Hearts, Lungs, Kidneys: Mild-to-Moderate COVID-19 Leaves a Mark

Months after mild-to-moderate COVID-19, there are signs of subclinical impact across the body—from cardiovascular to pulmonary and renal function—with uncertain long-term effects, according to a German cohort study.

The researchers say their results, published in the European Heart Journal, suggest that at least some level of screening may be appropriate in select patients to guide management.

The findings “didn’t really surprise us,” said senior author Stefan Blankenberg, MD (University Heart and Vascular Center and the German Center for Cardiovascular Research [DZHK], Hamburg), describing the differences between post-COVID-19 patients and controls as “very tiny, slight.” Reassuringly, their investigations didn’t turn up any signs of brain damage. Most impressive, he added, was the evidence of an increase in venous thrombosis among patients who’d contracted the disease.

However, based on what’s been seen in other population-based research, like the Framingham Heart Study and Atherosclerosis Risk in Communities (ARIC) Study, for example, there could be ramifications on a large scale, Blankenberg told TCTMD. “Once you extrapolate these little, tiny, subclinical changes, once 5, 10, 20, 30 years are up . . . you end up actually, as you do for LDL, troponin, and all these cardiovascular [risk factors], with a higher event rate.”

He pointed out it’s possible that these sorts of changes occur after other viral diseases, as well. Here, said Blankenberg, there does appear to be a shared mechanism among the multiorgan involvement: COVID-19’s prothrombotic effects.

Amanda Verma, MD (Washington University School of Medicine in St. Louis, MO), commenting for TCTMD, said she appreciates the paper’s look at the natural course of COVID-19 across different organ systems.

“Why we need studies like this is we really don’t know long-term consequences and we need guidance on what happens to patients over time,” she said. Whether something not causing overt symptoms now will cause future problems “is something that crosses your mind” when caring for patients after COVID-19.

Verma agreed that, at least on a day-to-day basis, the differences are small. “The question is: does that gap change over time? I think that’s the big concern because it is statistically significant,” she said.

None Required the ICU

Led by Elina Larissa Petersen (University Heart and Vascular Center, Hamburg), the study included 443 patients treated at University Medical Center Hamburg-Eppendorf who had PCR-confirmed COVID-19 between March and December 2020 at least 4 months prior. All cases were considered mild to moderate by virtue of not requiring ICU admission—only 7.2% were hospitalized—and assessment occurred at a median of 9.6 months after their initial positive SARS-CoV-2 test.

Petersen et al matched them by age, sex, and education with 1,328 controls from the ongoing population-based Hamburg City Health Study who were enrolled before the pandemic and during the same seasonal period as the COVID-19 patients.

Compared with controls, the individuals with COVID-19 had “substantially more-frequent” sonographically noncompressible femoral veins, suggestive of prior deep vein thrombosis. Cardiac assessment showed reduced left and right ventricular function on transthoracic echocardiography, as well as elevated high-sensitivity cardiac troponin I (hs-cTn I) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), but similar findings on cardiac MRI.

Cardiovascular Findings

Moreover, the post-COVID-19 patients had lower total lung volume (99.1% vs 102.4% of predicted value; adjusted P = 0.014) and higher specific airway resistance (77.3% vs 69.8% of predicted value; adjusted P = 0.001). Their liver function also was worse (eGFR reduced by 2.35 mL/min/1.73 m₂; adjusted P = 0.019). There were no differences when it came to brain volume, cerebral microbleeds, infarct residuals, cognitive function, or patient-related outcomes (ie, quality of life, depression, somatic symptoms, or generalized anxiety).

The EHJ paper contains a figure summarizing the subclinical findings.

“Systematic organ screening 6 to 9 months after mild-to-moderate SARS-CoV-2 infection is recommended,” the authors conclude.

To TCTMD, however, Blankenberg emphasized that this is merely “an intellectual suggestion,” rather than a “guideline.” He’s received feedback from general practitioners in Germany questioning this advice, he said, based on how small the differences were between COVID-19 patients and controls. But Blankenberg countered with data from a 2019 study he co-authored, published in the Lancet, showing that even very small degrees of LDL alterations can have an impact on long-term risk. The same can be said for renal function impairment, he added.

“If you accumulate all these multiorgan effects, it might have some influence. What we suggest is definitely very, very simple. If you do your blood check [to] your LDL, just test your renal function marker—it costs 10 cents,” said Blankenberg. NT-proBNP, though slightly more expensive, also could be tested at the same time. “It’s a staged approach. If there are alterations, you might wish to do an echo. And if you have signs or symptoms of venous thrombosis, you certainly need to check this [out]. So that’s our approach.”

There’s the open question of how these multiorgan effects will evolve with the arrival of vaccines—by virtue of timing, none of the current study’s participants were vaccinated—and the emergence of new variants. Blankenberg said their group will follow up this work by examining whether and how COVID-19 vaccines are leaving their mark.

Subclinical Signs vs Symptomatic Long-Haulers

Verma said it would be helpful to know whether the study’s COVID-19 patients experienced any symptoms alongside their seemingly subclinical changes, as well as any gender disparities, since in her experience long COVID disproportionally affects young women.

The paper, too, draws attention to these ongoing concerns. “Some patients continue to suffer from heterogeneous symptoms after the acute phase of critical illness,” which are described as post-COVID-19 syndrome or long COVID, respectively, for symptoms up to versus longer than 6 months, the researchers explain. “Clinical, imaging, or laboratory findings should accompany [these diagnoses].”

Fifty-plus years ago, we didn’t know that strep throat was going to cause heart problems down the road, and now we’re dealing with a lot of patients who need valve replacements. Amanda Verma

For Verma, who has treated around 500 patients with lingering COVID-19 symptoms, this advice is counterintuitive. “If you talk to other people who see [long-haulers], like myself, we’ll all tell you that the majority of testing is normal, but these patients have very real symptoms,” she observed. “A lot of these symptoms are very odd and uncharacteristic. It’s one of those things that once you see it you know it, but it’s hard to [describe].”

Clinicians are struggling to know the best strategies for getting answers. It may be that today’s technologies are “not up to speed yet,” she said. “I always tell patients: just because we didn’t have X-rays in the past doesn’t mean that people didn’t break their legs. We just couldn’t detect it.”

It’s important to interpret any results obtained through standard testing with an open mind, Verma suggested. “For instance, the Holter monitors that [patients] get, they get all come back normal. But then when you sit down and look at the raw data, [you ask] why is this person’s heart rate going up every 5 minutes? In the grand scheme of things, a heart rate of 120 during the day doesn’t sound dangerous, but if it’s going up every 5 minutes that’s not normal.”

Verma emphasized that, as once was true for rheumatic heart disease, understanding of COVID-19’s sequelae is in its infancy. “Fifty-plus years ago, we didn’t know that strep throat was going to cause heart problems down the road, and now we’re dealing with a lot of patients who need valve replacements,” she noted. “What are we going to find in 50-plus years that we didn’t know this virus was going to do?”

Among patients who lack symptoms post-COVID, it’s unclear how to target surveillance, Verma said. Perhaps an even greater obstacle to such monitoring is the strained healthcare system.

“Even with my symptomatic patients, I have to fight with insurance to get [additional] testing done because they’re saying, ‘Well, the other tests are normal.’ So if you have an asymptomatic patient, I think it’s going to be a challenge to get this approved by insurance and it’s going to cost the patient a lot of money.”

The current study, she said, may spur conversations about whether using a preventative, rather than reactive, strategy could be more cost-effective in the end.