Significant association of pre-existing asthma with an increased risk for ICU admission among COVID-19 patients: Evidence based on a meta-analysis.

In this Journal, Fernadez-de-las-Penas et al. reported a similar prevalence of long-term post-coronavirus disease (COVID) symptoms in patients with asthma compared to non-asthmatics, which suggests that asthma seems not to be a risk factor for more severe long-term post-COVID symptoms but also either was a “protective” factor for that. We have had a valuable opportunity to carefully read this interesting paper and additional published articles regarding the relationship between pre-existing asthma and clinical outcomes of patients with coronavirus disease 2019 (COVID-19). We noticed that a number of published studies have explored the impact of pre-existing asthma on the risk for intensive care unit (ICU) admission among patients with COVID-19, however, the conclusions drawn for the previous individual studies were inconsistent. Although, several meta-analyses have been performed to address this issue, they uniformly failed to find the significant association between pre-existing asthma and the risk for ICU admission among patients with COVID-19.3, 4, 5, 6, 7, 8, 9, 2 To our knowledge, the previous meta-analyses regarding the association between pre-existing asthma and the risk for ICU admission in COVID-19 patients had limited number of included studies (Sunjaya et al.’s paper has the most included studies, with 21). Moreover, many studies on this topic are emerging since then. Therefore, it is necessary to clarify the impact of pre-existing asthma on the risk for ICU admission among COVID-19 patients on the basis of the latest data.

This meta-analysis strictly abided by the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). An extensive search of the literature was performed in PubMed, Springer Link, Web of Science, Wiley Library, EMBASE, Scopus, Elsevier ScienceDirect and Cochrane Library to find all compliant articles published from January 1, 2020 to October 30, 2021. The following keywords were exerted on the search strategy: “COVID-19”, “2019-nCoV”, “SARS-CoV-2”, “2019 novel coronavirus”, “coronavirus disease 2019”, “severe acute respiratory syndrome coronavirus 2”, “asthma”, “asthmatic”, “ICU”, “intensive care unit admission” and “ICU admission”. The reference lists, cited by the included studies and relevant reviews, were eligible as an exploratory objective to identify extensive articles. The inclusion criteria included: (1) adult COVID-19 patients confirmed by reverse transcriptase-polymerase chain reaction (rt-PCR); (2) peer-reviewed original articles in English; (3) individual study populations being at least fifteen cases; (4) the key available data of the included studies, four-table data or effect (95% confidence interval (CI)), must be clearly stated. Case reports, repeated articles, review papers and preprints were eliminated.

The pooled risk ratio (RR) with corresponding 95% CI was utilized to evaluate the association between asthma and ICU admission among COVID-19 patients throughout a random-effects meta-analysis model. The heterogeneity of effect among the included studies was quantitatively presented by I2 statistic. Sensitivity analysis was conducted to check whether the result was robust or not. The potential publication bias was evaluated by Begg's test. The package “meta” of R software (Version 4.1.1) was applied. Significant association was not admitted until two tailed P < 0.05.

Eventually, seventy and seven eligible articles encompassing 854,405 COVID-19 patients were included in our meta-analysis. The included studies stemmed from 26 countries distributed in five continents - North America (n = 19 studies), Europe (n = 32 studies), Asia (n = 21 studies), South America (n = 4 studies) and Africa (n = 1 study). Seventy studies reported the association between asthma and ICU admission among hospitalized COVID-19 patients. The general information of included studies is summarized in Table 1 . Overall, this present meta-analysis showed that there was a significant association between pre-existing asthma and the increased risk for ICU admission among COVID-19 patients (RR: 1.17, 95% CI: 1.07–1.28; I2 = 86%, random-effects model) (Fig. 1 A). In the further subgroup analysis by continents, we observed that COVID-19 patients with asthma were at higher risk for ICU admission compared with those without asthma in Asia (RR: 1.59, 95% CI: 1.26–2.00) and Europe (RR: 1.17, 95% CI: 1.01–1.36), rather than in South America (RR: 0.91, 95% CI: 0.78–1.04), North America (RR: 0.96, 95% CI: 0.84–1.11) and Africa (RR: 1.55, 95% CI: 0.79–3.02). When the setting of patients was restricted to hospitalization, the significant association between asthma and the increased risk for ICU admission among COVID-19 patients still existed (RR: 1.19, 95% CI: 1.09–1.31). Subsequently stratified analyses based on age, sample size, study design and male percentage (%) showed that COVID-19 patients with asthma had a significantly higher risk for ICU admission compared to those without asthma among studies with < 60 years old (RR: 1.26, 95% CI: 1.06–1.51), studies with ≥ 1000 cases (RR: 1.21, 95% CI: 1.08–1.37), studies with male percentage ≥ 50% (RR: 1.22, 95% CI: 1.10–1.36) and retrospective studies (RR: 1.23, 95% CI: 1.09–1.38). The forest plot of sensitivity analysis demonstrated the robustness of our findings (Fig. 1B). There was no potential publication bias in Begg's test (P = 0.0641).

Table 1

The general information of the eligible studies in the meta-analysis.

Author	Location	Study design	Cases	Male (%)	Age	ICU		Non-ICU		Setting
						Asthma	Non-asthma	Asthma	Non-asthma
Lee SC (PMID: 33311519)	Korea	Retrospective study	6811	NR	NR	27	163	615	6006	Hospitalized
Bergman J (PMID: 33704634)	Sweden	Nationwide study	15,872	59.4	64.1 ± 18.4	211	2283	997	12,381	Hospitalized
Castilla J (PMID: 34199198)	Spain	Prospective study	2080	51.92	NR	23	223	124	1710	Hospitalized
Choi YJ (PMID: 32978309)	Korea	Retrospective study	7590	40.8	44.5	7	208	211	7164	All patients
Gude-Sampedro F (PMID: 33349845)	Spain	Retrospective study	2492	53.13	70.2 ± 15.4	14	270	89	2119	Hospitalized
Hansen ESH (PMID: 33527079)	Denmark	Retrospective study	5104	47	54.8 (40.5–72.3)	17	299	337	4451	All patients
Martos-Benítez FD (PMID: 33411264)	Mexico	Retrospective study	38,324	58.3	46.9 ± 15.7	Effect (95% CI): 0.89 (0.61–1.28)				Hospitalized
Schonfeld D (PMID: 33571300)	Argentina	National database	41,703	53.2	55 (37–72)	269	5383	2090	33,961	Hospitalized
Dennis JM (PMID: 33097559)	UK	Retrospective study	19,256	60.1	67 ± 16.88	669	4778	929	12,880	Hospitalized
Wang J (PMID: 33332437)	China	Retrospective study	562	51.6	47 (35.0–57.0)	22	31	46	463	Hospitalized
Almazeedi S (PMID: 32766546)	Kuwait	Retrospective study	1096	81	41 (25–75)	6	36	37	1017	Hospitalized
Beurnier A (PMID: 32732333)	France	Prospective study	112	53.6	60	11	33	26	42	Hospitalized
Calmes D (PMID: 33038592)	Belgium	Retrospective study	596	50.7	58.8	10	78	47	461	Hospitalized
Emami A (PMID: 32835530)	Iran	Retrospective study	1239	55.9	51.48 ± 19.54	1	97	24	1117	Hospitalized
Fong WCG (PMID: 33626216)	UK	Retrospective study	617	NR	NR	78	495	24	20	Hospitalized
Guan WJ (PMID: 33684635)	China	Retrospective study	39,420	49.9	55.7	41	5507	203	33,669	Hospitalized
Ho KS (PMID: 33647451)	USA	Retrospective study	4902	55.9	64.99 ± 16.92	45	1005	188	3664	Hospitalized
Kim S (PMID: 33012003)	Korea	Retrospective study	2043	35	56.1	5	120	61	1857	Hospitalized
Kipourou DK (PMID: 33902520)	Kuwait	Prospective study	3995	70.4	NR	31	284	204	3476	Hospitalized
Rosenthal JA (PMID: 33059035)	USA	Retrospective study	274	NR	NR	11	57	28	178	Hospitalized
Valverde-Monge M (PMID: 34149705)	Spain	Retrospective study	2539	50.2	62.7	7	142	106	2284	Hospitalized
Ortiz-Brizuela E (PMID: 32584326)	Mexico	Prospective study	140	60.7	49.0 (39.0–61.3)	0	29	2	109	Hospitalized
Zhao Z (PMID: 32730358)	China	Retrospective study	593	60.4	58.88 ± 17.49	16	179	25	373	Hospitalized
El Aidaoui K (PMID: 33033687)	Morocco	Retrospective study	134	54.5	53 (36–64)	5	40	5	84	Hospitalized
Yazdanpanah Y (PMID: 33058220)	France	Prospective study	246	57	62 (50–73)	7	64	14	161	Hospitalized
Hippisley-Cox J (PMID: 32737124)	UK	Prospective study	19,486	48.12	62.18 ± 20.84	178	1108	2586	15,614	All patients
Ken-Dror G (PMID: 33199428)	UK	Prospective study	429	56.4	70 ± 18	13	69	29	318	Hospitalized
Bermejo-Martin JF (PMID: 33317616)	Canada	NR	200	55.5	65 ± 19.5	2	98	6	94	Hospitalized
Caliskan T (PMID: 33331576)	Turkey	Retrospective study	565	NR	48 ± 19.664	4	87	17	457	Hospitalized
Samuels S (PMID: 33409769)	USA	Retrospective study	493	51.93	62.9 ± 18.3	10	137	32	314	Hospitalized
Holler JG (PMID: 33421989)	Denmark	Cohort study	2431	54.1	69 (53–80)	20	339	102	1970	Hospitalized
Crispi F (PMID: 33536488)	Spain	Prospective study	397	50.4	47 ± 12.2	3	57	39	298	Hospitalized
Bennett KE (PMID: 33880459)	Ireland	Retrospective study	2811	57.5	NR	50	388	108	2265	Hospitalized
Cummins L (PMID: 33942510)	UK	Retrospective study	1195	62	NR	14	138	152	891	Hospitalized
Castro MC (PMID: 33947740)	Brazil	Retrospective study	465,857	56.2	61 (47–73)	4947	167,526	8639	284,745	Hospitalized
Beltramo G (PMID: 34016619)	France	Retrospective study	89,530	53.05	65 ± 20	640	2633	14,464	71,793	Hospitalized
Wolfisberg S (PMID: 34375985)	Switzerland	Retrospective study	486	65	65.9 ± 14.7	6	86	23	371	Hospitalized
Panda S (PMID: 34468994)	China, India	Retrospective study	420	66.4	37 (24–50)	Effect (95% CI): 19.09 (1.55–147.19)				Hospitalized
Oliva A (PMID: 34501466)	Italy	Retrospective study	97	62	65 (58–78)	1	24	6	66	Hospitalized
Boudou M (PMID: 34531478)	Ireland	Retrospective study	3781	56.5	62.2	75	540	103	3063	Hospitalized
Murthy S (PMID: 33688026)	Canada	Cohort study	188	61.2	64 (53–75)	38	290	52	431	Hospitalized
Jimenez E (PMID: 33172949)	Spain	Retrospective study	572	60.2	53	4	46	43	479	Hospitalized
Gonzalo-Calvo D (PMID: 34048985)	Spain	Prospective study	79	72.22	68.0 (56.6–77.0)	0	36	3	40	Hospitalized
Alshukry A (PMID: 33216801)	Kuwait	Retrospective study	417	62.83	45.39 ± 17.064	15	67	26	309	Hospitalized
Alhumaid S (PMID: 34030733)	Saudi Arabia	Cohort study	1014	57	47.2 ± 19.3	11	194	15	794	Hospitalized
Li X (PMID: 33194455)	USA	Retrospective study	1108	57.3	61.94 ± 18.68	23	248	43	794	Hospitalized
Brandao Neto RA (PMID: 33411707)	Brazil	Prospective study	506	57.3	60.1 ± 15.1	11	289	11	195	Hospitalized
Statsenko Y (PMID: 33637550)	United Arab Emirates	Retrospective study	560	66.25	39.0 (33.0–49.0)	7	65	31	457	Hospitalized
Huang BZ (PMID: 34389242)	USA	Retrospective study	3404	NR	NR	107	845	377	2075	Hospitalized
Nersesjan V (PMID: 33438076)	Denmark	Prospective study	61	63	62.7	3	32	0	26	Hospitalized
Lendorf ME (PMID: 32800073)	Denmark	Retrospective study	111	60	68.7 (56–78)	2	18	10	81	Hospitalized
Bellos I (PMID: 33820751)	Greece	Cohort study	42	69	56.65 ± 14.12	1	9	3	29	Hospitalized
Hasani Azad M (PMID: 34196210)	Iran	Retrospective study	2351	52.5	47.02 ± 20.4	12	216	107	2016	Hospitalized
Suleyman G (PMID: 32543702)	USA	Case series	355	46.5	61.4	19	122	34	180	Hospitalized
Pink I (PMID: 34021897)	Germany	Retrospective study	99	73.7	57	1	51	1	46	Hospitalized
Ileri C (PMID: 33501850)	Turkey	NR	140	58.6	55 ± 16	2	12	14	112	Hospitalized
Zhou Y (PMID: 33109234)	China	Retrospective study	1087	48.3	61.94 ± 18.68	0	97	11	979	Hospitalized
Welder D (PMID: 34132393)	USA	Cohort study	658	52.7	61.4	15	124	79	440	Hospitalized
Hernandez-Galdamez DR.(PMID: 32747155)	Mexico	Cross-sectional study	23,084	NR	NR	143	1563	1358	20,020	Hospitalized
Darabi A (PMID: 34476916)	Iran	Case series	400	51.2	49.2	2	66	27	305	All patients
Hou W (PMID: 33746590)	USA	Retrospective study	593	60.4	58.3	16	179	25	373	Hospitalized
Lu JQ (PMID: 33976972)	USA	Retrospective study	1307	58.2	60.86 ± 17.72	6	98	81	1122	Hospitalized
Forrest IS (PMID: 34089483)	USA	Retrospective study	688	63.5	67.2	10	153	20	505	Hospitalized
Gette M (PMID: 34070021)	France	Retrospective study	292	63.7	68 (57–81)	5	44	16	227	Hospitalized
Izquierdo JL (PMID: 33090964)	Spain	Retrospective study	10,504	52.5	58.2 ± 19.7	9	74	750	9671	All patients
Robey RC (PMID: 34278556)	UK	Retrospective study	221	61	58	13	31	30	147	Hospitalized
Kim SR (PMID: 33260724)	Korea	Retrospective study	2959	39.8	53.15 (38.64–65.87)	5	128	75	2751	Hospitalized
Bagher Pour O (PMID: 34454118)	Iran	Prospective study	226	50.4	56.36 ± 18.54	7	105	4	110	Hospitalized
Wilfong EM (PMID: 34179689)	USA	Retrospective study	128	58.6	56.0 (45.4–67.8)	2	37	9	80	Hospitalized
Costa VO (PMID: 34411145)	Brazil	Retrospective study	58	22.1	34 ± 22.1	0	39	1	18	Hospitalized
Maeda T (PMID: 32720702)	USA	Retrospective study	224	56.7	63 ± 17	4	53	19	148	Hospitalized
Vrotsou K (PMID: 33795313)	Spain	Retrospective study	14,197	38.9	53.7 ± 17.4	88	3622	266	10,221	All patients
Moll M (PMID: 32710891)	USA	Retrospective study	210	48.1	62.21 ± 16.23	15	87	20	88	Hospitalized
Pawar RD (PMID: 34133005)	USA	Cohort study	396	54.3	64.8 ± 17.0	12	110	39	235	Hospitalized
Albu S (PMID: 33998551)	Spain	Cross-sectional study	30	63.3	54 (43.8–262)	1	15	2	12	Outpatient
Al Harthi S (PMID: 34567884)	Oman	Cross-sectional study	102	77.5	49.9 ± 14.7	0	19	1	82	Hospitalized
Nikitopoulou I (PMID: 34576169)	Greece	Cohort study	116	74.1	60.5	2	67	2	45	Hospitalized

Note: The age (years) was presented as mean ± standard deviation or median (interquartile range, IQR); CI, confidence interval; ICU, intensive care unit; NR, not clearly reported; UK, The United Kingdom; USA, the United States of America.

Fig. 1

(A) Forest plot indicated that coronavirus disease 2019 (COVID-19) patients with asthma had a significantly increased risk for admission to intensive care unit (ICU) compared to those without asthma: pooled risk ratio (RR) with its 95% confidence intervals (CI); (B) Sensitivity analysis for pooled RR and 95% CI by deleting one single study from overall pooled analysis each time showed that our results were robust.

In conclusion, our study demonstrated that pre-existing asthma was significantly associated with an increased risk for ICU admission among COVID-19 patients. Thus, COVID-19 patients with asthma should receive greater medical attention to prevent illness progression. Further well-designed studies based on risk factors-adjusted estimates are warranted to confirm our findings.

Data availability statement

The data that support the findings of this study are included in this article and available from the corresponding author upon reasonable request.

Funding

This study was supported by grants from the Key Scientific Research Project of Henan Institution of Higher Education (No. 21A330008), National Natural Science Foundation of China (No. 81973105), and Joint Construction Project of Henan Medical Science and Technology Research Plan (No. LHGJ20190679). The funders have no role in the data collection, data analysis, preparation of manuscript and decision to submission.

CRediT authorship contribution statement

Xueya Han: Data curation, Formal analysis, Writing – original draft. Jie Xu: Data curation, Formal analysis. Hongjie Hou: Data curation, Formal analysis. Haiyan Yang: Conceptualization, Data curation. Yadong Wang: Conceptualization, Data curation.

Declaration of Competing Interest

All authors report that they have no potential conflicts of interest.