Gereç ve Yöntem: Eylül 2020-Mayıs 2021 tarihleri arasında nefes darlığı ve halsizlik şikayetleri ile hastanemize başvuran, son başvuru tarihinden en az üç ay önce SARS-CoV-2 enfeksiyonu tanısı alan ve hem radyolojik hem de patolojik olarak organize pnömoni tanısı konan 17 hasta dahil edildi.

Bulgular: Hastaların tamamı daha önce COVID-19 nedeniyle hospitalize edilmişdi. COVID-19 tanısı ve organize pnömoni nedeniyle tekrar hastaneye yatış arasında geçen ortalama süre 4 aydı. Hastalarımızda organize pnömoninin tipik radyolojik özelliği olan buzlu camdan orta/alt akciğer konsolidasyonuna kadar değişen bilateral lobüler, subplevral dansite varlığı mevcuttu. Tüm hastalara akciğer parsiyel lobüler eksizyon işlemi uygulandı. Hastaların tamamında akciğer parankiminde granülasyon dokusu ve fibroblast proliferasyonu ile karakterize intraalveolar eksüda tespit edildi.

Sonuç: COVID-19 pnömonisi olan hastalarda, özellikle kalıcı veya tekrarlayan solunum semptomları ve devam eden akciğer infiltrate varlığında ikincil seconder organize pnömoninin düşünülmesi gerektiğine inanıyoruz. Böylece gereksiz cerrahi müdahaleler yerine doğru medikal yaklaşımların sağlanması mümkün olacaktır.

In some patients, symptoms of COVID-19 may last longer than five weeks. However, the predictors of the severity and course of COVID-19 are still not fully understood. Today, the definition of prolonged COVID-19 has not been clearly described. However, according to the guidelines on managing the long-term of COVID-19, the course of COVID-19 is divided into three periods: An acute period with signs and symptoms lasting up to 4 weeks; an ongoing symptomatic period during which signs and symptoms of COVID-19 last 4 to 12 weeks; and post-COVID-19 period with signs and symptoms lasting longer than 12 weeks and cannot be associated with alternative diagnoses. It is emphasized in the guideline that attention should be paid primarily in the presence of new or worsening symptoms that persist for more than four weeks ⁴. As the COVID-19 disease continues to spread worldwide, numerous medical articles are being published as a part of scientific efforts to characterize, treat and prevent the disease current COVID-19 guidelines cover acute disease management, preventive measures, and vaccination. Limited information is available for dealing with persistent symptoms after COVID-19 ^5,6. However, the medium and long-term clinical consequences of COVID-19 infections have not yet been elucidated.

The most common lung computed tomography (CT) finding in COVID-19 patients is the image of ground-glass opacity, which may be accompanied by consolidating abnormalities consistent with viral pneumonia. In addition, the pattern of organizing pneumonia (OP) on lung CT scans has been reported mainly as a late-phase complication ^7-9. Findings in subacute and chronic inflammation of the pulmonary parenchyma range from bronchiolitis obliterans with organizing pneumonia (BOOP) to extensive interstitial fibrosis. Since the BOOP pattern is highly non-specific and represents a typical tissue response to various stimuli, it is recommended to use organized pneumonia instead. Secondary organizing pneumonia (SOP) is a rare form of interstitial lung disease (ILD) called OP. OP, chronic lung injury, tissue response, is characterized by plugs of granulation tissue located in the lumens of the small airways and extending into the alveolar ducts and alveoli. These plugs consist of inflammatory cells, small vessels, and fibroblasts embedded in the myxoid matrix. Fibrous polypoid masses rising from the alveolar walls to adjacent air spaces fill the alveolar lumens. They are defined as intra-alveolar organized exudate consisting of myofibroblasts and connective tissue with interstitial inflammation. Viral infections are among the most common etiologies of SOP. In particular, there is a strong correlation between SOP and various conditions, including adenovirus, cytomegalovirus, herpes virus, human immunodeficiency virus, parainfluenza virus, and influenza virus ¹⁰. In addition, viruses that caused global epidemics, such as SARS, MERS, and influenza A in the previous years, have also been reported to cause SOP ^11-14.

Although the relationship between COVID-19 pneumonia and SOP is limited to a few case reports, the similarities between these two entities are increasingly being investigated ^15,16.

Histopathology publications on COVID-19 are not at the forefront of clinical and imaging studies. Histological studies are often limited to autopsy reports of patients who died from COVID-19 infection ¹⁷.

This study aimed to retrospectively evaluate the cases of healthy adults diagnosed with histologically confirmed organizing pneumonia and had shortness of breath and fatigue persist for at least three months in the post-COVID-19 period.

Study Design, Participants, and Data Collection: Patients admitted to our hospital with complaints of shortness of breath and fatigue between September 2020 and May 2021 who were diagnosed with SARS-CoV-2 infection confirmed by real-time PCR at least three months before the last admission and diagnosed with organizing pneumonia confirmed both radiological and pathologically with lung partial lobular excision material were included in this retrospective study. The diagnosis of COVID-19 infection was made by real-time RT-PCR test positivity of nasopharyngeal swab samples. Demographic characteristics, medical history, laboratory, radiological and pathological findings of the cases were obtained retrospectively from electronic medical records.

Cases under 18 years of age, with clinical findings and/or pneumonia findings consistent with COVID-19 on Thorax CT, but negative RT-PCR test, and comorbidities such as any rheumatological disease or malignancy, or chronic drug use were excluded from the study.

Statistical Analysis: Data analysis was performed with SPSS 22 software (SPSS, Inc., Chicago, Illinois). The normal distribution of the variables was tested using visual methods (histograms, probability plots) and analytical methods (Shapiro-Wilk's test). For continuous variables with normal distribution, mean±standard deviation (SD) were provided, whereas those without normal distribution were expressed using median [interquartile range (IQR)]. Categorical variables were expressed as counts and percentages.

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Table 1: Age and gender distribution of the cases

Our patients had bilateral lobular, sub-pleural densities varying from ground the ass to consolidation of the middle/lower lung, which is the typical radiological feature of OP ¹⁸. Consolidation was found in 12 (70.5%) patients, and the patient distribution according to their lung CT findings is given in Table 2.

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Table 2: Lung computed tomography findings of the cases

Partial lobular excision of the lung was performed in all patients. Intraalveolar exudate with interstitial inflammation, characterized by granulation tissue and fibroblast proliferation in the lung parenchyma, was detected in all patients (Figure 1, 2).

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Figure 1: Alveolar duct and granulation tissue extending into alveoli

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Figure 2: Fibrous plugs filling the alveoli

Baha and Yildirim. ²⁶ have found the mean age at OP diagnosis was 57.0+/-12.6, and the male gender was predominant. The most common symptoms were cough (71.4%), dyspnea (66.1%), and fatigue (64.3%), and dyspnea has been reported to last from 10 days to 2 years. In another study ^27, the mean age at presentation was 60.46±13.57, and fatigue, cough, fever, and dyspnea were the most common symptoms. In the present study, most of the patients were in the 20-29 and 40-49 age groups, and the mean age was 38 (±13.8). These results were consistent with the age range reported by Fang et al. ²⁸ in a study investigating COVID-19 patients with secondary OP. Our study also showed that OP was more common in males, the most common symptoms were fatigue, shortness of breath, and other symptoms included high fever and cough.

Some of the most common causes of secondary OP are medications, infections, rheumatological diseases, and malignancies. In a study, the most common causes of SOP were rheumatological diseases and malignancies ²⁶. In another study ^29, the most common cause of SOP was infection. In this study, SOP developed after the COVID-19 infection in all patients.

Many studies have unexplained the relationship between smoking and OP ^26,27,29. Lazor et al. ³⁰ have found that 71% of OP patients were non-smokers, and most of them were female. Only one male patient who had a smoking history in our study is compatible with this outcome.

Similar to our study, in studies evaluating the laboratory parameters of organizing pneumonia patients, the presence of high CRP and ESR are noteworthy. However, the reasons for these higher values have not been clarified ^31-33. CRP synthesis from hepatocytes during inflammation increases with the influence of cytokines such as interleukin 6 ³⁴. In the presence of OP, it has been shown that there is an increase in inflammatory cytokines ³⁵. In addition, considering the role of acute inflammation in the etiology of SOP, increased acute phase reactants can be expected.

The most common radiological findings in patients with organizing pneumonia are consolidation and ground-glass opacities, with often bilateral-peripheral involvement. It has also been shown that the lower lung zones are more affected ³⁶. Another study showed that middle zone involvement is prevalent ³⁷. Our findings were consistent with the literature and showed that the predominant involvement of the lung's lower zone and the central location was detected, respectively.

Histopathological examination is the most valid method to diagnose organizing pneumonia ³⁸. However, OP can be analyzed in appropriate clinical and radiographic findings ³⁶. Cazzato et al. ³⁹ have found that clinical and radiological findings usually support the diagnosis, but definitive confirmation requires histopathological examination in the diagnostic approach of patients with OP. In our study, the diagnosis was made by histopathological evaluation of all patients.

This is the first study to show the relationship between COVID-19 and SOP in a case series to the best of our knowledge. However, the study has some limitations. Our results need to be supported by well-designed, large-scale studies to determine the association between SOP and COVID-19 disease. In addition, the retrospective nature of the research and the relatively small sample size are among the limitations of the present study.

In conclusion, COVID-19 is a novel infection with severe medical conditions that have affected people worldwide for almost two years. Organizing pneumonia seen after COVID-19 pneumonia is one of the leading causes of lung injury manifested by different interstitial changes seen on CT scans. Despite few case reports to date, it has been suggested that OP is much more common in COVID-19 infection. In the light of all these findings, secondary OP, which represents an immunological process, should be considered among patients with COVID-19 pneumonia and should be evaluated to detect lung damage in the early period, especially in the case of persistent or recurrent respiratory symptoms and ongoing lung infiltrate. This study will increase clinicians' awareness of OP in the post-COVID period, resulting in reduced need for invasive mechanical ventilators and unnecessary antibiotic use and improved overall survival by enabling early diagnosis and treatment of the disease.

Source of funding: None.

Conflicts of interest: The authors have no conflicts of interest to declare

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