COVID-19 and protection of vaccination in patients with systemic sclerosis–associated interstitial lung disease

Abstract

Objectives:

Data on COVID-19 in patients with interstitial lung disease are scarce and whether SARS-CoV-2 may trigger interstitial lung disease progression remains unknown. We aimed to analyze outcomes of COVID-19 in patients with systemic sclerosis–associated interstitial lung disease, including possible thoracic radiographic progression.

Patients and Methods:

All 43 patients with systemic sclerosis–associated interstitial lung disease followed in our center (mean ± SD, 55.2 ± 11.6 years, 36 female) with confirmed SARS-CoV2 infection up to 1 September 2022 were analyzed. Individual interstitial lung disease extent on high resolution CT (HRCT) performed before (up to 3 months) and after COVID-19 (2–5 months) was compared.

Results:

At SARS-CoV-2 infection, 9/43 patients were unvaccinated, whereas 5, 26, and 3 had received 2, 3, or 4 doses of an mRNA vaccine, respectively. Thirty-one patients were either on monotherapy with immunosuppressives (mycophenolate, n = 7; cyclophosphamide, n = 2; methotrexate, n = 10; tocilizumab, n = 7; rituximab, n = 1; etanercept, n = 1), or their combinations (n = 3). Eight patients (20%), of whom four unvaccinated, required hospitalization for pneumonia and three (7%) died of acute respiratory failure (n = 2, both unvaccinated) or cardiac arrest. Lack of vaccination was the only independent predictor for hospitalization (OR = 7.98, 95% CI: 1.25–51.09) and marginally for death (OR = 32.7, 95% CI: 0.97–1110.98), regardless of the presence of diffuse systemic sclerosis, interstitial lung disease extent greater than 20% or immunosuppressive treatment. In 22 patients with available HRCT pairs (vaccinated = 20), the interstitial lung disease extent before COVID-19 (20.4%± 17.8%) remained unchanged (22.4% ± 18.5%) in all but one patient.

Conclusion:

SARS-CoV-2 vaccination is of outmost importance for every systemic sclerosis patient with interstitial lung disease. COVID-19 does not seem to promote progression of systemic sclerosis–associated interstitial lung disease in vaccinated patients, but further studies are warranted.

Introduction

As of 10 September 2022, the estimated number of deaths related to SARS-CoV-2 infection worldwide exceeds 15 million and will continue to rise for the years to come. ¹ On the other hand, it is well established that COVID-19 survivors may suffer from various short- and long-term sequelae,^2,3 including interstitial lung disease (ILD) which may be severe in some of them. In a systematic review and random effects meta-analysis of proportions using 60 studies of adults hospitalized with COVID-19 and viral pneumonitis, it was found that fibrotic sequelae were evident in 29% of chest CT scans at a median follow-up of 3 months. ⁴ Although the pathogenesis of SARS-CoV-2-associated ILD remains unclear, possible mechanisms, such as endothelial to mesenchymal transition, ⁵ excessive host immune responses leading to proinflammatory and profibrotic cytokine overproduction ⁶ or acute respiratory distress syndrome induced-lung fibrosis, ⁷ have been proposed. On these grounds, patients with pre-existing ILD during the pandemic are prone to severe COVID-19 with poor outcome.^8–13 Moreover, progression of pre-existing ILD in COVID-19 survivors has been suggested from small case series or case reports. ¹⁴ However, in many cases, it may be difficult to distinguish between progression of pre-existing ILD and a late COVID-19 recovery or a serious COVID-19 infection.^15,16

Systemic sclerosis (SSc) is characterized by obliterative vasculopathy in conjunction with an aberrant (auto)immune response leading to activation of fibroblasts and to tissue fibrosis, and may even share pathobiological aspects with COVID-19.^5,17 Besides the huge impact of COVID-19 pandemic on the clinical care of SSc patients,^18,19 it had become clear since the early 2020 that these patients are at high risk for a more severe disease and higher mortality rates.^20,21 An, as yet, unpublished study from the EUSTAR database on the COVID-19 outcomes of 178 SSc patients, registered during 2020, reported an overall hospitalization rate of 38% and an overall mortality of 12%. ²² As perhaps expected, the presence of ILD, one of the main features of SSc, ²³ was numerically associated with hospitalization, non-invasive or mechanical ventilation and death. ²²

Prompted by the paucity of relevant data, we aimed to examine the outcomes of COVID-19, including breakthrough infections after vaccination, in consecutive SSc patients with pre-existing ILD who are followed in a dedicated academic center during the first 2 years and a half of the pandemic. Moreover, we compared ILD extent in high resolution CT (HRCT) scans performed before and after COVID-19 to assess whether infection triggers progression of their lung disease.

Patients and methods

In this study, we retrospectively analyzed data from all patients with SSc-associated ILD (2013 EULAR-ACR classification criteria) who are being followed in the Rheumatology Unit of the First Department of Propedeutic Internal Medicine of the Athens University Medical School and had been infected with SARS-CoV-2 up to 10 September 2022. Infection was always confirmed either by polymerase chain reaction or antigen test. Demographics, SSc characteristics and medications, as well as data regarding COVID-19 vaccination status and COVID-19 disease course and outcomes were recorded.

The extent of lung involvement was assessed by two experienced pneumologists (V.T. and D.B.), based on the visual semi-quantitative score proposed by Goh et al.; ²⁴ HRCT images were scored at five levels: origin of great vessels, main carina, pulmonary venous confluence, halfway between the third and fifth section, and immediately above the right hemi-diaphragm. The total extent of ILD was estimated to the nearest 5% in each of the five sections. Global extent of disease on HRCT was computed as the mean of the scores. ²⁴ Discrepancies of more than 20% were resolved by consensus. In order to assess possible radiographic progression of ILD after COVID-19, we compared individual ILD extent between available HRCTs that had been performed within 3 months prior and 2 to 5 months after COVID-19.

The study protocol was approved by the ethics committee of Laikon University Hospital (approval number 267/26-04-2021) and all patients gave written informed consent.

Statistical analysis

Data are reported as mean ± SD. To search for predictors for hospitalization or death, multivariate regression analysis adjusting (a) for the presence of extent of ILD > 20% in HRCTs performed before COVID-19 (available in all patients), (b) the presence of diffuse SSc, (c) immunosuppressive treatment at the time of infection, and (d) the lack of vaccination was performed. Paired sample t-test was applied to compare HRCT scores before and after COVID-19 and a p-value < 0.05 was considered significant. Statistical analysis was performed using SPSS software (SPSS Inc., version 25.0).

Results

Features of 43 patients with SSc-associated ILD infected with SARS-CoV-2

In total, 43 patients (36 female, mean age = 55.2 ± 11.6 years, 25 with diffuse SSc) were included in the study. The extent of ILD in the last HRCT before COVID-19 varied from 3% to 70%. While 12 patients were not receiving immunosuppressive treatment at the time of infection, 31 patients were on immunosuppressive medications used for the management of SSc, including SSc-associated ILD. ²⁵ These patients were either on monotherapy with mycophenolate (n = 7), cyclophosphamide (n = 2), methotrexate (n = 10), tocilizumab (n = 7), rituximab (n = 1) and etanercept (n = 1) or combinations of the above (tocilizumab plus methotrexate, n = 1; tocilizumab plus mycophenolate, n = 1; and tocilizumab plus cyclophosphamide, n = 1). Moreover, 23 of 43 patients were on glucocorticoids (median dose of 5 mg equivalent to prednisolone) (Table 1).

Table 1.

Demographics, immunosuppressive treatment regimen, and COVID-19 clinical manifestations and outcomes in 43 patients with systemic sclerosis-associated interstitial lung disease.

	Unvaccinated	Vaccinated (mRNA vaccine)
n	9	34
Age, years (mean ± SD)	56.3 ± 14.9	54.9 ± 10.9
Female, n (%)	6 (67)	30 (94)
Disease duration, years, (mean ± SD)	10.9 ± 5.2	12.8 ± 8.2
Diffuse SSc, n (%)	6 (67)	19 (56)
Smoking, n (%)
Current	1 (12)	1 (3)
Former	4 (44)	14 (41)
Never	4 (44)	19 (56)
Body mass index (BMI)	24.1 ± 1.8	24.8 ± 3.7
Immunosuppressives, n (%)
Methotrexate	3 (33)	9 (27)
Mycophenolate	4 (44)	4 (12)
Cyclophosphamide	0	3 (9)
Tocilizumab	1 (11)	9 (27)
Etanercept	0	1 (3)
Rituximab	0	1 (3)
Glucocorticoids	5 (56)	18 (53)
None	1 (11)	6 (18)
COVID-19 clinical course, n (%)
Asymptomatic	0	4 (12)
Mild	5 (55)	26 (76)
Pneumonia hospitalization	4 (44)	4 (12)
COVID-19 related death, n (%)	2 (22)	1 (3)

SD: standard deviation.

At the time of SARS-CoV-2 infection, 9 out of 43 patients were unvaccinated whereas 5, 26, and 3 had received 2, 3, or 4 doses of an mRNA vaccine, respectively. Age, diffuse type, body mass index (BMI), and comorbidities (not shown) were comparable between unvaccinated and vaccinated patients (Table 1).

COVID-19 outcomes in patients with SSc-associated ILD

Asymptomatic breakthrough SARS-CoV-2 infection was evident in four of vaccinated patients (12%), whereas none of the unvaccinated patients was asymptomatic. A mild disease course not requiring hospitalization, including one or more of fever, malaise, headache, sore throat, nasal congestion, cough, myalgia/arthralgia, and diarrhea, was present in 26 (76%) vaccinated patients and 5 (55%) unvaccinated patients, respectively. Eight of the patients with mild disease course (vaccinated, n = 7) received nirmatrelvir/ritonavir.

The other eight patients developed pneumonia and required hospitalization and antiviral treatment with remdesivir. Of them, two unvaccinated patients died due to respiratory failure, whereas one double vaccinated patient with primary cardiac involvement died due to cardiac arrest. The remaining five patients were discharged and fully recovered within the next month without worsening of dyspnea associated with preexisting ILD.

In order to search for predictors of hospitalization and/or death, multivariate analysis was next performed. As our descriptive data suggested, vaccination status seemed a main determinant of COVID-19 outcome. Because of the number of patients allowing to include in multivariate regression analysis up to 4 different parameters, in addition to lack of vaccination we elected to include a greater of 20% extent of ILD in HRCT, the presence of diffuse SSc and administration of immunosuppressive treatment at the time of infection. Indeed, this analysis revealed that the lack of vaccination against SARS-CoV-2 was the only independent predictor for hospitalization (p = 0.028) and marginally for death (p = 0.052) (OR = 7.98, 95% CI = 1.25–51.09, and OR = 32.7, 95% CI = 0.966–1110.98, respectively) (Table 2). Further analysis, comparing patients who had received two doses with patients who had received three or four doses of an mRNA vaccine showed that booster vaccination was significantly associated with less severe (hospitalization or death) COVID-19 disease (40% vs 6.9%, respectively, p = 0.034).

Table 2.

Predictors of hospitalization and death in 43 patients with systemic sclerosis (SSc)-associated interstitial lung disease (ILD).

Risk factor	Hospitalization		Death
	OR	p	OR	p
Lack of vaccination	7.98 (1.25–51.09)	0.028	32.7 (0.966–1110.98)	0.052
Extent of ILD (>20%)	0.65 (0.11–3.93)	0.644	0.78 (0.03–2.365)	0.143
Diffuse SSc	0.55 (0.09–3.21)	0.506	1.56 (0.08–28.62)	0.766
Immunosuppressive treatment	1.75 (0.28–10.80)	0.546	3.01 (0.145–62.69)	0.477

ILD extent in HRCT before and after COVID-19

Twenty-two patients, among them three hospitalized with COVID-19 pneumonia, had undergone a chest HRCT scan within 3 months prior to COVID-19 infection as part of their regular follow-up, as well as between 2 and 5 months after COVID-19. Individual changes in the extent of ILD before and after COVID-19 in these 22 patients are depicted in Figure 1. Overall, the comparison between the HRCTs before and after COVID-19 revealed that the individual ILD extent before COVID-19 (range 3%–70%, mean ± SD: 20.4% ± 17.8%) and after COVID-19 (range from 3%–64%, mean ± SD: 22.4% ± 18.4%) remained unchanged. HRCTs from a representative patient with pneumonia due to SARS-CoV2 in whom ILD remained stable following recovery are shown in Figure 2. Conversely, a notable deterioration in the extent of lung disease that could be attributed to COVID-19 in a male vaccinated patient who did not require hospitalization is shown in Figure 3.

Figure 1.

Individual changes in the percent extent of interstitial lung disease (ILD) in 22 patients with systemic sclerosis after COVID-19.

Figure 2.

High-resolution computed tomography performed 4 months before (a) and 2 months after (b) COVID-19 pneumonia requiring hospitalization show similar ILD extent in a vaccinated 65-year-old female with SSc.

Figure 3.

Extent of interstitial lung disease (ILD) in high resolution computed tomography of a vaccinated 57-year-old man with SSc performed 12 months (a, d) and 6 months (b, e) before COVID-19 is almost similar, whereas 3 months after COVID-19 (c, f) ILD progression is evident.

Discussion

In this study, we examined the outcomes of COVID-19, including breakthrough infections after vaccination, in SSc patients with pre-existing ILD and assessed whether SARS-CoV-2 infection triggers progression of their lung disease. The two main points derived from our study are that (a) lack of vaccination was the only independent predictor for hospitalization and death in these patients and (b) no radiographic progression was noticed after SARS-CoV2 infection.

To the best of our knowledge, no previous study has reported COVID-19 outcomes in consecutive patients with idiopathic or systemic rheumatic-disease (SRD) associated ILD. ILD is a common manifestation and the leading cause of death among patients with SSc. ²⁶ However, COVID-19 hospitalization and death rates are significantly increased in unvaccinated patients with SSc compared to the general population, as confirmed in our 12-month study, analyzing data derived from merging large nationwide databases covering the entire Greek population.^27,28 Interestingly, all-cause mortality in SSc patients during the first pandemic year decreased by more than half comparing to previous years ²⁹ in our country, reflecting the extent and efficacy of self-protective measures taken by these patients. ²⁸ It should be noted that a similar reduction in all-cause mortality was also reported during the early phase of the pandemic in Greece for patients with idiopathic ILD, again possibly due to the implementation of austere public health measures against COVID-19, including lock-down. ³⁰

Our findings indicate a protective effect of COVID-19 vaccination against hospitalization and possibly also against death in SARS-CoV-2 infected patients with underlying SSc-associated ILD, corroborating the results of a previous study from our group, which shows that vaccinated patients with SRD and breakthrough COVID-19 have by far better outcomes compared with their unvaccinated counterparts. ³¹ In our cohort of SSc patients who contracted SARS-CoV-2, 9 out of 43 were unvaccinated. This makes sense, given that vaccines against COVID-19 only became available to patients with SRD in Greece from March 2021 onwards. Furthermore, despite proven safety and effectiveness, ³² vaccine hesitancy has also been an issue among patients with SRDs at least during the initial phases of the pandemic in Greece. ³³ Furthermore, it should be kept in mind that vaccine-induced immunity wanes over time, rendering the need for booster doses imperative to protect against COVID-19 associated hospitalization and death. ³⁴ Notably, 29 of our 43 patients had received a 3^rd or 4^th booster dose of an mRNA vaccine by the time they got infected with SARS-Cov-2 and analysis showed they had a less severe COVID-19 disease compared to fully vaccinated patients. Finally, outcomes of eight patients in our study could have been to some extent affected by the use of nirmatrelvir/ritonavir, since this treatment has shown efficacy in the SRD patient population. ³⁵

At the beginning of the pandemic, serious concerns were raised that SARS-CoV-2 could lead to progressive, fibrotic irreversible interstitial lung disease. ³⁶ Importantly, COVID-19 infection was not associated with deterioration of pre-existing ILD in our study. Differentiating COVID-19 pneumonia and SSc-ILD is possible in clinical practice. ³⁷ Following COVID-19 pneumonia, the presence of fibrotic like changes is associated with older age, acute respiratory distress syndrome, longer hospitalization, mechanical ventilation, and higher initial extent of disease on CT. ³⁸ In our cohort of 22 patients with available HRCT before and after COVID-19, only 3 were hospitalized due to pneumonia. Despite the small number, none of these patients exhibited progression of their underlying ILD. In contrast, progression of ILD could be attributed to a mild COVID-19 rather to SSc physical history in one vaccinated patient. SARS-CoV-2 may promote pulmonary fibrosis not only by direct injury of the lung parenchyma but also by causing immune dysregulation. The latter has been proposed as a possible mechanism of myocardial fibrosis in the absence of direct involvement of the myocardium. ³⁹ Intereukin-6, characteristic of COVID-19, is known to play a pivotal role in the pathogenesis of systemic sclerosis and represents a therapeutic target.^40,41 Also, systemic imbalance in the renin-angiotensin system in the context of COVID-19 promotes the development of lung fibrosis. ⁴² The development of a profibrotic microenvironment can pose significant risks especially in patients with SSc and pre-existing ILD given the fact that they represent the archetypical example of chronic progressive fibrotic disease. Thus, the general absence of exacerbation of pre-existing lung disease after COVID-19 is an observation of clinical value.

To conclude, breakthrough COVID-19 has by far better outcomes compared to COVID-19 in unvaccinated SSc patients with ILD who are at very high risk for hospitalization and death. Therefore, vaccination and repeated doses when advised ⁴³ are of outmost importance. In general, COVID-19 does not seem to promote progression of SSc-associated ILD, at least in vaccinated patients, but further studies are clearly warranted.