Elevated Natriuretic Peptides in Patients With Severe or Critical COVID-19: A Meta-Analysis

Abstract

Background

The worldwide COVID-19 pandemic caused by SARS-CoV-2 has resulted in an extraordinary increase in the number of patients who are severely critically ill. For many of these patients, cardiovascular risk factors are key contributors to the development of severe illness. Laboratory markers for cardiac damage and failure, such as natriuretic peptides, are reported to be elevated in patients with severe COVID-19.

Methods

We conducted a systematic review and meta-analysis to compare natriuretic peptide levels in patients with severe COVID-19 vs those with nonsevere COVID-19. PubMed and medRxiv were searched through April 7, 2020. The outcome of interest was the difference in B-type natriuretic peptide (BNP) or N-terminal-proBNP levels in patients with severe vs nonsevere COVID-19.

Results

We identified 9 retrospective cohort studies that had a total of 1,575 patients with COVID-19 who had their natriuretic peptides measured and were classified by disease severity. All studies were conducted in China. Patients with severe COVID-19 had significantly higher BNP levels than patients with nonsevere COVID-19 (mean difference, 69.56 pg/mL; 95% CI, 1.77–137.35 pg/mL; P = .04, I₂ = 83%). Similarly, patients with severe COVID-19 had significantly higher N-terminal-proBNP levels than patients with nonsevere COVID-19 (mean difference, 518.65 pg/mL; 95% CI, 152.40–884.90 pg/mL; P = .006, I₂ = 86%).

Conclusions

In this study, Chinese patients with severe COVID-19 had higher natriuretic peptide levels than those with nonsevere COVID-19. Studies from all countries affected by the virus will help to further delineate whether the cause is directly or indirectly of cardiac origin and whether preexisting heart failure has an influence on this disparity.

The COVID-19 outbreak, which originated in Wuhan, China, has proliferated globally to encompass nearly every country: As of August 26, 2022, COVID-19 was known to have infected approximately 596,873,121 persons and was responsible for more than 6,459,684 documented deaths.¹ Generally, older patients and patients with preexisting health conditions, such as obstructive pulmonary disease, chronic kidney disease, or cancer, may be at heightened risk for becoming symptomatic and experiencing critical illness.

Severe illness has been noted to be accompanied by comorbid cardiovascular disease, with hypertension accounting for a 2.5-fold higher risk of critical illness.^2,3 In a large retrospective study of deceased patients, the most frequent comorbid condition was hypertension, accounting for 15% of patients.⁴ Furthermore, infection with the SARS-CoV-2 virus has itself been associated with the development of new-onset cardiovascular outcomes, regardless of whether patients had preexisting cardiovascular illness.⁵

Cardiac injury, marked by elevated troponin levels, has been identified in several COVID-19 cohorts.^3,6 This was particularly apparent in patients with poor clinical status, such as those with acute respiratory distress syndrome (ARDS), those admitted to an intensive care unit (ICU), or those who died.^3,7,8 Elevated brain natriuretic peptide (BNP) or N-terminal proBNP (NT-proBNP) levels, which are a marker of elevated ventricular filling pressure, have also been shown to be associated with poor short-term mortality in patients with sepsis.⁹ However, the prognostic value of these natriuretic peptides in patients with COVID-19 remains largely unknown. Therefore, we conducted a systematic review and meta-analysis to assess the association between natriuretic peptides and illness severity in patients with COVID-19.

Patients and Methods

We conducted a systematic review of literature published up to April 7, 2020. Data sources included MEDLINE (PubMed and PubMed Central) and early prepublished literature (www.medrxiv.org). Search terms were as follows: BNP or NT-proBNP or natriuretic or laboratory; COVID or COVID-19 or 2019-nCoV or SARS-CoV-2 or SARS-CoV2 coronavirus 2019. We included human studies, retrospective single-center or multicenter studies, case series and case reports, and randomized controlled trials. We excluded duplicate publications, animal studies, systematic reviews and meta-analyses, and studies that did not pertain to the current COVID-19 pandemic or did not present laboratory values. Two authors (B.B. and T.A.) independently analyzed the search results and determined eligibility. A third author (T.K.) was consulted to resolve instances of ambiguity.

Further analysis was done to identify any publications that included patients from the same hospital to avoid double-counting individual patients. Several criteria informed the decision of which studies to include. First, studies were required to have included laboratory values from patients with severe or critical illness and from patients with nonsevere illness. Second, studies that included data from the same hospital were carefully examined for overlapping study period dates. If any 2 studies had overlapping dates, the study with the longer time span and the larger patient sample was preferred over the other. For example, if 2 different studies from the same hospital evaluated BNP values and had overlapping dates, the larger and longer study was included and the other was not. Conversely, if 2 studies from the same hospital had overlapping dates but one study evaluated only NT-proBNP and the other study evaluated only BNP, the study populations were deemed different and both were included.

Illness severity was defined in various ways across studies. Some studies defined severity at the time of admission according to American Thoracic Society guidelines for community-acquired pneumonia; others predefined severity on the basis of various parameters, such as arterial oxygen partial pressure, respiratory rate, or ICU admission.¹⁰ Most of the studies classified severe illness as a respiratory rates greater than or equal to 30 breaths per minute, oxygen saturation less than or equal to 93% (as measured by pulse oximeter), or a ratio of partial pressure of arterial oxygen to fractional inspired oxygen less than or equal to 300 mm Hg. Other criteria used in a few studies included ICU admission, imaging showing multilobular lesions or lesion progression. Despite this heterogeneity, efforts were taken to match patients with similar illness severity across studies. Authors of the selected manuscripts were not contacted to clarify discrepancies or to solicit additional data.

The pooled mean difference was calculated using inverse variance weighted random-effects models. All study results were combined using conversion formulas for estimating means and SDs from nonparametric data, as previously reported.¹¹ Statistical analyses were performed using Review Manager version 5.3.5 (The Nordic Cochrane Centre).

Results

In our literature search, we identified 9 eligible observational studies that included a total of 1,575 patients with COVID-19 (Fig. 1); no prospective studies or randomized controlled trials were identified. All of the included studies represented patients who were treated for SARS-CoV-2 infection at hospitals located in China. Of the 1,575 patients, 342 (21.7%) were identified as having severe illness. Individual study characteristics are presented in Table I.^12–20

Fig. 1.

Study selection

TABLE I.

Study Characteristics

	Bai X, et al20	Lu H, et al17	Peng YD, et al14	Zheng Y, et al18	Han H, et al13	Feng Y, et al16	Hong X, et al12	Chen T, et al15	Han Y, et al19
Study type	Retrospective, multicenter	Retrospective, multicenter	Retrospective, multicenter	Retrospective, multicenter	Retrospective, multicenter	Retrospective, multicenter	Retrospective, multicenter	Retrospective, multicenter	Retrospective, multicenter
Hospital name (location)	Wuhan Pulmonary Hospital (Wuhan) Tongji Hospital (Wuhan)	Shanghai Public Health Center (Shanghai)	Western District of Union Medical College (Wuhan)	Chengdu Public Health Clinical Medical Center (Chengdu)	Renmin Hospital of Wuhan University (Wuhan)	Jinyintan Hospital (Wuhan) Shanghai Public Health Clinical Center (Shanghai) Tongling People’s Hospital (Anhui)	Shantou Central Hospital (Guang dong)	Tongji Hospital (Wuhan)	Renmin Hospital of Wuhan University (Wuhan)
BNP or NT-proBNP measured	BNP	NT-proBNP	BNP	NT-proBNP	NT-proBNP	BNP	BNP	NT-proBNP	BNP
Patients with severe COVID-19, No. (%)	54 (40.6)	22 (8.3)	16 (14.3)	30 (35.7)	60 (22.0)	54 (11.3)	2 (16.7)	80 (46.2)	24 (51.1)
Qualifications for severe COVID-19 (one of the listed conditions)	(1) RR ≥30, or (2) SpO2 ≤93% on RA, or (3) PaO2/FiO2 <300 mm Hg, or (4) ICU admissiona	(1) RR ≥30, or (2) SpO2 ≤93% on RA, or (3) PaO2/FiO2 ≤300 mm Hg	(1) RR ≥30, or (2) SpO2 ≤93% on RA, or (3) PaO2/FiO2 <300 mm Hg	(1) RR ≥30, or (2) SpO2 ≤93% on RA, or (3) PaO2/FiO2 ≤300 mm Hg, or (4) pulmonary imaging findings,b or (5) other clinical conditions requiring hospitalization	(1) RR ≥30, or (2) SpO2 ≤93% on RA, or (3) PaO2/FiO2 ≤300 mm Hg	(1) RR ≥30, or (2) SpO2 ≤93% on RA, or (3) PaO2/FiO2 ≤300 mm Hg	N/A	Defined according to the NHCC’s 2020 guidance for control of coronavirus disease21	Defined according to the ATS guidelines for CAP10
Mean or median NT-proBNP level, pg/mL c
Severe COVID-19	467.2*	76.1**	20.4**	1,085.6*	290.9**	52.5**	380.8*	800.0**	501.2*
Nonsevere COVID-19	141.1*	32.9**	33.4**	66.9*	113.7**	34.5**	115.8*	72.0**	132.8*

ATS, American Thoracic Society; BNP, brain natriuretic peptide; CAP, community-acquired pneumonia; FiO₂, fraction of inspired oxygen; ICU, intensive care unit; NHCC, National Health Commission of China; NT-proBNP, N-terminal proBNP; PaO₂, partial pressure of arterial oxygen; RA, room air; RR, respiratory rate; SpO₂ , blood oxygen saturation [measured by pulse oximeter].

^aPatients in the ICU with 1 or more multiple organ failure, shock, or on mechanical ventilation.

^bPulmonary imaging showing multilobular lesions or lesion progression more than 50% within 50 hours.

^cSingle asterisks (*) denote mean values and double asterisks (**) denote median values.

In our analysis, BNP level was significantly higher in patients with severe COVID-19 than in patients with nonsevere COVID-19 (mean difference, 69.56 pg/mL; 95% CI, 1.77–137.35 pg/mL; P = .04, I₂ = 83%) (Figure 2). Similarly, NT-proBNP levels were significantly higher in patients with severe COVID-19 than in those with nonsevere COVID-19 (mean difference, 518.65 pg/mL; 95% CI, 152.40-884.90 pg/mL; P = .006, I₂ = 86%) (Figure 3).

Fig. 2.

Forest plots and supporting data comparing BNP levels in patients with severe vs nonsevere COVID-19 (P = .04) Units shown are pg/mL; P < .05 was considered significant.

BNP, brain natriuretic peptide; IV, inverse variance.

Fig. 3.

Forest plots and supporting data comparing NT-proBNP levels in patients with severe vs nonsevere COVID-19 (P = .006) Units shown are pg/mL; P < .05 was considered significant.

NT-proBNP, N-terminal pro-brain natriuretic peptide; IV, inverse variance.

Discussion

Given that this analysis of patients infected with the SARS-CoV-2 virus was completed early in the pandemic, all eligible publications were from China, the outbreak epicenter. We found that elevated BNP and NT-proBNP levels were significantly associated with severe or critical illness in these Chinese patients. Elevated BNP and NT-proBNP levels identify patients with acute dyspneic episodes who are having exacerbation of congestive heart failure.

Natriuretic peptide levels, which are elevated in response to myocardial stress, can also increase in disorders that indirectly influence the heart, such as pulmonary embolism, hypertension, sepsis, renal failure, and inflammatory and infiltrative diseases.²² There is ongoing debate as to whether elevated BNP levels in patients with severe COVID-19 are caused by heart failure exacerbations or are the result of new-onset cardiomyopathy. Also unclear is whether cardiac dysfunction is because of direct viral infection or to sequelae of the body's response to the virus. Patients with COVID-19 often experience ARDS, which can itself cause right-heart strain and increase natriuretic peptide levels. In patients without heart failure, elevations in natriuretic peptides may be caused by ventricular dysfunction after an acute coronary event, elevated stress levels, or myocarditis from the SARS-CoV-2 virus itself. Cardiac injury and arrhythmia were found to be more prevalent in patients with severe COVID-19 than in patients with less-severe COVID-19. Fulminant myocarditis also has been described in patients with COVID-19.^23,24

Angiotensin-converting enzyme 2 (ACE2), which is widely expressed, including in the lung, heart, gut, and vascular endothelium, has been identified as the SARS-CoV-2 receptor and plays an important role in target organ dysfunction, as ACE2 binding by the virus attenuates an organ-protective anti-inflammatory cascade.^25–27 Infection of the cardiac myocytes, where ACE2 is amply expressed, could help explain the pathogenesis of myocarditis seen in COVID-19 and may re-affirm coronavirus-associated heart damage found in current and earlier pathological studies.^26,28 The interplay between SARS-CoV-2 and ACE2 has been noted to increase angiotensin II levels, which in turn increases natriuretic peptide levels.²⁹

Cardiac injury in general has been noted in severe cases of COVID-19, with significant increases in troponin levels particularly noted in patients in the ICU vs those not in the ICU.⁸ In one single-center retrospective study, troponin levels were significantly higher in those who died from complications of COVID-19 than in survivors.⁷ In another retrospective study of 416 patients, NT-proBNP levels were significantly more elevated in those with cardiac injury than in those without.³⁰ Given the dearth of studies evaluating BNP and NT-proBNP levels in patients with cardiac injury, it is difficult to ascertain the association between elevated natriuretic peptides and cardiac injury markers. Gao et al showed that patients with severe COVID-19 and high NT-proBNP levels tended also to have higher cardiac injury marker levels.³¹ However, these same patients also displayed other elevated markers indicative of multiorgan system failure, confounding any attempt to definitively trace elevated natriuretic peptide levels directly to cardiac injury. There are several proposed mechanisms of cardiac injury due to SARS-CoV-2 in cases of severe COVID-19, including infection-related myocarditis and type 2 coronary events because of demand ischemia from severe ARDS. Future histopathological and imaging studies may help to unravel the etiology of cardiac injury.

It is possible that patients with severe COVID-19 and elevated natriuretic peptides have preexisting heart failure that makes them more susceptible to deterioration under the overwhelming burden of viral illness itself—presumably in response to a high-output state or to the conspicuous cytokine storm apparent in especially ill patients with COVID-19.^32,33 Activation of the inflammatory system with production and release of proinflammatory cytokines can contribute to decreased ventricular contractility.³⁴ A cytokine profile described as a hyperinflammatory condition, with features akin to hemophagocytic lymphohistiocytosis, develops in many patients with elevated cardiac injury biomarker levels. In such a hyperinflammatory state, cardiac dysfunction may well be part of a broader multiorgan systemic dysfunction, rather than a solitary myocardial event.^35,36 Moreover, the same culprit cytokines could conceivably create a thrombogenic and atherogenic milieu that could provoke a coronary event.³⁷ In a patient with existing heart failure and COVID-19, either condition could influence myocardial durability and thus contribute to the elevation of natriuretic peptides.

The studies in our meta-analysis were largely heterogeneous, with great variation in outcomes among the studies. This reasons for this effect are undoubtedly multifactorial. First and foremost, what constituted a severe case of COVID-19 differed from one study to the next. Whereas some studies defined a severe case as one that required ICU admission, others determined severity according to a specific set of subjective clinical parameters. In Feng's¹⁶ study, patients were classified as having severe COVID-19 if they met 1 of 3 predetermined conditions, including a specified increase in respiratory rate, oxygen desaturation lower than a specified percentage, or a partial pressure of arterial oxygen lower than a specified number. Some studies did not specifically address how severity was classified; others considered COVID-19 to be severe only if the patient ultimately died.

The studies were inconsistent as to when BNP and NT-proBNP levels were measured during a patient's hospital admission, nor was there any way to ascertain the timepoint at which BNP or NT-proBNP levels were measured, given the retrospective nature of the included studies. Patients can initially present with severe illness or can progress to severe illness from an initially less-severe status. Patients who present with less-severe illness may not have their BNP or NT-proBNP measured at all during admission. This potentially introduces bias, in that a large number of patients with less-severe infection may not have BNP or NT-proBNP values counted toward the mean, and thus the mean for these patients may have been underestimated or overestimated. In addition, all studies included in this meta-analysis essentially gave a snapshot view of how natriuretic peptide levels compared between patients with severe vs less-severe COVID-19; there was no indication that any of the patients were individually tracked through the course of their illness. In the future, it would be interesting to see the trends in patients' natriuretic peptide values over the course of their illness while hospitalized, as this may help clarify whether these peptides could predict illness outcomes or disease severity.

Another limitation of the study was that all patients were from China. It would be beneficial to see the outcomes of severity and natriuretic peptide measurements in patients from other countries affected by the SARS-CoV-2 virus. Nonetheless, we consider that this study sheds light on the known and emerging cardiovascular effects of the SARS-CoV-2 virus and confirms that the virus has a clear effect on myocardial durability in patients with COVID-19, even those with nonsevere symptoms.

Conclusion

Our meta-analysis results suggest that natriuretic peptides levels might help to identify patients at high risk for severe COVID-19. The etiopathology of elevated natriuretic peptides in severe COVID-19 is unknown. Upcoming studies from all countries affected by the virus will help to further delineate whether the cause is directly or indirectly of cardiac origin and whether preexisting heart failure has an influence on this disparity. A larger meta-analysis—especially one that includes data from more countries that have been affected by the virus and that elucidates the differences in BNP and NT-proBNP levels classified according to consistent severity criteria—would contribute to a more definitive understanding of the interplay between the heart and COVID-19.

Funding Statement

Funding/Support: None