Keywords
COVID-19 - chronic thromboembolic pulmonary hypertension - post-COVID - long COVID
- pulmonary endarterectomy
Introduction
The world has been dealing with coronavirus disease 2019 (COVID-19) and its complications
since December 2019. Although it has been more than 2 years with the pandemic, numbers
of patients have still been rising to date. More than 400 million cases and 6 million
deaths have been reported all over the world so far.[1] Due to the accumulating data and the vaccinations, we, the physicians, have built
a general opinion about the course of the disease. Unfortunately, long-term complications
are still not totally clear and we face with new clinical entities every day.[2]
[3]
[4]
[5]
[6] There are different studies about various biomarkers discussing the pathophysiology
behind this spectrum of diseases and symptoms.[7]
[8] Thrombosis and venous thrombosis associated with COVID-19 are one of the most feared
and well-documented complications of the disease.[9]
[10] Thus, guidelines and recommendations have been published regarding the use of prophylaxis
for thromboembolism.[11]
[12] Moreover, patients with pulmonary hypertension started emerging in the long-term
follow-ups during the assessment of resisting pulmonary symptoms. Even though there
are established treatment guidelines for pulmonary embolism (PE), 2 to 4% of the patients
develop chronic thromboembolic pulmonary hypertension (CTEPH). Although specific programs
exist all over the world, diagnosis of CTEPH is easily missed due to the lack of awareness
among physicians. To date, it has been well accepted that pulmonary endarterectomy
(PEA) is the only curative treatment of CTEPH.[13]
[14]
[15]
Here, we report our experience with 11 patients with post-COVID CTEPH who underwent
PEA and review our data regarding clinical features, management, and outcomes.
Methods
Between March 2011 and July 2022, 896 consecutive patients underwent PEA at our institution.
A total of 11 patients (seven males, four females) were surgically treated with post-COVID
CTEPH. Medical records of the 11 patients were retrospectively reviewed from a prospectively
conducted database in terms of demographics, clinical features, peri- and postoperative
complications, length of hospital stay, morbidity, mortality, and short- and long-term
results. Operative mortality was described as death in hospital or within 30 days
of surgery. The research board of our center approved the ethical application for
this study.
Patients who had PE during or after COVID-19 infection were followed up by our PE
team and the diagnosis of CTEPH was made by the presence of mismatched perfusion defects
on ventilation perfusion (V/Q) scan in conjunction with evidence of pulmonary hypertension
despite adequate anticoagulation for at least 3 months. Patients who had a past medical
history of PE, any kind of coagulopathy, or major risk factors were excluded from
the study. Pulmonary function tests including computed tomography pulmonary angiography
(CTPA), 6-minute walk test (6MWT), and right heart catheterization were performed
as a routine preoperative work-up for all patients. Our indications for PEA surgery
can be listed as: patients with mean pulmonary artery pressure (mPAP) of at least
20 mm Hg; pulmonary vascular resistance (PVR) of at least 300 dyn/s/cm−5; surgically accessible disease demonstrated on CTPA; and World Health Organization
(WHO) functional class greater than II. Institutional standard protocols were followed
for each patient in the management of perioperative anesthesia and postoperative care.[16]
They were followed up at every 3- to 6-month intervals by the multidisciplinary team.
Patients were functionally evaluated according to WHO functional class and examined
at each follow-up with CTPA, 6MWT, and echocardiogram.
Statistical Analysis
Statistical analyses were performed using statistical software (SPSS, version 25.0
for Windows; SPSS, Chicago, Illinois, United States). Discrete random variables were
presented as percentage and continuous random variables were presented as median and
range (minimum–maximum values). A p-value < 0.05 was considered statistically significant.
Results
Eleven patients (seven males, four females) with a median age of 52 (22–63) years
were diagnosed with post-COVID CTEPH and underwent PEA. The demographic and preoperative
characteristics of the patients are shown in [Table 1]. All patients described shortness of breath and fatigue as the chief complaint.
Functional capacity of the patients was WHO class III or IV.
Table 1
Patient demographics and preoperative characteristics
|
Characteristics
|
Value or n
|
|
Age (y)
|
52 (22–63)
|
|
Sex (n)
|
|
Female
|
4 (36.4%)
|
|
Male
|
7 (63.6%)
|
|
Duration from COVID-19 to surgery (mo)
|
12 (6–24)
|
|
Symptoms (n)
|
|
Shortness of breath
|
11 (100%)
|
|
Fatigue
|
11 (100%)
|
|
Cough
|
5 (45.4%)
|
|
Headache
|
4 (36.4%)
|
|
Syncope
|
1 (91%)
|
|
WHO class (n)
|
|
I
|
0
|
|
II
|
0
|
|
III
|
8 (72.7%)
|
|
IV
|
3 (27.3%)
|
|
6MWT (m)
|
255 (0–462)
|
|
FEV1 (L)
|
2.24 (1.18–3.05)
|
|
FEV1 (%)
|
75 (70–84)
|
|
FEV1/FVC
|
86 (77–128)
|
|
sPAP (mm Hg)
|
66.5 (28–92)
|
|
mPAP (mm Hg)
|
40 (24–54)
|
|
Cardiac index (L/min/m2)
|
2.49 (1.4–3.26)
|
|
Cardiac output (L/min/m2)
|
4.3 (3.02–6.91)
|
|
PVR (dyn/s/cm−5)
|
572 (240–1,192)
|
|
Comorbidities (n)
|
|
CAD
|
1 (9.1%)
|
Abbreviations: 6MWT, 6-minute walk test; CAD, coronary artery disease; COVID-19, coronavirus
disease 2019; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; mPAP, mean pulmonary
arterial pressure; PVR, pulmonary vascular resistance; sPAP, systolic pulmonary arterial
pressure; WHO, World Health Organization.
Note: The values are presented as number (%) or median (range).
Intraoperative Course and Complications
All PEAs were performed under deep hypothermia and intermittent circulatory arrest
(20°C). The rewarming phase began after completion of PEA on both sides. Patients
were kept intubated and transferred to the intensive care unit (ICU), where both postoperative
hemodynamic parameters and mPAP were closely monitored from the first postoperative
day until transfer from the ICU to the floor. The intraoperative and postoperative
data are summarized in [Table 2]. All postoperative hemodynamic measurements were monitored and recorded for all
the patients. Thirty-day mortality was observed in one patient (9.09%) due to sepsis
on the fifth postoperative day. One patient needed two-vessel coronary artery bypass
graft in addition to PEA. Images of the chronic thromboembolism and surgical specimen
are shown in [Fig. 1].
Table 2
Intraoperative and postoperative data
|
Value
|
|
CPB (min)
|
180 (215–149)
|
|
Aortic cross-clamp (min)
|
29 (4–67)
|
|
TCA (min)
|
19 (4–44)
|
|
ECMO (n)
|
0
|
|
MV time (d)
|
1 (1–2)
|
|
ICU (d)
|
2 (2–3)
|
|
LOS (d)
|
10 (8–14)
|
|
Postoperative mPAP (mm Hg)
|
24 (15–36)
|
|
Postoperative PVR (dyn/s/cm−5)
|
240 (195–377)
|
|
Postoperative WHO class I (n)
|
10 (90.1%)
|
Abbreviations: CPB, cardiopulmonary bypass; ECMO, extracorporeal membrane oxygenation;
ICU, intensive care unit; LOS, length of hospital stay; mPAP, mean pulmonary arterial
pressure; MV, mechanical ventilation; PVR, pulmonary vascular resistance; TCA, total
circulatory arrest; WHO, World Health Organization.
Note: The values are presented as number (%) or median (range).
Fig. 1 Images of preoperative CTPA and postsurgical specimen. CTPA shows enlarged main pulmonary
artery (yellow arrow) and chronic thromboembolism in the left main pulmonary artery (red arrow). CTPA, computed tomography pulmonary angiography; PE, pulmonary embolism.
Follow-up
Median PVR improved significantly from 572 dyn/s/cm−5 (240–1,192) to 240 (195–377) dyn/s/cm−5 (p < 0.005). Significant difference was also detected in median mPAP, as it decreased
from 40 mm Hg (24–54) to 24 mm Hg (15–36) following surgery (p < 0.005). Images of the surgical materials can be seen in the [Fig. 2]. Median time from COVID-19 disease to surgery was 12 months (6–24). Median length
of hospital stay of the survivors were 10 days (8–14). Median follow-up after PEA
was 8 (2–14) months for all the survivors and they all improved to WHO functional
class I and II.
Fig. 2 Pulmonary endarterectomy specimens resected from some of the post-COVID CTEPH patients.
Discussion
After the first COVID-19 case in China in 2019, the whole world turned into a new
era in many different capacities, and we still have been feeling its effect, especially
in the medical field. Even though we have come far with the management of the disease,
we are not out of the woods yet. We see different complications and presentations
of the post-COVID patients and try to identify them to build diagnostic and therapeutic
protocols.[5]
[17] Everyday, physicians encounter patients having various kinds of symptoms that they
did not have before COVID-19, and the management of these patients can be challenging
due to lack of data. There are different symptoms and diseases in various fields of
the medicine, and they have been assessed under the topic of long-COVID or post-COVID
syndrome.[18]
[19]
Venous thromboembolism (VTE) and PE were one of the first discovered complications
of COVID-19 since the beginning of the pandemic.[20] PE is one of the major clinical problems and has clinical presentation mimicking
many other diseases and the potential of unfavorable outcomes.[21] Even though there are well-established diagnostic and treatment algorithms, it is
easily underdiagnosed, resulting in inadequate treatment. It is estimated that the
annual mortality related to PE is around 300,000 in both United States and Europe.[22]
[23] Jimenez et al[24] reported the incidence of the VTE and PE in COVID-19 patients as 17 and 7.1%, respectively.
Additionally, Poissy et al reported a 20.6% incidence of PE among COVID-19 patients.[25] Thus, studies started to emerge presenting recommendations and protocols for the
prophylaxis of PE and VTE. Additionally, prophylactic low-dose heparin is one of the
few medications that are widely accepted by the medical authorities in the battle
with COVID-19. There are multiple theories explaining the pathophysiology of increased
risk of PE with COVID-19 infection. Poor pointed to the effect of microvascular in
situ immunothrombosis because of activated innate immune system.[26] On the other hand, Jayarangaiah et al blamed mainly the potentiating effect of immune
system and coagulation pathways on each other for the occurrence of VTE and PE.[27]
As we know, even with the established protocols and medications, 2 to 4% of all PE
patients develop CTEPH.[28]
[29] CTEPH can be defined as chronic stenosis and occlusion of the pulmonary arteries
due to obstructive intraluminal organized thromboembolic materials. It is categorized
as Group 4 pulmonary hypertension according to the 6th World Symposium on Pulmonary
Hypertension classification and diagnosed with having mPAP ≥ 20 mm Hg with a pulmonary
arterial wedge pressure of ≤15 mm Hg. These hemodynamic parameters must be supported
by the radiological verification after 3 months of anticoagulation. PEA is still the
only curative treatment when the disease is surgically accessible. Cueto-Robledo and
colleagues recently published the first case series of post-COVID CTEPH patients.
They followed up 77 COVID-19 patients with PE for 11 months and 3 (3.8%) of them developed
CTEPH.[30] All patients received medical treatment and none of these patients underwent PEA.
Their data showed a similar incidence of CTEPH with the regular population, but it
is very early to conclude. We need to review our data worldwide to identify the real
incidence of the disease. Moreover, we must be sure whether we can use the same protocols
as with the regular PE for the management of these patients. Although this is an important
study in the post-COVID era, no data exist about the outcomes of surgical treatment.
Our study presents the largest patient population of post-COVID CTEPH who underwent
PEA.
A limitation of our study is the low volume of the patient population, but this can
be explained by the lack of data due to the recent occurrence of the disease after
COVID-19. Another limitation is the absence of the comparison of the results with
the non-COVID CTEPH patients, but this study is designed to describe the characteristics
and surgical outcomes of a new group of patients for the first time in the literature
and to pave the way for the future studies with more patients. We expect to see more
post-COVID CTEPH patients in the following years. Therefore, we plan to design a future
study comparing both groups with higher volume of patients for better understanding
of this new entity.
CTEPH is a severe disease necessitating experienced teams for its management. Although
there are multiple CTEPH and PH centers all over the world, only 16% of the patients
find the chance to get diagnosed. Things are more complicated for the post-COVID CTEPH
patients. We should design more studies for the better understanding of the disease.
It is important to know whether we can treat these patients as we treat the other
CTEPH patients or we should find totally different options. There are multiple medications
for keeping pulmonary hypertension under certain levels to preserve right heart and
quality of life, but we do not know if these medications will be helpful in the management.
On the other hand, it is important to create awareness of the post-COVID CTEPH among
physicians dealing with post-COVID and long-COVID patients. It is in the best interest
of the patients to get referrals to experienced centers as early as possible for better
outcomes. Post-COVID CTEPH is another new entity that COVID-19 brought into medical
field and, given the circumstances, it looks like the number of patients will be increased
day by day. As we see a lot of long-term symptoms and clinical manifestations in patients
who had COVID-19, we should always remember CTEPH in the differential diagnosis.
