A total of 140 potential studies were identified through database and manual reference searches. After deduplication and screening a total of 29 studies for deemed eligible for the SR with only 20 studies considered for the meta-analysis. A detailed study selection process is depicted in a flow chart (Figure 1). The degree of agreement between review authors was 93% (27 studies agreed/29 studies) for inclusion of eligible studies and 92% for data extraction.
Characteristics of the included studies
From the 29 included studies: retrospective studies (n=21), case series (n=5), case reports (n=2) and cross sectional study (n=1), majority of studies were from China (n=27; 90%) with the remaining two studies each from Singapore and USA.13,15-17,19,30-53 The period of studies spanned from 11th of December 2019 to the 8th of March, 2020. The presence of SARS-COV-2 was confirmed using the molecular based technique of Reverse Transcriptase polymerase chain reaction (RT-PCR), while the diagnosis was based on the Chinese Center for Disease Prevention and Control (CDC) guidelines or WHO interim guidance. Table 2 summarises the main characteristics of eligible studies.
Characteristics of the included patients
The 29 studies involved 9991 diagnosed patients with SARS-CoV-2 of whom more than half consisted of females (n=5166, 51.7%). The mean or median age of the patients ranged from 40 years19 to 73 years. The common comorbidities or chronic disease presented among the included patients were diabetes, hypertension, kidney disease, acute cardiac injury, acute respiratory distress syndrome and shock. The major presenting symptoms were fever, dry cough, expectoration, fatigue, anorexia, myalgia, dyspnea, pharyngalgia, diarrhea, nausea, breathlessness, chest tightness and dizziness. In addition to supportive and palliative care, the main stay of treatment tailored to the condition of the patient included antivirals, antibiotics, corticosteroids or immunoglobulin administration. The demographics, comorbidities, presenting symptoms and treatment modalities of patients with COVID-19 are detailed in Table 3.
Abnormalities of the plasma proteins Albumin
A meta-analysis of 11 studies revealed that the pooled mean of albumin levels was 37.87 g/L [36.56, 39.17] with a significant level of heterogeneity (I2=98%, P<0.00001). Majority of the studies did not report the number of patients who showed changes in albumin levels. However, Yang W et al, 2020 and Huang C et al., 2020 reported elevation of albumin in 2.01% (n=3) and 20.6% (n=7) of affected patients, respectively (Figure 2A). Whereas, lower level of albumin reported widely varied from 6% (n=9) 47 to 100 % (n=5). 32
Globulin
The pooled mean of globulin level from three studies was found to be 28.22 g/L [27.05, 29.38] with a significant level of heterogeneity (I2=95%, P<0.00001). Only Zhang Y et al., 2020 reported an elevation of globulin in a third of the included patients (n=42; 36.5%) (Figure 2B).
Total protein
Total protein was only reported by Xu Z et al. and estimated to be 56 g/L in the patients with SARS-CoV-2 infection.
Alanine aminotransferase (ALT)
A total of 20 studies reported on ALT levels of the included patients. The pooled mean of ALT was found to be 28.18 U/L [25.98, 30.37] with a significant level of heterogeneity (I2=96%, P<0.00001). The proportion of patients with an elevated ALT level ranged from 3.75% (n=3)34 to 36.79% (n=117), 33,36,41,48 while a decrease from the lower limit of ALT levels varied from 2 (1.34%) to 67% (n=46) 44 (Figure 2C).
A sensitivity analysis performed by removing two studies 36,45 with outlier ALT values did not show a noticeable change in the pooled results revealing mean of 28.67 U/L [26.44, 30.91] with a significant heterogeneity (I2=93%, P<0.00001) (See Supplementary Data Figure S1)
Alkaline phosphatase (ALP)
A total of seven studies reported on levels of ALP in the included patients. The pooled mean for ALP was found to be 68.36 U/L [64.07, 72.65] with a significant level heterogeneity (I2=99%, P<0.00001). The proportion of patients with an elevated ALP levels ranged from 0.3% (n=1) to 6.6% (n=21),13,41 while a decrease from the lower limit of ALP levels was not reported by any study (Figure 2D).
Aspartate aminotransferase (AST)
A total of 20 studies reported on the levels of ALT present in the included patients. The pooled mean of ALT was found to be 31.30 U/L [29.91, 34.96] with a significant level of heterogeneity (I2=96%, P<0.00001). The proportion of patients with an elevation of AST ranged from 3.75% (n=3) 34 to 36% (n=9). 32 In contrast, a decrease from the lower limit of AST level (n=50; 72%) was reported only by Wang Z et al., 2020 (Figure 2E).
The sensitivity analysis performed by removing two studies with outliers did not alter the findings of original analysis of the mean 32.39 U/L [29.91, 34.88] with the heterogeneity of I2=997%; P<0.00001 (Supplementary Figure S2).
Total Bilirubin (TB)
A total of 12 studies reported on the levels of TB in the included patients. The pooled mean of TB was found to be 11.41 μmol/L [10.33, 12.49] with a significant level of heterogeneity (I2=96%, P<0.00001). The proportion of patients with an elevated TB level was ranged from 1.25% (n=1) 34 to 44.02% (n=140).13 Whereas, only Yang W et al., 2020 reported a decreased level of TB among seven patients (4.70%) (Supplementary Figure S3).
A sensitivity analysis by removing two studies demonstrated no noticeable change in the overall results (11.28 μmol/L [10.24, 12.32]) with the heterogeneity (I2=97%, P<0.00001) (Supplementary Figure S4).
Gamma-glutamyl transferase (GGT)
A total of five studies reported on the levels of GGT in the included patients. The pooled mean of GGT was found to be 44.71 U/L [24.10, 65.31] with a significant level of heterogeneity (I2=96%, P<0.00001). The proportion of patients with an elevated level of GGT ranged from 0.9% (n=3) 50 to 28.61% (n=91).41 However, none of the studies reported a decreased level of GGT among the affected patients (Figure 2F).
Prothrombin time (PtT)
A total of eight studies reported on the levels of PtT in the included patients. The pooled mean of PtT was found to be 10.30 seconds [5.18, 15.43] with a significant level of heterogeneity (I2=100%, P<0.00001). An elevation of PtT was reported by Zhang Y et al. and Yang W et al. among 52.2% (n=60) and 11.41% (n=17) of the patients, respectively. Whereas, a decrease from the lower limit in PtT was reported by Yao N et al. (7.5%, n=3), Wu J et al. (3.75%, n=3) and Yang W et al. (2.68%, n=4) (Figure 3A).
Activated Partial Thromboplastin Time (aPTT)