Laboratory abnormalities in patients with COVID-2019 infection

Letter to the Editor

Giuseppe Lippi* and Mario Plebani

https://doi.org/10.1515/cclm-2020-0198 Received for publication February 24, 2020

Keywords: coronavirus; COVID-19; laboratory medicine; laboratory tests; prognosis.

To the Editor,

Coronavirus disease 2019 (COVID-19), a form of respira- tory and systemic zoonosis caused by a virus belonging to the Coronaviridae family, originated from the town of Wuhan in China, is still spreading around the world, thus assuming the dramatic features of a pandemic emergency [1]. According to the recent statistics of the World Health Organization (WHO), the disease has already involved all continents, with over 80,000 diagnosed cases in 34 different countries, and nearly 2700 deaths until Febru- ary 26, 2020 [2]. Despite the severity of COVID-19 seems lower than that of the two previous coronavirus diseases, i.e. SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome), the long incubation period and the relatively low pathogenicity compared to that of the two previous homologous viruses are con- tributing to sustain and amplify the outbreak inside and outside China.

Although the clinical characteristic of COVID-19 have been broadly defined [3], an outline of the most repre- sentative laboratory abnormalities found in patients with COVID-2019 infection is still lacking to the best of our knowledge. It was previously highlighted that laboratory medicine plays an essential role in the early detection, diagnosis and management of many diseases [4]. COVID- 2019 makes no exception to this rule, whereby real-time

*Corresponding author: Prof. Giuseppe Lippi, Section of Clinical Biochemistry, Department of Neuroscience, Biomedicine and Movement, University Hospital of Verona, Piazzale L.A. Scuro, 10, 37134 Verona, Italy, Phone: +0039-045-8122970, Fax: +0039-045- 8124308, E-mail: giuseppe.lippi@univr.it

Mario Plebani: Department of Laboratory Medicine, University Hospital of Padova, Padova, Italy. https://orcid.org/0000-0002- 0270-1711

reverse-transcription polymerase chain reaction (rRT-PCR) enables direct virus identification, whilst detection of anti-COVID-19 antibodies by means of fully-automated immunoassays is the mainstay of serological surveil- lance [5]. Nevertheless, the role of laboratory diagnostics extends far beyond etiological diagnosis and epidemio- logic surveillance, whereby in vitro diagnostic tests are commonly used for assessing disease severity, for defin- ing the prognosis, for following-up patients, for guiding treatment and for their therapeutic monitoring [6]. There- fore, the aim of this article is to provide a brief overview on the most frequent laboratory abnormalities encountered in patients with COVID-2019 infection.

An electronic search was performed in Medline (PubMed interface), Scopus and Web of Science, using the keywords “2019 novel coronavirus” or “2019- nCoV”or “COVID-19” without date (i.e. up to February 24, 2020) or language restrictions. The title, abstract and full text (when available) of all articles identified according to these search criteria were scrutinized by the authors, and those describing significant laboratory abnormalities in patients with severe COVID-19 infec- tion were finally selected. The references of identified documents were also crosschecked for detecting addi- tional studies.

Overall, 217 articles could be originally identified using our search criteria, 206 of which were excluded after title, abstract or full text reading, because they did not report specific data on laboratory test results (data now shown, due to space constrains). Therefore, a total number of 11 studies were finally selected, eight of which reported the rate of abnormal laboratory test results, as summarized in Table 1 [7–14]. One additional study, pub- lished by Pan et al. and involving 21 patients (71% women; age range, 25–63 years) with non-severe COVID-19 infec- tion, did not clearly describe the rate of patients with laboratories abnormalities, but only reported the most frequent abnormalities, including increased values of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), lactate dehydrogenase (LDH) and D-dimer [15].

As regards prognostic laboratory data, which may be even more vital for the timely identification of patients at

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2 Lippi and Plebani: Laboratory findings in COVID-2019 infection

                                    

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Table 1: Main characteristics of the included studies.

Characteristics

Zhang et al. [7]

Huang et al. [8]

Chen et al. [9] Wuhan, China

Xu et al. [10] Zhejiang,

Liu et al. [11]

Wang et al. [12]

Chen et al. [13]

Chen et al. [14]

Location

Wuhan, China

Wuhan, China

China
62 (1 severe)

Shenzhen, China
12 (6 severe)

Shenzhen, China
34 children (no severe)
8years (median)
59% Hospitalized patients

Wuhan, China

Wuhan, China 9 pregnant

No. cases

140
(58 severe) 57years (median) 49% Hospitalized patients

41 (13 severe)

99 (17 severe)

29 cases (14 severe) 56years (median) 28% Hospitalized patients

Age

49years (median) 27% Hospitalized patients

56years (mean)
32% Hospitalized patients

41years (median) 44% Hospitalized patients

54years (mean)
33% Hospitalized patients

30years (mean) 100% Hospitalized patients

Women, % Setting

Laboratorydata Leukocytes Neutrophils Lymphocytes Eosinophils Platelets Hemoglobin CRP Procalcitonin ESR Albumin ALT AST Bilirubin Creatinine CK LDH Myoglobin Cardiac

↑30%; ↓25% N/R
↓63%
N/R

↑24%; ↓9% ↑38% ↓35%
N/R

↑21%; ↓21% N/R
↓69%
N/R

↑22% N/R ↓56% N/R N/R N/R ↑75% N/R N/R N/R ↑33% ↑33% N/R N/R N/R N/R N/R N/R

troponins Ferritin Glucose D-dimer

N/R N/R ↑43%

N/R N/R N/R

↑63% ↑52% ↑36%

N/R N/R N/R

N/R N/R N/R

N/R N/R ↑9%

N/R N/R N/R

N/R N/R N/R

↑12%; ↓20% N/R
↓75%
↓53%

↑8%
↑17%
↓55%
N/R
↓8% N/R ↑83% ↑8% N/R ↓50% ↑17% ↑8% ↑0% ↑17% ↑17% ↑92% ↑17% ↑8%

↑15%
↑15%
↓3%
N/R
N/R N/R ↑3% ↑3% ↑15% N/R N/R N/R N/R N/R N/R ↑29% N/R N/R

N/R N/R ↑91% ↑35% N/R N/R N/R N/R N/R N/R ↑7% N/R N/R N/R

↓5%
N/R
N/R ↑86% ↑8% ↑6% N/R ↑85% N/R ↓98% N/R ↑28% ↑37% ↑35%

↓17%
↓41%
↑93%
↑0%
N/R ↓52% ↑17% ↑24% ↑3% ↑7% N/R ↑69% N/R N/R

N/R ↑10% ↑33% ↑73% N/R ↑12%

↑18%
↑3% ↑13% ↑76% ↑15% N/R

N/R

↓50%

↑2%; ↓31% N/R ↑58%; ↓42% N/R ↓5% N/R N/R ↑11% N/R N/R N/R ↑16% N/R ↑5% N/R ↑27% N/R N/R

Laboratory data are reported as percent of patients with abnormalities defined according to the local reference ranges. ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK, creatine kinase; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; LDH, lactate dehydrogenase; N/R, not (clearly) reported.

higher risk of adverse outcome, an interesting report has been published by Wang et al. who examined the behavior of six laboratory parameters throughout 19 days of hospital admission in 138 patients with COVID-19 infection (33 with severe disease), five of whom died during their hospi- tal stay [16]. Several significant differences were noted between patients who needed admission to the intensive care unit (ICU) and those who did not, especially encom- passing higher white blood cell (WBC) count (1.5-fold), higher neutrophil count (1.7-fold), lower lymphocyte count (0.9-fold), as well as higher values of LDH (2.1-fold), alanine aminotransferase (ALT) (1.5-fold), aspartate aminotrans- ferase (AST) (1.8-fold), total bilirubin (1.2-fold), creatinine (1.1-fold), cardiac troponin I (2.2-fold), D-dimer (2.5-fold) and procalcitonin (1.2-fold). As regards this last parameter, the rate of patients with abnormal values admitted to the ICU was over 3-fold higher than that of those who were not (75% vs. 22%; p < 0.001). It has also been reported that non-survivors more frequently developed lymphopenia and leukocytosis, along with abnormal values of D-dimer, blood urea nitrogen and creatinine. In the study of Zhang et al. based on 140 COVID-19 patients (58 with severe disease) [7], significantly higher values of D-dimer (2-fold), CRP (1.7-fold) and procalcitonin (2-fold) could be observed in patients with severe disease compared to those with a milder form. In the study published by Huang et al. involv- ing 140 COVID-19 patients (13 with severe disease) [8], significant predictors of ICU admission were leukocytosis (2.0-fold increased in ICU patients), neutrophilia (4.4-fold increased), lymphopenia (0.4-fold, i.e. decreased), pro- thrombin time (PT; 1.14-fold increased), D-dimer (4.8-fold increased), albumin (0.8-fold, i.e. decreased), ALT (1.8- fold increased), total bilirubin (1.3-fold increased), LDH (1.4-fold increased) and procalcitonin, whose values were increased in 25% of patients who were admitted to the ICU compared with 0% who were not (p = 0.029). Similar find- ings emerged from the article published by Liu et al. who found that disease severity could be predicted by lympho- penia, neutrophilia, low values of albumin, as well as by increased values of LDH and CRP [11]. Finally, Tang et al. followed-up 183 patients with confirmed COVID-19 infec- tion (54% women; mean age, 54 years) during their hospi- tal stay [17], and found that coagulation parameters were more frequently deranged in those who died (n = 21) than in those who survived. Specifically, the values of PT, D-dimer and fibrin/fibrinogen degradation products (FDP) were found to be 1.14-, 3.5- and 1.9-fold higher in non-survivors than in survivors, respectively. Overall, 71.4% of patients who died fulfilled the criteria for diagnosing disseminated intravascular coagulation (DIC) compared to only 0.6% of those who survived.

Although some limitations must be acknowledged in our analysis of the current scientific literature (i.e. limited samples size, all COVID-19 cases originating from the same country, operative definitions are still underway, some clinical studies are still ongoing or undergoing pub- lication), the currently available data suggests that many laboratory parameters are deranged in patients with COVID-19 (Table 1), and some of these may also be con- sidered significant predictors of adverse clinical outcomes (Table 2). With the exception of the study of Liu et al. which only included children with mild COVID-19 infection, the most frequent abnormalities were lymphopenia (35–75% of cases), increased values of CRP (75–93% of cases), LDH (27–92% of cases), ESR (up to 85% of cases) and D-dimer (36–43% of cases), as well as low concentrations of serum albumin (50–98% of cases) and hemoglobin (41–50%). Many laboratory abnormalities were instead predictive of adverse outcome, as summarized in Table 2.

A particular mention shall be made for procalci- tonin and coagulation tests. The former test does not appear substantially altered in patients with COVID-19 at admission, but the progressive increase of its value seem- ingly mirrors a worse prognosis. This is not unexpected, whereby serum procalcitonin levels are typically normal in patients with viral infections (or viral sepsis), whilst its gradual increase probably mirrors bacterial superinfec- tion [18], which may then contribute to drive the clinical course towards unfavorable progression. The measure- ment of other innovative sepsis biomarkers, such as pre- sepsin, for example, would probably help in increasing the accuracy in identification of severe COVID-19 cases, as well as for improving the current approach used for mortality risk prediction [19]. As concerns hemostasis tests, the evidence that laboratory criteria for diagnosing

Table 2: Main laboratory abnormalities in patients with unfavorable progression of coronavirus disease 2019 (COVID-19).

– Increased white blood cell count – Increased neutrophil count
– Decreased lymphocyte count
– Decreased albumin

– Increased lactate dehydrogenase (LDH)
– Increased alanine aminotransferase (ALT)
– Increased aspartate aminotransferase (AST) – Increased total bilirubin
– Increased creatinine
– Increased cardiac troponin
– Increased D-dimer
– Increased prothrombin time (PT)
– Increased procalcitonin
– Increased C-reactive protein (CRP)

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4 Lippi and Plebani: Laboratory findings in COVID-2019 infection

 

DIC are present in nearly three-fourths of patients who died underscores the critical role of these tests in this and other clinical settings [20], thus suggesting that their assessment shall be considered a routine part of COVID- 19 patient monitoring.

Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.

Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

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