key: cord-0697470-b516otes
authors: Sharifpour, Ali; Safanavaei, Sepideh; Tabaripour, Rabeeh; Taghizadeh, Fatemeh; Nakhaei, Maryam; Abadi, Atikeh; Fakhar, Mahdi; Banimostafavi, Elham Sadat; Nazar, Eisa; Aliyali, Masoud; Abedi, Siavash; Mehravaran, Hossein; Zakariaei, Zakaria; Azadeh, Hossein
title: Alkaline phosphatase and score of HRCT as indicators for predicting the severity of COVID-19
date: 2021-06-24
journal: Ann Med Surg (Lond)
DOI: 10.1016/j.amsu.2021.102519
sha: fc3d6d4491e0a3d191b5ededde079db877494aaa
doc_id: 697470
cord_uid: b516otes

BACKGROUND: The clinical symptoms, blood laboratory data, O2 saturation and high-resolution computed tomography (HRCT) findings are critical factors in diagnosis of COVID-19 infection. METHODS: In this study, 105 hospitalized patients suspected of having COVID-19 were evaluated. Finally, the laboratory and HRCT and related factors data of 83 confirmed cases by HRCT and RT-PCR were analyzed. To compare the median of quantitative variables in the two groups, the Mann-Whitney U test was used. Also, to determine the factors associated with the positiveness of the HRCT result, a univariate logistic model was fitted. Moreover, receiver operating characteristic (ROC) curves were constructed to test the ability of the final model to predict the positiveness of HRCT result. RESULTS: 61.40% of the patients had a comorbidity disease. 89.20% had fever, 92.00% cough, 91.40% dyspnea. Abnormal CRP was seen in 77.80% of the patients, followed by 66.70% lymphopenia, and 60.30% neutrophilia. Also, ALP (abnormal vs. normal) and score of HRCT assessment variables had a significant effect on the positiveness of HRCT findings. 87.95% had abnormal HRCT with 41% bilateral multi lobar patchy ground glass opacity (GGO). Moreover, there was a statistically significant association between the level of O2 saturation and HRCT results. CONCLUSION: Our findings showed that male patients with middle age and comorbidity disease were more susceptible to the COVID-19 infection. Additionally, clinical features, blood laboratory findings, O2 saturation and HRCT findings are critical factors in the prognosis of COVID-19 infection.

A current outbreak of pneumonia related to a novel coronavirus, termed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was reported in Wuhan, Hubei province, China in December 2019. The infection spread across other countries around the world [1] . The World Health Organization (WHO) declared the outbreak a Public Health Emergency of International Concern on January 30, 2020 [2] . Symptoms of COVID-19 can be fever, dry cough, fatigue, shortness of breath, myalgia or even no symptoms [3] [4] [5] [6] [7] . Likewise, the studies revealed that older age, male gender, leukocytosis, and blood laboratory findings, also, comorbidities such as high lactate dehydrogenase level, cardiac injury, hypertension, diabetes mellitus, hypothyroidism, coronary artery disease, smoking and hyperglycemia, were related to weak prognosis in COVID-19 patients [8] [9] [10] . However, information concerning the clinical features of COVID-19 is still making it difficult for physicians to distinguish the causative agents without related laboratory analysis [11] [12] [13] . Furthermore, reverse transcription-polymerase chain reaction (RT-PCR), the gold standard for confirming diagnosis of COVID-19, has some restrictions, such as false negative results and limited sampling method and the rate of high false negative and unavailability of in the early stage of the outbreak restricted fast diagnosis of infection in patients [14] . The high resolution computed tomography (HRCT) of the chest is progressively recognized as a strong indicator for early diagnosis, and can be the key to the evaluation of COVID-19 suspected patients because the changes in chest imaging sometimes may be earlier than symptoms [15] . HRCT is strongly recommended because it is very sensitive to detecting early disease, assessing the nature and extent of lesions [16] . Other investigators examined chest HRCTs in infected patients and found high rates of ground-glass opacities and consolidation, sometimes with a rounded morphology and peripheral lung distribution [17, 18] .

Chest HRCT can identify the early phase lung infection [19] and prompt larger public health surveillance and response systems [20] . Currently, chest HRCT has been recommended as main evidence for confirmed clinical and laboratory diagnosis. Considering the previous studies, the purpose of the study is to make an early diagnosis, by describing the complete chest HRCT appearances, related laboratory analysis and clinical features of patients with COVID-19, who were hospitalized at the Imam Khomeini Hospital.

In this cross-sectional study, 105 patients suspected of having COVID-19 hospitalized in Imam Khomeini Hospital, during February 2020, were enrolled. Finally, the data of 83 confirmed cases by HRCT was analyzed. Demographic, clinical, HRCT features and laboratory data of the patients were extracted and analyzed. All HRCT images were blindly reviewed by two radiologists with clinical evidence experience. The severity of lung involvement was scored and classified into 3 categories (category 0: negative findings, category 1: less than 50% of the lung involvement, and category 2: up to 50%) of the lung involvement. The current study was reviewed and approved by the Research Ethical Committee (IR.MAZUMS. REC.1399.102).The work has been reported in line with the STROCSS criteria [21] . This study is registered with the Research Registry, and the UIN is researchregistry6824 (https://www.researchregistry.com/browse-the-registry#home/registrationdetails/60a18e6c9b22fb001bde9e86/).

Quantitative variables as mean ± SD and qualitative variables also were reported as frequency (%). Chi-square and Fisher's exact tests were used for categorical variable comparison. In addition, to compare the median of quantitative variables in the two groups, the Mann-Whitney U test was used. Then, first to determine the factors associated with the positiveness of the HRCT result, a univariate logistic model was fitted, and those variables which had P < 0.25 were entered into the multiple model. Receiver operating characteristic (ROC) curves were constructed to test the ability of the final model to predict the positiveness of HRCT result. All analysis was carried out in the SPSS version 20.0 and STATA Release version 12. P < 0.05 was considered statistically significant.

The mean age of the patients was 58.12±17.19, and 46 (55.40%) were males. There was not a statistically significant difference between the mean age of men and women (p > 0.05). 33 (89.20%) of the patients had fever, 46 (92.00%) cough, and 53 (91.40%) had dyspnea. In addition, 6 (7.23%) had a cold, and 9 (10.84%) had myalgia ( 

Based on the results from the chi-square test, there was a statistically significant association between the level of O2 saturation and HRCT results (p < 0.05). The mean ALP of the patients with negative and positive HRCT tests was 544.67516.51 and 313.84227.36, respectively.

Results from the Mann-Whitney test showed that there was not a statistically significant difference between the median of ALP in the two groups of HRCT results (p > 0.05). In patients with normal ALP, 24 (64.90%) of the cases had a positive HRCT and in abnormal ALP patients, 13 (35.10%) of cases had a positive HRCT, which there was a statistically significant association between the level of ALP and HRCT result based on the results from the chi-square test (p < 0.05) ( Table 3 ). Frequency distribution of past medical history (PMH) among patients with suspected COVID-19 under study presented in Table 4 , in which 51 (61.40%) of patients had PMH.

Multiple logistic regression showed that ALP (abnormal vs. normal) and score of HRCT assessment variables had a significant effect on the positiveness of HRCT result (P < 0.05). So, after controlling for other variables, the odds of a positive HRCT result with abnormal ALP were 0.04 times higher than those with normal ALP, and this difference is statistically significant (P 0.05).Furthermore, after controlling for the effects of other variables, each unit increase in the HRCT assessment score increased the patients' odds of having a positive HRCT result 5.17 times more than those who did not have an increase (P 0.05).But other variables had no significant effect on the positiveness of the HRCT result (P > 0.05) ( Table 5 ). The area under the ROC curve of the model was 0.96, which indicates the good predictive power of the model (Figure 2 ).

COVID-19 infection was seen typically in middle-aged, male gender and elderly patients, and patients with other diseases were more susceptible to the disease. A greater number of men was J o u r n a l P r e -p r o o f found than that of women, which was similar to previous studies [22, 23] . Women have a humoral immune response and a stronger innate immune response than men, making them less susceptible to many parasitic, fungal, bacterial, and viral diseases while being more susceptible to developing malignancies or autoimmune disease [24] .While these sex differences in rates of mortality may be due to sex-specific life styles (smoking, alcohol etc.) [9, 25, 26] . Cough, fever, and dyspnea were the main symptoms. abnormal lymphocyte, neutrophil, PLT, SGOT, and SGPT, increased CRP concentration and increased LDH concentration were the laboratory features of COVID-19 infection in the present study. According to other researchers [8] abnormal HRCT was seen in 88% of the patients as the main indicator to evaluate the COVID-19 disease severity. Furthermore, WBC count, O2 saturation, and ALT were associated with lung involvement significantly, statically.

According to a meta-analysis, the main clinical manifestations of COVID-19 were fever, cough, and dyspnea [22] . In a study with 208 patients, the median age was 50.5 years, 51.4% of them were men and 48.6% were women. 7.7% of the patients had pulmonary diseases, 19.7% hypertension, and 6.3% diabetes. In our study, 26.5% of the patients had diabetes, hypertension and Asthma. Among all symptoms, 70.2% and 55.3% belonged to fever and cough respectively.

In compatible cases, 20.2% had a lower white blood cell count and 29.3% had a lower lymphocyte count.74% of them had elevated CRP, and 11.1% had elevated LDH in the present study [8] . In a retrospective cohort study, the mean age of the patients was 59.5 years and 67% of patients were male [27] . In a study, of 138 hospitalized patients, the median age was 56 years and 54.3% were men. Common symptoms included fever 98.6%, and dry cough 59.4%.

Lymphopenia occurred in 70.3% of patients. HRCT showed bilateral patchy shadows or ground J o u r n a l P r e -p r o o f glass opacity in the lungs of all patients [28] . In a meta-analysis study, including a total of 50404 patients with 2019-nCoV infection, the incidence of fever was 90.9%, and cough was 70.8%.

Moreover, the incidence of abnormal chest CT was 95.6% [23] , abnormal HRCT in our study was 88%. In a study in Beijing of 262 patients, the median age of patients was 47.5 and 48.5% of them were men. The most common symptoms at the onset of illness were fever (82.1%), cough (45.8%), dyspnea (6.9%) [29] , compatible with our study. In the other study [30] of 140 hospitalized COVID-19 cases, a 1:1 ratio of men and women COVID-19 patients was found (50.7%), with a median age of 57.0. Fever (91.7%), cough (75.0%) were the most common clinical manifestations, whereas hypertension (30.0%) and diabetes mellitus (12.1%) were the most common comorbidities [30] . Bilateral patchy opacity or ground glass (89.6%) was the most common radiological finding. Lymphopenia (75.4%) and eosinopenia (52.9%) were seen in most cases. Eosinopenia with lymphopenia may be an indicator for diagnosis. Allergic diseases, asthma, and COPD are not risk factors for SARS-CoV-2 infection [30] . The most common comorbidities in our study were hypertension, diabetes mellitus and asthma. Also, bilateral multilobar patchy ground glass opacities, bilateral multilobar patchy ground glass opacities and bilateral alveolar consolidations were the most common radiological findings in the present study. Another study showed that of 1099 patients, the median age of the patients was 47 years; 41.9% of the patients were female. The common symptoms were fever and cough. Ground-glass opacity was the most common radiologic finding on chest CT (56.4%). 83.2% of the patients had lymphocytopenia. Patients often presented without fever, and many did not have abnormal radiologic findings [31] . Ground-glass opacity in the present study was the most common finding. Similar to our study, lymphocytopenia in COVID-19 patients was seen in the other studies [3, 32] . The most common manifestations in a metha analysis of 656 patients were fever J o u r n a l P r e -p r o o f (88.7%), cough (57.6%), and dyspnea (45.6%) [33] . Of 99 patients with 2019-nCoV pneumonia, the average age of the patients was 55·5 years, including 67 men and 32 women. 83% of the patients had fever, 82% cough, 31% shortness of breath, and 11% myalgia. According to imaging findings, 75% of patients showed bilateral pneumonia, 14% of patients showed multiple mottling and ground-glass opacity, and 1% of patients had pneumothorax [34] . Of the 10 cases, the average age was 56.5 years. 60% of the patients were males. A dry cough was the main symptom, followed by fever and fatigue. Chest computed tomography results were nonspecific, mainly with ground-glass attenuation and/or shadow images [35] . A study found that 72% of people had a fever, and 83% had a cough.33% of them had an abnormal chest radiograph finding or lung crepitation. Lymphopenia was present in 39% [36]. A total of 5700 patients were included with a median age of 63 years, and 39.7% were female. The most common comorbidities were hypertension 56.6%, and diabetes 33.8% [37] . During the course of a study, 21 COVID-19 positive patients were admitted to S.M.S Hospital, Jaipur. 66.66% of the patients were men and 80.90% were less than 60 years old. Almost 33.33% of patients were asymptomatic and of those who were symptomatic, cough was seen in 85.71%, followed by myalgia (64.28%), fever (78.57%), and dyspnea (28.57%). 14.28% of the cases had co morbidities in the form of diabetes mellitus, hypertension, hypothyroidism, or coronary artery disease. Moreover, 52.38% of the patients had lymphopenia [38] . These patterns in comorbidities and lymphopenia were seen in our study, too.

Chest CT is an important component in the diagnostic procedure for patients with suspected COVID-19 infection. Chest CT has limited sensitivity and negative predictive value early after symptom onset, and has little weakness in diagnosis of COVID-19 combined with personal J o u r n a l P r e -p r o o f history, clinical symptoms, and initial laboratory findings, and may therefore serve as a standard method for diagnosis of COVID-19 based on its features and transformation rule, the limited number of RT-PCR kits in some centers before initial RT-PCR screening [34, 39] . Although 12% of patients were without abnormal lung changes on initial CT images in the present study.

In a study, the most HRCT findings were bilateral parenchymal ground-glass opacities, without or with consolidation in the lung periphery. In particular, 75% of patients with chest HRCT findings related to COVID-19 pneumonia had negative results of concurrent nucleic acid tests [40] . Then, 21.70% of positive chest HRCT patients in the present study had normal CRP.

According to imaging examination in a study, 75% of patients showed bilateral pneumonia, 14% of patients showed multiple mottling and ground-glass opacity, and 1% of patients had pneumothorax [34] .

In a study, the CRP, ESR, and LDH presented a significantly positive correlation with the pneumonia severity on CT. The highest temperature and the severity of opacifications assessed on initial CT were significantly related to the progression of opacifications on follow-up CT [41] . In the present study, LDH had a significantly positive correlation with HRCT. In a study, GGO was the most common manifestation of COVID-19 pneumonia, which could be followed by consolidation and fibrosis. The Total CT score, GGO score and fibrosis score of male patients were significantly higher than females in the second week. Male patients had higher consolidation scores and fibrosis scores than females in the third week. The total CT score and GGO score had a weak to moderate correlation with arterial blood gas indices [5] . In our study, peripheral and central [42] . In a study, of 1014 patients, 59% had positive RT-PCR results, and 88% had positive chest CT scans. The sensitivity of chest CT in suggesting COVID-19 based on positive RT-PCR results was 97%. In patients with negative RT-PCR results, 75% had positive chest CT findings; 48% were categorized as highly likely cases, with 33% as probable cases.

60% to 93% of cases had positive CT consistent with COVID-19 prior to the initial positive RT-PCR results [43] .

A total of 14 articles, including 1,115 patients, pure GGO 69%, consolidation 47% and "air bronchogram sign" 46% were more common than the atypical lesion of "crazy-paving pattern" 15%. While 67% of patients showed a predominant peripheral distribution [4] . In a study, 52% of the participants were men, with a mean age of 495 years. The major pattern of abnormality observed was bilateral 79%, peripheral 54%, and GGO 65%. A weak relevance was between the fibrosis score and the value of PaO2 and SpO2 [44]. There was a statistically significant association between the level of O2 saturation and HRCT results in the present study. In a study, with a median age of 45, 98% of patients had evidence of abnormal CT compatible with viral pneumonia at baseline [14] .

It suggested the critical importance of combining the two methods in the early stage of the disease to exclude the SARS-CoV-2 infection. These CT performances of COVID-19 were similar to previous studies. Patients' O2 saturation decreased, which corresponded to changes in J o u r n a l P r e -p r o o f indices in patients with lung involvement. Bilateral GGO was higher in the present study. Our results support the use of chest CT for screening for COVD-19 for patients with clinical and laboratory features compatible with COVID-19 infection [27] . Additionally, a positive relevance was found between the HRCT score and O2 saturation. That was, a patient with a higher CT score tended to have lower O2 saturation.

In the present study, middle-aged, male gender and elderly patients, and patients with comorbidity were more susceptible to the COVID-19 infection. W.B.C count, O2 saturation, and ALP were related to lung involvement significantly. Cough, fever, and dyspnea were the main symptoms. Abnormal HRCT was a main indicator for evaluating the COVID-19 disease. As a whole, clinical features, blood laboratory findings, O2 saturation and HRCT findings are critical factors in the prognosis of COVID-19 infection. There were several limitations in this study.

First, none of the patients underwent a lung biopsy or autopsy, because of the comparatively better outcomes of the patients in this study. Therefore, the HRCT findings of the lung could not be verified by histopathology. Finally, this was a study with initial HRCT images during hospitalization, mainly demonstrated the early pulmonary lesions in patients with COVID-19.

Further longitudinal research was needed to focus on the long-term follow-up, to provide dynamic HRCT evaluation for pulmonary lesions and to obtain the data of long-term pulmonary function changes. 16) 0.57 # Score HRCT assessment: 0= no / normal, 1= < 25%, 2= 25%-50%, 3= 50%-75%, 4= > 75% J o u r n a l P r e -p r o o f

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The authors would like to thank the patients and Nurses for their kind assistance in achieving data. This study was supported by Mazandaran University of Medical Sciences, Iran.

J o u r n a l P r e -p r o o f

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