Hypersensitivity in the lungs is responsible for acute respiratory failure in COVID‐19 patients: Case series of patients who received high‐dose/short‐term methylprednisolone

Abstract Background COVID‐19 is a highly contagious respiratory disease caused by the SARS‐CoV‐2 virus. Patients with severe disease have a high fatality rate and face a huge medical burden due to the need for invasive mechanical ventilation. Hypoxic respiratory failure is the major cause of death in these patients. There are currently no specific anti‐SARS‐CoV‐2 drugs, and the effect of corticosteroids is still controversial. Methods The clinical data of 102 COVID‐19 patients, including 27 patients with severe disease, were analyzed. The serum levels of total IgE and anti‐SARS‐CoV‐2 specific IgE were compared in healthy controls and COVID‐19 patients, changes in the level of anti‐SARS‐CoV‐2 specific IgE and clinical response to methylprednisolone (MP) treatment were analyzed, and the effect of high‐dose/short‐term MP therapy for patients with critical illness and respiratory failure was determined. Results COVID‐19 patients had elevated serum levels of anti‐SARS‐CoV‐2 specific IgE, and patients with severe disease, especially critical illness, had even higher levels. Application of short‐term/high‐dose MP significantly reduced the level of these IgE antibodies and also blocked the progression of hypoxic respiratory failure. Hypoxic respiratory failure in patients with COVID‐19 is related to pulmonary hypersensitivity. Conclusions Hypersensitivity in the lungs is responsible for acute respiratory failure in COVID‐19 patients. Application of high‐dose/short‐term MP appears to be an effective life‐saving method for COVID‐19 patients who have hypoxic respiratory failure.


K E Y W O R D S
anti-SARS-CoV-2 specific IgE, COVID-19, hypersensitivity, hypoxic respiratory failure, methylprednisolone 1 | BACKGROUND Studies of COVID-19 patients should seek to more fully understand the regularity of different signs and symptoms and to identify the major causes of death. Most studies reported that the major cause of death in critically ill patients with COVID-19 pneumonia was hypoxic respiratory failure. These patients experience death from severe ventilation dysfunction, rather than the structural lung damage caused by the inflammation itself. [1][2][3][4] There are currently no specific anti-SARS-CoV-2 drugs, and the benefit of corticosteroids therapy is controversial. Two meta-analyses of prospective clinical trials of patients who were critically ill with COVID-19 reported that the use of systemic corticosteroids (compared with usual care or placebo) was associated with a reduced 28-day all-cause mortality and an increased number of ventilator-free days. 5,6 But another clinical study of patients who were critically ill with COVID-19 and had acute respiratory failure reported that low-dose hydrocortisone (compared with placebo) did not significantly reduce treatment failure, defined as death or persistent respiratory support at day 21. 7 Our research team successfully treated 102 patients who were hospitalized with COVID-19 pneumonia from January 2020 to April 2020. These patients included 27 patients with severe disease, 16 of whom had critical illness. There were no deaths or complications after treatment, and all patients were successfully recovered and discharged.
Based on our treatment experience and further in-depth research, we believe that some healthy adults are pre-sensitized to SARS-CoV-2-related antigens and that this occurred before the onset of COVID-19. 8,9 We propose that the mechanism of critical COVID-19 pneumonia is hypoxic respiratory failure caused by hypersensitivity of the lungs and that appropriate use of methylprednisolone (MP), such as high-dose/short-term therapy, can inhibit the progression to respiratory failure and provide satisfactory results.

| SARS-CoV-2 nucleic acid test
After admission, respiratory specimens from the nasopharynx and/or throat were routinely collected at 1 to 3-day intervals. Samples were assessed using an reverse transcription-polymerase chain reaction (RT-PCR) assay to confirm SARS-CoV-2 infection and were also screened for common respiratory pathogens, such as influenza A and B. 10

| Total serum IgE test
The sandwich method was used to measure total serum IgE by electrochemiluminescence (Human IgE ELISA kit, Roche Diagnostics GmbH). First, 10 μL of a peripheral blood sample, a biotinylated anti-IgE monoclonal antibody, and a ruthenium (Ru)-labeled anti-IgE monoclonal antibody were mixed to form a sandwich complex.
Then, streptavidin-coated microparticles were added and the complex formed through the reaction between biotin and streptavidin.
This reaction mixture was sucked into the measuring cell, the particles are adsorbed onto the electrode by the magnet, and the unbound substance was washed away using a cleaning solution. Then, a voltage was applied to the electrode to produce chemiluminescence, which was measured by a photomultiplier. The machine automatically calculated the results from a standard curve. The instrument uses a two-point calibration method, obtained by scanning the reagent barcode or electronic barcode into the original standard curve.

| Statistical analysis
Categorical variables were expressed as numbers and percentages, and continuous variables were expressed as means and standard deviations or as medians or interquartile ranges. Mean values were compared using an independent samples t-test and a one-way analysis of variance when the data were normally distributed and homoscedastic. The Mann-Whitney U test and the Kruskal-Wallis H test were used to compare data that had non-normal distributions.
The proportions for categorical variables were compared using the chi-squared test, but Fisher's exact test was used when the number of data was limited. All statistical analyses were performed using SPSS version 26.0 (IBM). For unadjusted comparisons, a two-sided pvalue below 0.05 was considered significant.

| Demographic and clinical characteristics at admission
We included 102 patients with confirmed COVID-19 who were treated by our medical team, 27 of whom (26.5%) had severe disease (Table 1) However, the severe group had five patients with SOFA scores greater than 9 (p = 0.001), two patients with SOFA scores greater than 11, and four patients who experienced shock (p = 0.005).

| Blood test results
We analyzed the blood data of the controls and patients (Figure 1).

Comparisons of the granulocyte composition of all 102 COVID-19
patients with healthy controls indicated that the patients had lower levels of lymphocytes, eosinophils, and basophils (all p < 0.05).
Furthermore, the severe disease group had lower levels of all three cell types than the non-severe disease group (all p < 0.05). Relative to the healthy controls, COVID-19 patients also had lower levels of albumin and higher levels of immunoglobulin (both p < 0.05); relative to the non-severe disease group, the severe disease group had a lower level of albumin and a higher level of immunoglobulin (both p < 0.05). Relative to the non-severe disease group, the severe disease group had a higher level of c-reactive protein and a lower oxygenation index (both p < 0.05).

| Anti-SARS-CoV-2 specific IgE levels
Our measurements of total serum IgE indicated that the healthy controls had higher levels than the COVID-19 patients (63.81 vs. 19.43 IU ml −1 , p = 0.038; Figure 2). We do not yet know the reason for the lower total serum IgE level in COVID-19 patients, but this is an intriguing result. Measurements performed at admission also CHEN ET AL.

| Efficacy of MP in treatment of COVID-19 hypoxic respiratory failure
Notably pneumonia, we recommend use of short-term medium or high doses of MP as the main treatment. We recommend against continuous low-dose corticosteroids therapy for these patients to avoid downregulation of immune functions.