key: cord-0880678-8s5bm36g authors: Marvisi, Maurizio; Ferrozzi, Francesco; Balzarini, Laura; Mancini, Chiara; Ramponi, Sara; Uccelli, Mario title: First report on clinical and radiological features of COVID-19 pneumonitis in a Caucasian population: factors predicting fibrotic evolution date: 2020-08-22 journal: Int J Infect Dis DOI: 10.1016/j.ijid.2020.08.054 sha: 77c80fc676dfbc04202e3b8407446194081a4ddf doc_id: 880678 cord_uid: 8s5bm36g Abstract Background At the end of February, the Lombardy region (Northern Italy) was involved in the pandemic spread of the new COVID-19. We herein summarize the clinical and radiological characteristics of 90 confirmed cases and analyze their role in predicting the evolution to fibrosis. Methods We retrospectively analyzed the clinical and radiological data of 90 patients with COVID-19 pneumonitis. All subjects underwent an HRCT study on the day of admission and 8 weeks later, and were treated with lopinavir + ritonavir (Kaletra) 400/100 mg 2 times a day or darunavir + ritonavir 2 times a day, and Hydroxychloroquine 200 mg 2 times a day. Pulmonary fibrosis was defined according to the Fleischner Society glossary of terms for thoracic imaging. Results Twenty- three patients developed pulmonary fibrosis (25.5%): 15 were males, whose mean age was 75 ± 15 years. The majority were active smokers (60.8%) and had comorbidities (78.2%), above all hypertension (47.8%) and diabetes (34.7%). Interestingly, in our series of cases “reversed halo sign” is frequent (63%) and seems to be a typical pattern of COVID-19 pneumonitis. The group of patients showing fibrosis had a higher grade of systemic inflammation (ESR and PCR), and appeared to have a bone marrow inhibition with a significant reduction in platelets, leukocytes and hemoglobin. Conclusions To conclude, our data showed that reversed halo sign associated with ground glass pattern may be a typical HRCT pattern of COVID-19 pneumonitis. The evolution to pulmonary fibrosis is frequent in older males and in patients with comorbidities and bone marrow involvement. At the end of February, the Lombardy region (Northern Italy), and in particular the province of Cremona, J o u r n a l P r e -p r o o f was the first European area involved in the pandemic spread of the new COVID-19. The virus was reported to utilize angiotensin-converting enzyme-2 (ACE2) of pneumocytes as the cell receptor into humans, causing firstly pulmonary alveolar damage and subsequently parenchymal changes. At present, the diagnosis of COVID-19 pneumonia is based on clinical symptoms, contact history of epidemic area, imaging diagnosis and nucleic acid detection. However, false negatives in nucleic acid detection have been reported, and the clinical symptoms may be atypical, giving rise to misdiagnosis and the spread of contagion.1,2 Therefore, imaging becomes particularly important. High resolution contrast CT scan (HRCT) seems to play a key role in the diagnosis and prognosis of these patients. 1 Bilateral distribution of ground glass opacities (GGO) with or without consolidation in posterior and peripheral lungs was the cardinal hallmark of COVID-19. However, with the further analysis of increasing cases, a variety of interesting CT imaging features have been found, including halo sign, reversed halo sign and crazy paving. 3,4,5On the other hand, data regarding the evolution of pulmonary lesions are sparse, above all in Caucasian populations. Lessons learned from previous experiences with other viral pulmonary infections, above all SARS (Severe acute respiratory syndrome) and influenza A (H7N9), and preliminary reports from China, suggest that some pulmonary consequences are predictable in some phenotypes of patients with COVID 19 infection. Different clinical factors may play a pivotal role in determining the appearance of residual fibrotic evolution: age, smoking habits, clinical history, only to mention but a few. 6 We herein summarize the clinical and radiological characteristics of 90 confirmed cases and analyze their role in predicting the evolution to fibrosis. CT examination (Philips 256 CT scanner, low dose < 1mSv)) was first performed at admission within a range of 1 to 10 days after onset of symptoms, with an average of 5.5 days. Patients were informed of the date of their follow-up CT scan on the day of discharge because all subjects presented residual pulmonary symptoms (cough, dyspnea at rest or during exercise) and clinical signs of residual disease (inspiratory squeaking and end inspiratory crackles). The CT scan was performed 60 days after admission (60±5 days). Because the study is a retrospective analysis, no standard CT protocol was applied. All CT images were reconstructed to 1.25-mm thin slices. Multiple CT scans for each individual patient were manually reviewed by the same group, and the decision was reached in consensus. Pulmonary fibrosis was defined according to the Fleischner Society glossary of terms for thoracic imaging: reticulation, architectural distortion, traction bronchiectasis and honeycombing. 7 The study was approved by the local ethical committee and an informed consent was signed by all patients on the day of the follow-up HRCT. Continuous variables were compared with the Mann-Whitney U test or Wilcoxon test; categorical variables were expressed as number (%) and compared by χ2 test or Fisher's exact test if appropriate. A two-sided α J o u r n a l P r e -p r o o f of less than 0.05 was considered statistically significant. Statistical analyses were done using GraphPad Prism 8.0. As shown in TABLE 1, our population included 90 pts, 60 of whom were men (66%); the mean age was 66±15 years. Common symptoms at onset of illness were fever (72 pts-80%), cough (46 pts -51%), and myalgia/fatigue (15 pts-16.6%); less common symptoms were sore throat (10 pts-11.1%), diarrhea (8 pts-8.9%), and headache (3 pts -3.3%). In addition, 70 of the 90 pts (77.7%) had lymphopenia, and 30 (33%) mild anemia. The vast majority of subjects (n =81; 90%) were treated with supplemental oxygen (mean oxygen flow 6±4 l\min), six with non-invasive mechanical ventilation (4 with CPAP, 2 with BiPAP). (Table 3) The majority of subjects developed bilateral lung disease (90%); the others had unilateral involvement. 54.4% of patients developed diffuse GGO; 46.6% developed both GGO and consolidations. (Table 2) The area and number of GGOs or consolidations decreased or disappeared in 50% of cases; the density of GGO increased and changed into consolidation in 20% of cases; the edge of consolidation shadow became contracted in 15 % of cases. Patients were discharged after an average hospital stay of 14±5 days. All subjects were discharged after two RT-PCR nose and throat specimens resulted negative. Long term oxygen therapy (LTOT) at discharge was prescribed, in accordance with the European Respiratory Society indications, to sixteen subjects (17.9%) -ten at rest, the others during exercise. "Halo sign" refers to the ground-glass shadow around the mass or nodule. "The "reversed halo sign" (Atoll J o u r n a l P r e -p r o o f sign) is characterized by focal, round or half-moon shape with ground-glass density in the center, and almost completely (more than 3/4) surrounded by high-density consolidation shadow (Fig 1) . 7 Interestingly, in our series of cases "reversed halo sign" is frequent (70 pts; 63%) and seems to be a typical pattern of COVID-19 pneumonitis in this series of cases (Table 2 ). In our series of cases only 2 pts had pleural effusion (1 of these had pericarditis, 1 developed a pneumothorax that required the placement of a pleural drain), and 2 patients had pneumatocele. Seven patients developed localized fibrosis, usually in a localized area of GGO. Twenty-three pts developed bilateral pulmonary fibrosis (Fig 2) with a typical non-specific interstitial pneumonia (NSIP) pattern, in accordance with the Fleischner Society criteria, (25.5%): 15 were males, whose mean age was 75±15 years. The lung diffusing capacity for carbon monoxide (DLco\Va) was significantly lower in these 23 subjects than in the non-fibrosis group (58±13 % versus 91±13 %; p< 0.001). The majority were active smokers (14 pts; 60.8%) and had comorbidities (18 pts; 78.2%), above all hypertension (11 pts; 47.8%) and diabetes (8 pts; 34.7%) ( Table 3 ). The group of pts showing fibrosis had a higher grade of systemic inflammation (ESR, PCR and ddimer), and appeared to have a bone marrow suppression with a significant reduction in platelets, leukocytes and hemoglobin (Table 3 ). Consistently with several recent reports regarding the CT findings of 2019-nCoV infected pneumonia, our results showed that CT manifestations were featured by predominant ground glass opacities that are usually peripheral and bilateral involving middle and lower lung fields.1,2, 3 Jiong W et al studied 80 consecutive subjects and suggested that the most commonly involved lung segment was the dorsal segment of the right lower lobe (69/80, 86%), and that the most frequent CT abnormalities observed were ground glass opacity (73/80 cases, 91%), consolidation (50/80 cases, 63%), and interlobular septal thickening (47/80 cases, 59%). To our knowledge, this is the first prospective study evaluating the evolution of pulmonary lesions in a Caucasian population. In our series, more than 1 patient out of 3 (36%) was seen to develop pulmonary fibrosis. The vast majority of these are male smokers, and have comorbidities, higher inflammatory markers (CRP and ESR), increased D-dimer and involvement of the bone marrow. These data are concordant with those of Yang Z et al that evaluated, performing a short CT follow-up (a week), the prognostic value of some clinical parameters in predicting imaging progression. The white blood cells, platelets, neutrophils, monocyte-lymphocyte ratio and age were significantly higher in imaging progression patients compared to that in imaging progression-free ones.12Moreover, these parameters have been reported to be important prognostic factors, and a D-dimer value greater than 1µg\ml could help clinicians to identify pts with poor prognosis at an early stage. 13 Interestingly, in our Caucasian population, the reversed halo sign is very common and seems to be a pattern peculiar to COVID 19 pneumonitis. On the one hand, our study has important limitations, above all the prospective design, the small number At this juncture three questions require a rapid answer. What will be the impact of pulmonary fibrosis secondary to COVID-19 infection on the pulmonary function and quality of life of our patients? Why do some phenotypes show diffuse alveolar damage, mononuclear cells and macrophage infiltration in air space, and a diffuse thickening of the interstitial space? Is there any role for some drugs, in particular steroids, in decreasing the risk of a fibrotic evolution? To conclude, our data showed that reversed halo sign associated with ground glass pattern may be a typical HRCT pattern of COVID-19 pneumonitis. The evolution to pulmonary fibrosis is frequent in older male smokers and in patients with comorbidities and bone marrow involvement. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention Online ahead of print Coronavirus Disease 2019(COVID-19): Role of Chest CT in Diagnosis and Management Chest CT manifestations of new coronavirus disease 2019(COVID-19): a pictorial review Clinical and High-Resolution CT Features of the COVID-19 Infection: Comparison of the Initial and Follow-up Changes Long-term Pulmonary Consequences of Coronavirus Disease 2019 (COVID-19). What We Know and What to Expect Diagnostic Criteria for Idiopathic Pulmonary Fibrosis: A Fleischner Society White Paper Chest CT Findings in Patients with Coronavirus Disease 2019 and Its Relationship with Clinical Features Interpretation of CT signs of 2019 novel coronavirus (COVID19) pneumonia Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study COVID-19): A Systematic Review of Imaging Findings in 919 Patients Predictors for imaging progression on chest CT from coronavirus disease 2019 (COVID-19) patients Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Reversed halo sign". Peripheral and bilateral consolidations We have no conflict of interest All authors had access to the data. All authors contributed to the writing of the text.