Inflammatory burden and persistent CT lung abnormalities in COVID-19 patients

Inflammatory burden is associated with COVID-19 severity and outcomes. Residual computed tomography (CT) lung abnormalities have been reported after COVID-19. The aim was to evaluate the association between inflammatory burden during COVID-19 and residual lung CT abnormalities collected on follow-up CT scans performed 2–3 and 6–7 months after COVID-19, in severe COVID-19 pneumonia survivors. C-reactive protein (CRP) curves describing inflammatory burden during the clinical course were built, and CRP peaks, velocities of increase, and integrals were calculated. Other putative determinants were age, sex, mechanical ventilation, lowest PaO2/FiO2 ratio, D-dimer peak, and length of hospital stay (LOS). Of the 259 included patients (median age 65 years; 30.5% females), 202 (78%) and 100 (38.6%) had residual, predominantly non-fibrotic, abnormalities at 2–3 and 6–7 months, respectively. In age- and sex-adjusted models, best CRP predictors for residual abnormalities were CRP peak (odds ratio [OR] for one standard deviation [SD] increase = 1.79; 95% confidence interval [CI] = 1.23–2.62) at 2–3 months and CRP integral (OR for one SD increase = 2.24; 95%CI = 1.53–3.28) at 6–7 months. Hence, inflammation is associated with short- and medium-term lung damage in COVID-19. Other severity measures, including mechanical ventilation and LOS, but not D-dimer, were mediators of the relationship between CRP and residual abnormalities.


Setting
In the Reggio Emilia province (Northern Italy, 532,000 inhabitants), Local Health Authority (LHA) hospital care is provided by six hospitals, with five emergency departments (ED) and one imaging department with centralized image reading. During the first pandemic wave, which lasted in Italy until May 2020, patients in the Reggio Emilia province with severe COVID-19 pneumonia were hospitalized primarily in the two main hospitals.

Methods for computing CRP descriptors
CRP peak: the highest value in (mg/dl) registered during the disease course CRP integral: the area under the polygon designed by the linear interpolation between measured points in the graph with days from symptom onset and CRP mg/dl observed during the disease course (expressed as mg/dl*day). Computationally it is the ∑ 1 , where n is the day of disease from symptom onset and the CRPn is the value of CRP registered or interpolated on the n th day.
If more than one CRP value was registered in one day, the average was considered. If for one or more days there was no CRP measured, the value was estimated by linear interpolation using the closest known values; for the days between symptom onset and the first measurement, a triangle was estimated interpolating the values from symptom onset and the first value assuming CRP=0 at day one of symptom onset; the course of inflammation ended when CRP reached a value of <1 mg/dl. For patients having the last measurement (usually at discharge) higher than 3 mg/dl we estimated the right tail of the curve using the average descending slope of the observed complete curves (ie, those with last observed value <1 mg/dl) with a similar CRP value (+/-1) at the same day from symptom onset (or at the closest time). Curves ending with a value between 1 and 3 mg/dl were not completed through an estimate of the right tail. Indeed, the change in total values would be negligible, increasing the percentage of estimated data.
CRP velocity: the peak value divided by the number of days from symptom onset to the day of peak value (mg/dl/days).

Methods for follow-up CT scan acquisition parameters
Follow-up CT scans were performed using a 128-slice scanner (Somatom Definition Edge, Siemens Healthineers), without contrast media injection, with the patient in supine position during endinspiration. Scanning parameters were tube voltage 120 KV, automatic tube current modulation, collimation width 0.625 or 1.25 mm, acquisition slice thickness 2.5 mm, and interval 1.25 mm.
Images were reconstructed with a high-resolution algorithm at slice thickness 1.0/1.25 mm.

Methods for mediation analysis
Using the method provided by VanderWeele (13), we fitted natural effect models to estimate the natural direct (NDE) and natural indirect (NIE) effects of CRP peak on CT abnormalities at 2-3 months and CRP integral at 6-7 months on odds ratio (OR) scales. We also report the proportion of the mediation effect of each measure of disease severity estimated using logarithm of OR (14).  Figure 2: A) Distribution of CRP descriptors (peak, a; velocity of increase, b; and integral, c) and percentage of the curve which was estimated by means of imputation (d). The right tail of the curve was not estimated in 186 (71.8%) patients. In fact, a complete CRP curve (ending value <1 mg/dl) was available in 130 patients, and 56 other patients had an ending value between 1 and 3 mg/dl, which was approximated to 0. B) integral values with and without adding the right tail.  The following variables were included for building the models with a backward strategy: CRP peak, CRP integral, CRP velocity, age, sex. Smoke, asthma, and COPD were also tested but did not improve the models' performance. Pseudo R 2 , Akaike information criterion (AIC), and area under ROC curve (AUROC) are reported for each model. For standardized variables we report OR for one standard deviation increase of the variable; for age we report the OR for one year increase.