Baldawa and Junaidi: Co-relation between high resolution computerised tomography (HRCT) score and effectiveness of remdesivir treatment in covid-19 positive pregnant patients


Introduction

From its outbreak in late Dec 2019 in Wuhan China , novel coronavirus -19 infection has created havoc worldwide , not sparing even the pregnant women. 1, 2 Until now the major studies - Adaptive Covid 19 Treatment Trial -1 (ACTT-1) by NIH3 and the SIMPLE study by Gilead Sciences have shown promising results of Remdesivir in NONPREGNANT population but have excluded pregnant women. So there is a need to evaluate its effectiveness in pregnant women as well. Since our institute was transformed into a COVID CENTRE due to acute shortage of covid beds during the pandemic, we felt the need of the hour was also to cater to covid 19 positive PREGNANT patients.

Materials and Methods

Design – Retrospective Observational Study

Table 0

Total score (numerical)

Severity (category)

7 or less

Mild

8–17

Moderate

18 or more

Severe

N = In our study Covid 19 nasopharangeal swabs were performed on 73 of our antenatally registered near term pregnant patients, out of which 12 patients came positive. 81 confirmed covid positive pregnant patients were referred from outside for admission to our hospital at varied weeks of gestational age. Patients were divided in MILD, MODERATE & SEVERE CATEGORY depending on their HRCT scores on admission.4 25-point CT severity score by Chang et al. (devised for assessment of ARDS in patients with SARS in 2005) was used for this categorisation. Total sum of the individual 5 lobar scores indicates the overall severity. 4

HRCT Severity Score

Figure 0
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Gives Total HRCT Score out of 25.

0- Each lobe score = 0 - 5

1- No opacity

2- Upto 5% opacity

3- 5-25% opacity

4- 25-50% opacity

5- 50-75% opacity

6- More than 75% opacity.

Out of the 93 confirmed covid 19 positive pregnant patients, 15 patients were admitted to Intensive Care Unit(ICU) after physician consultation due to their disease severity and received Remdesivir therapy. Remaining 78 pateients were of MILD CATEGORY with HRCT score of 7 or less and did not require ICU admission and hence were excluded from receiving Remdesivir therapy.

These 15 patients were divided into 2 groups

Group A- (Moderate Category) including covid -19 positive pregnant patients with HRCT score of 8 to <17/25 had 8 patients.

Group B- (Severe Category) including covid -19 positive pregnant patients with high HRCT Score of >18/25 had 7 patients.

Enrollment = from March 2020 till June 2021

Analysis = Intention to treat

Primary Outcome = To assess clinical improvement of patient after 5 days of initiation of Remdesivir therapy in terms of

  1. Oxygen requirement (litres/ min)

  2. Spo2 levels (%)

  3. Length of hospital stay (in days)

  4. Death rate (%)

  5. HRCT score on day 10 after initiation of remdesivir therapy(out of 25)

Secondary Outcome =

  1. To assess side effects of Remdesivir therapy on the mother.

  2. To assess effects of Remdesivir on the baby in utero during antenatal period and after delivery.

Summary of Remdesivir Action, Initiation Criteria, Dosage, Monitoring & Discontinuation criteria at our Institute

Mechanism of action of remdesivir

Remdesivir is the only FDA-approved prodrug for the treatment of COVID-19 patients. The active form of remdesivir forms an adenosine triphosphate analog that inhibits the viral RNA-dependent RNA polymerase (RdRp). Remdesivir resembles an RNA building block. Shortly after adding remdesivir, the enzyme RdRp stops being able to add more RNA subunits. This halts genome replication.

Initiation criteria

  1. Age > 18 yrs.

  2. Pregnancy at various weeks of gestational age.

  3. Lab confirmed SARS CoV-2 Infection by RTPCR.

  4. Evidence of lower respiratory tract infection at time of admission based on one of the following –

    1. Radiographic Ground glass opacities and HRCT score ranging from > 8 / 25 & above.

      1. HRCT score from 8/25 upto 17/25 = Moderate disease.

      2. HRCT score >17/25 = Severe disease.

    2. Spo2 < 94% On Room air.

    3. Requiring Supplemental Oxygen or Mechanical Ventilation (BIPAP).

  5. No limit to duration of symptoms before admission.

Exclusion criteria

  1. Mild disease with HRCT score < 7/25

  2. Spo2 > 94%.

  3. Pt. who did not require ICU admission.

Dosage of Remdesivir Therapy

Standard therapy

200 mg of intravenous Remdesivir on day 1 followed by 100 mg of IV Remdesivir for the next 4 days.

Prolonged therapy

Continued administration of intravenous Remdesivir 100mg per day after standard therapy of 5 days for the next 5 days. Total duration of therapy for 10 days.

Monitoring during remdesivir therapy

  1. Blood levels of Complete Blood Count(CBC), C- Reactive Protein(CRP), AST(SGOT), ALT(SGPT), Serum Creatinine, D- dimer, Serum LDH, were noted before initiation of therapy and on day 5 after initiation of therapy for monitoring of maternal side effects.

  2. Ultrasound of fetus with Obstetric Doppler study was done at around 28-30 weeks of gestation to evaluate for any fetal abnormalities in terms of fetal growth, liquor and fetal blood supply. Regular weekly NON STRESS TEST (NST) was also done to evaluate fetal well being after 32 weeks of gestation. Also after delivery, baby was thoroughly evaluated by a paediatrician to note for any side effects on the baby.

Discontinuation criteria

  1. AST & OR ALT > 5 times the upper limit of normal

  2. Impaired eGFR <30 ml/ min or patient requiring hemodialysis or hemofiltrarion

  3. Allergy to the drug

Figure 1

Flow Chart demonstrating patient inclusionprocess

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We have used the “Online Calculator soup” for calculating our results. The mean with confidence interval of 95% was calculated for variables like patients age in years, weeks of gestation, patients oxygen saturation for group A and group B. Also mean was calculated for clinical parameters like days of oxygen requirement & duration of hospital stay for patients in group A & group B. To determine differences between the group variables & to determine whether this difference is statistically significant or not, the Independent sample t tests and the Pearson chi squared tests were performed.

History of 8 confirmed covid positive pregnant patients with HRCT score 8 to <17/25 (GROUP A) is tabulated in table 1a. The mean age group is 30.37 + 4.45 years. The mean weeks of gestation of pregnancy was 32 weeks + 4.9 weeks. The most common presenting symptom was fever and cough. The mean Spo2 was 89.75 + 1.98%. The most common co- morbidity was pregnancy induced hypertension.

History of 7 confirmed covid positive pregnant patients with HRCT score >17/25 (Group B) is framed in table 1b. The mean age group is 30.42 + 5.12 years. The mean weeks of gestation of pregnancy was 30.1 weeks + 5.08 weeks. The most common presenting symptom was fever, cough and breathlessness. The mean Spo2 was 85.42 + 3.82%. The most common co- morbidity was pregnancy induced hypertension.

Clinical Parameters Of Group A pregnant patients are demonstrated in table 2a. The oxygen requirement rapidly decreased with initiation of remdesivir therapy. The mean duration of oxygen requirement was for 9.62+ 2.77 days. The mean duration of hospital stay was 11.62 + 3.37days. Death rate was 0% and the fetal outcome was good with no baby developing respiratory illness.

Clinical parameters of Group B covid positive pregnant patients with high HRCT score of >17/25 are demonstrated in table 2b. The oxygen requirement remained high and few patients also required non invasive ventilation (BIPAP) even after initiation of remdesivir therapy. The mean duration of oxygen requirement was for 19.14+ 2.26 days. The mean duration of hospital stay was 19.57 + 2.69 days. Death rate was 42.86% and the fetal outcome was good with no baby developing respiratory illness in the mothers who survived. The length of hospital stay and the death rate was significantly more in Group B compared to Group A.

Discussion

During this ongoing covid pandemic, its need of the hour to evaluate the effectiveness of drugs which may be helpful in its treatment. Remdesivir has shown promising results in clinical improvement in covid 19 patients, but it has not been evaluated in pregnant patients. 5 In our retrospective study, remdesivir therapy was associated with a significantly shorter time to clinical improvement. The mortality rate was lower in the remdesivir group, and the results too were statistically significant. The magnitude and direction of these associations were similar to those shown in ACTT-1. 6

Our study included Covid -19 positive pregnant women than previous remdesivir clinical trials where pregnant women were totally excluded. Our results provide important evidence that remdesivir therapy is associated with decreased time to clinical improvement in covid -19 positive pregnant women.

In most of the studies in literature like by Beigel JH et al, the remdesivir group has received 5 days of therapy, which supports recommendations for an initial 5-day course for most patients. However in the study by Goldman JD et al, there was use of 10 day treatment and the comparison of 5 days vs 10 days showed similar efficacy. 7 Also the study by Spinner CD at al showed that 5 days course, but not a 10-day course, was associated with a significant improvement in disease severity. 8 As per the study by Kapczynski et al. 9 our finding that a 5-day treatment course was associated with a clinical benefit is important, due to global shortages of remdesivir and the potential for even greater supply constraints moving forward .Hence it is advisable to wisely use the present available remdesivir resources.

In our study there was no death in the Covid -19 positive pregnant patients with moderate disease who received remdesivir early, corresponding with the RECOVERY TRIAL conducted by Horby P et al. 10 The results of our study also co-relates with the ACTT-4 trial where patients breathing ambient air or nasal cannula oxygen benefitted more from treatment with remdesivir, whereas patients receiving higher levels of respiratory support, such as mechanical ventilation, did not benefit. 11 This emphasises the fact that early initiation of remdesivir therapy when patient is mildly breathless with less oxygen  requirement and better oxygen saturation, will have better clinical outcome compared to those COVID positive pregnant patients who present late and have more severe symptoms. Hence its co-relation with HRCT score is important. patients with low HRCT Score respond better to remdesivir herapy compared to tose with high HRCT Score. There are other ongoing trials like ACTT -4 to study the effectiveness of remdesivir combined with dexamethasone on one arm and remdesivir in combination with baricitinib on the other.11 Their results are still awaited and will be a guide to future treatment protocols.

Conclusions

This study suggests that remdesivir was associated with a significant decrease in the time to clinical recovery among Covid 19 positive pregnant patients admitted early to the hospital with low HRCT Score .for treatment of COVID-19. These results provide further evidence that remdesivir is effective in reducing the duration of COVID-19 illness, that a 5-day treatment course may be sufficient, and that patients with mild and moderate disease likely benefit most. The high mortality in severely affected group inspite of receiving remdesivir suggests that late onset of remdesivir when the disease has already progressed as suggested by high HRCT Score is of less or no benefit. Thus early use of remdesivir when symptoms are mild to moderate is effective and beneficial in reducing hospital stay and Covid-19 related morbidity and mortality.

Conflict of Interest

The author declares no potential conflicts of interest with respect to research, authorship, and/or publication of this article.

Source of Funding

None.

References

1 

C Wang P W Horby F G Hayden G F Gao A novel coronavirus outbreak of global health concernLancet2020395102234703

2 

WHO Director-General’s opening remarks at the media briefing on COVID-19. 11 March 2020https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-

3 

JH Beigel K Tomashek L Dodd A Mehta B Zingman A Kalil Remdesivir for the Treatment of Covid-19 — Final ReportN Engl J Med20203831918132610.1056/NEJMoa2007764

4 

G Saeed W Gaba A Shah A Al Helali E Raidullah A Al Ali Correlation between Chest CT Severity Scores and the Clinical Parameters of Adult Patients with COVID-19 PneumoniaRadiol Res Pract20211710.1155/2021/6697677

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DP Harrington LR Baden JW Hogan A large, simple trial leading to complex questionsN Engl J Med20213846576710.1056/NEJMe2034294

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JH Beigel KM Tomashek LE Dodd Remdesivir for the treatment of Covid-19-preliminary report: reply. N Engl J Med20203831099410.1056/NEJMc2022236

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JS Goldman DCB Lye DS Hui GS-US-540-5773 Investigators. Remdesivir for 5 or 10 days in patients with severe Covid-19N Engl J Med20193831918273710.1056/NEJMoa2015301

8 

CD Spinner Rl Gottlieb GJ Criner GS-US-540-5774 Investigators. Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: a randomized clinical trial JAMA20203241110485710.1001/jama.2020.16349

9 

A Kapczynski P Biddinger R Walensky Remdesivir could be in short supply: here’s a fix. The New York Times. July 28, 2020. Accessed February 8, 20212020https://www.nytimes.com/2020/07/28/opinion/remdesivir-shortage-coronavirus.html

10 

P Horby WS Lim JR Emberson RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19-preliminary reportN Engl J Med202010.1101/2020.06.22.20137273

11 

Adaptive COVID-19 treatment trial 4 (ACTT-4). ClinicalTrials.gov identifier: NCT04640168. Updated February 3, 2021. Accessed December 7, 2020https://clinicaltrials.gov/ct2/show/NCT04640168



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Article History

Received : 15-11-2021

Accepted : 02-12-2021

Available online : 23-12-2021


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https://doi.org/10.18231/j.ijmpo.2021.040


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