Primary Care Relevant Risk Factors for Adverse Outcomes in Patients With COVID-19 Infection: A Systematic Review

Michelle Bentivegna; Cassie Hulme; Mark H. Ebell

doi:10.3122/jabfm.2021.S1.200429

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Table 1.

Characteristics of Included Studies

Author, Year	Country	Patients Studied	Mean or median age	% Male	Definition of Bad Outcome	Mortality Rate, %
Yu, 2020³²	China	Adults with COVID-19 from 27 hospitals in Jiangsu Province with a CT scan	48 (median)	53.0	Composite of ICU admission, acute respiratory failure occurrence, or shock during hospitalization	15.0
Wang, 2020³³	China	Adults with COVID-19 who were discharged from 2 hospitals (Wuhan and Hubei Province)	51 (median)	53.3	Death	17.8
Chen, 2020³⁴	China	Adults with COVID-19 classified as moderately, severely or critically ill in 1 hospital in Wuhan	68 (median)	62.4	Death	41.2
Zhou, 2020³⁵	China	Adults with COVID-19 who had been discharged or died in 2 Wuhan hospitals	56 (median)	62.3	Death	28.0
Liu, 2020³⁶	China	Adults with COVID-19 pneumonia in 3 tertiary hospitals in Wuhan	38 (median)	50	Clinical deterioration	14.1
Liang, 2020¹⁹	China	Adults with COVID-19 from 575 hospitals in 31 regions of China	48.9 (mean)	57.3	Composite of admission to ICU, invasive ventilation, death	3.2
Xie, 2020³⁷	China	Adults with COVID-19 who had been discharged from or died in 2 hospitals in Wuhan	62 (median)	53.8	Death	50.5
Yan, 2020³⁸	China	Adults with COVID-19 in 1 hospital in Wuhan	58.83 (mean)	58.7	Death	46.4
Cao, 2020³⁹	China	Adults with COVID-19 in 1 hospital in Shanghai	50.1 (mean)	51	Admission to ICU	NR
Hu, 2020⁴⁰	China	Adults with COVID-19 in 1 hospital in Wuhan	61 (median)	51.4	Death or progression	10.8
Luo, 2020⁴¹	China	Adults with COVID-19 with a clinical outcome in 1 hospital in Wuhan	57 (median)	50.3	Death	28.2
Petrilli, 2020⁴²	United States	Adults with laboratory confirmed critical COVID-19 in 1 hospital in New York City	54 (median)	49.5	Composite of ICU, mechanical ventilation, discharge to hospice or death.	24.3
Wu, 2020⁴³	China	Adults with COVID-19 pneumonia in 1 hospital in Wuhan	51 (median)	63.7	ARDS	21.9
Li, 2020⁴⁴	China	Adults with laboratory confirmed severe COVID-19 infection	57 (median)	58	Death	14.7
Jang, 2020⁴⁵	Korea	Adults with COVID-19 hospitalized at a tertiary hospital in Daegu, Korea	56.9 (mean)	43.6	Compositive of ARDS, ICU care, or death	7.3
Xu, 2020⁴⁶	China	Adults with laboratory-confirmed COVID-19 admitted to 16 tertiary hospitals from 8 provinces in China	46.1 (mean)	54	Composite of death, ICU, or requiring mechanical ventilation.	4.7
Zhou, 2020⁴⁷	China	Adults with laboratory-confirmed COVID-19 collected from 47 locations in Sichaun	43 (median)	56.6	Vasopressors or respiratory failure + 3 of: respiratory rate >30, PaO₂/FIO₂ ≤250 mm Hg, infiltrates, confusion, BUN ≥20 mg/dL, leukopenia, hypothermia, thrombocytopenia, or hypotension.	NR
Hou, 2020⁴⁸	China	Adults with laboratory-confirmed COVID-19 hospitalized at Beijing hospitals	50.9 (median)	43.6	Progression defined as having a clinically advanced type of COVID-19, ICU admission, or death during hospitalization	5.0
Zhang, 2020⁴⁹	China	Adults with laboratory-confirmed COVID-19 in 1 hospital in Wuhan, China	38.0 (median)	41.4	Disease deterioration including the transfer to ICU and death	13.5
Liu, 2020⁵⁰	China	Adults with laboratory-confirmed COVID-19 in 1 hospital in Wuhan, China	65.5 (median)	35.0	Severe disease defined as having shortness of breath, RR ≥30 bpm, O₂ sat ≤93%, PaO₂/FIO₂ ≤ 300 mm Hg, and progression on imaging	NR
Zhu, 2020⁵¹	China	Adults with confirmed COVID-19 at 1 hospital in Zhejiang, China	50.9 (mean)	35.4	Severe disease defined as shortness of breath, RR ≥30 bpm, O₂ sat ≤93%, PaO₂/FIO₂ ≤300 mm Hg, or lesion progression	NR
Hu, 2020⁵²	China	Adults with laboratory-confirmed critical COVID-19 in 1 hospital in Wuhan, China	60.8 (mean)	50.9	Death	18.0

COVID-19, coronavirus 2019; CT, computed tomography; RR, respiratory rate; O₂ sat, oxygen saturation; BUN, blood urea nitrogen; ICU, intensive care unit; ARDS, acute respiratory distress syndrome.

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Table 2.

Association between Categorical Variables and Mortality or Severe Disease in Patients with COVID-19

Variables	Studies	Total Patients	RR (95% CI)
Outcome = death
Demographics and vital signs
Oxygen saturation < 90% to 93%	3	718	6.07 (4.27–8.63)
Respiratory rate >20 to 30 breaths/min	4	841	3.80 (2.13–6.78)
Age ≥60 to 65 years	3	483	2.62 (1.91–3.58)
Male sex	9	2213	1.24 (1.08–1.43)
Comorbidities
Coronary heart disease	9	2213	5.27 (2.89–9.58)
Chronic kidney disease	5	1562	5.11 (2.18–12.0)
Chronic obstructive pulmonary disease	9	2213	3.79 (2.51–5.72)
Hypertension	9	2213	2.34 (1.80–3.05)
Diabetes mellitus	9	2213	2.15 (1.46–3.15)
Symptoms
Dyspnea	3	1073	3.47 (1.67–7.18)
Fever	6	1530	1.10 (0.95–1.28)
Cough	5	1366	1.02 (0.93–1.13)
Laboratory tests
Procalcitonin ≥0.25 to 0.5 ng/mL	4	728	9.59 (3.71–24.8)
Increased LDH	3	831	5.16 (0.72–37.09)
D-dimer ≥1.0 mg/L	4	718	2.56 (2.10–3.13)
D-dimer ≥0.5 mg/L	3	569	1.54 (1.32–1.80)
D-dimer 0.5-1.0 mg/L	4	718	0.45 (0.31–0.64)
D-dimer ≤0.5 mg/L	4	718	0.19 (0.12–0.30)
Lymphocyte count < 0.8 to 1.1 × 109/mL	4	841	2.07 (1.51–2.84)
WBC ≥4 × 109/mL	3	567	1.07 (0.81–1.41)
WBC < 3.5 - 4 × 109/mL	3	567	0.34 (0.20–0.56)
WBC 4 to 10 × 109/mL	3	567	0.65 (0.54–0.78)
Outcome = severe disease
Male sex	11	4582	1.30 (1.11–1.53)
Comorbidities
Coronary heart disease	9	4364	3.69 (1.75–7.77)
Chronic kidney disease	3	3516	3.02 (0.63–14.6)
Diabetes mellitus	11	4582	2.57 (1.59–4.17)
Chronic obstructive pulmonary disease	7	1033	2.47 (1.34–4.52)
Hypertension	11	4582	2.29 (1.61–3.26)
Symptoms
Dyspnea	7	1473	6.28 (3.10–12.7)
Fever	10	4504	1.13 (1.05–1.22)
Cough	9	1775	1.11 (0.87–1.42)
Laboratory tests
Procalcitonin >0.05 ng/mL	3	448	4.06 (0.65–25.3)
C-reactive protein >5 to 0 mg/L	3	448	1.68 (1.47–1.93)

Variables reported by fewer than 3 studies are not included but can be found online.
RR, risk ratio; CI, confidence interval.

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Table 3.

Weighted Mean Differences between Patients With and Without the Outcome

Risk Factor	Studies	Patients	WMD (95% CI)
Outcome = death
CRP (mg/L)	4	1016	40.4 (27.4–53.3)
Age (years)	7	1418	18.5 (15.4–21.6)
D-dimer (mg/L)	4	870	7.8 (6.1–9.4)
Heart rate (beats/minute)	3	486	5.3 (1.7–8.9)
Neutrophil count (×10⁹/mL)	3	679	4.3 (2.7–5.8)
WBC count (×10⁹/mL)	6	1314	4.0 (3.4–4.6)
Respiratory rate	3	486	3.1 (1.5–4.7)
Procalcitonin (ng/mL)	3	763	0.34 (0.27–0.40)
Oxygen saturation (%)	4	823	−8.9 (−11.9 to −5.9)
Lymphocyte count (×10⁹/mL)	6	1314	−0.41 (−0.50 to −0.32)
Outcome = severe disease
CRP (mg/L)	4	731	34.2 (15.4–53.1)
Age (years)	8	2223	14.1 (10.9–17.6)
Neutrophil count (×10⁹/mL)	5	752	0.94 (−0.42 to –2.3)
WBC count (× 10⁹/mL)	5	954	0.73 (−0.63 to 2.1)
D-dimer (mg/L)	5	604	0.30 (0.06–0.55)
Lymphocyte count (×10⁹/mL)	5	948	−0.44 (−0.52 to −0.36)
Outcome = severe disease or death
CRP (mg/L)	4	4531	60.5 (47.9–73.2)
Age (years)	5	4641	15.9 (10.4–21.3)
Neutrophil count (×10⁹/mL)	4	1912	2.6 (2.1–3.2)
WBC count (×10⁹/mL)	3	322	2.0 (0.98–3.0)
Procalcitonin (ng/mL)	3	4420	0.13 (−0.30 to 0.56)
Oxygen saturation (%)	3	2940	−4.4 (−7.3 to −1.4)
Lymphocyte count	5	4641	−0.63 (−1.0 to −0.22)

Variables reported by fewer than 3 studies are not included but can be found in the online Appendix B.
WMD, weighted mean differences; WBC, white blood count; CRP, c-reactive protein.

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Table 4.

Summary of Variables Included in Multivariate Models to Predict an Adverse Prognosis for COVID-19

Variable	Zhang, 2020 (J Clin Virol)	Zhou, 2020 (PLOS One)	Xu, 2020 (Theranostics)	Liu, 2020 (J Clin Virol)	Jang, 2020 (JKMS)	Hou, 2020 (Infect Dis)	Wang, 2020 (Crit Care)	Zhou, 2020 (Lancet)	Liu, 2020 (Chin Med J)	Liang, 2020 (JAMA Intern Med)	Xie, 2020 (medRxIV)	Yan, 2020 (medRxiv)	Hu, 2020	Luo, 2020 (Clin Infect Dis)	Petrilli, 2020 (BMJ)	Li, 2020	Number of Models Including This Variable
Demographics
Age (increasing)			x			x	x	x	x	x	x		x	x	x	x	11
Male sex	x						x										2
Vital signs
Temperature (elevated)		x			x				x								3
Oxygen saturation (decreased)					x						x						2
Comorbidities
Presence of comorbidities	x		x							x							3
Diabetes mellitus					x								x				2
Tobacco use									x				x				2
History of cancer										x					x		2
Hypertension		x															1
Cardiovascular disease		x															1
Heart failure															x		1
Chronic liver disease		x															1
Chronic kidney disease		x															1
Use of hypnotic													x				1
Symptoms
Dyspnea		x								x							2
Cough		x															1
Hemoptysis										x							1
Loss of consciousness										x							1
Laboratory results
C-reactive protein (elevated)	x			x		x			x			x		x	x		7
Lymphocyte count (decreased)	x		x			x					x	x			x		6
Lactate dehydrogenase (increased)										x	x	x				x	4
WBC count (increased)			x										x				2
Neutrophil count (increased)													x	x			2
Troponin (increased)													x		x		2
Procalcitonin (increased)				x											x		2
D-dimer (increased)								x							x		2
Interleukin-6 >32.1 pg/mL				x													1
CK-MB (elevated)					x												1
Albumin (decreased)									x								1
Neutrophil/lymphocyte ratio										x							1
Direct bilirubin (increased)										x							1
Serum creatinine (increased)															x		1

WBC, white blood count; CK-MB, creatine kinase-MB.

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Table 5.

Proposed Clinical Prediction Rules in the Medical Literature

Study	Predictor Variables	Outcome Predicted	Validation (Country)	Type of CPR With Outcome
Lu, 2020^*	Age, CRP	Death	Internal validation (China)	Classification tree:
				Low: 0% mortality
				Mod: 6% mortality
				High: 33% mortality
Xie, 2020	Age, LDH, lymphocytes, SpO2	Death	External validation in 1 hospital (China)	Probability assessment using full logistic model as nomogram
Yan, 2020	LDH, CRP, lymphocytes	Death	Internal validation (China)	Classification tree
Yu, 2020	Age, sex, diabetes mellitus, lymphocytes, procalcitonin	Death	Internal validation (China)	Risk score
				High risk (>3 points): 22.8%
				Low risk (≤3 points): 5.4%)
Shi, 2020	Age, sex, hypertension	Death or severe disease	Internal validation (China)	0 factors: 0%
				1 factor: 6%
				2 factors: 19%
				3 factors: 40%
Galloway, 2020	Age, sex, race, oxygen saturation, chest radiograph, neutrophils, CRP, albumin, creatinine, diabetes mellitus, hypertension, chronic lung disease	Death or critical care	Internal validation (UK)	Risk score
				High risk (≥4 points): 40.7%
				Low risk (<4 points): 12.4%
Petrilli, 2020	Age, SpO₂, procalcitonin, troponin, CRP, hypertension	Severe disease	Internal validation (US)	Classification tree
Liang, 2020	Age, neutrophil/lymphocyte ratio, LDH, direct bilirubin, chest radiograph, hemoptysis, dyspnea, unconsciousness, comorbidities, cancer	Severe disease	External validation in 3 hospitals (China)	Logistic regression model requiring online calculator
Zhou, 2020	Temperature, cough, dyspnea, hypertension, chronic liver disease, chronic kidney disease, cardiovascular disease	Severe disease	Internal validation (China)	Nomogram
Kaeuffer, 2020²⁰	Age, BMI, sex, dyspnea, neutrophil count, lymphocyte count, CRP	Severe disease	External validation	Risk score:
				Low risk (≤6): 13%
				Moderate risk (6–14): NR
				High risk (>14): 66%
Knight, 2020²¹	Age, sex, number of comorbidities, respiratory rate, SpO₂, level of consciousness, urea level, CRP	Mortality	External validation	Risk score from 0 to 21 points
				Low risk (0–3): 1.2%
				Intermediate risk (4–8): 9.9%
				High risk (9–14): 31.4%
				Very high risk (≥15): 61.5%

↵* Study included some patients with suspected but not confirmed COVID-19. Preprint at MedRxIV: Lu J, et al. ACP risk grade: a simple mortality index for patients with confirmed or suspected severe acute respiratory syndrome coronavirus 2 disease (COVID-19) during the early stage of outbreak in Wuhan (https://doi.org/10.1101/2020.02.20.20025510).
CPR, clinical prediction rule; CRP, c-reactive protein; LDH, lactate dehydrogenase; BMI, body mass index.

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Table 2.

Study Quality Assessment Using the Quality of Prognostic Studies Tool

Authors	Study Participation	Study Attrition	Prognostic Factor Measurement	Outcome Measurement	Study Confounding	Statistical Analysis and Reporting
Yu et al, 2020	M	L	L	L	L	L
Wang, 2020	M	L	L	L	L	L
Chen, 2020	M	H	L	L	H	L
Zhou, 2020	M	L	L	L	L	L
Liu, 2020	M	L	L	L	L	L
Liang, 2020	M	L	L	L	L	L
Xie, 2020	M	L	L	L	L	L
Yan, 2020	M	H	L	L	L	L
Cao, 2020	M	L	L	L	H	L
Hu, 2020	M	H	L	L	L	L
Luo, 2020	M	L	L	L	L	L
Petrilli, 2020	M	H	L	L	L	L
Wu, 2020	M	H	L	L	H	L
Li, 2020	M	H	L	L	L	L
Jang, 2020	M	L	L	L	L	L
Xu, 2020	M	H	L	L	L	L
Zhou, 2020	M	L	L	L	L	L
Hou, 2020	M	L	L	L	L	L
Zhang, 2020	M	H	L	L	L	L
Liu, 2020	M	L	L	L	L	L
Zhu, 2020	M	L	L	L	L	L
Hu, 2020	M	L	L	L	L	L

L, low risk of bias; M, moderate risk of bias; H, high risk of bias.

Variables	Study Participation	Study Attrition	Prognostic Factor Measurement	Outcome Measurement	Study Confounding	Statistical Analysis and Reporting
High risk of bias	Specialized population (ie, pregnant, elderly) or subset of very ill patients only	Incomplete outcome ascertainment (some patients still hospitalized)	Unclear definition for prognostic factors	Outcome not defined	No multivariate analysis performed	Selective reporting of results, no clear analytic strategy
Moderate risk of bias	Only inpatients	Complete ascertainment but >10% loss to follow-up	Post hoc selection of cut points	Unclear definition
Low risk of bias	Inpatient and outpatient	Complete ascertainment and <10% loss to follow-up	Typical cutoffs used, clearly defined	Clear and reproducible definition	Multivariate analysis reported	Full reporting, analytic strategy clearly described

Association between categorical variables and mortality, severe disease, or both in patients with COVID-19

Risk Factor	Studies	Patients	RR (95% CI)
Outcome = Death
Age <39 to 40 years	1	274	0.01 (0.00–0.21)
Age <45 years	1	107	0.21 (0.06–0.79)
Age >45 years	1	107	1.79 (1.38–2.32)
Age >75 years	1	107	10.42 (3.58–30.33)
Age ≥40 years	1	274	1.49 (1.33–1.66)
Age ≥60 to 65 years	3	483	2.62 (1.91–3.58)
Age 40–60 years	1	274	0.55 (0.34–0.89)
Age 45–59 years	1	107	0.19 (0.03–1.34)
Age 60–75 years	1	107	2.03 (0.97–4.23)
Any comorbidity	1	692	2.99 (2.37–3.77)
Chronic kidney disease	5	1562	5.11 (2.18–11.98)
COPD	9	2213	3.79 (2.51–5.72)
Coronary heart disease	9	2213	5.27 (2.89–9.58)
Cough	5	1366	1.02 (0.93–1.13)
CRP >100 mg/L	2	243	4.16 (2.71–6.37)
CRP ≥3 mg/L	1	102	1.19 (1.04–1.36)
CRP increased	1	581	1.42 (1.29–1.55)
D-dimer ≤0.5 mg/L	4	718	0.19 (0.12–0.30)
D-dimer >21 mg/L	1	247	17.53 (5.54–55.49)
D-dimer ≥0.5 mg/L	3	569	1.54 (1.32–1.80)
D-dimer ≥1.0 mg/L	4	718	2.56 (2.10–3.13)
D-dimer 0.5–1.0 mg/L	4	718	0.45 (0.31–0.64)
D-dimer increased	1	371	2.63 (1.91–3.63)
Diabetes mellitus	9	2213	2.15 (1.46–3.15)
Dyspnea	3	1073	3.47 (1.67–7.18)
Fever	6	1530	1.10 (0.95–1.28)
Heart rate >100	1	274	1.66 (1.23–2.25)
Heart rate ≥125	1	191	12.55 (0.61–257.13)
Hypertension	9	2213	2.34 (1.80–3.05)
LDH increased	3	831	5.16 (0.72–37.09)
Lymphocyte count <0.5	1	274	7.84 (3.84–16.00)
Lymphocyte count <0.8 to 1.1	4	841	2.07 (1.51–2.84)
Lymphocyte count ≥1	1	274	0.17 (0.09–0.31)
Lymphocyte count 0.5–0.8	1	274	1.53 (1.07–2.19)
Lymphocyte count 0.8–1	1	274	0.81 (0.46–1.43)
Lymphocytes decreased	1	547	2.10 (1.87–2.36)
Male sex	9	2213	1.24 (1.08–1.43)
Neutrophil count >6.3	1	274	6.29 (3.94–10.04)
Neutrophils increased	1	544	6.12 (3.86–9.70)
Oxygen saturation <90 to 93	3	718	6.07 (4.27–8.63)
Procalcitonin <0.05 ng/mL	1	236	0.02 (0.00–0.15)
Procalcitonin <0.1 ng/mL	1	164	0.44 (0.31–0.64)
Procalcitonin >0.05 ng/mL	1	102	1.79 (1.45–2.22)
Procalcitonin ≥0.1 to 0.25 ng/mL	1	164	2.53 (1.34–4.79)
Procalcitonin ≥0.25 to 0.5 ng/mL	4	728	9.59 (3.71–24.82)
Procalcitonin ≥2.0 ng/mL	1	236	24.71 (1.44–423.13)
Procalcitonin 0.05–0.5 ng/mL	1	236	1.31 (1.04–1.65)
Procalcitonin 0.5–2.0 ng/mL	1	236	13.13 (4.10–42.04)
Procalcitonin increased	1	455	1.48 (1.18–1.85)
Respiratory rate <24	1	274	0.48 (0.38–0.60)
Respiratory rate >20 to 30	4	841	3.80 (2.13–6.78)
Respiratory rate 24–30	1	274	3.02 (1.79–5.10)
SBP <90 mm Hg	2	274	5.70 (1.23–26.34)
SBP ≥140 mm Hg	1	274	2.16 (1.49–3.12)
SBP 90–140 mm Hg	1	274	0.62 (0.51–0.76)
Troponin >34.2	1	101	6.96 (2.61–17.17)
WBC < 3.5 to 4	3	567	0.34 (0.20–0.56)
WBC ≥4	3	567	1.07 (0.81–1.41)
WBC ≥9.5 to 10	3	567	5.73 (2.48–13.27)
WBC 4–10	3	567	0.65 (0.54–0.78)
WBC increased	1	630	16.08 (9.05–28.58)
Outcome = severe disease or death
Age ≥40 years	1	323	1.13 (1.07–1.19)
Age ≥60 to 65 years	1	323	2.06 (1.56–2.74)
Chronic kidney disease	1	1590	4.45 (1.76–11.29)
COPD	2	1913	5.63 (1.07–29.69)
Coronary heart disease	1	1590	3.15 (1.75–5.57)
Cough	2	1821	1.06 (0.96–1.17)
CRP ≥3 mg/L	1	306	1.13 (1.07–1.19)
Diabetes mellitus	2	1913	3.24 (2.41–4.36)
Dyspnea	2	1717	3.09 (2.59–3.68)
Fever	2	1859	1.01 (0.96–1.07)
Hypertension	2	1913	2.00 (1.06–3.78)
LDH increased	1	87	3.32 (1.75–6.32)
Lymphocyte count <2.0	1	305	1.57 (1.33–1.84)
Male sex	2	1901	1.19 (1.06–1.33)
Neutrophil count >7.5	1	305	3.02 (2.28–3.99)
WBC ≥9.5 to 10	1	305	9.14 (3.94–21.24)
Outcome = severe disease
Age <39 to 40 years	1	198	0.29 (0.08–1.11)
Age >75 years	1	2729	1.69 (1.49–1.93)
Age ≥40 years	1	198	1.39 (1.15–1.68)
Age ≥50 years	1	198	1.62 (1.23–2.14)
Age ≥60 to 65 years	2	564	2.53 (1.89–3.40)
Age ≥70 years	1	198	4.71 (2.33–9.53)
Age 40–49 years	1	198	0.67 (0.17–2.61)
Age 50–59 years	1	198	0.13 (0.01–2.11)
Age 60–69 years	1	198	1.74 (0.90–3.33)
Asthma or COPD	1	2729	1.05 (0.88–1.24)
Chronic kidney disease	3	3516	3.02 (0.63–14.60)
COPD	7	1033	2.47 (1.34–4.52)
Coronary heart disease	9	4364	3.69 (1.75–7.77)
Cough	9	1775	1.11 (0.87–1.42)
CRP >5 to 10 mg/L	3	448	1.68 (1.47–1.93)
D-dimer ≥0.5 mg/L	2	877	3.10 (1.45–6.64)
Diabetes mellitus	11	4582	2.57 (1.59–4.17)
spnea	7	1473	6.28 (3.10–12.74)
Fever	10	4504	1.13 (1.05–1.22)
Heart rate ≥90	1	366	0.88 (0.43–1.79)
Hypertension	11	4582	2.29 (1.61–3.26)
LDH increased	1	110	2.65 (1.93–3.63)
Lymphocyte count <0.8 to 1.1	2	308	27.36 (0.96–778.27)
Lymphocyte count >3.2	1	198	0.13 (0.02–0.90)
Male sex	11	4582	1.30 (1.11–1.53)
Neutrophil count <1.8	1	198	0.26 (0.02–4.12)
Neutrophil count >6.3	1	308	4.13 (2.31–7.37)
Oxygen saturation <88	1	2729	3.69 (3.06–4.46)
Oxygen saturation <96	1	366	1.39 (0.77–2.52)
Procalcitonin >0.05 ng/mL	3	448	4.06 (0.65–25.29)
Respiratory rate >20 to 30	2	477	2.11 (0.20–22.05)
SBP ≥110 mm Hg	1	366	1.07 (1.01–1.13)
WBC <3.5 to 4	1	198	0.67 (0.17–2.61)
WBC ≥9.5 to 10	2	308	5.52 (2.41–12.66)

COPD = chronic obstructive pulmonary disease; RR, risk ratio; CI, confidence interval; CRP, c-reactive protein; LDH, lactate dehydrogenase; WBC, white blood count; SBP, systolic blood pressure.

Association between Continuous Variables and Mortality, Severe Disease, or Both in Patients with COVID-19: Full Data Set

Risk Factor	Studies	Patients	WMD (95% CI)
Outcome = death
Age	7	1418	18.5 (15.4–21.6)
Systolic blood pressure	1	105	12.5 (0.64–24.3)
Mean arterial pressure	2	381	8.0 (4.3–11.8)
D-dimer (mg/L)	4	870	7.6 (6.1–9.4)
Heart rate	3	486	5.3 (1.7–8.9)
CRP (mg/L)	4	1016	40.4 (27.4–53.3)
Neutrophil count	3	679	4.3 (2.7–5.8)
WBC count	6	1314	4.0 (3.4–4.6)
Respiratory rate	3	486	3.1 (1.5–4.7)
Procalcitonin	3	763	0.34 (0.27–0.40)
Oxygen saturation	4	823	−8.9 (−11.9 to −5.9)
Lymphocyte count	6	1314	−0.4 (−0.5 to −0.3)
Outcome = severe disease or death
CRP (mg/L)	4	4531	60.5 (47.9–73.2)
Age	5	4641	15.9 (10.4–21.3)
Systolic blood pressure	1	110	8.6 (0.07–17.1)
Neutrophil count	4	1912	2.6 (2.1–3.2)
WBC count	3	322	2.0 (0.98–3.0)
Respiratory rate	2	211	1.5 (0.02–3.3)
Heart rate	2	211	0.99 (−3.7, 5.5)
D-dimer (mg/L)	1	2729	0.31 (0.27–0.36)
Procalcitonin	3	4420	0.13 (−0.30 to 0.56)
Mean arterial pressure	1	101	−6.1 (−17.8 to 5.6)
Oxygen saturation	3	2940	−4.4 (−7.3 to −1.4)
Lymphocyte count	5	4641	−0.63 (−1.0 to −0.22)
Outcome = severe disease
CRP (mg/L)	4	731	34.2 (15.4–53.1)
Age	8	2223	14.1 (10.9–17.6)
Oxygen saturation	1	78	12.3 (2.6–22.1)
Heart rate	1	78	7.3 (−21.4 to –36.0)
Neutrophil count	5	752	0.94 (−0.42 to 2.3)
WBC count	5	954	0.73 (−0.63 to 2.1)
D-dimer (mg/L)	5	604	0.30 (0.06–0.55)
Procalcitonin	2	276	0.05 (−0.08 to 0.19)
Respiratory rate	1	78	0.00 (−15.6 to 15.6)
Lymphocyte count	5	948	−0.44 (−0.52 to −0.36)

WMD, weighted mean differences; COPD = chronic obstructive pulmonary disease; CI, confidence interval; CRP, c-reactive protein; LDH, lactate dehydrogenase; WBC, white blood count; SBP, systolic blood pressure.