The paradox of pulmonary arterial hypertension in Italy in the COVID-19 era: is risk of disease progression around the corner?

Discussion

To accurately understand the risk of COVID-19 and inform decision- and risk-matrices going forward, the iPHNET community undertook an audit of patients with PAH between March 1 and May 1, 2020, to coincide with the first peak of COVID-19 within Italy. These data represent the largest assessment of the impact of SARS-CoV-2 infection on patients with PAH to date based on patient-level information.

The main finding of the present study was the significant decrease in the number of PAH outpatient visits and PAH-related tests across Italy during the COVID-19 outbreak. Indeed, case volumes of outpatient clinics downsized to 20–30% during the pandemic of the equivalent period in the previous year. The second unexpected finding to emerge from our study, and shown for the first time, is the low morbi-mortality rates in the PAH cohort despite the apparent toned-down level of care from the previous year. Finally, we found an exceptionally low incidence of COVID-19 among PAH patients in contrast to those with other chronic lung and heart diseases, but still with a very high mortality rate.

Identifying the mechanisms behind the unusual behaviour of a severe disease like PAH in relation to COVID-19 is beyond the scope of the present study. Nevertheless, it is tempting to speculate that a number of factors, rather than a unique determinant, contributed to the phenomenon.

Chronic diseases like PAH are considered to be fragile clinical conditions; therefore, close monitoring of specific sets of parameters, largely included in current European and US risk scores, positively influences patient outcomes, reducing intercurrent acute events and related hospitalisations, when applied in clinical practice [8, 10, 11]. Tragically, COVID-19 has placed an enormous strain on the healthcare systems of nations in which it has spread widely, and the disease has specific implications on clinical practice. In Italy the Government established a stepwise strategy starting from the complete lockdown of initial foci in Northern Italy on February 20, 2020, and subsequent adoption of progressively more stringent lockdown measures for the entire nation as of March 8, 2020 [12]. All systematic activities at centres, including elective hospitalisation and procedures, were cancelled and non-urgent outpatient visits were discouraged. Although the degree of disruption to usual practice varied across regions owing to differences in population density, rates of community spread, time to peak disease burden and resource availability, institutions were stretched in an effort to preserve resources and avoid exposure of patients to the hospital environment, where COVID-19 has been more prevalent. In PAH centres, patients’ scheduled clinic visits were postponed, leading to a dramatic reduction in the number of overall outpatient visits compared with the previous year. Periodic risk assessment through the European and REVEAL score tools were often unfeasible; 6MWTs and pro-BNP measurement were largely unavailable to clinicians. Elective hospitalisation for RHC needed to be postponed multiple times, again causing a significant reduction in the number of procedures compared with the same period of the previous year. These data are in agreement with the estimates of cumulative data from a large cross-sectional anonymous survey of programme directors at accredited pulmonary hypertension centres in the USA [13] and from an international survey [14], and confirm the substantial impact of COVID-19 on clinical operations at centre level.

It would be expected that downsizing these systematic activities would significantly increase hospitalisations for heart failure and negatively impact on patients’ outcomes, leading to higher mortality rates when compared to standard of care. However, this was paradoxically not the case for PAH, as evidenced by lower mortality rates compared with the same period of the previous year and even lower hospitalisation rates for right heart failure.

In our opinion, this could be at least in part related to the great changes that the last two decades have witnessed in Italy in the field of PAH. While the pandemic was evolving, without predetermined planning, networking among clinicians and the sharing of experiences between high- and low-volume centres throughout the country brought many benefits that allowed clinicians to reassure and maintain doctor–patient relationships and promoted the adoption of similar procedures with key features of programmes for periodic follow-up and patient support [15]. As a result, close communication with patients became a prime characteristic of all pulmonary hypertension centres, a critical issue to ensure ongoing delivery of optimal cardiac care, with less systematic activities encouraging more effective remote interfacing between clinicians and PAH patients (figure 5). Because all procedures that were originally scheduled for the next 2 months were cancelled, patients were subsequently categorised and reprioritised in the majority of centres. Given the limitations of telemedicine among PAH centres, a large proportion of outpatients received a follow-up call within 1–2 weeks of the initial encounter to ensure they were stable prior to scheduling future check-ins according to their tier of risk. According to common sense, patients known to be low risk and found to be stable on a phone-call basis were managed conservatively and in-person visits were postponed until a safer date. For patients known to be intermediate risk, case decisions were individualised, taking into account the risk of COVID-19 exposure versus the risk of a delay in disease progression recognition and treatment escalation, and usually resulting in check-in calls every 1–3 months. By contrast, high-risk patients usually received at least weekly or biweekly check-in calls and when possible were offered the option to keep the original appointment, especially in Central and South Italy where the spread of COVID-19 was less pressing. In cases where there was a likelihood of rapidly worsening symptoms, an intervention was deemed urgent and patients were hospitalised under safe, controlled procedures when possible or, more frequently, as in North Italy, through the emergency department.

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FIGURE 5

Schematic illustration of remote interfacing between clinicians and pulmonary arterial hypertension (PAH) patients following less systematic activities during the COVID-19 outbreak. WHO: World Health Organization.

This empirical approach requires close and attentive follow-up of patients at a future date to identify disease progression that potentially occurred during the COVID pandemic. Indeed, less aggressive escalation of treatment was recorded in the 2020 period compared with 2019.

A further important finding from our study covers the unknown incidence of acquired SARS-CoV-2 infection and COVID-19 among PAH patients in Italy. Indeed, the risk for patients with PAH has not yet been quantified because patients with uncommon diseases may not be accurately reported with specific diagnostic information in the administrative healthcare datasets that are used for large observational studies. The incidence of SARS-CoV-2 infection, reported for the first time in an Italian PAH cohort, was 1.0%, while the incidence of COVID-19 was very close to that reported for the overall Italian population in the same period (0.46% versus 0.34%) [16], and similar to the estimated rate in the US PAH population (0.29%) [13]. With regards the distribution throughout the regions of the country, in North Italy the incidence of COVID-19 among PAH patients during the study period was 0.87% (seven cases), very close to that reported in the general population (0.76%). Similar results were found for Central Italy, with 0.17% (one case) versus 0.20%, and South Italy, with 0.14% (one case) versus 0.11%. Our observation is in contrast with other studies that have identified patients with chronic diseases, e.g. diabetes mellitus, ischaemic heart disease and other non-PAH chronic pulmonary diseases, as a vulnerable group with a high incidence of COVID-19 with a poor outcome [17–21], including a case–control study conducted in Italy [22]. In Tuscany (Central Italy), between March and April 2020, a higher incidence of COVID-19 infection was found among patients with chronic diseases such as diabetes mellitus, ischaemic heart disease and chronic obstructive pulmonary disease compared with the general population: 0.32%, 0.38% and 0.43%, respectively [22]. An increased risk of COVID-19 infection was shown in patients with chronic diseases even adjusting for age, sex and other comorbidities.

This result may partially reflect the self-isolation chosen by many patients during the pandemic, leading to apparent protection from COVID-19. In addition, because the vast majority of patient–physician interactions during the COVID-19 outbreak were remote, clinicians from PAH centres provided clear guidance on when to request phone consultations or urgent in-person evaluations to minimise risk of transit-related and hospital-related infection. Frequent, transparent communication gave patients confidence that their care was not being neglected, avoiding in-person attempts to get in touch with the clinical team. Finally, we may further consider the reduced angiotensin converting enzyme 2 (ACE-2) expression shown in PAH [23], the contrasting viral entry mechanism, and the potential protective effects of PAH-targeted therapies against SARS-CoV-2 infection as suggested by some authors [24, 25].

Nevertheless, these data demonstrate that patients with PAH are at increased risk of death following hospitalisation for COVID-19, with 100% mortality rates, in keeping with data already reported for other severe chronic diseases [26–28].

The final, not unexpected, finding from our study was the dramatic reduction in the number of new PAH diagnoses across Italy during the COVID-19 pandemic. This was in line with other diseases, even when acute conditions were considered as acute coronary syndromes [29, 30], and mainly reflects patients’ fear of contagion, especially after the media reported the infection spread across hospitalised patients and healthcare personnel due to the lack of appropriate personal protection equipment at an early stage of the pandemic. A further explanation is related to the shift-based allocation of clinicians needed to operate in other hospital COVID areas. This might have induced an attitude towards deferral of less urgent cases at the healthcare system levels with a consequent reduction in referral to PAH centres of patients with suspected PAH. This may have led to delays in patients' treatment initiation with important prognostic implications in the near future.

Interestingly, when written in Chinese the word crisis (weiji) is composed of two characters. One represents danger (wei), while the other opportunity or crucial point (ji). Our National Health System has speculated on implementing telemedicine many times over the last two decades. Now that the Loosened Health Insurance Portability and Accountability Act (HIPAA) [31] rules have enabled the use of alternative modes of patient communication, such as personal phones for medical calls, e-mailing and web conferencing applications to facilitate a video encounter, the benefits now outweigh the risks and the Italian Government can use this opportunity to enhance and support the conversion of local hospital administration from traditional visits to telehealth visits [32, 33]. Indeed, telehealth applications are one of the main goals of the Recovery Plan of the Italian Government [34], in accordance with the Annual Sustainable Growth Strategy of the European Committee, where remote devices will be implemented and expanded throughout the country.