Predictive value of IL-62/LC at baseline for clinical worsening
Among the 93 patients included in the convenience sample, 74 received moAbs at the ASY/MID stages, whereas 19 were treated at the MOD/SEV stages. The study outcome was reached in 28 patients overall (14 in the ASY/MID group and 14 in the MOD/SEV disease group: 19% vs. 74%, OR: 11.6, Fisher’s exact test p < 0.001, 95% confidence interval: 3.3–48.3). Several algebraic relationships between IL-6 and LC have been explored, leading to the IL-62/LC ratio being the best candidate predictor to consider. The mean values of IL-62/LC were 1.12 (SD: 3.18) in patients who did not subsequently worsen and 7.88 (SD: 13.63) in those who did. A statistically significant difference was found when comparing IL-62/LC ratios between the two groups (Mann–Whitney U test, p < 0.001).
Table 2
shows the significant (p = 0.010) predictive value of the IL-62/LC ratio combined with dichotomized clinical classes according to logistic regression with respect to outcome. Additionally, several possible additive and multiplicative models correcting for sex, age, BMI, and hypertension were explored, never obtaining any further significant term in predicting outcome.
Measure/group | Estimate | Standard Error | z | p value |
Intercept | -2.13 | 0.4 | -5.31 | < 0.001 |
IL-62/LC | 0.59 | 0.26 | 2.32 | 0.02 |
Oxygen-requiring group | 3.08 | 0.72 | 4.26 | < 0.001 |
Interaction term | -0.58 | 0.26 | -2.25 | 0.02 |
Table 2. Predictive value of the IL-62/LC ratio combined with dichotomized clinical classes according to logistic regression analysis.
Based on the results shown in Table 2, it was possible to consider a further proposed predictive index (ppi) that discriminates the outcome probability stratifying the patient sample into the two aforementioned risk classes, according to the following relationships:
[low risk, ASY MID] ppilow = -2.13 + 0.59 * (IL-62/LC)
[high risk, MOD SEV] ppihigh = 0.95 + 0.01 * (IL-62/LC)
To further investigate the predictive role of the IL-62/LC ratio, ROC curve analysis was performed to compare the performances of IL-6, IL-1/LC and IL-62/LC for predicting clinical worsening (see Fig. 1).
Legend to Fig. 1: The reciprocal value of the lymphocyte count (LC− 1) was analyzed instead of LC to preserve graph convexity. IL-62/LC, as distinguished in ppi between ASY/MID and MOD/SEV disease, exhibits superior accuracy and area under the curve value.
Table 3
reports the cut-offs, sensitivity, specificity and area under the curve (AUC) for IL-6, IL-1/LC and IL-62/LC ppi.
Predictor | Cut-off | Sensitivity | Specificity | AUC |
IL-6 | 19 | 68 | 72 | 79 |
1/LC | 11.4 * 10− 4 | 61 | 65 | 66.3 |
IL-62/LC ppi | -1.74 | 75 | 80 | 87.1 |
Table 3. Results of the analysis of receiver operating characteristic curves for IL-6. 1/LC and IL-62/LC ppi.
Legend to Table 3: ppi, proposed predictive index.
Clinical description of patients treated with combination therapy (intended sample) and correlation with IL-6 2 /LC (convenience sample)
In 22 patients of the intended sample with a very high risk of progression to severe COVID-19 due to incomplete vaccination, immunocompromised status and/or severe and multiple comorbidities, we prescribed combined therapy composed of moAbs and nirmatrelvir/ritonavir 150/100 mg (three pills two times a day for five days) or molnupiravir 400 mg (four pills two times a day for five days) or remdesivir short course regimen (200 mg/ev the first day and 100 mg/ev the second and the third day). None of these patients died.
Among these 22 patients treated with combination therapy in the ASY/MID stages, 18 were tested for IL-6 serum levels and LC. IL-62/LC was under the risk cut-off in all except one patient affected by myeloma treated with sotrovimab plus nirmatrelvir/ritonavir, who recovered without reaching the study endpoint. Only 2 of 18 patients reached the study end-point. The first was a female affected by chronic lymphocytic leukemia and hypogammaglobulinemia treated with ibrutinib who needed admission due to COVID-19. She required oxygen therapy with a low-flow nasal cannula (2 L/min) for three days, and then she improved until recovery. The second patient was a severe cardiopathic male patient admitted for implantation of a cardiac resynchronization defibrillator (CRT-D) who developed ventricular tachycardia and respiratory failure during hospitalization not attributable to COVID-19. The remaining 16 patients who did not meet the study endpoint received moAbs for the following indications: 3 patients were not vaccinated against SARS-CoV-2; 7 patients had hematological malignancies, such as lymphoma/lymphatic leukemia (n = 5), myeloma (n = 1) or Waldenström macroglobulinemia (n = 1); 2 patients had cancer (an elderly female diagnosed as infected by SARS-CoV-2 a few days after surgery for colon cancer and a middle-aged woman who had ovarian cancer); 2 patients received kidney transplantation and were taking immunosuppressive drugs; 1 patient, a middle-aged male affected by systemic lupus erythaematosus treated with mycophenolate; and 1 patient, a young woman who developed tricuspid endocarditis associated with intravenous drug abuse. Only 4 of the 13 vaccinated patients in this group had detectable IgG against the spike protein of SARS-CoV-2. Finally, 5 of the patients with hematological diseases received anti-CD20 moAbs in the year preceding moAb administration.
For the remaining 4 of 22 patients who received combined therapy and whose IL-6 serum level at baseline was not available, 3 patients had lymphoma, and 1 had multiple sclerosis treated with anti-CD20 moAbs. Interestingly, none of these patients reached the study endpoint.