Diagnostic Criteria for Hyperinflammatory Syndrome in COVID-19 Patients

COVID-19 is a systemic disease with a wide range of clinical manifestations caused by infection with the novel coronavirus 2, severe acute respiratory syndrome, betacoronavirus (SARS-CoV-2).

Among other cellular targets, SARS-CoV-2 directly infects macrophages and monocytes through the angiotensin-converting enzyme 2 (ACE2) receptor, resulting in intracellular infection and macrophage activation. In some patients, this process results in a hyperinflammatory syndrome associated with acute respiratory distress syndrome and target organ damage.

Although not fully characterized, the hyperinflammatory syndrome observed in COVID-19 shares similarities with other hyperinflammatory disorders such as secondary hemophagocytic lymphohistiocytosis, macrophage activation syndrome, macrophage activation-like sepsis syndrome, and cytokine release syndrome. .

These disorders, sometimes known as cytokine storm syndromes , share overlapping clinical manifestations and a common pathway of macrophage activation and a self-perpetuating cycle of cytokine production, but there is no consensus regarding classification criteria. and diagnosis.

Although a cytokine storm syndrome has been proposed in COVID-19, data suggest that quantitative concentrations of circulating cytokines could be much lower in COVID-19 than in other conditions, including non-COVID-19 acute respiratory distress syndrome. .

Better characterization of the inflammatory state of COVID-19 is urgently needed in the context of emerging treatments. Immunomodulatory therapies, including corticosteroids, cell signaling inhibitors, and anti-cytokine antibodies, have been proposed to attenuate the inflammatory response and prevent organ failure.

Clinical trials of these therapies in COVID-19 have generally not been enriched for evidence of hyperinflammation, which could explain the discordant results in the trials compared to retrospective evaluation after implementation (NCT04315298 and NCT04317092).

Although diagnostic criteria exist for hemophagocytic lymphohistiocytosis (both secondary and familial), macrophage activation syndrome, and cytokine release syndrome, these criteria have only been validated in very specific populations. Because both the disease characteristics and the patient population in COVID-19 are different, directly applying the diagnostic criteria of other hyperinflammatory disorders to COVID-19 is problematic.

Lack of clarity contributes to uncertainty over definitions of the target population of clinical trials and clinical indications for immunomodulation. To address this gap, we developed new diagnostic criteria for the hyperinflammatory syndrome observed in some patients with COVID-19 by comparing published clinical data for this syndrome with those for secondary hemophagocytic lymphohistiocytosis, macrophage activation syndrome, and cytokine release syndrome. We then validated the criteria in a cohort of hospitalized patients with COVID-19.

We identified 299 patients admitted to the hospital between March 13 and May 5, 2020, with COVID-19, representing 2,535 days of hospitalization. Data were complete for fever, hematologic dysfunction, and liver inflammation. 184 (62%) patients had documented ferritin concentrations, 158 (53%) had D-dimer values, and 298 had data for at least one cytokinemia marker (IL-6, triglycerides, or CRP).

Median age was 56 years (IQR 43-68); 132 (44%) patients were female and patients had a median of 2 (1-4) comorbidities.

The combined number of hospital days for maximum oxygen requirement was as follows: 1213 (48%) of 2535 for 0-3 L/min, 228 (9%) for 4-6 L/min, 48 (2%) for more than 6 L/min but not with high-flow nasal cannula or non-invasive positive pressure ventilation, 157 (6%) for high-flow nasal cannula or non-invasive positive pressure ventilation and 857 (34%) for mechanical ventilation.

The mean daily cHIS score was 2 (IQR 1-3). At some point during their stay, 161 (54%) patients achieved a daily cHIS score of 2 or more.

Discussion

Although doctors and researchers have generally agreed that severe COVID-19 is associated with dysregulated inflammation (with an emphasis early in the pandemic on a cytokine storm), the nature of this inflammation is poorly understood. Notably, the mean circulating concentrations of inflammatory cytokines reported in COVID-19 have now been observed to be an order of magnitude lower than in other hyperinflammatory syndromes, including non-COVID-19 acute respiratory distress syndrome.

Similarly, early suggestions that COVID-19 induces secondary hemophagocytic lymphohistiocytosis have now also been revised given the clear lack of cytopenias, hepatosplenomegaly, fibrinogen uptake, or markedly elevated soluble IL-2 receptor-α (also known as sCD25). in COVID-19.

However, a growing understanding of the immunopathology of COVID-19 suggests that uncontrolled activation of macrophages and monocytes due to a dysfunctional interferon response to SARS-CoV-2 infection has a key role in the subsequent inflammatory response and organic injury. Other mechanisms, including genetic polymorphisms related to the inflammatory response, could also play a role.

In recognition of the general similarities and still distinctive manifestations of COVID-19 hyperinflammation compared to other hyperinflammatory disorders, we have proposed and validated a clinical rating scale for cHIS.

The strength of the proposed cHIS scale derives from a rational framework to characterize this disease in the context of previously described hyperinflammatory disorders, the relevance for reporting the prognostic implications of individual biomarkers in cohorts of patients with COVID-19 and associations in a validation multicentric. cohort (robust to multiple sensitivity analyses) between an elevated score and clinical outcomes, and the fact that the score is based on clinically available laboratory biomarkers.

Furthermore, by modeling cHIS as a time-dependent variable in a multistate model, our data suggest that the more cHIS characteristics a patient has on a given day, the greater the likelihood of future clinical deterioration.

The main implication of our findings is the definition of target populations for clinical trials and the identification of candidates for clinical use of immunomodulatory therapies.

In non-COVID-19 acute respiratory distress syndrome, a strategy to stratify patients on the basis of hypoinflammatory versus hyperinflammatory phenotypes has been proposed as a means of targeting immunomodulatory therapies in patients who are most likely to benefit.

Applying a similar approach to COVID-19 could clarify which subgroups of patients might benefit from corticosteroids, selective cytokine antagonists, or macrophage-targeting cell signaling modifiers, and when in the course of the disease it is more benefit is likely to be obtained. For example, recent work suggests differential efficacy of corticosteroids depending on the presence of inflammation.

It is also conceivable that the discrepant results with IL-6 inhibition in highly selected real-world observational cohorts and recent clinical trials (NCT04315298 and NCT04317092) may in fact be related to trial enrollment of immunologically undifferentiated target populations.

Important next steps are heterogeneity analyzes of treatment effects from trials with undifferentiated patients with COVID-19 and larger prospective cohorts with purposive sampling of additional inflammatory markers. We recommend that clinical trials and protocols for immunomodulatory therapies pay attention to the presence of actual markers of inflammation.

This study must be interpreted in the context of important limitations . Although the diagnostic criteria were selected a priori based on existing literature and without reference to patient data in the multihospital cohort in which the criteria were independently validated, the relatively modest sample size and low mortality observed could limit generalizability to other populations in which patient demographics, clinical characteristics, and management may differ.

Our study also has the characteristic drawbacks of its retrospective design , including potential threats to data accuracy, missing data, and indication and temporal biases. We have attempted to address these issues using imputation and multistate modeling, but independent, external, and preferably prospective validation is needed to confirm these observations.

The cHIS scale appears to reflect COVID-19-specific inflammation patterns. It was adapted from related hyperinflammatory syndromes and independently validated by linking to outcomes. Therefore, the proposed cHIS criteria exhibit construct, content, and face validity.

These criteria may have prognostic value and utility in identifying patients for research trials and clinical uses of anti-inflammatory therapies. Further validation in large external cohorts, including trial populations, is urgently indicated.