Association between Chest CT Severity Scores and SARS-CoV-2 Vaccination among COVID-19 Patients: A Cross-sectional Study from Pune, India

1. Chief Radiologist, Department of Radiology, Star Imaging and Research Centre, Pune, Maharashtra, India. 2. Undergraduate Student, Government Medical College Byramjee Jeejeebhoy and Sassoon General Hospitals, Pune, Maharashtra, India, 3. Undergraduate Student, Smt. Kashibai Navale Medical College and General Hospital, Pune, Maharashtra, India. 4. Undergraduate Student, Government Medical College Byramjee Jeejeebhoy and Sassoon General Hospitals, Pune, Maharashtra, India. 5. Research Associate and Radiologist, Department of Radiology, Star Imaging and Research Centre, Pune, Maharashtra, India. 6. Founder, Star Imaging and Research Centre and Associate Professor (Honorary), Department of Radiology, B.J. Government Medical College, Pune, Maharashtra, India.

Abstract

Introduction: The novel Coronavirus disease-2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is seen to primarily affect the human respiratory system. Chest CT Severity Score (CTSS) provides a semi-quantitative assessment of pulmonary involvement in COVID-19 patients. COVID-19 pandemic mitigation measures such as SARS-CoV-2 vaccination are being deployed worldwide. However, with the emerging variants of concern of SARS-CoV-2, a high prevalence of post vaccination breakthrough infections is seen.

Aim: To assess the association of CTSS with the vaccination status in a cohort of COVID-19 patients referred to a tertiary diagnostic centre and to evaluate the association of CTSS with other clinical parameters including co-morbidities in these patients.

Materials and Methods: This cross-sectional observational study was conducted at a tertiary care diagnostic imaging centre in the city of Pune, Maharashtra, India. Data of 1002 symptomatic, adult patients who underwent chest CT and SARS-CoV-2 Reverse Transcription Polymerase Chain Reaction (RT-PCR)/Rapid Antigen Test (RAT) laboratory test between March 13, 2021 and June 22, 2021, were collected. COVID-19 Reporting and Data System (CO-RADS) categories and the corresponding semi-quantitative CTSS were calculated for each patient. Based on their vaccination status, patients were categorised into three groups: unvaccinated, partially vaccinated and fully vaccinated. The association of CTSS with various categories of vaccination status, demographics, co-morbidities and stages of the disease of the patients, was evaluated.

Results: Of the 1002 COVID-19 patients, 768 (76.6%) were unvaccinated, 190 (19.0%) were partially vaccinated and 44 (4.4%) were fully vaccinated. Mean CTSS in the fully vaccinated cohort was significantly lower (3.75±4.7) than that in the partially vaccinated (6.05±5.7) and unvaccinated (8.29±4.9) patients (mean 3.75 vs. 6.05 vs. 8.29, respectively; (p<0.05). Mean CTSS in patients with no co-morbidities was significantly lower than that in patients with hypertension and diabetes (7.12 vs. 8.75 vs. 10.39, respectively; (p<0.05).

Conclusion: Significant association was noted between the Chest CTSS and the vaccination status, age, gender, co-morbidities and stage of disease in this large cohort of COVID-19 patients. The study reiterates that full vaccination aids in reducing the severity of lung involvement in COVID-19 infection.

Computed tomography, Coronavirus disease-2019, Diagnostic imaging, Immunisation, Severe acute respiratory syndrome coronavirus 2

High Resolution Computed Tomography (HRCT) of the chest plays a pivotal role in assessing the severity of lung involvement in novel Coronavirus disease-2019 (COVID-19) infection (1),(2),(3). The COVID-19 Reporting and Data System (CO-RADS) and the corresponding CT Severity Score (CTSS) introduced by Radiological Society of the Netherlands provide a semi-quantitative assessment of virus induced pulmonary involvement (4),(5).

Mass vaccination is considered to be an important tool for COVID-19 disease prevention. India’s COVID-19 vaccination program was expanded to include all citizens ≥18 years of age, even as the country witnessed a massive surge in infections during the 2nd wave of the pandemic (6). The ChAdOx1n CoV-19/Covishield and BBV152/Covaxin are the two vaccines approved for emergency use in India (7). However, vaccines do not confer complete immunity against the viral disease and vaccine breakthrough infections are being reported (8),(9).

Studies have reported that chest CTSS correlates with the extent of lung damage in COVID-19 patients and therefore, may be used as a novel indirect indicator of vaccine effectiveness in the real world settings (2),(3),(10). Studies comparing the chest CTSS and vaccination status among Indian patients with COVID-19 infection are scarce (one of these studies was a preprint at the time of writing this paper) (11),(12),(13).

On this background, the present study aimed to assess the association between chest CTSS and vaccination status in a cohort of Indian patients with COVID-19 infection. The secondary objective of this study was to assess the correlation between CTSS and the clinical parameters including co-morbidities in these patients.

Material and Methods

This cross-sectional, observational study was conducted at the imaging clinics of a tertiary diagnostic centre, in Pune, Maharashtra, India, between March 13, 2021 and June 22, 2021. This tertiary care diagnostic imaging centre receives referrals from various parts of Pune district. The study was approved by Institutional Ethics Committee (ECR/311/INST/MH/2013/RR-19) and informed consent was obtained from all the patients.

Sample size calculation: Optimum sample size for the study was estimated using the formula: N=(1.96)² PQ/L². Where, N=Sample size, 1.96=Standard normal deviate set corresponding to 95% confidence interval (CI), P=Percentage of vaccinated population in Pune district till June 2021, Q=100-P and L=Permissible error in estimation i.e., 10% of P.

Percentage of vaccinated population in Pune district till June 2021 (P), was calculated using the formula: P=total number of SARS-CoV-2 vaccinations done in Pune district till June 2021 i.e., 32, 17, 978 persons×100/total population of Pune district i.e.,1,00,89,916 persons, estimated in accordance with the Aadhaar uidai.gov.in December 2020 data (14),(15),(16). Thus, the sample size calculated for this study was 820 patients (Table/Fig 1). Taking into consideration the possible loss to follow-up of 20 % in an urban setting, the estimated optimum sample size for this study was further increased to 984 patients (Table/Fig 1). The present study therefore included 1002 patients with COVID-19 infection.

Inclusion criteria:

• Age ≥18 years;
• Patients suspected to have symptoms of COVID-19 infection;
• Patients who were referred for HRCT chest between March 2021 and June 2021;
• Patients with a positive SARS-CoV-2 Reverse Transcription Polymerase Chain Reaction (RT-PCR)/Rapid Antigen Test (RAT).

Exclusion criteria: Pregnant women, patients <18 years of age and patients with a negative RT-PCR/RAT test were excluded from the study.

Study Procedure

Data collection: Clinical data, laboratory data (SARS-CoV-2 RT-PCR/RAT tests) and vaccination data of the study patients were collected from electronic medical records, patient’s clinical history sheets, and from telephonic interviews. Clinical information collected from all study patients included: age, gender, co-morbidities and stage of illness based on the time interval between onset of symptoms and acquisition of chest HRCT scan.

Chest HRCT evaluation: As a standard of practice, non contrast chest HRCT scans of the COVID-19 patients were performed on a multidetector CT scanner (Philips Ingenuity 128 Slice CT; Philips Healthcare, Amsterdam, Netherlands and GE 32 Slice; GE Healthcare, Waukesha, USA) with the patient in supine position, during end inspiration. Scanning parameters were in line with the manufacturer’s standard recommendations for a routine thorax scan. All CT images were reconstructed to thin slices using the Multiplanar Reformatting (MPR) technique. Appropriate infection prevention and control measures were arranged for the CT technologists and the patients.

The HRCT images of the COVID-19 patients were independently examined on standardised workstations, by two radiologists with 15 years’ experience in reporting chest CT images. These radiologists were blinded to the vaccination as well as co-morbidity status of the study patients. Chest CT scores for the first 30 study patients were recorded by the two radiologists independently. Intra Class Correlation (ICC), which is a useful statistic for estimating Inter-Rater Reliability (IRR), was calculated for these reads. The ICC for the initial 30 chest HRCT reads were found to be 0.997 with average measures (p-value=0.0001) and the estimated IRR was 99.7% (Table/Fig 2). Hence,the chest HRCT scans of the remaining study patients, were randomly assigned to the two experienced radiologists for independent interpretation and scoring of the HRCT images.

Chest CT images of these patients were evaluated using the standard, international nomenclature based on COVID-19 Reporting and Data System (CO-RADS) (Table/Fig 3)a (4). Further, in patients with characteristic findings of COVID-19 lung involvement, a semi-quantitative CT severity scoring was performed; using the scoring system which depends on the visual assessment of the extent of anatomic involvement (on a scale from 0-5) of each of the 5 lobes of the lungs (Table/Fig 3)b (17). The total CTSS is the sum of the individual lobar scores and it ranges from 0=no involvement to 25 maximum involvement (17). Based on the total CTSS, the severity of lung involvement in the patients was further graded into mild (CTSS of 0-8), moderate (CTSS of 9-15) and severe (CTSS of 16-25) categories. Thereafter, CT scans were further categorised into five stages based on the duration of time interval between initial symptoms’ onset and performance of chest HRCT (Table/Fig 3)c (18).

Vaccination status: The study patients were categorised into the following three groups, based upon their vaccination status at the time of a positive laboratory confirmation of COVID-19 infection.

1) Unvaccinated (never received a COVID-19 vaccine dose);
2) Partially vaccinated (received one dose of a two dose vaccine series, or <14 days elapsed after the 2nd dose);
3) Fully vaccinated (received two doses of a two dose vaccine series and ≥14 days elapsed since the second dose).

Statistical Analysis

Statistical analysis of the data was perfomed using Epi info software. Descriptive statistics of patient’s demographics and clinical results were reported as numbers (n) and percentages (%). Quantitative continuous variables were presented as mean±standard deviation. Analysis of Variance (ANOVA) test was applied to assess the significance of association between mean CTSS and various categories of vaccination status and clinical parameters of the study participants. Kruskal-Wallis test was used for confirmation of results of multiple comparisons. The differences in grades of chest CTSS between the various categories of patients based on their demographic, co-morbidity and vaccination status and stage of disease; were examined using Chi-square (χ²) test. Multivariate linear regression analysis was used to determine the association of CTSS with the vaccination status (unvaccinated or vaccinated), co-morbidity status (presence or absence of co-morbidity) and stages of disease on CT. For all the statistical tests; p-value <0.05 was considered statistically significant.

Results

Mean age of the 1002 patients enrolled for the study was 49.0 years±15.6 years and men constituted 64.4% of the study population. Study patients were classified into three age group categories based on the prioritisation of vaccination among the Indian population as per the directives of National Expert Group on Vaccine Administration for COVID-19 (NEGVAC) (6).

Co-morbidity data was available in 949/1002 patients. Amongst these, 249 (26.2%) patients had some co-morbidities: either hypertension or Diabetes Mellitus (DM), or a combination of both DM and hypertension, which depicts the baseline demographic and clinical characteristics of the patients (Table/Fig 4).

Out of the 1002 patients, 768 (76.6%) were unvaccinated. Details of the categorisation of the study cohort depending on their CTSS, stage of lung involvement on CT and vaccination status are presented in (Table/Fig 5). Various grades of severity of lung involvement seen on the chest HRCT images of the study patients with COVID-19 infection are illustrated in (Table/Fig 6). Breakthrough infections (defined as SARS-CoV-2 infections occurring ≥14 days after completing the second dose of a two dose COVID-19 vaccination series); occurred in 44 (4.4%) patients.

Association of CTSS with age groups and gender: The study results showed significant difference in the mean CTSS when all the age group categories in the study population were compared together (p<0.01). Mean CTSS of the persons ≥60 years of age was higher than that of persons in the 45-59 years age group and 18-44 years age group (Mean CTSS 9.34 vs. 8.35 vs. 6.00, respectively) (Table/Fig 7)a. Similarly, significant difference was observed in the grades of chest CTSS of patients depending upon their age group categories. As depicted in (Table/Fig 7)b, moderate as well as severe grades of CTSS were increasingly seen in the 45-59 years and ≥60 years age group categories.

The mean CTSS in male patients was significantly higher than that in the female patients (Mean CTSS 8.0 vs. 7.05 respectively) (p=0.01, p<0.05). Mild grade of CTSS was seen in greater percentage of female patients (64.1%); as compared to male patients (56%). Significant difference was detected in the grades of CTSS when compared together, based on the gender of study participants (p=0.027, p<0.05).

Association of CTSS with co-morbidities: Mean CTSS in patients with no co-morbidity was significantly lower than that in patients with comorbidities such as hypertension alone, hypertension with diabetes mellitus and diabetes alone (7.12 vs. 8.75 vs. 9.46. vs. 10.39, respectively (p<0.05) (Table/Fig 8). Mild CTSS was seen in majority of the patients (64.3%) with no co-morbidities; whereas, highest percentage of cases (20%) with severe CTSS were seen in patients with diabetes mellitus (Table/Fig 9). Significant difference was seen in the mean CTSS as well as in the grades of CTSS, when all groups were compared together, based on their co-morbidity status (p<0.01).

Association of CTSS with vaccination status: Majority of the vaccinated persons in the study cohort belonged to >60 years and 45-59 years age group. Breakthrough infections were identified in 44 (4.4%) of the vaccinated cohort. When multiple comparisons were made, mean CTSS was significantly higher in the unvaccinated cohort (mean±SD:8.29±4.9) versus the partially vaccinated patients (mean±SD:6.05±5.7) versus the fully vaccinated patients (mean±SD:3.75±4.7) (p<0.01) (Table/Fig 10). The difference in mean CTSS between the partially vaccinated and fully vaccinated groups was also found to be significant (p=0.035, p<0.05).

The percentage distribution of mild, moderate and severe grades of CTSS amongst the unvaccinated, partially vaccinated and fully vaccinated groups of patients is illustrated in (Table/Fig 11). Majority of the fully vaccinated patients (86.4%) demonstrated mild CTSS; whereas highest percentage of severe CTSS (11.5%) was reported in the unvaccinated patient group. This difference in the grades of CTSSCTSS observed in the different patient categories depending on their vaccination status, was statistically significant (p<0.01).

Association of CTSS with the two types of COVID-19 vaccines: Amongst the vaccinated cohort, 207 (88.5%) patients had received Covishield and 27 (11.5%) persons had received Covaxin. The difference between mean CTSS of patients who had received Covishield (Mean±SD:5.61±4.9) and that of patients who had received Covaxin (Mean±SD: 5.67±4.6); was statistically insignificant (p=0.954, p>0.05).

Association of CTSS with stage of lung involvement on CT: Statistically significant difference was noted in the mean CTSS among the five stages of lung involvement on CT based on the period between onset of symptoms and acquisition of CT scan (p<0.01), (Table/Fig 12).

Further, occurrence of mild grade of CTSS in majority (89.3%) of the patients belonging to the fully vaccinated cohort with no co-morbidity, was demonstrated in the two-way cross tables. None (0%) of these patients recorded severe CTSS. On the contrary, a large percentage of unvaccinated patients with co-morbidity; demonstrated either moderate or severe CTSS (Table/Fig 13).

Taking into account, the confounding effect of all the included independent variables, multivariate linear regression analysis showed that presence of co-morbidity and higher stage of disease were associated with higher CTSS; whereas partially/fully vaccinated patients recorded lower CTSS when compared with unvaccinated patients (adjusted R2 is 0.230) (Table/Fig 14).

Discussion

In the course of evolution of the COVID-19 global pandemic, several studies have shown that various patient related factors such as age, gender, duration of symptoms, along with the number and type of co-morbidities; influence the clinical severity and outcomes of patients with COVID-19 infections (3),(17),(18),(19),(20),(21),(22). Scientific literature till date has demonstrated the correlation between the clinical severity of COVID-19 disease and chest CTSS in COVID-19 patients (1),(2),(3),(23),(24),(25).

Further, National SARS CoV-2 vaccination drive is underway in India as part of the global efforts to abate the onslaught of the pandemic (6). Even so, post vaccination breakthrough infections, mainly attributable to the emergence of new variants of SARS-CoV-2 virus; are being reported all over the world, as well as in India (8),(9),(26),(27).

In these settings, the present study assessed the association between CTSS and vaccination status in RT-PCR/RAT confirmed, symptomatic COVID-19 patients, during the second wave of the pandemic in India. The association between CTSS and clinical parameters of these patients were also investigated. Results of this study demonstrated that patients with partial and full vaccination record significantly lower mean CTSS and also report lower percentage of patients with severe grade of CTSS; when compared with the unvaccinated patient population (Table/Fig 10),(Table/Fig 11). These results corroborated with those of previously conducted, similar Indian studies comparing chest CTSS amongst the unvaccinated and vaccinated COVID-19 patients (one of these studies was a preprint at the time of writing this paper) (11),(12),(13). In comparison with these studies, the present study included a larger cohort of patients. In the present study, majority (86.4%) of the fully vaccinated patients with breakthrough infections, demonstrated mild CTSS and only 1 patient (2.3%) recorded severe CTSS. In line with previous literature reports, this data also illustrated that majority of the patients with post vaccination breakthrough infections suffer from mild disease (11),(12),(13),(26),(27). All of the above mentioned results in the present study can be ascribed to the effectiveness of vaccines in preventing severe COVID-19 disease.

Patients of different age groups in the Indian population are receiving vaccines in a phased manner, as prioritisation of vaccination to the elderly population at an increased risk for developing severe COVID-19 infection; is crucial (6). Therefore, the younger age group (18-44 years) made a sizeable contribution to the unvaccinated category (91.1%) in the current study cohort. Similar to the observations reported by previous studies, this study recorded a higher mean CTSS along with a greater percentage of patients with severe CTSS, in the middle aged (45-59 years) and elderly (>60 years) population (3),(19). One reason for this observation could be the stage of the pandemic when this study was conducted and another possible reason may be that COVID-19 infection elicits a stronger inflammatory response in the elderly population since they are more likely to have concomitant co-morbidities (19).

Higher mean CTSS and greater percentage of cases with moderate and severe grades of CTSS were seen in the male population in this study. Saeed GA et al., and Jin J-M et al., have reported in their respective studies that, men are at a higher risk of severe COVID-19 disease as compared to women and our results support their observation (3),(20).

As expected, the authors of the present study found a significantly higher mean CTSS in patients with one or more co-morbidities, when compared with patients with no co-morbidities (Table/Fig 8) (21). Also, severe CTSS was more commonly recorded in the patients with diabetes mellitus alone followed by patients with both DM and hypertension; further followed by those with hypertension alone (Table/Fig 9) (22). Overall, these findings are in agreement with the existing literature reports that have documented the impact of co-morbidities on clinical outcomes of patients with COVID-19 (21),(22). In the current study cohort of breakthrough infections, the fully vaccinated patient with severe CTSS was 75 years of age and had co-morbidities such as diabetes and hypertension.

Pan F et al., and Ding X et al., in their respective studies found that the chest CT features and CT scores of patients with COVID-19, changed with duration of symptoms (17),(18). Consistent with these studies, the present study reported significantly lower mean CTSS and milder grades of CT scores in patients in the early stages of the disease. The mean CT scores were seen to progressively increase from stage 1 to stage 5.

Limitation(s)

The study cohort did not include asymptomatic and RT-PCR false negative persons; who are likely to promote spread of COVID-19 infection. Another limitation was self reporting and under reporting of co-morbidities in some of the enrolled patients. Data on obesity, ischaemic heart disease, chronic renal disease and prior lung disease was not available. Details about the clinical categorisation and treatment received by the study patients were also not available. Follow-up chest CT scans were performed in some patients on the basis of clinical indication. However, such serial chest CT scans were not included in the study analysis. Further multicentric studies involving larger groups of COVID-19 patients are recommended to validate the results of this study and to evaluate the impact of SARS-CoV-2 vaccination on the overall patient outcomes.

Conclusion

Significant association between the chest CTSS and the vaccination status, age, gender, co-morbidities and stage of disease was seen, in this large cohort of COVID-19 patients from a tertiary care diagnostic centre in Pune, Maharashtra, India. This study conducted in real world settings, reiterates that full vaccination aids in reducing the severity of lung damage in COVID-19 infections. It therefore, underscores the role played by vaccines in curbing the current COVID-19 pandemic.

Acknowledgement

The authors would like to thank Mrs. Aruna Deshpande MSc.(Statistics), for her help in statistical analysis.

DOI and Others

DOI: 10.7860/JCDR/2022/53056.16482

Date of Submission: Oct 31, 2021
Date of Peer Review: Jan 07, 2022
Date of Acceptance: Mar 06, 2022
Date of Publishing: Jun 01, 2022

AUTHOR DECLARATION:
• Financial or Other Competing Interests: Funded by Maharashtra Medical Research Society, Joshi Hospital, Pune, Maharashtra, India.
• Was Ethics Committee Approval obtained for this study? Yes
• Was informed consent obtained from the subjects involved in the study? Yes
• For any images presented appropriate consent has been obtained from the subjects. Yes

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ETYMOLOGY: Author Origin