The Crazy-paving Pattern in Chest CT of Coronavirus Disease 2019 Patients; an Alarming Sign for Hospitalization

Background: The outbreak of coronavirus disease 2019 (COVID-19) becomes an enormous threat to all human beings. Via this retrospective study conducted on medical records of conrmed COVID-19 pneumonia patients on admission, we investigate the CT manifestation and clinical and laboratory risk factors associated with progression to severe COVID-19 pneumonia and assessed the association among clinical and laboratory records, CT ndings, and epidemiological features. The medical records and radiological CT Features of 236 conrmed COVID-19 patients were reviewed at one public hospital and one respiratory clinic in Quom, from 1 August to 30 September 2020. Results: Among a total of 236 conrmed Covid-19 cases, 62 were infected with moderate to severe COVID-19 disease and required hospital admission, and 174 were followed up on outpatient bases. A signicant difference was veried in the mean age between outpatients and hospitalized groups. The incidences of bilateral lung involvement, consolidation, linear opacities, crazy-paving pattern, air bronchogram sign, and the number of lobe involvement were signicantly higher in hospitalized groups. However, only the crazy-paving pattern was signicantly associated with an SpO2 level lower than 90%, with clinical sign of cough severity. Our data indicate that this pattern is also signicantly associated with inammatory levels and the presence of this pattern along with SpO2 level lower than 90%, older age, diabetes, on admission are independent risk factors for COVID-19 progression to severe level. Conclusions: The crazy-paving pattern can predict the severity of COVID-19, which is of great signicance for the management and follow-up of COVID-19 pneumonia patients. The clinical factors of aging, male gender, and diabetes, may be risk factors for the crazy-paving pattern, whereas severe coughing is considered to be the most important clinical symptom related to this pattern, and SpO2 level lower than 90%, which is a matter of more severity.


Background
Since December 2019 that the rst o cial human cases of coronavirus disease 2019 (COVID- 19), was reported in Wuhan City, China, its global spread has become an enormous threat to all human beings and the lives of millions of people around the world are still in danger (1). Iran has been dealing with theCOVID-19 crisis since 19th February 2020, and Quom was among one of the rst metropolitan areas that reported the disease. Interestingly respiratory tract infections caused by novel coronavirus SARS-CoV-2 (2019-nCoV) can range from mild infection with good prognosis to severe form that progress to acute respiratory distress syndrome (ARDS) in the early stages, and consequently requiring hospitalization. The probability of progression to severe cases was estimated at around 15.7 to 26.1% all COVID-19 patients (2)(3)(4). Primary management of patients at risk of progression may facilitate treatment strategies and optimized utilization of the medical resource, especially now that clinicians are facing a serious shortage of beds and hospital facilities.
Computed tomography (CT) examination plays an important role in both the initial screening and the auxiliary diagnosis of COVID-19 (5). Although nucleic acid ampli cation test (NAAT) of the respiratory tract or sometimes blood specimens is still the gold standard method to con rm the disease (6), both American and Chinese researchers strongly recommend CT imaging as the main basis for the diagnosis of COVID-19 in the current situation (7)(8)(9)(10). A previous study conducted on a series of 51 patients with chest CT and RT-PCR assay performed within 3 days showed that the sensitivity of CT for COVID -19 infection was 98% compared to RT-PCR sensitivity of 71% (p < .001) (11). Meanwhile, the close relationship between the extents of lung lesions and the clinical symptoms makes it an irreplaceable method for the preliminary screening of COVID-19 (7). Some clinicians also believe that the severity of COVID-19 and its progression can be judged best by CT imaging as well (7,12,13).
Via this retrospective study conducted on medical records of con rmed COVID-19 pneumonia patients on admission, we investigate the CT manifestation and clinical and laboratory risk factors associated with progression to severe COVID-19 pneumonia and assessed the association among clinical and laboratory records, CT ndings, epidemiological features, and in ammation.

Results
Among a total of 236 con rmed Covid-19 cases (mean age (SD), 51.08 (13.80); range, 18-84 years; 53.3% male), 62 (mean age (SD), 54.86 (14.88); range, 29-83 years; 57.1% male) were infected with moderate to severe COVID-19 disease and required hospital admission and 174 mild cases with a mean age of 49.8 years (SD,13.24; range, 18-84 years; 52.1% male) were followed up on outpatient bases. The ground-glass opacity (GGO) was the common chest CT features in both outpatients and hospitalized groups with no signi cant differences (96.0% of outpatients and 100% hospitalized groups) ( Table 1). Bilateral Lung Involvement which was present in 80.5% of patients, was signi cantly higher among the hospitalized group than outpatients (93.5% vs. 75.9%) ( Table 1). The incidences of consolidation, linear opacities, crazy-paving pattern, air bronchogram sign, and the number of lobe involvement were also signi cantly higher among hospitalized groups (Table 1). However, only the crazy-paving pattern was signi cantly associated with in ammatory levels and hypoxemia (SpO2 < 90% in room air at rest; OR 4.506; 95% CI, 1.530-13.270). Each categorical variables data are reported as percentage and signi cant level of a two-sided α (p Value) less than 0.05 is marked by "*".
Although no difference was observed in the ratio of men and women between outpatients and hospitalized groups, the crazy-paving pattern was higher among men with a signi cant difference by the chi-square test (P < 0.05; OR 0.408; 95% CI, 0.211-0.788) ( Table 2). Interestingly, we also found that this pattern is signi cantly higher among older (OR for age above 50 years old = 2.684; 95% CI, 1.408-5.117) and patients with underlying diabetes (OR 2.102; 95% CI, 1.015-4.352) ( Table 2). Most clinical symptoms were similar between COVID-19 patients with a crazy-paving pattern and those without the mentioned pattern, except for severe cough (OR 2.529; 95% CI, 1.008-6.344) and palpitation (Table 3). Regarding the laboratory ndings, the increased values of C-reactive protein (CRP), neutrophil ratio, and erythrocyte sedimentation rate (ESR) were signi cantly higher among patients who indicated the crazy-paving pattern in their chest CT-imaging (Table 4). Lymphocytes decreased was present among 41.7% of patients indicating the crazy-paving pattern in chest CT.  Each categorical variables data are reported as percentage and signi cant level of a two-sided α (p Value) less than 0.05 is marked by "*". Each categorical variables data are reported as percentage and signi cant level of a two-sided α (p Value) less than 0.05 is marked by "*".

Discussion
Our data indicated that the crazy-paving pattern in a radiological Chest CT can predict the severity of COVID-19. The crazy-paving pattern is a radiological sign which is characterized by the presence of scattered or diffuse ground-glass attenuation with a linear pattern superimposed on chest CT imaging, resembling irregularly shaped paving stones (Fig. 1) (14). The linear pattern is associated with interlobular septal thickening and intralobular lines and can also be caused by the presence of intralobular brosis, or a linear deposition of material within the airspaces (14). Although the crazypaving pattern was initially described as a pathognomonic sign of alveolar proteinosis, nowadays it counts as a non-speci c pattern that reported later in a variety of diffuse acute and chronic lung diseases including bacterial or viral pulmonary infection and adult (acute) respiratory distress syndrome (ARDS) (14,15). The overall distribution of COVID-19 patients with the crazy-paving pattern in different studies is around 5-36% (12). In this study we noticed a signi cantly higher incidence of the crazy-paving pattern among hospitalized patients (OR 4.084; 95% CI, 2.138-7.803), suggesting that this manifestation could serve as an alert in the management of patients. This is in concordance with a recently published study from china (13). Based on the pathological knowledge of SARS, the crazy-paving pattern in COVID-19 may be also caused by the alveolar edema and interstitial in ammatory of acute lung injury (16,17). Therefore, as previously mentioned, it can be the signal of COVID-19 entering progressive or peak stage (18). 18.6% of patients with the crazy-paving pattern presented with hypoxemia (SpO2 < 90% in room air at rest), while hypoxemia occurred in only 4.8% of patients with no sign of this pattern. It is well known that hypoxemia is an alarming symptom and matter of concern for both the patients and the physicians, especially in the decision-making strategies for managing patients on a hospitalization basis.
The clinical factors of aging, male gender, and diabetes, may be risk factors for the crazy-paving pattern, which may be the result of their weakened immune function and comorbid with other kinds of infections, especially among diabetes patients. Sever cough seems to be the most important clinical symptom related to the crazy-paving pattern that may cause by the in ammatory affection of the pleura. Based on the previous hypothesis the sever dry cough in COVID-19 patients with the crazy-paving pattern may be explained by the high viscosity of mucus and the damage of dilated bronchioles that causes insu cient sputum motility (12).
41.7% of patients indicating the crazy-paving pattern in chest CT were also suffered from the lymphocytes decrease, indicating immune function inhabitation due to consuming a large number of immune cells. Damage to lymphocytes have been associated with disease exacerbations in subjects with COVID-19 and introduced as an important index in the evaluation of disease severity (19,20). The increased values of the neutrophil ratio and CRP in patients with the crazy-paving pattern may be also related to cytokine storm induced by virus invasion, which was mentioned by the various studies (19,21).
GGO was the most common CT nding among COVID-19 pneumonia patients with no signi cant difference between hospitalized and outpatients groups. Bilateral distribution of GGO with or without consolidation in posterior and peripheral lungs was initially described as the cardinal hallmark of COVID-19 (3,22). Consolidation on the other hand was signi cantly more frequent in severe cases, probably due to the in ammatory exudation in the alveoli. In a review study on the chest CT manifestations of COVID-19, the consolidation has been introduced as an indication of disease progression (12).

Conclusions
In conclusion, our data indicate that the crazy-paving pattern is signi cantly associated with in ammatory levels and the presence of this pattern along with SpO2 level lower than 90%, older age, diabetes, on admission are independent risk factors for severity and progression of COVID-19. Therefore we believe this pattern has the potential to predict the risk of progression, therefore can be used as a guide for designing a model for decision-making of hospital admission.

Consent for publication
All authors concur with the submission and have seen a draft copy of the manuscript and agree with its publication.
Availability of data and material The full SPSS datasets can be uploaded if it is desired.

Competing interests
All authors had access to study data and none has any con ict of interest to declare. Authors'contributions MRM was the key contributor in conceptualization, methodology, investigation, data curation, writing, and project administration.
MGB was a major contributor in imaging methodology and interpretation.
AM was a major contributor in resources, conceptualization, methodology, review, and supervision.
FM was a major contributor in resources, methodology, review, editing, and supervision.
MY was a major contributor in conceptualization, methodology, validation, review, and editing.
AS, was a major contributor in formal analysis, data curation, analysis, and interpretation.
MA was a major contributor in project administration, data curation, analysis, and interpretation writing, original draft preparation.
The nal version of the manuscript was reviewed by all authors for accuracy and completeness. The crazy-paving pattern. The crazy-paving pattern can be observed in left upper lobe.