Comparison of clinical features and prognosis in patients with cryptogenic and secondary organizing pneumonia

Organizing pneumonia (OP) is an interstitial lung disease histologically characterized by patchy filling of the lung alveoli and respiratory bronchioles by loose plugs of granulation tissue [1, 2]. OP was first described histologically during the early 20th century [3] and has been regarded as a distinct pathological entity since the 1980s [1, 4]. Histological, clinical, and radiological advances have increased understanding of OP, which is presently classified as an interstitial lung disease [5, 6].

OP is initiated by lung injuries, with the alveolar epithelium reacting to produce granulation tissue [6]. Despite having the same pathologic patterns, OP can be classified as either cryptogenic OP (COP) or secondary OP (SOP). SOP can be caused by infection, drug toxicity, drug intoxication, inhalation of toxic gases, aspiration of gastric contents, connective tissue diseases (CTD), organ transplantation, radiotherapy, vasculitis, tumors, pulmonary infarction, hypersensitivity pneumonitis, eosinophilic pneumonia, and other interstitial lung diseases [2, 7]. COP can be diagnosed by excluding SOP, based on clinical history, characteristics, laboratory tests, radiologic findings, and associated pathologic findings [8, 9]. Clinical confusion has arisen in the differential diagnosis of COP or SOP, as differences in their characteristics have not been clearly identified [10‐15]. The present study investigated whether any characteristics could distinguish between COP and SOP. The causes, clinical characteristics, laboratory results, radiologic findings, and prognosis were therefore compared in patients with pathologically proven SOP and COP.

Of the 85 patients with pathologically confirmed OP on lung biopsy, 16 (18.8%) were diagnosed with COP and 69 (81.2%) with SOP. Infectious pneumonia was the most frequent cause of SOP, occurring in 57 patients (82.6%), followed by cancer and radiation pneumonitis. The bacteria causing infectious pneumonia were confirmed in 45 patients (65.2%), either by culture or PCR testing. Acinetobacter baumanii was the most frequently identified, followed by Stenotrophomonas, Tuberculosis, Streptococcus, Staphylococcus, Klebsiella, and fungi. In one patient each, SOP was caused by CTD, hypersensitivity pneumonitis, and chronic eosinophilic pneumonia, and was drug (adalimumab)-related in one patient (Table 1).

Median ages of patients in the COP and SOP groups were 64 and 71 years, respectively, with no significant between-group difference. The percentages of men were higher than those of women in both groups, but the difference in gender distribution was not significant. Reasons for biopsy included the pneumonia pattern in 61 patients (71.8%) and the mass form in 24 (28.2%). Median body mass index (BMI) was significantly higher in the COP than in the SOP group (24.1 kg/m² vs. 21.7 kg/m², P = 0.030). The median time from the first visit to diagnosis was 13 days in both groups, whereas the median time from symptom onset to hospital admission was significantly longer in the COP than in the SOP group (4 weeks vs. 1 week, P = 0.006). Fever was significantly more common in the SOP group (P = 0.024). The most common symptoms in all patients were cough, sputum, shortness of breath, fever, hemoptysis, and chest pain. Chronic liver disease was significantly more frequent in the COP group (P = 0.020). There was a significant difference in CURB-65 score [25], an index of the severity of pneumonia (P = 0.017) (Table 2).

Vital signs and PF ratios did not differ between the two groups, nor did leukocyte and neutrophil counts and concentrations of C-reactive protein (CRP). By contrast, eosinophil counts and concentrations of procalcitonin, pro-brain natriuretic peptide (proBNP), D-dimer, creatinine, and lactate differed significantly between the two groups at admission. Lymphocyte counts in BAL fluid were significantly higher in the COP than in the SOP group (P = 0.012). Of the 41 (48.2%) patients who underwent PFT, 16 (39.0%) had normal lung function, 12 (29.3%) had a restrictive ventilator defect, nine (22.0%) had an obstructive ventilator defect, and four (9.8%) had mixed defects. PFT results, however, did not differ significantly between these two groups (Table 3).

Chest CT showed no between-group differences in the extent of pneumonia, whereas effusion was more common in the SOP group (P = 0.036), parenchymal bands or fibrotic pattern and perilobular opacity was more common in the COP group (P = 0.005, 0.022, respectively). Chest CT identified 12 patients with focal OP, including seven (43.8%) in the COP group and five (7.2%) in the SOP group (P < 0.001) (Table 4).

Four patients (5.8%) in the SOP group required ventilator use and five (7.2%) in this group required inotropics, but there were between-group differences. Antibiotic use was significantly higher in the SOP than in the COP group (P = 0.013), but there was no between-group difference in steroid use. The 30 day and in-hospital mortality rates, as well as outcome and recurrence rates, did not differ between the two groups (Table 5).

Subgrouping of the 69 patients with SOP cases into those who were (n = 31) and were not (n = 38), treated with steroids showed that pneumonia recurrence was significantly more frequent in the former group (P = 0.035). However, there were no differences between these subgroups in 30 day and in-hospital mortality rates and in outcome of OP (Table 6). Median neutrophil counts on complete blood count (CBC) were significantly higher in the recur group (80.2%) than in the non-recur group (66.0%) (P = 0.027). Lymphocyte count on CBC was also significantly lower in the recur group (5.6%) than in the non-recur group (7.9%) (P = 0.005) (Data not shown).

OP is a pathologic diagnosis term, defined as the presence of means polypoid intraluminal plugs of proliferating fibroblasts and myofibroblasts within alveolar ducts and spaces with varying degrees of bronchiolar involvement. OP can be regarded as a nonspecific pathological pattern of lung responses to injury [6]. In the absence of a specific cause, this condition is diagnosed as COP [9]. The 2002 American Thoracic Society/European Respiratory Society classification recommended using COP rather than the term bronchiolitis obliterans organizing pneumonia (BOOP) because BOOP may be confused with airway disease and, histologically, bronchiolitis obliterans may be concomitant or absent [26]. OP may be a clinical manifestation of a nonspecific repair process in response to a local or distant injury [12]. Based on this definition, SOP was diagnosed in patients with a pathologic OP pattern resulting from identified causes. Distinguishing between COP and SOP is important because the underlying disease, not OP itself, must be managed in patients with SOP. Descriptions of OP are based on an autopsy study of patients with unresolved bacterial pneumonia prior to the advent of antimicrobial therapy [7, 27, 28]. Although OP was thought to be due to infection alone, it was later recognized as a variety of conditions, including interstitial disease, drug toxicity, and connective tissue disorders. Several studies have described the differences between COP and SOP [10‐15].

The major difference between these earlier studies [10‐15] and the present study is that the SOP group in the latter included a high percentage of patients with infectious pneumonia. Because the clinical symptoms of COP and SOP are similar, it is difficult to diagnose SOP, especially infectious pneumonia, based only on clinical symptoms. In a previous study of 57 patients, 27 were diagnosed with SOP, with eight patients having SOP due to infection, the most frequent cause of SOP in that study [11]. The present study also found that infectious pneumonia was the most frequent cause of SOP. In our center, patients who experience slow clinical improvement after being diagnosed with infectious pneumonia are evaluated by lung biopsy to determine whether other conditions may have accompanied infection. Moreover, many patients with infection in the present study were evaluated by lung biopsy, which may have led to the high rate of infection-related SOP diagnoses. In addition, our study was performed after the development of more recent diagnostic techniques, including culture of respiratory samples, multiplex PCR, and respiratory virus panel tests, enabling more accurate identification of bacteria and viruses, and thus the increased diagnosis of SOP. A study performed from 2001 to 2008 found that only two (9.5%) of 21 patients had SOP caused by infections [12]. However, the difficulty of distinguishing between SOP and COP, and the inability to identify a pathogen, may have resulted in some patients with SOP being diagnosed with COP.

The median age of patients in the present study was 70 years, higher than the average ages reported in previous studies of 50–60 years [10‐12, 14]. Moreover, BMI was significantly lower (P = 0.030) and the duration of clinical symptoms before admission significantly shorter (P = 0.006) in the SOP group. The latter was likely due to the more rapid onset and progression of clinical symptoms in the SOP group, resulting in a shorter duration of symptoms. Among the symptoms, fever was more frequent in the SOP group (P = 0.024). A previous study reported that, although most secondary BOOPs were related to chemotherapy and radiotherapy, the clinical symptoms of secondary BOOP were more evident [14]. Our study also found that chronic liver disease was more frequent in the COP group (P = 0.020). Advanced liver disease in the pulmonary parenchyma has been reported to lead to lymphocytic or OP [29], which may explain this result. CURB-65, an index of pneumonia severity, was significantly different between COP and SOP, indicating that SOP is more severe than COP (P = 0.017).

Serum concentrations of procalcitonin, proBNP, D-dimer, creatinine, and lactate were found to be significantly higher in the SOP than in the COP groups. This increase in SOP was thought to be related to the fact that the main cause of SOP was infectious pneumonia [30] and the severity of SOP was higher than that of COP [31‐34]. Lymphocyte counts in BAL fluid were significantly higher in the COP than in the SOP group (P = 0.012). Lymphocytosis >25% in BAL fluid is considered a marker of COP [35]. Although a previous study reported that lymphocyte counts in BAL fluid were significantly lower in patients with COP than with SOP, BAL fluid was assessed in only five patients with SOP and 27 patients with COP, with the mean lymphocyte counts in the BAL fluid of the COP group being much lower, 16%, than reported elsewhere [12]. As in previous studies, we found that PFT did not differ between the COP and SOP groups.

CT evaluation showed that pleural effusion was significantly more frequent in the SOP than in the COP group (P = 0.036). This finding is in good agreement with the results of previous studies, with effusion being more frequent in patients with SOP than in those with COP [12, 14]. Parenchymal bands or fibrotic pattern and perilobular opacity was more frequent in COP (P = 0.005, 0.022, respectively). Parenchymal bands may be secondary to pleuroparenchymal fibrosis [17, 36]. Perilobular opacity is thought to result from residual inflammation in the healing phase [17]. The lesions with surrounding GGO or consolidation are thought to have developed into parenchymal bands, fibrotic pattern or perilobular opacity [36]. Focal OP was more frequent in the COP than in the SOP group (P < 0.001). Because focal OP has a different clinical course from other radiologic features of OP [19, 20], focal OP was specifically identified in the present study. This finding differs from the previous study in which the number of focal SOP was greater than the number of focal COP [21]. However, similar to the present study, the previous study showed that symptoms were more frequent in focal SOP than in focal COP, and that the main causes of focal SOP were acute infection and granulomatous inflammation [21].

Antibiotic use was significantly greater in the SOP group (P = 0.013), although there was no between-group difference in steroid use. Although COP was found to improve more rapidly with corticosteroids, relapses were more common when treatment was discontinued [8, 13, 24, 37]. Several studies have reported no significant difference in treatment response and clinical course between COP and SOP [10, 12], although one study found a higher mortality rate in patients with SOP, narrowly defined as OP due to a connective tissue disorder, hematologic malignant neoplasms, chemotherapy, or leukemia, than in those with COP [13], suggesting that the underlying disease affects patient prognosis. The present study found no difference in treatment-related outcomes between the COP and SOP groups. Pneumonia recurrence in the SOP group, however, was significantly more frequent in patients who were than were not treated with steroids (P = 0.035). This finding was likely due to the low rate of lymphocytosis in the BAL fluid of patients with SOP, which may have reduced responses to steroids and increased the recurrence of pneumonia due to underlying diseases. Among patients with SOP, those who experienced pneumonia recurrence had a significantly higher neutrophil count (P = 0.027) and a significantly lower lymphocyte count (P = 0.005) than those who did not experience recurrence. High neutrophil counts in patients with infectious SOP cases indicate that infection control is poor, with SOP recurring because of a lack of improvement in the underlying disease.

This study has the following limitations. Because this was a retrospective study of OP diagnosed by lung biopsy, critically ill patients were excluded if lung biopsy was difficult. Because steroids tend to be used only in patients with relatively severe pneumonia, there was likely a selection bias regarding the steroid effect. In this study, steroid dose, duration, and criteria for use were not standardized, making it difficult to interpret treatment-related outcomes. Moreover, recurrence could not be confirmed as a recurrence of OP, as it was not determined histologically by re-biopsy. The frequency of CTD related SOP was low, possibly because patients' symptoms were unintentionally missed, and autoimmune testing for CTD was not confirmed in all patients and only limited testing was performed.

This study found that the most frequent cause of SOP was infection, with symptoms progressing more rapidly in patients with SOP than with COP. Several parameters in blood and BAL fluid differed significantly in the SOP and COP groups. Pleural effusion was more common in the SOP than in the COP group. PFT results, response to treatment, and treatment results were similar between these two groups. Subanalysis of the SOP group showed that the recurrence rate was higher in those who were than were not treated with steroids.