Hematologic and coagulopathy parameter as a survival predictor among moderate to severe COVID-19 patients in non- ICU ward: a single-center study at the main referral hospital in Surabaya, East Java, Indonesia

Introduction

In December 2019, China reported a mysterious pneumonia case of unknown cause which had spread rapidly in Wuhan city. The World Health Organization (WHO) named this virus as the 2019 novel coronavirus (2019-nCoV),^1,2 and the name was changed to Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) by the Coronaviridae Study Group (CSG) of the International Committee on Taxonomy of Viruses; the official name of the disease caused by the virus is COVID-19.^2,3 COVID-19 is a major health concern at this time, especially for the elderly, due to the SARS-CoV-2 virus.^4,5 This coronavirus has become the main pathogen, causing an outbreak of respiratory disease until it has been declared a pandemic, and spreading rapidly throughout the world, including Indonesia.⁶ COVID-19 has become a global problem today due to the high transmission and mortality rates.⁷

As reported by Huang et al., patients with COVID-19 present primarily with fever, myalgia or fatigue, and dry cough.⁷ Although most patients are considered to have good prognoses, elderly patients, as well as those with underlying chronic conditions, may have worse outcomes. Severe patients may experience shortness of breath and hypoxemia within one week of disease onset, which can rapidly progress to acute respiratory distress syndrome (ARDS) or end-organ damage. Chronic cardiac and metabolic disease, the presence of acute inflammation as well as decreased organ (heart, kidney, liver, and hematology) function experienced by patients at the beginning of treatment, can increase the risk of death due to COVID-19 infection.^8,9

The need for COVID 19 patients to be hospitalized varies widely from country to country as it depends on the prevalence of community testing and admission criteria.^2,10 However, it is estimated that one in 5–10 adult patients with disease severity and sufficient criteria to be hospitalized. Most of the patients with severe acute respiratory infections or severe acute respiratory syndrome were managed according to the case definition of WHO. The criteria for intensive care also vary from country to country. Old age, chronic disease, and male gender are consistently associated with increased mortality.¹⁰

Hematologic and coagulation parameters were important for predicting the severity of COVID-19. The occurrence of disseminated intravascular coagulation (DIC) is a common finding in deceased COVID-19 patients.¹¹ In addition, administering anticoagulant therapy to high-risk patients is effective in reducing mortality.^12,13

The first COVID-19 case in Indonesia was announced on March 2, 2020, about four months after the first case in China.¹⁴ The first cases in Indonesia in March 2020 were two cases; and after that on March 6, two cases were found again. COVID-19 cases continue to grow. In the beginning, there were hundreds of cases added; and until now, the number of cases has increased to thousands. On March 17, 2020, the government of East Java reported the first case of COVID-19, and as of July 31, 2020, there were 22,098 confirmed cases with a fairly high mortality rate of 7.6%.¹⁶ Meanwhile, in Surabaya City in July 2020, there were 8,691 confirmed COVID-19 patients. The RSUD Dr. Soetomo (RSDS) Surabaya is one of the referral centers for probable COVID-19 patient cases in East Java. Based on the total cases, it is necessary to collect data, including clinical manifestations, risk factors, hematologic parameters, and coagulation which aggravate the condition of COVID-19 patients.¹⁷

Several studies related to clinical manifestations and risk factors for COVID-19 patients have been reported previously; however, this research is based on relatively small sample size, and the risk factors that lead to poor clinical outcomes have not yet been well explained. In addition, deceased patients in probable and confirmed cases of COVID-19 at RSDS Surabaya had often presented with comorbidities, such as diabetes mellitus, high blood pressure, heart disease, hematological disorders, old age, chronic lung disease, stroke, and kidney disorders. This leads to discussion around which comorbid, hematologic parameters and coagulation factors may become predictive of COVID-19 mortality.

Methods

This was a retrospective analytical study, performed by taking secondary data on patients with probable COVID-19 cases who were treated at the special isolation room (non-intensive care) of the Department of Internal Medicine of the teaching hospital of RSUD Dr. Soetomo between May and September, 2020. The sample consisted of deceased and survived patients at the special isolation room (non-intensive care) of Internal Medicine of RSUD Dr. Soetomo, who had been hospitalized with probable COVID-19. The inclusion criterion was hospitalization with probable COVID-19 in patients who were more than 18 years old. The exclusion criterion was incomplete care clinical data. This research began with sample selection including all COVID-19-probable hospitalized patients (a total of 538 probable cases); then a diagnosis of COVID-19 was examined using reverse-transcription polymerase chain reaction (RT-PCR), carried out through nasal swab. RT-PCR results showed 297 patients were positive (55.2%) and 241 patients were negative (44.8%). Of the 297 positive patients with COVID-19, 80 patients had incomplete medical record data, therefore, 217 patients met the inclusion criterion and were included in the study (see Figure 1).

Figure 1. Patient COVID-19 data selection process.

Approval from the local ethics committee was obtained for this research; written informed consent was obtained from patients during hospitalization. Then from the hospital infromation database system, we retrieved patient characteristics such as age, gender, comorbidities, signs and symptoms, and laboratory results, including hemoglobin, white blood cell (WBC), neutrophil, lymphocyte, and platelet counts, D-dimer level, C-reactive protein (CRP), prothrombin time (PT), and activated partial thromboplastin time (aPTT).

Results

As many as 538 patients with probable COVID-19 were included during the study period. Based on the total, 288 (53.5%) were males, with the mean ± SD age of 51.69 ± 13.67 years. More than half of the patients (63.7%) had elemental diseases, including diabetes mellitus (34%), hypertension (32.5%), and CKD (22.7%). All the patients with probable COVID-19 experienced symptoms on arrival, including complaints of shortness of breath (48.7%), cough (40%), fever (32%), and limp (24%). Some patients also complained of diarrhea and headache but the percentage was low at 10.2% and 3.2%, respectively.

Survival analysis

The Kaplan–Meier graph showed that there was a significant association between mortality and leukocyte count, neutrophil count, NLR, PT, and CRP (p < 0.05, respectively) (see Figure 2). Lower survival rate was shown from leukopenia, leukocytosis, neutrophillia, high NLR, high CRP, and prolonged PT (p = 0.015; p = 0.018, p = 0.003, p = 0.035, and p = 0.03, respectively).

Figure 2. Kaplan-Meier survival curves white blood cell count (WBC), neutrophil count, lymphocyte count, neutrophil-lymphocyte ratio (NLR), platelet count, aPTT, prothrombin time, D-Dimer, and CRP.

Discussion

Significant differences were found in the demographic and clinical variables, and hematologic and coagulation parameters between the deceased and surviving COVID-19 patients. We included age in the risk factor for COVID-19 mortality, whereas the age had a p-value <0.05. The age factor appeared to be crucial for the outcome of COVID-19. The average age of the deceased patients was 58 years old and was significantly older than the surviving patients. This was in accordance with previous studies which stated that 80% of deaths in COVID-19 were of adulthood, therefore, old age can be said to be a risk factor for COVID-19 mortality.^15,16 Increasing age also increased the percentage of COVID-19 mortality from 5% in the youngest age patients, to 55% at the oldest age.¹⁷

Gender was proven to be a risk factor for mortality in COVID-19 patients, which was higher for men than for women. This was due to the fundamental differences in the immunological systems of men and women, differences in lifestyle, and the prevalence of smoking.¹⁸ In this research, although statistically insignificant, the percentage of the number of male COVID-19 patients was higher, both overall and in the group of deceased patients. The higher mortality rates were associated with the higher chronic comorbidities in men, e.g., diabetes mellitus, kidney disease, hypertension, heart disease, lung disease, and smoking.¹⁹

The comorbid factors of diabetes mellitus, heart disease, and chronic kidney disease in COVID-19 patients could be the risk factors of death in this research, with a p-value of <0.05. This result was similar to the meta-analysis study conducted by Mantovani et al., who stated that the prevalence of diabetic patients hospitalized due to COVID-19 was 14.34%, and 11.06% in patients in Asian countries. Meanwhile, the prevalence in non-Asian countries was higher, which was 23.34%. The risk of worsening the condition to require treatment in intensive care was two times greater in diabetes patients.²⁰ Likewise, elderly patients with diabetes belonged to the group at risk of death.²¹

For the hematologic parameters in this research, the leukocyte, neutrophil counts, lymphocyte count, and NLR were significantly different in the deceased patients than in the surviving patients. This research results were consistent with several previously published studies.^22,23 On the other hand, the platelet count in this research was comparable between the groups of deceased and surviving patients. This was in contrast with the results of a meta-analysis that concluded by Lippi et al., who showed that thrombocytopenia was associated with increasing severity risk and mortality of COVID-19.²⁴ Differences in pathophysiological mechanisms in each patient may lead to insignificant findings in this research. Many researchers have studied the changes in peripheral blood cell counts in COVID-19, and the results were that in infected patients, the white blood cell and neutrophil count increased, while the lymphocyte and platelet counts decreased.²⁵ In the other cases, coagulation abnormalities (prolonged PT and aPTT) and intravascular coagulopathy (DIC) were so correlated with low platelet count.²⁶

The extreme inflammation is usually evidenced by elevated serum of CRP, IL-6, and PCT which indicate the increasing of COVID-19 severity.²⁷ High levels of CRP and procalcitonin in COVID-19 patients are also associated with the progression of ARDS, myocardial injury, and death.^27,28 The presence of secondary bacterial infection would be an additional explanation of this increase in inflammatory biomarkers. This is consistent with this research which showed that serum CRP levels were significantly higher in the cohort of deceased COVID-19 patients. Therefore, we believe that the use of CRP as a biomarker in monitoring the progress and severity of COVID-19 patients will be beneficial.

In a systematic review, Vidali et al. concluded a correlation between increasing D-Dimer levels and the incidence of complications and death from COVID-19. Significantly higher serum D-dimer levels were showed in COVID-19 patients with acute respiratory distress syndrome (ARDS) and the group of deceased patients.²⁹ However, our results showed that D-dimer levels were comparable between both groups of deceased and survived patients, this result could be due to differences in measurement methods as disclosed by Favaloro et al. who stated several things regarding the measurement and reporting quality of D-dimers such as the measurement method, cut-off value, or D-dimer unit [D-dimer unit (DDU)] can lead to different research results.³⁰

PT and aPTT prolongation may occur during severe COVID-19, yet the increase is less severe than that observed in bacterial sepsis and DIC.³⁴ A meta-analysis conducted by Henry et al.²⁸ found that patients with severe and fatal COVID-19 had significantly higher coagulation parameters (especially PT) than patients with the non-severe disease. This is consistent with this research where there was an increase in aPTT (but not statistically significant) and a significant increase in PT with p < 0.05 in the group of deceased patients. Although it is not completely clear how SARS-CoV-2 activates the coagulation cascade, it may be associated as a byproduct of cytokine storms.³¹ Researchers detected a significant extension in coagulation tests in this research, consistent with previously published studies.^25,32 The mechanism of these changes is still not fully explained, however, the extension of the coagulation test, i.e., increased PT and aPTT, can be considered as a marker of disease severity and activation of the coagulation cascade and virus-induced cytokine storm.^31,33

For as much as this research was a retrospective study, several parametes were not completely listed such as level of ferritin, fibrinogen, procalcitonin, and IL-6, hence we considered this as one of our research limitation. Since the development of complications that have occured in patients are not thoroughly documented, we can not confidently say that inflammatory and coagulation factor disorders are more common in severe COVID-19. The only outcome measure of this research was patient mortality in hospital. Although researchers evaluated platelet count and D-dimers, the International Society on Thrombosis and Hemostasis (ISTH) scores of the research’s patients were not calculated, and therefore, patients who had mild-to-moderate coagulation disorders and those who had a DIC could not be distinguished.

Conclusion

This research indicates that hematologic and coagulation parameters are increased in the majority of COVID-19 patients and the group of deceased patients. While the neutrophil count and WBC increase, the lymphocyte count decreases significantly along with the increase in disease severity. Coronary heart disease is an independent predictor of mortality.

Data availability

Consent

Written informed consent was received from the patients during hospitalization.