This study investigated the association of cHIS and new clinical disorders following SARS-CoV-2 infection and identified risk factors associated for developing these new clinical disorders. The major findings are: (i) Compared to non-cHIS patients, cHIS patients were older, had fewer female, more Blacks, higher prevalence of pre-existing comorbidities, (ii) cHIS status was significantly associated with the development of new cardiovascular disease (HR = 1.24 [1.04,1.47] p < 0.05), chronic kidney disease (1.24 [1.01, 1.53] p < 0.05), and obesity (1.61 [1.31,1.98], p < 0.001) but not hypertension, diabetes, COPD, and asthma, (iii) patients ≥ 50 years old show higher incidence of new individual disorders compared to patients < 50 years old.
Manson et al. assessed the outcomes of hyperinflammation in 269 COVID-19 patients admitted to their UK hospital system in March 202020. Hyperinflammation was defined as a C-reactive protein concentration greater than 150 mg/L or doubling within 24 h from greater than 50 mg/L, or a ferritin concentration greater than 1500 µg/L. They found patients with hyperinflammation were significantly associated with the risk of next-day escalation of respiratory support or death.
Webb et al. established the cHIS criteria to develop a scoring system that would accurately predict in-hospital mortality and initiation of invasive mechanical ventilation4. In their cohort of 299 patients primarily from the first wave of COVID pandemic, they found that cHIS patients with > 2 score threshold were older, more male, and had more diabetes, hypertension, arrhythmias, congestive heart failure, liver disease, obesity and had more elevated lab profiles on admission. Furthermore, they found that their cHIS threshold > 3 predicted in-hospital mortality and initiation of invasive mechanical ventilation with AUC of 0.92 and 0.81 respectively. Our results provided further support of the validity of cHIS score as a good predictor of worse acute outcomes in a more diverse population, with large proportion of Black and Hispanic.
In addition, we also applied the cHIS score to investigate the long-term outcomes of COVID-19 patients who experienced hyperinflammation during acute COVID-19 illness. Our study provided alarming statistics that hyperinflammation during acute COVID-19 illness were at higher risks for new incident hypertension, cardiovascular disease, kidney disease, and obesity at the population. Pro-inflammatory cytokines like TNF-α and IL-6 can damage the vascular endothelium, impairing its ability to produce nitric oxide, a crucial vasodilator, thereby increasing vascular resistance and blood pressure21. Cytokine storms could enhance the production of reactive oxygen species (ROS), leading to oxidative stress that damages vascular tissues and contributes to hypertension22. Inflammatory cytokines could also activate the sympathetic nervous system, resulting in increased heart rate and blood pressure. They could also stimulate the renin-angiotensin-aldosterone system (RAAS), causing vasoconstriction and sodium retention, which further elevates blood pressure.
The chronic inflammation plays a significant role in the development of new cardiovascular diseases. Persistent inflammation promotes the formation of atherosclerotic plaques by recruiting inflammatory cells such as macrophages to the blood vessel walls, leading to plaque buildup and cardiovascular events23. Moreover, cytokine storms can cause direct myocardial damage, resulting in myocarditis and heart failure. Inflammation also increases the risk of thrombosis by altering the coagulation pathway, promoting the formation of blood clots that can cause heart attacks and strokes24. Lastly, prolonged inflammation can lead to adverse cardiac remodeling, affecting heart function and contributing to heart failure25.
Inflammatory cytokines can damage the glomeruli, the kidney’s filtering units, leading to impaired kidney function26. Persistent inflammation also promotes interstitial fibrosis, or scarring, of kidney tissue, which progressively reduces kidney function over time27. Additionally, endothelial dysfunction within the kidneys, similar to that seen in blood vessels, impairs blood flow and filtration efficiency. The inflammation-induced damage to the glomeruli can cause protein leakage into the urine, known as proteinuria, which is a key indicator of CKD progression26.
Obesity is also closely linked to chronic low-grade inflammation, where adipose tissue secretes pro-inflammatory cytokines that contribute to systemic inflammation28. These inflammatory cytokines interfere with insulin signaling pathways, leading to insulin resistance, a critical factor in the development of obesity and type 2 diabetes. Inflammation also disrupts normal metabolic processes, resulting in dysregulation of appetite, energy expenditure, and fat storage29. Moreover, inflammation can cause the release of free fatty acids from adipose tissue, leading to lipotoxicity, which is harmful to other organs such as the liver and pancreas.
To our knowledge, this is the first study that reported the long-term effects of acute COVD-19 related hyperinflammation on new incident major clinical disorders.
Confounders
Confounders such as hypertension, diabetes, COPD, asthma, CVD, CKD, smoking, and obesity play a crucial role in influencing outcomes and they are interrelated5,6,7. These conditions often contribute to systemic inflammation, metabolic dysregulation, and vascular dysfunction, which can predispose individuals to developing new clinical disorders. Hypertension and cardiovascular disease are closely linked, as chronic high blood pressure leads to endothelial damage, increased arterial stiffness, and heightened cardiovascular risk. Similarly, preexisting hypertension exacerbates kidney damage by impairing renal perfusion and accelerating CKD progression. Diabetes is a well-established risk factor for multiple organ dysfunctions, including cardiovascular and renal complications, due to chronic hyperglycemia-induced endothelial damage and inflammation. COPD and asthma, while primarily respiratory conditions, are associated with systemic inflammation and oxidative stress, potentially influencing cardiovascular and metabolic outcomes. Smoking and obesity are both major contributors to chronic disease progression. Smoking induces oxidative stress, promotes vascular damage, and increases the risk of CVD, CKD, and hypertension. Obesity is a key driver of metabolic syndrome and systemic inflammation, increasing susceptibility to hypertension, CVD, and CKD. Age is also major confounder. Age also interacts with other confounders. Our outcomes were adjusted for these confounders.
Limitations
Our study has several limitations. These findings were restricted to patients who returned to our health system. It is also possible that patients who returned were more likely to have more severe COVID-19. Montefiore is the predominant health system in the Bronx and its environs. Most patients had prior interactions with our health system before COVID-19 and continued to seek care within our system for various medical reasons over the study period. Patient data obtained via electronic medical records only included those who returned for any medical reason, including but not limited to routine office visits. It is also possible that some patients had previously undiagnosed conditions, which could result in misclassification of disorders as new onsets. However, this misclassification likely occurred to similar extents in both groups and should not alter our conclusions. Incidence of new disorders across the pandemic might be affected by other factors, including the vaccination rate, strain of SARS-CoV-2, testing rate, naturally acquired immunity, treatments, population profile, and disease severity. Vaccine status was not reliably recorded if patients received vaccines outside our healthcare system and it was not analyzed with respect to our outcomes. Testing for variant strain was rare and thus not available. Although variant strain could be obtained based on when infection occurred across the pandemic, there were often overlaps of multiple strains and thus, we did not analyze strains with respect to our outcomes. We analyzed COVID-19 severity with respective to outcome as it was good predictor. Immunity was not tested unless there was a clinical indication which was rare. COVID-19 treatments were heterogenous, included multiple combinations, changed across the pandemic, and were difficult to extract accurately; thus, it was difficult to compare systematically. The effects of these confounders on outcomes are complex and were difficult to assess. Future studies will need to include longer follow-ups and larger patient cohorts. As with any retrospective study, there could be other unintended patient selection biases and latent confounds.
