showed elevated inflammatory markers including Ferritin, CRP and D-dimers as compared to those who were discharged alive.
CONCLUSION: LDRT was feasible, safe and shows promise in the management of severe COVID-19 pneumonia including in patients progressing on conventional systemic treatment. Additional phase II trials are warranted to identify patients most likely to benefit from LDRT.

Introduction

The natural history of COVID-19 pneumonia follows a predictable initial course consisting of initial infection followed by flu like symptoms accompanied by mild fever, body, and joint ache, altered taste and fatigue [1]. Symptoms peak around day 7 followed by a resurgence of immune response resulting in nearly 80% of patients recovering without major sequela [2]. Twenty percent of patients develop progressive shortness of breath and require oxygen therapy to keep pulse oxygen saturation > 94% [3], Remdesivir to halt viral replication [4] and Dexamethasone to ameliorate the enhanced inflammatory response that is felt to contribute to worsening lung function [5]. High-Resolution Computer Tomogram (HRCT) findings reveal patchy inflammation with ground glass pattern and intra alveolar edema. Increasing oxygen requirement is often followed by worsening pulmonary infiltrates and signs and symptoms of acute respiratory distress syndrome (ARDS) often leading to need for mechanical ventilation. The basis of this ARDS is felt to be related to an exuberant cellular inflammatory response lead by release of cytokines by pulmonary macrophages and immune effector cells, resulting in capillary leak syndrome, worsening gas exchange and progression of the patchy ground glass pattern on HRCT [6]. The global mortality rate of patients suffering progressive ARDS and cytokine storm can range between as 13–73% [7]. The anti-IL6R monoclonal antibody Tocilizumab has received regulatory approval and shown to be beneficial to avert intubation, improve survival and discharge from hospital in patients not on mechanical ventilation [8, 9]. Central to the worsening pulmonary picture appears to be an inflammatory response localized to the lung, accompanied by cytokine release leading to a systemic cytokine storm with fever, hypotension, and worsening gas exchange. Given this context it would seem relevant that treatment approaches targeted at inflammatory cells within the lung parenchyma would be useful in preventing the cascade of cytokine release and subsequent relentless progression into a cytokine storm and ARDS [10-12].

Despite initial skepticism, low dose radiation therapy (LDRT) has been successfully used to treat non-malignant conditions since early 1900s [13]. These have included bacterial and viral lobar and bronchopneumonia, as well as interstitial and atypical pneumonia [14]. Additional animal studies have supported these clinical findings and shown that low dose radiation treatment exerts an anti-inflammatory effect that leads to a rapid reversal of clinical symptoms, facilitating disease resolution [15, 16]. The capacity of low doses of radiation to suppress inflammatory responses was most recently successfully reintroduced by the team from Emory University in the treatment of COVID-19 pneumonia [17]. Subsequently several centers have demonstrated comparable positive results depending on the timing of the LDRT intervention [18-21].

The pandemic has unmasked disparities between nations with inequitable distribution of proven therapies for the prevention and treatment of COVID-19 pneumonia. For this reason, Africa needs to develop cost effective and feasible alternatives for the treatment of COVID-19 pneumonia. Currently, access to Radiation therapy within LMIC(Low and Low Middle Income Countries) is limited, but with reliable electricity, increased placement of radiation therapy units, and capability to treat patients, LDRT could potentially as a “drug” one can make on site at low cost.

There is limited data currently predicting the optimal cohort that would most benefit from treatment with LDRT. The optimal timing for the institution of LDRT also remains unknown. Furthermore, inflammatory markers are often poor surrogates when used after the patients have been treated with multiple immunomodulatory drugs.

We conducted a pilot Ib/II investigator-initiated single center trial to assess the safety, feasibility, and toxicity of LDRT in patients with severe COVID-19 pneumonia. In addition, we assessed the improvement in oxygenation at day 3 following LDRT and the ability to avoid mechanical ventilation at day 7 post LDRT.

Materials and methods

The study was approved by the Institutional Ethics and Review Committee at the Aga Khan University Hospital, Nairobi (AKUHN), a tertiary teaching and referral hospital in Kenya (#IERC/2020-111), as well as by the national health regulatory authorities. The trial was registered with the Pan African Clinical Trials Registry(PACTR202009769021840). All study patients were awake and alert and competent to provide consent as deemed by their referring MD. The patient had at least 24h to review the consent form prior to signing consent. All patients provided physical consent following a face to face visit by the investigator and in each case consent was verbally reconfirmed at the time of LDRT administration. An independent witness was present in the room at the time of consenting and this was documented by the witness signature on the consent form.

Objectives

The primary objective of this study was to assess the feasibility, safety, and toxicity of a single dose of LDRT administered to patients with severe COVID-19 pneumonia. The secondary objectives were to determine improvement in oxygen requirement within 3 days following LDRT, ability to avoid mechanical ventilation within 7 days following LDRT and to determine time to discharge/death following LDRT.

Cohort

Patients were eligible if they were age ≥ 18 years with PCR and HRCT confirmed COVID-19 pneumonia in conjunction with characteristic symptoms and need for oxygen to maintain a pulse oximeter saturation of > 94%. Patients had to demonstrate clinical progression following conventional therapy available at the institution. Clinical progression was defined as inability to improve oxygenation despite current treatment, need to increase oxygenation and ventilatory support, and/or declining clinical status with standard of care management. Patients who received immunomodulatory therapy, including Tocilizumab, were only eligible if they had no documented clinical improvement 72 hours after receiving the drug. Exclusion criteria included patients with pre-existing lung comorbidity such as severe COPD, severe uncontrolled asthma, heart failure or concomitant active systemic infection. Patients with pre-existing dependency on supplemental oxygen prior to diagnosis of COVID-19, Pregnant and/or planning to get pregnant within the next 6 months or hemodynamic instability that would preclude transfer to the radiation therapy suite were all excluded from the trial.

All patients received standard of care treatment with medications available within the institution and according to existing best practice at the time. This included oral or intravenous steroids (Dexamethasone/methylprednisolone), systemic antibiotics or Remdesivir. Patients with laboratory and clinical picture compatible with a cytokine storm syndrome received Tocilizumab as part of their treatment. All patients were encouraged to adopt a prone position to improve oxygenation.

Treatment

Eligible patients received a single 100cGy fraction to the whole lung without shielding of the heart. Enrolled patients were transported on a stretcher with portable oxygen (max 15 L/min via nasal cannula or an FiO2 of 0.8 delivered via non-invasive ventilation or high flow oxygen therapy device) from the High Dependency Unit (HDU) or Intensive Care Unit (ICU) to the Radiation therapy (RT) suite using a dedicated patient hallway and elevator.

Where possible we used diagnostic CT scan DICOM images downloaded to our treatment planning system to calculate the monitor units/exposure for treatment. The dedicated CT simulator in the radiotherapy unit was only used if DICOM CT images were not available or unsuitable for calculations. When using the diagnostic CT images, the isocenter was established at the midpoint of the lung volumes. As all the treatments were planned using the Eclipse planning software (V.15), the software automatically corrected for lung density. The treatment was pre-planned to reduce the time spent in the unit. Static portal images were used to ensure proper coverage. The clavicle, as identified on the CT and clinically on the patient, was used as the reference set up point. For most patient the LDRT was administered in supine position, however, for patients rapidly de-saturating while supine we administered LDRT in prone position.

Study patients were treated after all regular patients had completed their treatments and strict institutional COVID-19 guidelines including sterilization of treatment room were observed. We instituted a 10-hour interval between the last COVID patient treated and first regular patient treated on the following day. All staff involved used personal protective equipment (PPE). Patients had their vital signs and pulse oxygen measured every 15 min for a total of 1h, then hourly for 4 hours following LDRT, and subsequently every 4h for the first 24h and then every 6h thereafter.

Assessment

Serial laboratory tests, including complete blood counts (CBC), urea electrolytes & creatinine (UEC), liver function tests (LFT), D dimer, Ferritin and C-reactive protein (CRP) were performed on all patients prior to LDRT and on days 3, 7, 11, 14, 28 and at time of discharge. Disease severity was classified using the ordinal scores into: 1-discharged, 2-non-hospital ICU ward not requiring oxygen, 3-non-hospital ICU ward requiring oxygen, 4-ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen, 5-ICU requiring intubation and mechanical ventilation, 6-ICU, requiring extracorporeal membrane oxygenation (ECMO) or mechanical ventilation and additional organ support (e.g., vasopressors, renal replacement therapy), 7-death. Ordinal scores were tracked on Day 1, 2, 3, 7, 14/28 and/or at discharge. Serums samples collected were stored at -20 degrees Celsius for assessment of inflammatory cytokines at a future time point. The Phase Ib/II pilot study was designed to treat an initial 5 patients followed by review and assessment of feasibility, safety, and toxicity by the DSMC. In the absence of any dose limiting toxicity the study proposed to treat a total of 10 patients. Dose limiting toxicity was defined as a change in clinical and respiratory status within 24 hours post LDRT. Patients were followed for 28 days, or to discharge/death.

Endpoints

Primary Endpoints included safety/feasibility, and toxicity following LDRT. Safety/feasibility was defined as percentage (%) of patients able to complete LDRT without treatment related SAE at 24h following LDRT. Toxicity was defined as the % patients without worsening of vital signs to assess clinical and respiratory status at 24h following LDRT (CTCAE acute toxicity criteria). Secondary Endpoints were defined as follows: % patient able to be weaned off pre-LDRT ventilatory or oxygen support at 3d post LDRT, % patients able to come off (or avoid) mechanical ventilation within 7 days following LDRT and % patients discharged or expired at 14d/28d post LDRT. Hematologic parameters were followed to determine any acute hematologic toxicity following LDRT

Statistical analysis

Descriptive statistics was presented as frequencies and percentages for categorical data whereas medians and interquartile ranges for continuous data. All analyses were performed using the R statistical software and SPSS (IBM Version 20).

Results

We enrolled a total of 10 patients on our study (Table 1). The median age was 59 years (range 42–72). Most of our patients were males (80%) and eighty percent (80%) of our patients were of African descent with 20% of Asian descent. Hypertension followed by diabetes was the commonest comorbidity. All patients had received Dexamethasone prior to study enrollment, 20% had received Remdesivir, and 70% had received Tocilizumab at least 72 hours prior to LDRT with no clinical improvement. Fig 1 shows the CONSORT flow.

Table 1

Baseline characteristics of patients enrolled in the study.

Patient	PT 1	PT 2	PT 3	PT 4	PT 5	PT 6	PT 7	PT 8	PT 9	PT 10
Age	57	66	42	60	42	72	64	58	42	60
Gender	M	F	M	M	M	M	M	F	M	M
Days from Onset of Symptoms to Admission	13	4	2	5	4	6	6	5	4	8
Days from Admission to LDRT	23	10	10	7	4	8	7	13	6	15
Days from symptom onset to LDRT	36	14	12	12	8	14	13	18	10	23
% Lung Involvement on HRCT At Admission	80–90	70–80	50–60	30–40	50–60	10	10	50	40–50	50

Fig 1

Flow diagram of participants.

The clinical parameters of the study patients at the time of LDRT are shown on Table 2.

Table 2

Patient clinical parameters at the time of LDRT.

Patient Study Number	PT 1	PT 2	PT 3	PT 4	PT 5	PT 6	PT 7	PT 8	PT 9	PT 10
Ordinal score at time of LDRT	4	4	4	4	4	4	3	3	4	4
Therapy prior to LDRT:
a. Oxygen	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y
b. Steroids	Y	Y	Y	Y	Y	Y	Y	Y	Y	Y
c. Remdesivir	N	N	N	N	N	N	N	N	Y	Y
d. Tocilizumab	Y	Y	Y	Y	N	N	N	Y	Y	Y
Oxygen parameters at time of LDRT:	HFNC FIO2-0.7	NIV FIO2-0.9	NRM 15L	HFNC FIO2-1.0	NIV FIO2-1.0	FM 10L	HFNC FIO2-1.0	FM 5L	NIV FIO2-1.0	NIV FIO2-0.6
Outcome	A	A	A	A	A	D	D	D	A	D

Abbreviations: Y: Yes; N: No; HFNC: High Flow Nasal Cannula; NIV: Non-Invasive Ventilation; NRM: Non-Rebreather Mask; FM: Face Mask. Ordinal score: 1: discharged, 2: non-hospital ICU ward not requiring oxygen, 3: non-hospital ICU ward requiring oxygen, 4: ICU/non-ICU requiring NIV or high flow nasal cannula, 5: ICU requiring intubation and mechanical ventilation, 6: ICU requiring ECMO/organ support, 7: death; FiO2: fractionated oxygen requirement. A-alive, D-Dead

Seventy percent (70%) of our patients were receiving non-invasive ventilation (NIV) at the time of enrollment with a fractionated oxygen requirement (FiO2) between 60–100%. All patients had a HRCT scan at the time of admission that revealed between 10–90% lung involvement. Median time from symptom onset to admission was 5 days (range: 2–13) and median to time from COVID-19 diagnosis to LDRT was 10 days (range: 5–20). Approximate transfer time from HDU/ICU to the RT suite and back was less than 30 min. Delivery of LDRT, including patient set-up took about 10 minutes. All patients received a single fraction of 100cGy delivered to the whole lung via opposing fields with no shielding of the cardiac silhouette

All patients tolerated LDRT with no appreciable change in the systolic & diastolic blood pressure, pulse rate, temperature, spO2 and respiratory rate during the four hours post-LDRT observation period.

All patients had stable clinical parameters following LDRT and 4 patients had improvement in oxygen requirement by day 3. Six patients had improvement in their oxygen parameters by day 7. Six of 10 patients enrolled on study were discharged home (3 patients were initially discharged on oxygen). Median time to discharge was 16.5 days (range: 4–28). All six patients who were ultimately discharged showed improved inflammatory markers (Ferritin and/or CRP) as well as d-dimers (Fig 3). Four patients died and median time to death was 11 days (range: 5–17) post LDRT. Death was due to sepsis (n = 1) or worsening COVID-19 and ARDS (n = 3). Three of the four patients were intubated on day 9, 8 and 11 post LDRT respectively. The fourth patient declined resuscitation measures. All 4 patients who ultimately died experienced worsening inflammatory markers. The CRP, ferritin and D-dimers for all patients from treatment to discharge or death are depicted in Fig 2. Fig 3 (spaghetti plot) shows the values for the individual patients grouped into alive/discharge or died. There appears to be a trend of a higher baseline and an upward trajectory in CRP, D-dimer and Ferritin for the patients who died as compared to the patients who were alive at the end of the study. The same data provided as a box plot is included as a S1 Fig. Hematological indices were monitored regularly post enrolment and revealed no acute toxicity post treatment (Fig 2).

Fig 3

Spaghetti plots depicting inflammatory and Hematologic parameters for all patients from admission to discharge/death, comparing those who lived versus those who died.

Fig 2

Inflammatory and Hematological parameters for all patients from enrolment to discharge/death.

Discussion

Investigators from Emory University were the first to study the safety of LDRT in COVID-19 pneumonia [17]. Their cohort of 10, primarily elderly COVID-19 PCR positive patients on oxygen per nasal cannula (1.5-6l/min) were treated early in their clinical course (median of 4.5 days’ post hospitalization) using whole lung doses of 1.5 Gy. Compared to historical age matched control patients treated with LDRT demonstrated a significant improvement in the time to recovery, time to discharge and intubation free rates. In December 2021, the same investigators published data from a phase II trial which enrolled 20 patients receiving Dexamethasone and/or Remdesivir to receive a single dose of 1.5Gy. This cohort included younger patients (median age 64.5 years), median time to LDRT was 3 days and the patients were excluded if they required more than 15L of oxygen. They reported a reduction in intubation rates from 32% to 14%, 80% survival of patients treated with LDRT, reduction in time to clinical recovery and time to discharge compared to age matched controls [18]. In contrast, the patients in our study were younger, had higher oxygen requirements with majority being on noninvasive positive pressure ventilation, received LDRT late in their hospitalization (median of 10 days post hospitalization), and a majority had received systemic therapy including Tocilizumab.

Since the initial experience at Emory University, several investigators have conducted similar studies on a diverse set of COVID-19 patients using varying doses of LDRT (Table 3). Sharma et al from the All India Institute of Medical Sciences (AIIMS) enrolled 10 patients (mean: 51 years) with moderate to severe COVID-19 within a median of 3 days following hospital admission and received 70cGy to both lungs [19]. They found a response/ recovery rate of 90% with no evidence of acute toxicity. Hess et al and Ameri et al similarly enrolled 5 patients each and administered LDRT at 1.5Gy and 0.5Gy respectively [17, 20]. Patients were enrolled within 5 days of admission and achieved a response rate approaching 80%. Sanmamed et al had a similar cohort to our study with younger patients but treated much later in their disease course at a median time from admission of 52 days with 30% of their patients having received Tocilizumab. They demonstrated that the 8 surviving patients had declining inflammatory markers (CRP, D-dimers, ferritin) within a week following LDRT [21]. Most of these studies were conducted prior to the broad use of systemic anti-viral therapy (Remdesivir) or anti-inflammatory treatment (Tocilizumab). Only 30% of their patients were discharged home still requiring oxygen likely reflecting a degree of irreversible lung damage following prolong COVID-19 pneumonia associated hospitalization.

Table 3

Summary table with select publications investigating role of LDRT in COVID-19 management.

PUBLICATION	N	MED. AGE	LDRT DOSE	TIME TO LDRT	PRIOR THERAPY	OUTCOME
Hess et al 2020 [17]	5	90	1.5Gy	5 days	Azithromycin	• Alive: 4• Mechanically ventilated: 1
Hess et al 2021[18]	20	64.5	1.5Gy	3 days	Dexamethasone	• Alive: 16• Dead: 4
					Remdesivir
Sharma et al [19]	10	51	70 cGy	3 days	Steroids	• Alive: 9• Dead: 1
Ameri et al [20]	10	75	0.5Gy/1.0Gy	2–4 days	None	• Alive: 5• Dead: 5
Sanmamed et al [21]	9	66	100cGy	52 days	Steroids	• Alive: 8• Dead: 2
					Tocilizumab (n = 3)
					Remdesivir (n = 1)

Our study is the first to be conducted in sub-Saharan Africa. In Kenya, a population of over 47 million has access to a total of only 12 radiation therapy units across 47 counties [22-24]. Our primary objective was to assess the feasibility to safely administer LDRT within a tertiary care university center at a time when majority of the in-patient beds were occupied by patients with severe COVID-19 pneumonia. Transport and treatment from the hospital bed to the radiation therapy unit and back took less than 30 min and all patients tolerated the treatment well with no alteration of clinical parameter over the 24h following LDRT. Our patients were younger (median: 59 years) with a comorbidity profile similar to patients in other trials. However, compared to other trials, our patients were sicker with high oxygen requirement and enrolled after having failed protocol mandated standard of care treatment which included Tocilizumab in 7 of the 10 patients. Patient treated with Tocilizumab had to be observed for lack of response for at least 72h prior to being considered for LDRT, thus further delaying onset of LDRT. While no radiographic imaging was performed prior to LDRT, all our patients demonstrated clinical signs of extensive lung involvement associated with high oxygen requirements necessitating use of non-invasive ventilation [17, 19, 20].

Of the 6 patients who were discharged home (median time 16.5 days (range:4–28), three went home off oxygen while 3 required home oxygen for up to 1–2 months post discharge. We noted a downward trend in inflammatory markers in these patients as compared to patients who died. However, the small sample size and incomplete data points for some patients weakens this observation. Of the 4 patients who died, 2 were Tocilizumab naive but developed cytokine storm at 5 and 7 days post LDRT respectively, necessitating administration of Tocilizumab and subsequently required intubation. Cause of death for the 4 patients (median time to death 11.0 days (range:5–17) was COVID-19 progression for three patients and bacterial sepsis for one patient. Our study ably demonstrated the feasibility and safety of LDRT in the treatment of severe COVID-19 pneumonia in a low resource setting. None of the patients enrolled in our study experienced any dose related acute toxicity. While long term toxicity was beyond the scope this trial none of our living patients have reported pulmonary or hematologic toxicity.

The cost of a single fraction of LDRT at our institution is USD 30 and compares very favorable to the average cost of Tocilizumab at USD 1,300 for a 400 mg dose. The cost for Remdesivir is approx. USD1000 for a 5-day treatment. The average daily charge for an ICU bed for an intubated patient in Kenya is approx. USD 699 [25] and this does not take into account the additional charges for high intensity clinical care of a COVID-19 patient. While efficacy was not the primary endpoint, 60% of our patients were discharged and avoided intubation during a critical phase of their illness. Cost constraints limited out ability to perform HRCT prior to LDRT to determine extent of lung involvement at the time of LDRT. In the limited sample of PAO2/FIO2 (P/F) ratio, we did observe a decline in P/F in patients who did not survive, and this accompanied the worsening inflammatory markers. Whether P/F and inflammatory markers would be predictive parameter to determine selection of patients and timing of LDRT remains to be determined. We were unable to identify a matched control group since patients not enrolled on this trial had incomplete documentation and limited laboratory tests during their hospitalization. In the absence of universal health coverage standard of care is often dependent on affordability.

In the context of a low resource setting where the patient often bears most of the cost of care, the question whether LDRT could be instituted early and would be more cost efficient as opposed to delayed after having exhausted all, often more expensive, conventional options remains to be addressed and will require well designed clinical trials which should include pharmaco-economic endpoints. Future waves of COVID-19 infection may well provide the platform to address these critical questions from the clinical, ethical, and socio-economic standpoint. Randomized studies are currently ongoing to rigorously determine the effectiveness of LDRT. These results if conclusive may allow an objective discussion regarding the early administration of LDRT in a low resource setting where such capability exists. Unfortunately, most sub-Saharan nations do not have the luxury of having sufficient radiation therapy facilities even to meet the needs of their cancer patients. However, if future phase II/III provide evidence for the cost effectiveness of radiation therapy as a treatment for COVID-19 pneumonia, this may add impetuous for low resource nations to see the broader utility of radiation therapy units.

Conclusion

Low dose radiation therapy is a feasible option with no acute toxicity in the management of severe COVID-19 in the setting of a low resource country especially at institutions that have the capability to deliver radiation therapy. Our findings are comparable to what has been observed by other investigators and demonstrates the utility of LDRT in this setting. Given that COVID-19 has yet to be eradicated, and with ongoing new waves of severe infection predicted, the issue of employing LDRT early in the clinical management of severe COVID-19 pneumonia needs to be studied further, especially in a setting where the availability of expensive immune modulating agents is limited or unaffordable.

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Comparison of the inflammatory and hematological parameters between patients that died versus those that survived post LDRT.

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10 Jan 2022

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Reviewer #1: The authors report use of radiation therapy in a phase IB/II as a novel treatment for patients hospitalized with COVID-19 pneumonia. This controversial topic is important because it challenges the current perspective on the use of radiotherapy primarily for neoplastic disease. However, it needs to be reported in a way to adequately address concern and skepticism that ionizing radiation may be ineffective in treating viral pulmonary infection and also may result in acute or late toxicity.

This clinical trial combines assessing the risks of clinical toxicity (phase IB) with the potential to assess clinical benefit (phase II) and has IRB approval. The authors capture a great deal of important clinical information in this report, but it may be helpful to provide more detail in some areas.

Also, many investigators at elite institutions in non-LMICs may not appreciate the value of less conventional treatments given scarcity and poor access to vaccines and expensive medical therapies. It may be worth highlighting this point more in the introduction and discussion.

Given the small size of this trial, most of what we can interpret would be related to acute treatment toxicity. Unlike the Emory study, which reported data compared to similar patients not receiving radiation, this trial can give some sense of how patients fared after LDRT but there will be selection biases on who is included in the trial.

For the abstract:

1. P. 9, line 29: Not sure the remdesevir/tocilizumab information is needed, unless there is room. That doesn’t define the cohort included. Consider discussing tocilizumab use and number of patients in cytokine storm at time of LDRT in Results.

2. P. 9, lines 31-3: Exclude, would favor more information on how safety and clinical endpoints were defined and reported.

3. P. 9 Will discuss below but for results start with defining key aspects of cohort, and it should include reporting some metrics of its acute safety defined in manuscript’s Methods.

4. P.10, lines 44-47: Consider moving the discussion of LMIC limited resources to Introduction, and limit conclusions to acute toxicity, confirm other phase I trials and indicating need for larger phase II/III trials

For the body of the manuscript:

Introduction

The authors correctly discuss some of the pathophysiology of COVID-19 pneumonia and the need for more effective therapies. But there is a reason many of the early reported trials are in LMICs – the pandemic has worsened disparities and even ‘proven’ vaccine and therapies are not shared equitably on a global scale. So alternative strategies may need to be developed.

Radiation therapy may be limited access in LMICs but with reliable electricity and capacity to treat patients, LDRT is a “drug” you can make on site at low cost. The authors may want to emphasize this point a bit more as the value proposition and a rationale for clinical trials that might not seem necessary to some.

Caveat on this point will be that p.12 lines 83-87 capture a limitation in many African nations – poor access to radiotherapy for cancer care already. That is a limitation currently but also an opportunity to address in the Discussion as a potential future rationale for infrastructure investment in radiation facilities that may have value for cancer but also for infection, if phase III trials ultimately demonstrate clinical benefit.

One of the considerations in discussing LDRT for patients cytokine storm is that the anti-inflammatory effects has been hypothesized to work best before the cytokine storm takes place. Because the clinical trial permitted inclusion of patients already in the storm phase receiving tocilizumab, some may perceive this factor as a relative weakness of the trial. Consider framing it in a way you can touch up on it in the Introduction that fits with reporting it and then recognizing it as a potential weakness in the trial. Many are still trying to define if it works and an optimal cohort that benefits.

Methods

1. p. 13 lines 94-103: Discuss trial approval and eligibility (lines 99-103) first, along with exclusion criteria. Was the inclusion permitted based upon no clinical improvement (defined how?) or clinical progression despite dexamethasone and oxygen?Anticipate that many in the clinical oncology/radiation oncology community may have concerns with the inclusion of young patients that may have less need for LDRT (more likely to recover) and more risk of late effects not captured in a phase IB trial. Were there other exclusion criteria other than not on mechanical ventilation (e.g. prior thoracic radiation, prior chemotherapy, others)?

2. It may be helpful to have subsections in italics (or separate paragraphs) for Cohort, Patient Assessment, Treatment (describing the LDRT), defining endpoints and then statistical/analytic methods.

3. P.14, line 114: Some more detail, even if brief, would be helpful. Planned in CT simulator, clinical setup on linear accelerator? Prescribed to isocenter, with or without heterogeneity corrections? Part of assessing feasibility includes the ability to deliver the treatment, so the authors should provide more information for the reader to assess the difficulty of accomplishing the protocol therapy. Lines 128-135 should be with line 114.

4. The authors should provide more detail on safety monitoring to meet the stated primary objective. How do you define/report feasibility? Hematologic toxicity is probably the primary immediate safety risk, given the large amount of bone marrow irradiated and likely including a lot of the spleen. Other trials have reported baseline and trends in hematologic indices, which would be helpful in this case. The authors focus more on vital signs, but presumably hematologic indices can also be reported since they were assessed (line 118).

5. Secondary objectives are reasonable, were these based upon other trials or developed prior to publication of other reports? It’s all a rapidly developing area, but it deserves some clarity here.

Results

1. P. 15, line 146: For a small trial, IQR may be less relevant than full range, especially given some concerns about younger patients treated. Consider reporting total range, not IQR.

2. P.16, line 156 and other tables: label each column by patient (PT) not LD for low dose treatment.

3. P.16, line 156: Table 1 reports performance status at admission as 0. What scale is used, and if admitted presumably ill enough to not be a 0? Consider omitting.

4. P.16, line 156: Table 1 should report time from symptoms to LDRT. Consider moving performance status down in the table and including all temporal related metrics together.

5. Baseline clinical parameters should include hematologic data.

6. P.17, line 162 Table 2: no description of ordinal score in text to permit interpretation.

7. P. 18, lines 172-174 should be with the following paragraph, bringing all the radiation details together.

8. P.19, line 181: Table 3 – Need to include hematologic parameters as priority over inflammatory markers to demonstrate safety first. And consider reporting if toxicity recorded as yes/no or toxicity grade, rather than reporting numeric hematologic indices

9. P.19, lines 181: Table 3 – what is the difference between “–“ and “n/a” – did some labs not get drawn? Patient 3 (LD3) has three empty cells. Needs clearer organization for the reader to interpret.

10. P.19, line 181: Table 3 – patient 10 is listed too early, biased by end outcome (death). Patients should be presented similarly through all Tables.

11. For the inflammatory markers of interest, consider graphing it in a figure, rather than tabular format.

Discussion

1. P. 20, line 199: the Emory study was still essentially still a phase I, so didn’t evaluate effectiveness as much as safety.

2. The authors’ trial included a lot of patients with symptoms for a fairly long time and who required tocilizumab. It may be that the timing of intervention was too late in the pathophysiology of evolving COVID pneumonia. Despite the interest in LDRT, a randomized trial of intubated patients showed no clinical benefit. The authors need to put their trial cohort (younger, more advanced disease than Emory) on spectrum of severity compared to other trials. Part of the learning from these early trials will be defining an optimal cohort for phase II or III trials.

3. The authors should emphasize the safety of LDRT for acute effects, after clearly presenting them in Results. There also needs to be some acknowledgement of late effects as something beyond the scope of this trial that should be included in safety monitoring in future clinical trials.

4. Making the cost argument is valid. Given that treating patients once tocilizumab is needed for cytokine storm, should LDRT be considered earlier in the disease process for trials? It could result in cost savings if LDRT works. If not, why not?

5. P.24, lines 270-272: This point on scarcity of linear accelerators needs to fit coherently from Introduction to Discussion. An opportunity to highlight need for investment to help cancer patients regardless of LDRT trial findings, made stronger if future studies of LDRT show a benefit.

Conclusion

1. Emphasize feasibility and acute safety.

2. Recovery rate is can’t be attributed to LDRT success in line 277.

3. Lines 281-2: recommend being genetic as ‘drug therapy’ rather than specifying immune modulating agents. Other effective drug classes may also be too expensive.

4. Lines 282-3: Final sentence not necessary

Reviewer #2: The authors present the fist study from African content on the use of LD-RT for COVID-19 ARDS. The study adds significant value to the current, limited understanding of the role of LD-RT for COVID-19 ARDS, and it's potential reproducibility of signal across other institutions across the world. Reproducibility of the signal across the world, in a different cohort of patients from Africa adds significant value, and is scientifically a notable accomplishment.

The authors also do a good job on only doing a small, feasibility study of 10 patients and asking the first level, simple safety and potential efficacy signal. Their patient selection of advanced, oxygen dependent patients is also reasonable. They chose patients that were not responding to other therapies and offered them the option of LD-RT and appears to find some clinical benefit. Their results of 6 patients improving is also in line with findings from others. There appears to be a correlation between inflammatory reductions post LD-RT and those patients that improve.

Mino edits:

1) Line 216, page 21. Did you mean to say 100 cGy instead of "gGy"?

2) Can the authors discuss preLD-RT rises in CRP, Ferritin, and other biomarkers and compare them with post LD-RT changes? In the work by Hess et al, they saw signficant rising trends preLD-RT, and then preciptiious drops in some of these post LD-RT. Of these biomarkers, CRP appeared to be the most correlated. Did the authors see this in their own data sets (comparing pre/post LD-RT biomarker changes).. See Hess et al. Radiotherapy and Oncology. Vol 165. December 2021. Pages 20-31.

https://www.sciencedirect.com/science/article/pii/S0167814021087594?dgcid=rss_sd_all

3) The authors can also use the reference by Hess et al to add the comment that LD-RT could potentially have independently benfits patients, despite having gotten Remedesivir and Steroids.

4)The authors can add the following preclinical studies to also support their notion that LD-RT may potentiall help COVID-19 ARDS : (Meziani et al. Int. J. Radiation Oncology Biology and Physicis. Volume 110. Issue 5. P 1283-1294. August 01, 2021). This is preclinical study looking at LD-RT in mouse using three different ARDS models and demonstarted that LD-RT helped convert inflammatory environment into an anti-inflammatory environment.

Second paper to considering adding: Jackson et al. Low Dose Radiotherapy forCOVID-19 Lung Disease: Preclincical Efficay in Bleomycin Model"... 2022. Jan 1; 112(1): 197-211. Int J. Radiation Oncology Biol & Physics. https://pubmed.ncbi.nlm.nih.gov/34478832/

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1 Feb 2022

A Pilot Phase Ib/II Study of Whole-Lung Low Dose Radiation Therapy (LDRT) For the Treatment of Severe COVID-19 Pneumonia: First Experience from Africa

PLOS ONE: Reviewer comments with responses

Reviewer #1

The authors report use of radiation therapy in a phase IB/II as a novel treatment for patients hospitalized with COVID-19 pneumonia. This controversial topic is important because it challenges the current perspective on the use of radiotherapy primarily for neoplastic disease. However, it needs to be reported in a way to adequately address concern and skepticism that ionizing radiation may be ineffective in treating viral pulmonary infection and also may result in acute or late toxicity.

Response:

The reviewers point is well taken since there remains skepticism about the anti-inflammatory and immune modulating role of LDRT and its relevance as a “therapeutic agent” in the treatment of COVID 19 pneumonia. Our work, together with that of others demonstrates the feasibility, lack of acute toxicity and potential benefit of LDRT in this context. We have revised various aspect within our manuscript to reflect the reviewers input.

This clinical trial combines assessing the risks of clinical toxicity (phase IB) with the potential to assess clinical benefit (phase II) and has IRB approval. The authors capture a great deal of important clinical information in this report, but it may be helpful to provide more detail in some areas.

Also, many investigators at elite institutions in non-LMICs may not appreciate the value of less conventional treatments given scarcity and poor access to vaccines and expensive medical therapies. It may be worth highlighting this point more in the introduction and discussion.

Response:

The reviewer’s insight and input is much appreciated and we have revised our manuscript and added some details to incorporate this suggestion.

Refer to P. 5 Line 91-96

Given the small size of this trial, most of what we can interpret would be related to acute treatment toxicity. Unlike the Emory study, which reported data compared to similar patients not receiving radiation, this trial can give some sense of how patients fared after LDRT but there will be selection biases on who is included in the trial.

Response:

As pointed out in our manuscript, our selection criteria were much more stringent than in the Emory study especially since our IRB required that all conventional therapy, including Tocilizumab, be offered and only those patients not improving be eligible to receive LDRT. Unfortunately, in the absence of an electronic medical record and lack of universal health coverage, patients not on study often have incomplete documentation and limited laboratory and diagnostic tests performed. Consequently, it has not been possible to identify an accurately matched control group as was done by the colleagues at Emory. We have added this as a limitation in our discussion.

Please Refer to Page 19 Lines 327-330

For the abstract:

1. P. 9, line 29: Not sure the remdesevir/tocilizumab information is needed, unless there is room. That doesn’t define the cohort included. Consider discussing tocilizumab use and number of patients in cytokine storm at time of LDRT in Results.

Response:

The authors accept this suggestion by the reviewers and have omitted the statement from the abstract.

2. P. 9, lines 31-3: Exclude, would favor more information on how safety and clinical endpoints were defined and reported.

Response:

The authors accept this suggestion by the reviewer and have omitted information relating to IRB approvals. Safety endpoint were defined as acute toxicity within 24h of LDRT and have been outlined in the abstract and methods section.

Refer to P. 2 Line 36-38 & P. 9 Line 181-189

3. P. 9 Will discuss below but for results start with defining key aspects of cohort, and it should include reporting some metrics of its acute safety defined in manuscript’s Methods.

Response:

Our revised manuscript reflects the suggestion made the reviewer. We have included metrics of acute safety from LDRT at the beginning of the Results section in the Abstract.

Refer to P. 3 Line 41-44

4. P.10, lines 44-47: Consider moving the discussion of LMIC limited resources to Introduction, and limit conclusions to acute toxicity, confirm other phase I trials and indicating need for larger phase II/III trials

Response:

We have revised our Discussion as suggested by the reviewer to include the issue of limited resources within the LMIC, highlighted (lack of) acute toxicity and alluded to the need for additional clinical trials to determine the optimal role and timing of LDRT in the treatment of COVID 19 pneumonia. We have also provided additional data (Fig 2 and 3) to demonstrate the importance of inflammatory markers to potentially predict outcome and, underscore the lack of acute hematologic toxicity. We have moved information regarding scarcity of resources and poor access to medical therapies in LMIC to the Background and Introduction. We have also included a statement on the need for further clinical trials to identify patients that are most likely to benefit from LDRT.

Refer to P. 2/3 Line 21-23 & 54-55.

For the body of the manuscript:

Introduction

The authors correctly discuss some of the pathophysiology of COVID-19 pneumonia and the need for more effective therapies. But there is a reason many of the early reported trials are in LMICs – the pandemic has worsened disparities and even ‘proven’ vaccine and therapies are not shared equitably on a global scale. So alternative strategies may need to be developed.

Radiation therapy may be limited access in LMICs but with reliable electricity and capacity to treat patients, LDRT is a “drug” you can make on site at low cost. The authors may want to emphasize this point a bit more as the value proposition and a rationale for clinical trials that might not seem necessary to some.

Response:

The reviewer’s point is well taken and we have included relevant commentary in our Discussion and also revised our Introduction.

Refer to P. 5 lines 91-96

Caveat on this point will be that p.12 lines 83-87 capture a limitation in many African nations – poor access to radiotherapy for cancer care already. That is a limitation currently but also an opportunity to address in the Discussion as a potential future rationale for infrastructure investment in radiation facilities that may have value for cancer but also for infection, if phase III trials ultimately demonstrate clinical benefit.

Response:

The use of LDRT in COVID 19 pneumonia has not been explored in the LMIC. Ours is the first publication to study this modality, which as the reviewer points out may serve as a very affordable modality if more radiation therapy units were available in the LMIC. Sub Saharan Africa only has approx. 200 linear accelerators for a patient population of nearly 1 billion across 54 countries. We hope that peer reviewed publications from the LMIC like ours will demonstrate the value of radiation therapy units beyond they anti-cancer role and consider the capability of radiation therapy units to deliver LDRT, especially in the new normal environment of ongoing Covid 19 surges that have significantly impacted the LMIC. If ongoing trials confirm the effectiveness of LDRT, a single dose of LDRT would be the most cost effective modality, after steroids and oxygen, for the treatment of Covid 19.

Refer to P. 20 Line 332-340

One of the considerations in discussing LDRT for patients cytokine storm is that the anti-inflammatory effects has been hypothesized to work best before the cytokine storm takes place. Because the clinical trial permitted inclusion of patients already in the storm phase receiving tocilizumab, some may perceive this factor as a relative weakness of the trial. Consider framing it in a way you can touch up on it in the Introduction that fits with reporting it and then recognizing it as a potential weakness in the trial. Many are still trying to define if it works and an optimal cohort that benefits.

Response:

The reviewer’s point is well taken in that the treatment to counter the cytokine related pulmonary toxicity is best applied in the early setting of the cytokine storm. Our IRB felt it would be unethical to administer experimental LDRT ahead of FDA approved agents specifically aimed at combating the effects of systemic cytokines e.g. Tocilizumab. Our study was thus to allow patients to receive Tocilizumab and only enroll onto the LDRT study if they demonstrated no benefit. We are hopeful that our manuscript demonstrating the feasibility and lack of acute toxicity would support revisiting the role of LDRT for future COVID 19 waves especially in the LMIC. Various clinical trial strategies could be considered to test early administration of LDRT e.g. Tocilizumab +/- LDRT in patients showing early signs of cytokine storm, or compassionate use of LDRT early following failure of steroid therapy. Future trials may well receive support (or otherwise) from ongoing clinical trials referenced in our manuscript.

Refer to P. 5&6 lines 98-101

Methods

1. p. 13 lines 94-103: Discuss trial approval and eligibility (lines 99-103) first, along with exclusion criteria. Was the inclusion permitted based upon no clinical improvement (defined how?) or clinical progression despite dexamethasone and oxygen?

Response:

Our Method section has been revised to clarify the eligibility criteria

Anticipate that many in the clinical oncology/radiation oncology community may have concerns with the inclusion of young patients that may have less need for LDRT (more likely to recover) and more risk of late effects not captured in a phase IB trial. Were there other exclusion criteria other than not on mechanical ventilation (e.g. prior thoracic radiation, prior chemotherapy, others)?

Response:

The study included ALL patients (regardless of age) who had failed to benefit from conventional therapy and at risk for mechanical ventilation which in the LMIC carried a mortality of nearly 80% at the time. Pre-existing lung morbidity was an exclusion criterion, as were abnormal hematologic parameters below a defined threshold.

This has been revised in the manuscript.

Refer to P. 7 lines 123-135.

2. It may be helpful to have subsections in italics (or separate paragraphs) for Cohort, Patient Assessment, Treatment (describing the LDRT), defining endpoints and then statistical/analytic methods.

Response:

We have included subsections in our revised manuscript

Refer to P. 6-10 lines 117-198.

3. P.14, line 114: Some more detail, even if brief, would be helpful. Planned in CT simulator, clinical setup on linear accelerator? Prescribed to isocenter, with or without heterogeneity corrections? Part of assessing feasibility includes the ability to deliver the treatment, so the authors should provide more information for the reader to assess the difficulty of accomplishing the protocol therapy. Lines 128-135 should be with line 114.

Response:

We have revised our manuscript and provided details regarding radiation planning and attempted to convey the technical difficulties associated with delivery RT in the LMIC under COVID 19 precautions.

Refer to P. 7-8 lines 144-166.

4. The authors should provide more detail on safety monitoring to meet the stated primary objective. How do you define/report feasibility? Hematologic toxicity is probably the primary immediate safety risk, given the large amount of bone marrow irradiated and likely including a lot of the spleen. Other trials have reported baseline and trends in hematologic indices, which would be helpful in this case. The authors focus more on vital signs, but presumably hematologic indices can also be reported since they were assessed (line 118).

Response:

The reviewer’s point is well taken to remind us of the potential for BM toxicity associated with RT. However, single LDRT in the literature has not been shown to cause BM suppression at the doses used. Figures 2 and 3 provide data supporting lack of clinically significant acute bone marrow suppression

Refer to P. 14 lines 234 & 237

5. Secondary objectives are reasonable, were these based upon other trials or developed prior to publication of other reports? It’s all a rapidly developing area, but it deserves some clarity here.

Response:

Secondary endpoints were based on previous studies as well clinically relevant parameters and that could be successfully accomplished within the constraints of the LMIC.

Results

1. P. 15, line 146: For a small trial, IQR may be less relevant than full range, especially given some concerns about younger patients treated. Consider reporting total range, not IQR.

Response:

The reviewer’s point is well taken and we have revised the manuscript to reflect the same.

Refer to P.10 lines 201-202

2. P.16, line 156 and other tables: label each column by patient (PT) not LD for low dose treatment.

Response:

Our revised manuscript has omitted the original Table 3 previously and provided the data in a block diagram (currently Figure 2 &3) which encompasses the relevant information in a more concise and easily readable format. All other tables have been formatted as suggested by the reviewers

3. P.16, line 156: Table 1 reports performance status at admission as 0. What scale is used, and if admitted presumably ill enough to not be a 0? Consider omitting.

Response:

We agree with the reviewers and have omitted the same from Table 1.

4. P.16, line 156: Table 1 should report time from symptoms to LDRT. Consider moving performance status down in the table and including all temporal related metrics together.

Response:

We have revised Table 1 as per the suggestion by the reviewer and have added a column with time from symptom onset to LDRT within the manuscript.

Refer to P. 11 Table 1

5. Baseline clinical parameters should include hematologic data.

Response:

The reviewers point is well taken and we have included two new figures (Figure 2&3) with information regarding the hematological data from the participants in the study.

Refer to P. 14 lines 234 & 237

6. P.17, line 162 Table 2: no description of ordinal score in text to permit interpretation.

Response:

Ordinal score has been defined in the Method section.

Refer to P.8&9 lines 171-176

7. P. 18, lines 172-174 should be with the following paragraph, bringing all the radiation details together.

Response:

We have revised the flow of our revised manuscript as suggested by the reviewer

8. P.19, line 181: Table 3 – Need to include hematologic parameters as priority over inflammatory markers to demonstrate safety first. And consider reporting if toxicity recorded as yes/no or toxicity grade, rather than reporting numeric hematologic indices.

Response:

The reviewers’ point is well taken and we have omitted the table in place of box plots that provide the data in a more meaningful and understandable manner (Fig 2 and 3).

Refer to P. 14 lines 234 & 237

9. P.19, lines 181: Table 3 – what is the difference between “–“ and “n/a” – did some labs not get drawn? Patient 3 (LD3) has three empty cells. Needs clearer organization for the reader to interpret.

Response:

The reviewer’s point is well taken and we have omitted the table in place of box plots that provide the data in a more meaningful and understandable manner.

10. P.19, line 181: Table 3 – patient 10 is listed too early, biased by end outcome (death). Patients should be presented similarly through all Tables.

Response:

Table 3 has been omitted from the manuscript and replaced by box plots that reflect the inflammatory and hematological indices of the patients.

11. For the inflammatory markers of interest, consider graphing it in a figure, rather than tabular format.

Response:

We appreciate the reviewer’s comment and have omitted the table and now included Fig. 2 & 3 which provides the data in a box plot.

Refer to P. 14 lines 234 & 237

Discussion

1. P. 20, line 199: the Emory study was still essentially still a phase I, so didn’t evaluate effectiveness as much as safety.

Response:

We agree with the reviewer that our focus has to be feasibility and toxicity and that the clinical benefit a secondary, albeit important, observation. We have included recently published data from a phase II trial published from Emory in Dec 2020 that evaluated effectiveness.

Refer to P.15 line 259-264

2. The authors’ trial included a lot of patients with symptoms for a fairly long time and who required tocilizumab. It may be that the timing of intervention was too late in the pathophysiology of evolving COVID pneumonia. Despite the interest in LDRT, a randomized trial of intubated patients showed no clinical benefit. The authors need to put their trial cohort (younger, more advanced disease than Emory) on spectrum of severity compared to other trials. Part of the learning from these early trials will be defining an optimal cohort for phase II or III trials.

Response:

The reviewer makes an important point in that we need to put our trial in the context of other studies done in more developed countries. As previously mentioned, our patient population, while younger, was a sicker cohort than in the Emory (and other publications), and a majority had received Tocilizumab. We have revised our Discussion to encompass the reviewer’s point, including proposals for future clinical trials.

3. The authors should emphasize the safety of LDRT for acute effects, after clearly presenting them in Results. There also needs to be some acknowledgement of late effects as something beyond the scope of this trial that should be included in safety monitoring in future clinical trials.

Response:

We have now included hematologic toxicity data in Fig 2 & 3 and demonstrate no acute clinically significant hematologic toxicity. We agree that late toxicity are beyond the scope of our study but none of the 6 patients currently alive have presented with pulmonary or hematologic morbidity (data not included)

Refer to P. 18 Lines 314 & 315

4. Making the cost argument is valid. Given that treating patients once tocilizumab is needed for cytokine storm, should LDRT be considered earlier in the disease process for trials? It could result in cost savings if LDRT works. If not, why not?

Response:

The reviewer’s point is well taken and we have covered this suggestion across the Introduction and Discussion sections.

5. P.24, lines 270-272: This point on scarcity of linear accelerators needs to fit coherently from Introduction to Discussion. An opportunity to highlight need for investment to help cancer patients regardless of LDRT trial findings, made stronger if future studies of LDRT show a benefit.

Response:

We whole heartedly agree with the reviewer in that more RT units are needed in the LMIC, firstly to treat patients with cancer but in the new normal of Covid 19 could also LDRT. We have attempted to include this aspect in our Discussion.

Refer to P. 20 lines 340-344

Conclusion

1. Emphasize feasibility and acute safety.

Response:

We have revised the manuscript based on the suggestion by the reviewer.

Refer to P. 20 lines 347-349

2. Recovery rate is can’t be attributed to LDRT success in line 277.

Response:

We agree with the reviewer and have omitted the same from the manuscript.

3. Lines 281-2: recommend being genetic as ‘drug therapy’ rather than specifying immune modulating agents. Other effective drug classes may also be too expensive.

Response:

The reviewer’s point is well taken and we have covered this suggestion across the manuscript

4. Lines 282-3: Final sentence not necessary

Response:

The reviewer’s point is well taken and we have omitted the sentence from the manuscript and also revised the Discussion.

Reviewer #2:

The authors present the first study from African content on the use of LD-RT for COVID-19 ARDS. The study adds significant value to the current, limited understanding of the role of LD-RT for COVID-19 ARDS, and it's potential reproducibility of signal across other institutions across the world. Reproducibility of the signal across the world, in a different cohort of patients from Africa adds significant value, and is scientifically a notable accomplishment.

The authors also do a good job on only doing a small, feasibility study of 10 patients and asking the first level, simple safety and potential efficacy signal. Their patient selection of advanced, oxygen dependent patients is also reasonable. They chose patients that were not responding to other therapies and offered them the option of LD-RT and appears to find some clinical benefit. Their results of 6 patients improving is also in line with findings from others. There appears to be a correlation between inflammatory reductions post LD-RT and those patients that improve.

Minor edits:

1) Line 216, page 21. Did you mean to say 100 cGy instead of "gGy"?

2) Can the authors discuss pre LDRT rises in CRP, Ferritin, and other biomarkers and compare them with post LDRT changes? In the work by Hess et al, they saw significant rising trends preLD-RT, and then precipitous drops in some of these post LD-RT. Of these biomarkers, CRP appeared to be the most correlated. Did the authors see this in their own data sets (comparing pre/post LD-RT biomarker changes).. See Hess et al. Radiotherapy and Oncology. Vol 165. December 2021. Pages 20-31.

https://www.sciencedirect.com/science/article/pii/S0167814021087594?dgcid=rss_sd_all

3) The authors can also use the reference by Hess et al to add the comment that LD-RT could potentially have independently benefits patients, despite having gotten Remedesivir and Steroids.

4)The authors can add the following preclinical studies to also support their notion that LD-RT may potential help COVID-19 ARDS : (Meziani et al. Int. J. Radiation Oncology Biology and Physics. Volume 110. Issue 5. P 1283-1294. August 01, 2021). This is preclinical study looking at LD-RT in mouse using three different ARDS models and demonstrated that LD-RT helped convert inflammatory environment into an anti-inflammatory environment.

Second paper to considering adding: Jackson et al. Low Dose Radiotherapy for COVID-19 Lung Disease: Pre-clinical Efficacy in Bleomycin Model"... 2022. Jan 1; 112(1): 197-211. Int J. Radiation Oncology Biol & Physics. https://pubmed.ncbi.nlm.nih.gov/34478832/

Reviewer 2 combined Response:

We greatly appreciate the reviewer’s comments. Our revised manuscript includes the additional references provided and we are grateful for these additions, which serve to strengthen our submission. We have corrected the typo graphical error (Comment #1) and included a box plot for provides pre(Day 1)/post data on the relevant biomarkers (as suggested in comment #2). We are unable to include trends for inflammatory markers (Pre-LDRT) due to incomplete data from the patient medical records. We have also incorporate the input from Comment #3 and #4 including the references provided with relevant revision of the text. We are very grateful for the reviewers input and suggestion.

26 May 2022

4 Jun 2022

A Pilot Phase Ib/II Study of Whole-Lung Low Dose Radiation Therapy (LDRT) For the Treatment of Severe COVID-19 Pneumonia: First Experience from Africa

Dear Dr Kimple,

We very much appreciate the review of our revised manuscript and the very helpful comments provided by the reviewer. We have responded to each of the comments and revised our manuscript accordingly. The revised manuscript includes the revisions as well as additional references. We thank the reviewers for their comments for which has served to strengthen our submission. We look forward to a positive decision by the editorial team.

Herewith please find our responses to each of the reviewer comments/suggestions:

Reviewer #1:

Comment:

Thank you to the authors for resubmitting this manuscript. It has improved substantially and reads well. only two stylistic points to consider:

1. Lines 88-89 - consider citing the other studies here but leave that to author preference

2. Line 306: 'discharge' would be better as past tense 'discharged'.

Response:

The reviewer’s insight and input is much appreciated and we have revised our manuscript and incorporated these suggestions.

Refer to P. 5 Line 88-89 and P. 18 Line 313(previously line 306)

Reviewer #3:

Comment:

Nicely written paper, I have some minor comments:

1. Why is no trial registration number reported?

Response:

The reviewer’s comments are well received and we have now included the trial registration number in the manuscript. The trial registration number had been previously submitted via the submission portal during the original submission.

Refer to P. 6 Line 109-110

2. Replace the figures in figure 3 with spaghetti-plots (i.e. individual lines per patient), "dead" or "Discharged" can be different line types but each patient can have a different colour. By doing this with figure 3 it will complement figure 2 (which shows the distribution at each time point) with the individual progress per patient over time.

Response:

We very much appreciate the insightful input from Reviewer # 3 and the suggestion to use a spaghetti plot as opposed to the box plot for Fig. 3. We have followed this advice. However, the small sample size and missing data points for some of the patients makes the spaghetti plot less definitive in demonstrating the upward trend in inflammatory markers in those patients who died. This trend seems to be more apparent when data is summarized into a boxplot for each inflammatory marker. For this reason, we have opted to include the original boxplots as supplementary material.

Refer to Figure 3 Page 14 Line 238-239, 250-255 and Page 18 Line 328-331

Submitted filename: Response to Reviewers 2 6 22.docx

Click here for additional data file.

14 Jun 2022

A Pilot Phase Ib/II Study of Whole-Lung Low Dose Radiation Therapy (LDRT) For the Treatment of Severe COVID-19 Pneumonia: First Experience from Africa

PONE-D-21-35607R2

Dear Dr. Saleh,

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thank you for your patience with the review process for this manuscript.

Reviewers' comments:

23 Jun 2022

PONE-D-21-35607R2

A Pilot Phase Ib/II Study of Whole-Lung Low Dose Radiation Therapy (LDRT) For the Treatment of Severe COVID-19 Pneumonia: First Experience from Africa

Dear Dr. Saleh:

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