key: cord-292417-hauq93v2
authors: Xue, Mingshan; Zhang, Teng; Hu, Haisheng; Huang, Zhifeng; Zhen, Yingjie; Liang, Yueting; Zeng, Yifeng; Jin, Tengchuan; Zhou, Luqian; Zhang, Xiaohua Douglas; Sun, Baoqing
title: Predictive effects of IgA and IgG combination to assess pulmonary exudation progression in COVID‐19 patients
date: 2020-08-17
journal: J Med Virol
DOI: 10.1002/jmv.26437
sha: 
doc_id: 292417
cord_uid: hauq93v2

Our study intended to longitudinally explore the prediction effect of IgA on pulmonary exudation progression in COVID‐19 patients. The serum IgA was tested with chemiluminescence method. Autoregressive moving average (ARMA) model was used to extrapolate the IgA levels before hospital admission. The positive rate of IgA and IgG in our cohort was 97% and 79.0%. The IgA was peaked in 10‐15 days after admission, and IgG was peaked at the time of admission time while HRCT and chest PA & LAT (posteroanterior oblique and lateral views) were peaked in 20‐25 days after admission. We found that the time difference between their peaks was about 10 days. Viral RNA detection results showed that the positive rate in sputum and feces were the highest. Blood gas analysis showed that deterioration of hypoxia with the enlargement of pulmonary exudation area. And alveolar‐arterial oxygen difference (A‐aDO(2)) and oxygenation index were correlated with IgA and IgG. The results of biopsy showed that the epithelium of lung was exfoliated and the mucosa was edematous. In severe COVID‐19 patients, the combination of IgA and IgG can predict the progress of pulmonary lesions and is closely related to hypoxemia and both also play an important defense role in invasion and destruction of bronchial and alveolar epithelium by SARS‐CoV‐2. This article is protected by copyright. All rights reserved.

Our study intended to longitudinally explore the prediction effect of IgA on pulmonary exudation progression in COVID-19 patients. The serum IgA was tested with chemiluminescence method. Autoregressive moving average (ARMA) model was used to extrapolate the IgA levels before hospital admission. The positive rate of IgA and IgG in our cohort was 97% and 79.0%. The IgA was peaked in 10-15 days after admission, and IgG was peaked at the time of admission time while HRCT and chest PA & LAT (posteroanterior oblique and lateral views) were peaked in 20-25 days after admission. We found that the time difference between their peaks was about 10 days. Viral RNA detection results showed that the positive rate in sputum and feces were the highest. Blood gas analysis showed that deterioration of hypoxia with the enlargement of pulmonary exudation area. And alveolar-arterial oxygen difference (A-aDO 2 ) and oxygenation index were correlated with IgA and IgG. The results of biopsy showed that the epithelium of lung was exfoliated and the mucosa was edematous. In severe COVID-19 patients, the combination of IgA and IgG can predict the progress of pulmonary lesions and is closely related to hypoxemia and both also play an important defense role in invasion and destruction of bronchial and alveolar epithelium by SARS-CoV-2.

Acute diffuse alveolar damage with extensive pulmonary exudation is the dominant feature of COVID-19, and it could progress to acute respiratory distress syndrome (ARDS) within a short time in some severe patients[1]. It is not just caused by the virus mass replication but also associated with hyperactive immune responses [2] . Pathologically, bronchial inflammatory cells infiltration, epithelial and cilia desquamating, and hyaline membrane forming were observed [3] . Meanwhile, the negative effects of COVID-19 lung exudation on ventilation function deserve attention. In some patients, the improvement of ventilator-assisted ventilation is not significant, which eventually resulted in severe hypoxemia and death [4, 5] .

Serum antibodies play an important role in the defense against SARS-CoV-2 virus in the replication and infiltration of pulmonary epithelium [6] . IgG accounts for 75% of total Ig which is the main component of antibody in serum and IgA, second to IgG, the main and mild antibody in humans, classified into secretory and serotypes IgA, the later accounts for 85% of the total IgA, IgA and IgG both can eliminate antigens in a non-inflammatory form [7] [8] [9] [10] . Extensive pulmonary exudation in severe COVID-19 patients was noted in autopsy and case reports as one of its important features and distinguished from other viral pneumonitis, associated with prognosis [11] [12] [13] . IgA and IgG play an important role in the fight against SARS-COV-2 as a major defensive barrier in the lung can lead to antigen antibody reaction leading to excessive inflammatory response cause lung exudation increasing, although they did not have enough specificity to assess the overall progression of the disease accurately [10, 14] . However, the association with local immune response and imbalance leading to pulmonary exudation is still of concern.

This study included 21 COVID-19 patients diagnosed in the First Affiliated Hospital of Guangzhou Medical University from February 1 to April 6, 2020, including 14 severe COVID-19 patients and 7 mild COVID-19 patients. Among them, 14 severe COVID-19 patients were transferred to our hospital after deterioration during the treatment period, so there is a time interval between the time of first symptom and the time of antibody detection in hospital. The average time interval was 8 days. This study was approved by the ethics Committee of First Affiliated Hospital of Guangzhou Medical University with approval number of 2020-77.

High resolution CT with 1 mm thin layer was used for imaging detection. We adopted quantitative analysis system and calculated the percentage of lesion area (patch shadow, fiber strip shadow and ground-glass opacities) in the total lung window of each cross section in jugular notch, sternoclavicular joint, aortic arch and left atrium.

Because of the limitation of physical condition in severe patients, their changes of lung condition were examined with bedside chest PA&LAT (posteroanterior oblique and lateral views). The time interval between each examination was about 1 or 2 days. Chest PA & LAT is faster and more efficient than high resolution computed tomography (HRCT) in emergency admission patients. In this study, chest PA & LAT was mainly used on severe patients, while the HRCT was still used on patients with milder clinical presentation.

In this study, we used the (SARS-CoV-2) IgA and IgG antibody detection kit (Kangrun Biotech, Guangzhou, China) and automatic chemiluminescent immune analyzer (KAESER 1000, Kangrun Biotech, Guangzhou, China).

A total of 3 patients had lung tissue biopsies performed and the samples were collected from lesional areas (Subcutaneous puncture).

Autoregressive moving average(ARMA)model is an important model for the analysis of time series [15] . This model has been applied to analyze and predict continuous monitoring of clinical and physiological data [16, 17] .

All quantitative data in this study were expressed as median (interquartile range [IQR]) and the difference were assessed by non-parameter test (Mann-Whitney test). The significant level less than 0.05 (P<0.05) indicated significant difference. 

A total of 21 COVID-19 patients were included in our study. The basic information of the patients was listed in Table 1 . The information showed that the length of stay and the level of IgA in severe patients are significantly higher than in mild patients. The IgG level was highest during the acute onset of illness at the early stage of admission, and then decreases with the remission that earlier than IgA. However, IgG didn't show a significantly difference between the common and the severe group. In general, the level of inflammation was higher in severe patients, with decrease of oxygenation index, increase of alveolar arterial oxygen differential pressure A-aDO 2 and increase of respiratory index. These indicators showed significant difference between severe patients and mild patients. In addition, inflammatory cytokines, IL-2, IL-6, IL-10 and TNF-α, were significantly increased in severe patients.

In our study, the positive rate of IgA and IgG was 97% and 79.0% respectively. We collated all IgA and IgG data of severe patients within 65 days of hospitalization and used ARMA model to predict the IgA level between the symptom begin and admission time. The changes of IgA and IgG levels were showed in Figure 1 . We found that IgA levels peaked around the 10-15 days of hospitalization and while IgG levels were decrease all the time.

We collated the data of lung involvement area (chest PA&LAT and CT) in severe COVID-19 patients. The results in Figure 2 show that the lung involvement area in severe COVID-19 patients was present on admission and began to rise. The lung involvement area was peaked in 20-25 days and then began to decrease (Figure 2A ). According to the patient records, 4 patients were still in intensive care, without the decrease in lung involvement area and remission in condition. Therefore, these four patients were assigned into a deterioration group, while the rest were in remission group. We found that the lung involvement area is decreased in remission group ( Figure 2C ), while the lung involvement area is not decreased in deterioration group ( Figure 2D ).

We also calculated the cross correlation between IgA level and chest PA&LAT and CT lung involvement area ( Figure 2B) . The results showed that there is a positive correlation between IgA level and lung involvement area. In particular, the correlation between IgA level and lung involvement area was high (chest PA&LAT: r=0.6663, P<0.05; CT: r=0.7681, P<0.05) when the lag days of IgA was 10 days. The results showed that the IgA levels reach the peak value earlier than the lung involvement area about 10 days in advance.

It is important to note that the pulmonary lesions not only reduce/increase as a sign of remission/deterioration, lesions density decreases/increases also can be thought of ease/aggravate. As a result, we evaluated the changes HRCT values. We found 25 -30 days HRCT value up to -258.8 (-475.0, -108.1), 55 -60 days HRCT value of the minimum -642.9 (-736.9, -582.5), from 5 days to peak time and IgA level high. And significant correlation (P < 0.05) was observed at 20 days. However, due to the small amount of HRCT data, we could not make a fitting prediction.

The highest positive rate was found in the sputum (severe: 62.5%, mild: 54.1%). The total positive rate of pharyngeal swabs and nasopharyngeal swabs results were also summarized (severe: 39.6%, mild: 0% and severe: 26.8%, mild 10.3%). And also feces (severe: 51.0%, mild: 2.9%) and anal swab (severe: 28.9%, mild: 0%) detection results. Moreover, the positive rate of gastric juice in severe patients was 17.5%.

The correlation analysis between IgA and IgG and blood gas index showed that both two was significantly correlated with A-aDO 2 , oxygenation index and respiration index, all P <0.05 ( Figure 3A ). In addition, according to the degree of hypoxia reflected by the oxygenation index of severe patients. It showed the more hypoxic the patient, the larger the area of lung exudation, the higher the level of IgA and IgG ( Figure 3B ).

In this study, 3 patients with severe COVID-19 underwent lung biopsy (lower lobe of the lung), all of which indicated that part of the lung epithelium was exfoliated, submucosal edema, and with few lymphocytes infiltrated, presenting chronic inflammatory changes of the mucosa.

In our study, the level of IgG and increased to highest when the first symptoms began, and IgA peaked after admission 15-20 days, which were earlier than the chest PA & LAT and CT to the maximum lung exudation area, and both showed significant correlation with the oxygen partial pressure difference (A-aDO 2 ) and oxygenation index (OI) of arterial alveolar blood. At the same time, lymphocytes were significantly decreased and IL-2, IL-6, IL-10 and TNF-α levels were significantly increased in severe patients of COVID-19. We considered the excessive activation of immune systems, which induce the release of a large quantity of inflammatory mediators and the latter led to destruction of lung epithelial cells. Therefore, the clinical manifestations (fever and respiratory symptoms) of the severe COVID-19 patients are worse, and some of them need to be admitted to ICU for treatment with mechanical ventilation.

In this study, it was also found that whole lung lobes were involved and there was n\o central tendency in any particular lobe in severe patient, which was different from other epidemic pneumonia. Under the influence of virus invasion and inflammatory factor storm, the patients may develop acute bronchitis and diffuse alveolar damage. The damage of lung epithelium, capillary endothelium and connective tissue caused significant increase in lung exudation and/or formation of a transparent membrane. The imaging findings showed pulmonary patchy shadows, ground glass and consolidation. IgA and IgG is the first line of defense against virus invasion in bronchoalveolar epithelium which appeared earlier than the expansion of the lung exudation, and there was a significant correlation between the two. Therefore, we concluded that the combination of IgA and IgG could be used as a predictive indicator to evaluate the level of lung exudation in patients with severe COVID-19.

Interestingly, the sputum and fecal nucleic acid positive rate of severe patients was higher (62.5% and 51.0%). To rule out the possibility of intestinal nucleic acid test positive for swallowing sputum, we also tested gastric juice and found that the positive rate was only 17.5%. Therefore, it can be proved that COVID-19 virus mainly invades the respiratory and intestinal tract. Meanwhile, the virus-induced immunomodulatory imbalance caused inflammatory storm further aggravates the lung damage, resulting in alveolar epithelial detachment, mucosal edema, and further lung exudation, resulting in the worsening of hypoxemia and life-threatening. IgA and IgG showed significantly correlated with A-aDO 2 and oxygenation index. According to the oxygenation index grouping that could reflect the degree of hypoxia which was also found that as the lung exudates, the oxygenation index decreases. In combination with lung biopsy results, we consider that the virus infiltrated and destroyed bronchial and alveolar epithelium in severe patients of COVID-19, and that IgA and G plays a major immunomodulatory role in submucosal circulation.

As an important antibody to the airway epithelium of the lung, IgA and IgG plays an important defense role against invasion and destruction of bronchial and alveolar epithelium by SARS-CoV-2, and can be used as a predictor to reflect the degree of lung exudation in critical COVID-19 patients to evaluate the progress and prognosis.

All of the data in the article were collected from clinical or laboratory of our hospital sources and partly was still being studied. Therefore, the data cannot be fully shared for the time being.

We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted. 

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