Outcomes of Covid-19 organizing pneumonia in critically ill patients
Authors: Ana Silva Rocha, Mariana Meireles, Helena Vilaça, Teresa C. Guimarães, Marta Dalila Martins, Lígia Rodrigues Santos, Alice Castro, Mari Mesquita
Journal: Journal of Infection (2021)

Efficacy of corticosteroids in COVID-19 pneumonia has been reported in numerous studies.1The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working GroupAssociation between administration of systemic corticosteroids and mortality among critically Ill patients with COVID-19 a meta-analysis.JAMA. 2020; 324: 1330-1341https://doi.org/10.1001/jama.2020.17023Crossref PubMed Scopus (1661) Google Scholar However, Yang et al. concluded that corticosteroids have a negative impact, suggesting that not all patients benefit from the therapy.2Yang Z. Liu J. Zhou Y. Zhao X. Zhao Q. Liu J. The effect of corticosteroid treatment on patients with coronavirus infection: a systematic review and meta-analysis.J Infect. 2020; 81 (JulEpub 2020 Apr 10. PMID: 32283144; PMCID: PMC7195158): e13-e20https://doi.org/10.1016/j.jinf.2020.03.062Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar Features of organizing pneumonia (OP) have been observed in radiological and histopathological studies from these patients.3Bao C. Liu X. Zhang H. Li Y. Liu J. Coronavirus disease 2019 (COVID-19) CT findings: a systematic review and meta-analysis.J Am Coll Radiol. 2020; 17: 701-709Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar, 4Polak S.B. Van Gool I.C. Cohen D. von der Thüsen J.H. van Paassen J A systematic review of pathological findings in COVID-19: a pathophysiological timeline and possible mechanisms of disease progression.Mod Pathol. 2020; ([published online ahead of print, 2020 Jun 22]): 1-11https://doi.org/10.1038/s41379-020-0603-3Abstract Full Text Full Text PDF PubMed Scopus (328) Google Scholar, 5Wang Y. Jin C. Wu C.C. Zhao H. Liang T. Liu Z. et al.Organizing pneumonia of COVID-19: time-dependent evolution and outcome in CT findings.PLoS ONE. 2020; 15e0240347https://doi.org/10.1371/journal.pone.0240347Crossref PubMed Scopus (36) Google Scholar OP has usually a good response to corticosteroids. The possible correlation between the radiological pattern and clinical evolution has important implications. This study provides information on patient selection and clinical application of corticosteroids. Adult patients admitted to a respiratory intermediate care unit (RICU) from November 18th, 2020 to February 18th, 2021 were prospectively enrolled. Institutional review boards authorised the study. Informed consent was waived. A confirmed case of COVID-19 pneumonia was defined as a patient with compatible symptoms and PCR-confirmed infection. Only patients needing advanced noninvasive respiratory support (NIRS) with high flow nasal cannula (HFNC), continuous positive airway pressure (CPAP) and/or noninvasive ventilation (NIV) were included. All patients had a "do intubate" (DI) or "do not intubate" (DNI) order defined at admission. Information regarding demographics, comorbidities, blood test results and mode and usage of NIRS were recorded. The severity of respiratory failure was assessed by PaO2/FiO2 ratio before NIRS institution. Several outcomes were evaluated: length of stay, need for endotracheal intubation (ETI) and in-hospital mortality. OP was diagnosed, based on radiology reports, in the presence of bilateral patchy consolidation areas with subpleural and/or peribronchial distribution; perilobular pattern, with thick, ill-defined linear opacities with a polygonal or arcade appearance; and/or reverse halo sign.3Bao C. Liu X. Zhang H. Li Y. Liu J. Coronavirus disease 2019 (COVID-19) CT findings: a systematic review and meta-analysis.J Am Coll Radiol. 2020; 17: 701-709Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar Bacterial infection was excluded by clinical evaluation, procalcitonin levels, urinary antigens and blood cultures at admission. Pulmonary embolism was excluded using D-dimer levels and, if increased, CT pulmonary angiogram. OP was treated, according to BTS 2008 guidelines6Bradley B. Branley H.M. Egan J.J. Greaves M.S. Hansell D.M. Harrison N.K. Hirani N. Hubbard R. Lake F. Millar A.B. Wallace W.A. Wells A.U. Whyte M.K. Wilsher M.L. British Thoracic Society Interstitial Lung Disease Guideline Group, British Thoracic Society Standards of Care Committee; Thoracic Society of Australia; New Zealand Thoracic Society; Irish Thoracic Society. Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society.Thorax. 2008; 63: v1-58https://doi.org/10.1136/thx.2008.101691Crossref PubMed Scopus (788) : methylprednisolone 500–1000 mg for 3–5 days, followed by 0.75–1 mg/Kg prednisone. Patients improving under 6 mg dexamethasone were switched to prednisone and methylprednisolone pulses were used as a rescue therapy if clinical deterioration and FiO2≥35%. GGO group was treated with 6 mg dexamethasone.7Horby P. Lim W.S. Emberson J.R. Recovery: collaborative group, dexamethasone in hospitalized patients with Covid-19.N Engl J Med. 2021; 384: 693-704https://doi.org/10.1056/NEJMoa2021436Crossref PubMed Scopus (6997) Google Scholar Side effects were recorded. Baseline characteristics of patients with OP and GGO were compared. Continuous and categorical variables were compared using Student's T test and Chi-squared or Fisher's exact test, respectively. The association between OP and outcomes was calculated using a logistic regression model adjusted for age, CCI, DNI order and PaO2/FiO2. A two-sided test of <0.05 was considered statistically significant. 190 patients were admitted to RICU. At the time of the study, the hospital was attending 10% of the national cases of COVID-19 needing hospitalization. Due to this burden, CT scan was performed in 112. Fig. 1 illustrates patients' allocation according to CT scan findings and outcomes. Table 1 lists patients characteristics and clinical outcomes according to cohort. Male gender was predominant and the mean age was 67.5 ± 12.1 years. OP group was significantly younger. The PaO2/FiO2 ratio was higher in OP group.Table 1General characteristics and clinical outcomes according to cohort.Demographic and clinical characteristicsTotalCohortp-valueGGOOPPatients1124765Age, years67.5 (12.1)73.1 (9.0)63.4 (12.4)<0.001Male76 (67.9)35 (74.5)41 (63.1)0.203CCI, points3.4 (1.9)3.8 (1.6)3.1 (2.1)0.069DNI order60 (53.6)32 (68.1)28 (43.1)0.009Length of symptoms, days8.5 (3.7)8.0 (3.5)8.9 (3.9)0.241Laboratory findingsLeucocytes, 10⁹ cells per L7.9 (4.1)9.0 (5.1)7.1 (2.9)0.012Lymphocyte, 10⁹ cells per L0.9 (0.4)0.9 (0.4)1.0 (0.4)0.322C-reactive protein, mg/L152.6 (79.9)171.3 (82.4)139.0 (75.8)0.034Procalcitonin, ng/mL0.5 (0.7)0.6 (1.0)0.4 (0.5)0.076Ferritin>1500 ng/mL32 (30.8)15 (35.7)17 (27.4)0.037Lactate dehydrogenase, U/L444.1 (174.2)485.9 (178.5)413.9 (165.9)0.030Interleukin-6, pg/mL138.4 (336.1)228.6 (513.8)80.2 (96.1)0.025D-dimer, μg/mL2407.0 (8239.4)3032.3 (10,023.3)1967.3 (6762.8)0.509PaO2/FiO2, mmHg94.9 (35.1)86.3 (29.5)101.8 (37.9)0.024NIRSHFNC95 (67.0)37(78.7)58 (89.2)0.126CPAP/NIV37 (33.0)19 (40.4)18 (27.7)0.157TreatmentCorticosteroids111 (99.1)46 (97.9)65 (100.0)0.420Remdesivir7 (6.3)3 (6.4)4 (6.2)0.961Clinical outcomes and relative probabilityTotalCohortp-valueOPOR (95% CI)Length of stay, days15.4 (12.1)15.6 (9.6)1.000 (1.000–1.000)0.495ETICrude17 (18.3)7 (10.8)0.08 (0.02–0.39)0.002Adjusted#: adjusted for age, CCI, DNI order and arterial oxygen tension/inspiratory oxygen fraction ratio.0.06 (0.01–0.44)0.003Hospital mortality41 (36.6)5 (7.7)Crude0.03 (0.01–0.08)<0.001Adjusted#: adjusted for age, CCI, DNI order and arterial oxygen tension/inspiratory oxygen fraction ratio.0.03 (0.01–0.11)<0.001Data are presented as n (%) or mean (SD). GGO: ground glass opacities; OP: organizing pneumonia; CCI: Charlson comorbidity index; DNI: "do not intubate"; PaO2/FiO2: arterial oxygen tension /inspiratory oxygen fraction; NIRS: noninvasive respiratory support; HFNC: high flow nasal cannula; CPAP: continuous positive airway pressure; NIV: nonivasive ventilation; ETI: endotracheal intubation.# : adjusted for age, CCI, DNI order and arterial oxygen tension/inspiratory oxygen fraction ratio. Open table in a new tab Data are presented as n (%) or mean (SD). GGO: ground glass opacities; OP: organizing pneumonia; CCI: Charlson comorbidity index; DNI: "do not intubate"; PaO2/FiO2: arterial oxygen tension /inspiratory oxygen fraction; NIRS: noninvasive respiratory support; HFNC: high flow nasal cannula; CPAP: continuous positive airway pressure; NIV: nonivasive ventilation; ETI: endotracheal intubation. All patients were treated with corticosteroids. Mean time to dexamethasone was 8.5 ± 3.5 days and to OP treatment was 13.0 ± 5.5 days. 75.4% of OP patients were treated with pulse methylprednisolone and the remaining with prednisone 0.75–1 mg/Kg. There were no reports of bacterial infection in patients treated with NIRS but 10 patients who needed invasive mechanical ventilation had hospital acquired infection (3/7 in OP group vs. 7/10 in GGO group, p = 0.350). Psychosis occurred in 2 patients with OP under methylprednisolone pulses. There were no records of acute diabetic complications or gastrointestinal hemorrhage. Length of stay was similar between groups. 25.9% needed ICU admission (24.6% in OP group vs. 31.9% in GGO group, p = 0.394). The global in-hospital mortality was 36.6%, 76.6% in GGO group vs. 8.6% in the OP group (p < 0.001). OP was associated with a significant reduction in need for ETI and in-hospital mortality after adjustment for confounders. To our knowledge this is the first prospective study to evaluate OP outcomes. Since RECOVERY, many clinical trials have stablished the benefit of corticosteroids in COVID-19 patients.1The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working GroupAssociation between administration of systemic corticosteroids and mortality among critically Ill patients with COVID-19 a meta-analysis.JAMA. 2020; 324: 1330-1341https://doi.org/10.1001/jama.2020.17023Crossref PubMed Scopus (1661) Google Scholar,7Horby P. Lim W.S. Emberson J.R. Recovery: collaborative group, dexamethasone in hospitalized patients with Covid-19.N Engl J Med. 2021; 384: 693-704https://doi.org/10.1056/NEJMoa2021436Crossref PubMed Scopus (6997) Google Scholar However, the specific mechanisms of corticosteroids in treating COVID-19 are not totally understood. The hypothesis that OP in COVID-19 is more frequent than in other viral infections may explain this steroid-responsive effect. We found OP in almost 60% of our patients. PaO2/FiO2 ratios were extremely low and more than 50% of our patients received a "do not intubate" order, supporting the severity of acute illness and baseline frailty of our population. This might justify the global in-hospital mortality rate. Interestingly, the need for ETI and mortality rate was significantly lower in the OP group, even after adjustment for age, comorbidities, "DNI order" and severity of acute respiratory distress syndrome. Additionally, biological markers associated with worse outcomes, such as leucocyte count, C-reactive protein, lactate dehydrogenase, interleukin-6 and ferritin levels,8Zeng F. Huang Y. Guo Y. Yin M. Chen X. Xiao L. et al.Association of inflammatory markers with the severity of COVID-19: a meta-analysis.Int J Infect Dis. 2020; 96: 467-474https://doi.org/10.1016/j.ijid.2020.05.055Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar were significantly lower in the OP group. These results support the theory that OP presence is by itself an independent predictor of good prognosis. In fact, literature reports that approximately 70% of OP patients will respond to corticosteroids.9Cordier J.F. Cryptogenic organising pneumonia.Eur Respir J. 2006; 28: 422Crossref PubMed Scopus (405) Google Scholar Identifying and timely treating this condition may avoid unnecessary ETI and drastically reduce mortality. An important concern is that the increasingly adopted dexamethasone protocol may be insufficient, especially in critical care patients, as OP management requires higher doses, prolonged treatment and careful tapering.6Bradley B. Branley H.M. Egan J.J. Greaves M.S. Hansell D.M. Harrison N.K. Hirani N. Hubbard R. Lake F. Millar A.B. Wallace W.A. Wells A.U. Whyte M.K. Wilsher M.L. British Thoracic Society Interstitial Lung Disease Guideline Group, British Thoracic Society Standards of Care Committee; Thoracic Society of Australia; New Zealand Thoracic Society; Irish Thoracic Society. Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society.Thorax. 2008; 63: v1-58https://doi.org/10.1136/thx.2008.101691Crossref PubMed Scopus (788) Considering the critically ill nature of our patients, the positive impact on outcomes and the absence of significant side effects, this approach seems to be beneficial. Nevertheless, the adequate minimal dose of corticosteroids for COVID-19 OP are unknown, particularly because of the secondary nature of the disease. One limitation of this study is the absence of histopathologic confirmation. Second, as all OP patients were treated, we cannot guarantee that the benefit found was due to OP by it-self or due to the use of high dose of corticosteroids. Finally, larger studies are necessary to confirm these results. In conclusion, our study showed that radiological features of OP are frequent. Critically ill patients should undergo a chest CT scan in order to identify this condition as treatment with high doses of corticosteroids seems to reduce the need for ETI and hospital mortality. None declared. None.