Asthma in older adults with severe coronavirus disease 2019: Clinical outcomes and predictors of mortality.

To date, numerous studies have evaluated the relationship between coronavirus disease 2019 (COVID-19) and asthma; however, the impact of asthma on COVID-19–associated outcomes remains controversial and not fully understood.1, 2, 3 It is possible that these contradictions can be explained in terms of asthma heterogeneity. There are data to suggest that asthma in older adults is phenotypically different from that in young patients, particularly when physiological changes associated with the aging process are taken into account. Because old age is a well-known factor of a poor prognosis in COVID-19, it is of great interest to study the course of COVID-19 in older patients with asthma.

This observational study was conducted in the Pulmonology department of a university-affiliated hospital between May 12, 2020 and December 27, 2020. Given that this was a retrospective study, the requirement for informed consent was waived. We enrolled patients older than 65 years old with physician-diagnosed asthma admitted with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection confirmed by real-time polymerase chain reaction, radiological findings compatible with severe COVID-19 pneumonia, and blood oxygen saturation on admission of less than 92% (on room air). The exclusion criteria were nonasthma chronic lung diseases. The diagnostic criteria of allergic asthma were those of the guidelines of the Global Initiative for Asthma: exposure to the allergen induces or aggravates the symptoms and the skin prick test and serum specific immunoglobulin E test exhibiting positive responses to at least 1 allergen. Demographic, clinical, and laboratory data were recorded at admission. We recorded the Charlson comorbidity index (CCI), which calculates the score for comorbidities according to the relative risks of 19 major diseases, including ischemic heart disease, diabetes, and hypertension. We also analyzed the outcomes of COVID-19, such as transfer to the intensive care unit, the need for noninvasive and invasive mechanical ventilation, and 28-day mortality.

The objectives of this study were: (1) to investigate the influence of asthma in older adults on COVID-19 outcomes, and (2) to identify predictors of in-hospital mortality of older patients with asthma and COVID-19. Cox proportional hazard models were used to estimate the association between asthma and in-hospital mortality; the models were adjusted for age, sex, and comorbidities.

Of the 2435 patients hospitalized with COVID-19 infection, 69 patients met the necessary diagnostic criteria (2.8%). Baseline characteristics of the study population are detailed in Table 1 . Most patients had a nonallergic asthma phenotype (44 patients, 63.8%) and multiple comorbidities (the median CCI was 5.3). A total of 19 of the included patients (27.5%) were receiving Global Initiative for Asthma step 4 to 5 therapies; 12 patients (17.4%) and 4 patients (5.8%) were treated before admission with maintenance oral steroids and biologic therapy (omalizumab [n = 2], mepolizumab [n = 2]), respectively.

Table 1

Demographic, Clinical, and Laboratory Characteristics of Older Patients With Asthma and Severe Coronavirus Disease 2019

Parameters	Allpatients(n = 69)	Survived patients(n = 60)	Deceasedpatients(n = 9)	P valuea
Age, y	71 (67-80)	70 (66-80)	72 (68-85)	.33
Sex (male/female)	30/39	24/36	6/3	.16
Smoking history, pack-y	45 (32-50)	48 (45-55)	32 (20-45)	.52
BMI, kg/m2	28.2 (24.7-33.2)	28.1 (23.2-33.8)	28.0 (27.3-32.4)	.69
CCI, points	5.3 (4-7)	5.0 (3-6)	7.0 (6-7.5)	.003
Arterial hypertension, n (%)	31 (44.9)	25 (41.7)	6 (66.7)	.30
Ischemic heart disease, n (%)	18 (26.1)	14 (23.3)	4 (44.4)	.26
Atrial fibrillation, n (%)	25 (36.2)	20 (29.0)	5 (55.6)	.52
Obesity, n (%)	30 (43.5)	25 (41.7)	5 (55.6)	.42
Diabetes mellitus, n (%)	20 (28.9)	17 (28.3)	3 (33.3)	.54
Chronic kidney disease, n (%)	9 (13.0)	6 (10.0)	3 (33.3)	.14
Allergic asthma phenotype, n (%)	22 (31.9)	22 (36.7)	0 (0)	.05
Oral steroids, n (%)	12 (17.4)	8 (13.3)	4 (44.4)	.04
Biologic therapy, n (%)	4 (5.8)	4 (6.7)	0 (0)	.58
Body temperature, °Сb	37.1 (36.9-37.6)	37.0 (36.8-37.5)	37.8 (37.5-38.5)	.006
Respiratory rate, min−1	23 (22-24)	23 (22-24)	25 (24-26)	.02
Heart rate, min−1	83 (74-94)	82 (74-95)	84 (75-90)	.57
SpO2/FiO2	207 (175-229)	209 (171-229)	206 (187-323)	.64
Leukocytes, 109/L	6.2 (4.7-8.9)	6.1 (4.6-8.2)	8.9 (6.1-9.3)	.13
Neutrophils, 109/L	4.6 (2.8-10.8)	3.8 (2.8-6.2)	7.3 (5.1-8.2)	.05
Lymphocytes, 109/L	0.9 (0.6-1.4)	1.0 (0.7-1.4)	0.7 (0.4-0.9)	.06
Neutrophil/lymphocyte ratio	4.5 (2.6-10.3)	3.5 (2.3-7.2)	10.7 (7.1-11.2)	.02
Eosinophils, %	0.6 (0.3-2.0)	1.0 (0.3-3.0)	0.4 (0.2-1.3)	.15
Eosinophils, 109 /L	0.1 (0.07-0.2)	0.1 (0.03-0.2)	0.1 (0.07-0.1)	.46
Fibrinogen, g/L	5.1 (4.2-8.9)	4.9 (3.9-7.8)	11.4 (10.3-12.4)	.04
D-dimer, mg/L	0.9 (0.4-1.1)	0.7 (0.4-1.2)	1.0 (0.8-5.0)	.21
CRP at admission, mg/L	40.0 (14.4-73.2)	34.9 (10.6-70.9)	50.0 (35.1-105.9)	.17
CRP at day 5, mg/L	17.7 (3.5-30.2)	8.6 (2.8-24.3)	39.1 (20.3-170.9)	.007
Creatinine, µmol/L	90.8 (80.2-103.3)	90.2 (78.4-100.1)	97.8 (82.4-110.9)	.39
Glucosа, mmol/L	6.6 (5.7-8.1)	6.5 (5.5-7.8)	8.0 (7.3-10.2)	.02
ALT, U/L	28.7 (17.7-42.8)	30.4 (16-44)	24.5 (19.2-58)	.79
AST, U/L	34.4 (25-49.6)	31.5 (24.9-47.3)	36.5 (28-60.5)	.59
LDH, U/L	536 (399-694)	445 (382-664)	701 (532-1155)	.03
CT, % of lung involvement	30 (25-70)	30 (25-50)	50 (25-75)	.66

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; CCI, Charlson comorbidity index; CRP, C-reactive protein; CT, computed tomography; FiO2, inspired oxygen fraction; IQR, interquartile range; LDH, lactate dehydrogenase; SpO2, oxygen saturation.

NOTE. Continuous variables are presented as median value (IQR).

Mann-Whitney test was used.

The highest temperature during the day was recorded.

During hospitalization, all patients received the standard therapy including prophylactic enoxaparin, intravenous dexamethasone, and tocilizumab. Supplemental oxygen was administered in all patients (100%); noninvasive ventilation and invasive mechanical ventilation were used in 6 (8.6%) and 7 (10.1%) patients, respectively. Twelve patients (17.3%) were transferred to the intensive care unit and the 28-day mortality rate was 13% (9 patients). All patients who died had nonallergic asthma. There was a significant difference in the proportion of patients with severe asthma among deceased and surviving patients (56% vs 13%; P =.01). Patients who died from COVID-19 used maintenance oral steroids more often than survivors (44% vs 13%, P =.04).

Patients who died had higher CCI, higher body temperature at admission, higher respiratory rate, and a higher baseline blood neutrophil count, neutrophil/lymphocyte ratio, fibrinogen, lactate dehydrogenase, glucose levels, and C-reactive protein at day 5 compared with survivors. The Cox regression analysis identified the following variables predicting poor outcomes: CCI (risk ratio [RR], 1.67 [1.11-2.53]), body temperature (RR, 3.73 [1.31-10.6]), severe asthma (RR, 2.75 [1.08-6.99]), nonallergic asthma (RR, 7.95 [1.06-14.30]), and the long-term oral steroid use (RR, 2.57 [1.01-6.53]). The risk of death was not associated with an increased or decreased eosinophil count (Cox regression; P =.57 and P =.53 for percentage and absolute values, respectively).

In a recently published study, Eggert et al reported that among patients with asthma positive for SARS-CoV-2, the allergic asthma phenotype was associated with a reduced risk of hospital admissions, meaning that certain phenotypes of asthma may be protective. The role of allergic asthma diminishes with age; hence a different phenotype presents in older adults with normal eosinophils and elevated sputum neutrophils. Interestingly, in our study, all deceased patients had a nonallergic asthma phenotype. In addition, as recently reported in a study by Schleich et al, older adults with asthma are characterized by poorer lung function and higher bronchial neutrophilic inflammation. Recent publications have suggested that allergic status and type 2 inflammation may decrease susceptibility to SARS-CoV-2 infection and protect against the most severe consequences of COVID-19. Ferastraoaru et al in their retrospective study found that, in patients with asthma, preexisting blood eosinophilia greater than or equal to 150 cells/mL was protective from COVID-19–associated admission. In our cohort of older adults with asthma, we were unable to find differences in eosinophilia levels between deceased and surviving patients. However, it cannot be ruled out that the blood eosinophil counts did not differ significantly owing to the outpatient and inpatient use of systemic steroids. In our study, therapy with maintenance oral steroids in older adults with asthma was a risk factor for poor prognosis. Similar data were presented in a recent study by Adir et al, who also reported that systemic steroid use was significantly associated with an increased risk of severe COVID-19 and all-cause mortality. In contrast to the study by Adir et al, in our study, all patients had severe COVID-19 and all received intravenous dexamethasone during hospitalization. Despite this, long-term use of steroids turned out to be a factor of poor prognosis.

Our study has several limitations. It was a retrospective study performed in a single-center, and statistical analysis and interpretation of our study results are further limited by its relatively small sample size.

Therefore, our study provided evidence that nonallergic asthma phenotype, asthma severity, systemic steroid use, and comorbidities may be risk factors for poor outcomes in older patients with asthma and severe COVID-19. However, further large cohort studies are needed to evaluate the effect of asthma severity and phenotypes on COVID-19 outcomes in older adults.