Result
Literature search &description of studies
We identified 965 potentially relevant studies using the search terms described in the method section. After screening titles and abstracts, a total of 809 publications were excluded. 102 out of the remaining 156 publications were excluded after full-text examination based on our in- and exclusion criteria. Overall, 54 studies were included in our present analysis, including 23 cohort studies (Arai et al., 2005; Arai et al., 2000; Chalmers, Singanayagam, Murray & Hill, 2008; Feng et al., 2020; Gao et al., 2020; Harada & Sekizawa, 2006; Huang et al., 2020; Ishifuji et al., 2017; Jung, Choi, You & Kim, 2020; Li, Wang, Chen, Zhang & Deng, 2020; Li et al., 2020; Mehra, Desai, Kuy, Henry & Patel, 2020a; Mehta et al., 2020; Meng et al., 2020; Mortensen et al., 2012; Mortensen et al., 2008; Mortensen, Restrepo, Anzueto & Pugh, 2005; Myles, Hubbard, Gibson, Pogson, Smith & McKeever, 2009; Sekizawa, Matsui, Nakagawa, Nakayama & Sasaki, 1998; Shah et al., 2014; Tan, Qiu, Xing, Ghosh, Chen & Mao, 2020; Teramoto & Ouchi, 1999; Yang et al., 2020), 12 randomized controlled trials (1997; Amat-Santos et al., 2020; Dahlof et al., 2002; Hou et al., 2006; Kanda, Ebihara, Yasuda, Takashi, Sasaki & Sasaki, 2004; Kasanuki et al., 2009; Kober et al., 1995; Lee et al., 2015; Ohkubo et al., 2004; Schrader et al., 2005; Weber, 1997; Widimsky, Kremer, Jerie & Uhlir, 1995), 14 case-control studies (de Abajo et al., 2020; El Solh, Brewer, Okada, Bashir & Gough, 2004; Gnavi, Demaria, Picariello, Dalmasso, Ricceri & Costa, 2020; Henry, Zaizafoun, Stock, Ghamande, Arroliga & White, 2018; Mancia, Rea, Ludergnani, Apolone & Corrao, 2020; Marciniak, Korutz, Lin, Roth, Welty & Lovell, 2009; Myles, Hubbard, McKeever, Pogson, Smith & Gibson, 2009; Okaishi et al., 1999; Reynolds et al., 2020; Takahashi et al., 2005; van de Garde, Souverein, Hak, Deneer, van den Bosch & Leufkens, 2007; van de Garde, Souverein, van den Bosch, Deneer & Leufkens, 2006; Zhang et al., 2020; Zhou et al., 2020), three nested case-control studies (Dublin, Walker, Jackson, Nelson, Weiss & Jackson, 2012; Etminan, Zhang, Fitzgerald & Brophy, 2006; Mukamal, Ghimire, Pandey, O’Meara & Gautam, 2010) and two case-crossover studies (Liu, Shau, Chang, Wu & Lai, 2013; Liu, Shau, Wu & Lai, 2012) (Supplementary figure 1).
As for the primary and secondary pneumonia releated outcomes, totally 36 studies were included. All the randomized controlled trials were multicenter, except one done by Hou et al.(Hou et al., 2006) Seven of them compared ACE inhibitors with controls (1997; Hou et al., 2006; Kanda, Ebihara, Yasuda, Takashi, Sasaki & Sasaki, 2004; Kober et al., 1995; Lee et al., 2015; Ohkubo et al., 2004; Widimsky, Kremer, Jerie & Uhlir, 1995), four compared ARBs with controls (Dahlof et al., 2002; Kasanuki et al., 2009; Schrader et al., 2005; Weber, 1997). Regarding demographic distribution, two were done worldwide (Ohkubo et al., 2004; Weber, 1997), four in Europe (1997; Kober et al., 1995; Schrader et al., 2005; Widimsky, Kremer, Jerie & Uhlir, 1995) (Germany, Czech Republic and Slovakia, Austria, Denmark and Italy), four in Asia (Hou et al., 2006; Kanda, Ebihara, Yasuda, Takashi, Sasaki & Sasaki, 2004; Kasanuki et al., 2009; Lee et al., 2015) (China, Japan), and one study was located in both Europe and the United States (Dahlof et al., 2002). Among observational studies, ten were carried out in Asia,(Arai et al., 2005; Arai et al., 2000; Harada & Sekizawa, 2006; Ishifuji et al., 2017; Liu, Shau, Chang, Wu & Lai, 2013; Liu, Shau, Wu & Lai, 2012; Okaishi et al., 1999; Sekizawa, Matsui, Nakagawa, Nakayama & Sasaki, 1998; Takahashi et al., 2005; Teramoto & Ouchi, 1999) ten in the United States and Canada (Dublin, Walker, Jackson, Nelson, Weiss & Jackson, 2012; El Solh, Brewer, Okada, Bashir & Gough, 2004; Etminan, Zhang, Fitzgerald & Brophy, 2006; Henry, Zaizafoun, Stock, Ghamande, Arroliga & White, 2018; Marciniak, Korutz, Lin, Roth, Welty & Lovell, 2009; Mortensen et al., 2012; Mortensen et al., 2008; Mortensen, Restrepo, Anzueto & Pugh, 2005; Mukamal, Ghimire, Pandey, O’Meara & Gautam, 2010; Shah et al., 2014), five in Europe (Chalmers, Singanayagam, Murray & Hill, 2008; Myles, Hubbard, Gibson, Pogson, Smith & McKeever, 2009; Myles, Hubbard, McKeever, Pogson, Smith & Gibson, 2009; van de Garde, Souverein, Hak, Deneer, van den Bosch & Leufkens, 2007; van de Garde, Souverein, van den Bosch, Deneer & Leufkens, 2006), 18 studies were retrospective and seven were prospective. 20 studies evaluated ACE inhibitors, six ARBs. Supplementary tables 1- 3 summarize the main characteristics of the included studies.
With regard to the COVID-19-infected patients, 18 studies published clinical data whether ACE inhibitors and ARBs are associated with COVID-19 infection or clinical outcomes in patients with COVID-19 in PubMed. One of them was a global study (Mehra, Desai, Kuy, Henry & Patel, 2020a), however, this study has been retracted at Jun 4th concerning about the quality of the information in the database, thus we only qualitatively summarized this study. Ten of them were conducted in China (Feng et al., 2020; Gao et al., 2020; Huang et al., 2020; Li, Wang, Chen, Zhang & Deng, 2020; Li et al., 2020; Meng et al., 2020; Tan, Qiu, Xing, Ghosh, Chen & Mao, 2020; Yang et al., 2020; Zhang et al., 2020; Zhou et al., 2020), two in the USA(Mehta et al., 2020; Reynolds et al., 2020), two in Italy (Gnavi, Demaria, Picariello, Dalmasso, Ricceri & Costa, 2020; Mancia, Rea, Ludergnani, Apolone & Corrao, 2020), two in Spain (Amat-Santos et al., 2020; de Abajo et al., 2020) and one in Korea(Jung, Choi, You & Kim, 2020). The included studies consist of 12 cohort studies (Feng et al., 2020; Gao et al., 2020; Huang et al., 2020; Jung, Choi, You & Kim, 2020; Li, Wang, Chen, Zhang & Deng, 2020; Li et al., 2020; Mehra, Desai, Kuy, Henry & Patel, 2020a; Mehta et al., 2020; Meng et al., 2020; Tan, Qiu, Xing, Ghosh, Chen & Mao, 2020; Yang et al., 2020; Zhou et al., 2020), five case-control studies (de Abajo et al., 2020; Gnavi, Demaria, Picariello, Dalmasso, Ricceri & Costa, 2020; Mancia, Rea, Ludergnani, Apolone & Corrao, 2020; Reynolds et al., 2020; Zhang et al., 2020) and one randomized controlled trials (Amat-Santos et al., 2020) (Supplementary table 4).
Primary outcomes:incidence of pneumonia
The effect of ACE inhibitor treatment on the incidence of pneumonia was analyzed in 25 studies (a total of 330,780 patients coming from five randomized controlled trials (1997; Kober et al., 1995; Lee et al., 2015; Ohkubo et al., 2004; Widimsky, Kremer, Jerie & Uhlir, 1995), seven cohort studies (Arai et al., 2005; Arai et al., 2000; Harada & Sekizawa, 2006; Ishifuji et al., 2017; Sekizawa, Matsui, Nakagawa, Nakayama & Sasaki, 1998; Shah et al., 2014; Teramoto & Ouchi, 1999), eight case-control studies (El Solh, Brewer, Okada, Bashir & Gough, 2004; Henry, Zaizafoun, Stock, Ghamande, Arroliga & White, 2018; Marciniak, Korutz, Lin, Roth, Welty & Lovell, 2009; Myles, Hubbard, McKeever, Pogson, Smith & Gibson, 2009; Okaishi et al., 1999; Takahashi et al., 2005; van de Garde, Souverein, Hak, Deneer, van den Bosch & Leufkens, 2007; van de Garde, Souverein, van den Bosch, Deneer & Leufkens, 2006), three nested case-control studies (Dublin, Walker, Jackson, Nelson, Weiss & Jackson, 2012; Etminan, Zhang, Fitzgerald & Brophy, 2006; Mukamal, Ghimire, Pandey, O’Meara & Gautam, 2010) and two case-crossover studies(Liu, Shau, Chang, Wu & Lai, 2013; Liu, Shau, Wu & Lai, 2012)). Overall, the use of ACE inhibitors was associated with a significant 27% reduction in risk of pneumonia compared with controls (pooled OR, 0.73; 95% CI, 0.64 to 0.83; p<0.001; I2=78.5%), for further details see Figure 2.
The effect of ARB treatment on the incidence of pneumonia was analyzed in 10 studies (a total of 275,621 patients coming from four randomized controlled trials, (Dahlof et al., 2002; Kasanuki et al., 2009; Schrader et al., 2005; Weber, 1997) one cohort study (Shah et al., 2014), one case-control study (Henry, Zaizafoun, Stock, Ghamande, Arroliga & White, 2018), two nested case-control studies (Etminan, Zhang, Fitzgerald & Brophy, 2006; Mukamal, Ghimire, Pandey, O’Meara & Gautam, 2010) and two case-crossover studies (Liu, Shau, Chang, Wu & Lai, 2013; Liu, Shau, Wu & Lai, 2012).
Pooled results showed that the risk of pneumonia was not significantly different between patients who did or did not use ARBs (pooled OR, 0.90; 95% CI, 0.79 to 1.02; p=0.11; I2=53.3%).
However, two individual study types revealed a potential effect of ARBs on the risk of pneumonia. The odds ratios were 0.84 (95% CI, 0.72 to 0.98; p=0.03; I2=0%) in randomized controlled trials and 0.52 (95% CI, 0.36 to 0.76, p=0.001) in the cohort study, respectively (Figure 3).
Secondary outcome: pneumonia-related mortality
Data of pneumonia-related deaths were available in 10 studies, one of which was comparing ARBs with control summarized qualitatively (Mortensen et al., 2012), nine studies comparing ACE inhibitors with controls (four randomized controlled trials (Hou et al., 2006; Kanda, Ebihara, Yasuda, Takashi, Sasaki & Sasaki, 2004; Lee et al., 2015; Ohkubo et al., 2004), and five cohort studies (Chalmers, Singanayagam, Murray & Hill, 2008; Mortensen et al., 2012; Mortensen, Restrepo, Anzueto & Pugh, 2005; Mortensen, Restrepo, Copeland, Pugh & Anzueto, 2008; Myles, Hubbard, Gibson, Pogson, Smith & McKeever, 2009) were included in the meta-analysis.
Pooled results showed that ACE inhibitors were associated with a significant 27% reduction in risk of pneumonia-related mortality (OR, 0.73; 95% CI, 0.59 to 0.90; p=0.004; I2=60.1%) compared with controls (Figure 4).
For ARBs, a meta-analysis for the secondary end-point mortality was not possible due to the lack of enough eligible studies. Mortensen et al. (Mortensen et al., 2012), conducted the only eligible study providing data on ARB and pneumonia related mortality. They showed in a cohort of 22,996 patients where 839 subjects were treated with ARBs that treatment with ARBs reduced the pneumonia-related mortality (OR, 0.47; 95% CI, 0.30 to 0.72).