NSG is an extremely rare granulomatosis, only about 200 cases were reported in English literature in pubmed. Its etiology and pathogenesis still remains unclear. Some scholars believed that some kind of infection, such as aspergillus, chlamydia pneumoniae and immune disorder mechanism post infection involved in the pathogenesis of the NSG [2–4]. Heinrich et al.  firstly reported that reduced peripheral blood CD4/CD8 T cell ratio and increased CD4/CD8 T cell ratio at the lesions indicating immune dysfunction is involved in the pathogenesis. The antigen-antibody complexes eventually induce immune disorders and disease. Compared to the other organs, lung is rich with blood supply and the deposit of antigen-antibody is common, which makes lung the most frequently involved organ for NSG. This could also explain the occurrence of NSG associated with various autoimmune diseases, such as biliary cirrhosis, ankylosing spondylitis and rheumatoid arthritis [6, 7].
The average age for the onset of NSG is between 40–60 years and is dominant in female. NSG's clinical manifestations are normally mild and unspecific such as chest pain (63%), cough (38%), fever (30%) and general malaise (31%). In addition to the lung, multiple reports showed NSG is accompanied with skin erythema nodosum, uveitis, and involvement of the stomach, liver and central nervous system [2, 5, 6, 8–14].
In the present case, clinical manifestations such as recurrent fever and chest pain were consistent with previous reports. The current case also showed characteristics of NSG image: solitary or multiple nodules or lumps shadow of lung associated with local pleural thickening in chest radiography; Chest CT showed visible pulmonary nodules distributed subpleurally or along the bronchi and some nodules were empty. Other reported clinical manifestations included hilar lymphadenopathy (28%), pleural effusion (11%) and nodular lesions within the vacuoles (8%) [5, 6, 8, 15, 16]. NSG also shares the similarities of the migratory and varied lesions with disease like pulmonary vasculitis . It was reported that positron emission computed tomography (F-18FDG / PET-CT) had been used to check NSG patients, which was able to show the actual NSG extent, detect the SUV value of NSG lesions and guide the surgical biopsy at the same time .
Diagnosis of NSG mainly relies on pathological findings, non-caseating epithelial cell granulomas, granulomatous vasculitis and necrosis which are the main pathological features of NSG. Chronic granulomatosis caused by tuberculosis, atypical mycobacteria, fungi and parasites should be excluded for differential diagnosis. Non-caseating epithelial cell granulomas of NSG may invade the vessel wall and lumen to form granulomatous vasculitis and lesions of coagulation necrosis; lymphocytes, multinucleated giant cells and other inflammatory cells can infiltrate pulmonary blood vessel walls and cause severe stenosis or occlusion of the vessel lumen with perivascular granuloma formation [1, 6, 11, 16, 19]. The granulomatous vasculitis can lead to the ischemic necrosis surrounding the blood vessels, a unique pathological feature of NSG. In severe cases, it can cause extensive intrapulmonary coagulation necrosis and intrapulmonary hemorrhage, alveolar bleeding and widely distributed hemosiderin cells [7, 11, 20–23].
In the present case severe granuloma and necrosis at the lung nodules was observed. In consistent with the previous reports, microscopic observation showed the severe pathological vascular inflammation and necrosis (Figures 2 and 3). It's arguably believed that NSG and sarcoidosis are the same disease since NSG has pathological features of both sarcoidosis and vasculitis , they share similar non-caseating epithelial cell granulomas [2, 20, 24]. However, NSG does has distinct clinical features from sarcoidosis such as both negative serum angiotensin converting enzyme (SACE) and Kveim test. Moreover, no lung hilar and mediastinal lymph nodes are present in NSG patients and no asteroid bodies and Schaumann bodies, which are often found in sarcoidosis patients ; Granulomatous vasculitis and coagulation necrosis of NSG are generally more severe than sarcoidosis. NSG laboratory findings are also different from the systemic vasculitis (such as: Wegener granulomatosis) where the serum C-ANCA, P-ANCA are negative in NSG patients, and the granulomatous type and prognosis of NSZZG are also different. Although there are some same identical points on clinical manifestation between NSG and limited Wegener’s disease, such as either negative serum ANCA or lacking of evidence of glomerulonephritis, but actually they are completely different diseases, especially in pathological findings. The main pathological features of limited Wegeners’ in the lung including liquefaction and coagulation necrosis lesions, as well as a large number of eosinophils, and a small amount of lymphoplasmacytic infiltration, the destructive vasculitis can be found in the small pulmonary arteries and small veins. Comparing to this case, although a large number of necrosis and vasculitis could be found in the lesion, but not like NSG, the necrosis form in this case presented more like infarction necrosis post vascular obstruction due to the granulomatosis vasculitis, there was also no significant liquefaction in necrotic lesion. The inflammation cells in this case mainly composed of lynphocyte cells, rather than eosinophils cells. In this case, although there were different degrees of vascular inflammation and thickening of the vessel wall, most of the vascular wall structure still existed, rather than the destructive vasculitis such as in limited Wegners’ disease. In general, according to the pathological features in microscope of this case, we believed that this was a classical NSG case .
NSG is sensitive to corticosteroid treatment but relapse is not rare [11, 19]. Although NSG is considered as a disease with good prognosis generally, the reported cases with poor prognosis are increasingly common with in-depth understanding of the disease as well as the extended follow-up period. In a multi-center retrospective study of 14 cases with follow-up time of 18–114 months, 50% of patients demonstrated poor prognosis: 1 patient died of central nervous system infection; two cases presented lung cancer in long-term follow-up; 4 cases has recurrence . Other reports also presented severe complications with long term maintenance therapy of corticosteroids such, such as fungal infections, lung tumor and even death [2, 6–8, 26]. Therefore, clinical management requires particular attention to the NSG cases under long term long term corticosteroid treatment. Once the symptoms get worse with recent solitary nodule or cavitary lesion, further examination including biopsy is required.
In the present case, low-dose oral corticosteroid therapy was effective but hemoptysis with fever occurred during gradual reduction of corticosteroids with the image of the lower right hilar neoplasm. We considered several possibilities such as 1) NSG relapse and lung granuloma invading the vessel wall resulting in bleeding; 2) secondary pulmonary infection, such as tuberculosis, or fungal infection; 3) secondary lung tumor. Endobronchoial biopsy by flexible bronchoscope forcep normally is considered the routine approach for differential diagnosis, however unexpectedly fatal hemoptysis happened after biopsy and led to death, a rare complication which was not present in previous NSG reports. Based on the available literature, biopsy forceps clamp caused hemoptysis after bronchoscopy is common in bronchial dieulafoy disease [27, 28]. However, the patient had no past medical history of hemoptysis before, the previous chest CT scan and flexible bronchoscopy exam also did not show the basal segment abnormalities at the right lower lobe. Given the severe epithelial cells granulomatous vasculitis and extensive necrotic lesions in the pathological findings of VATS, we speculated NSG relapsed during the reduction of corticosteroid treatment. The recurrence site located in the lower right lung nearly hilar and severe granulomatous vasculitis and necrosis invaded the bronchial lumen of the basal segment as well as adjacent artery leading to the formation of bronchovascular fistula, and endobronchial biopsy procedure with mechanical force caused further damage to the bronchus and blood vessel wall. Previously two reports also showed complications of hemoptysis in the long-term follow-up process of NSG [9, 29]. After reviewing of enhanced chest CT images, we could observe a clear contrast agent enhancement at basal segment of the right lower lobe suggesting NSG granuloma may invade the blood vessels of basal segments at the right lower lung. Necrosis-like lesions caused by infection or tumor unlikely would cause such massive and rapid bleeding during biopsy. Unfortunately, the patient’s family refused autopsy. In one case study, serum interleukin-2 receptor restored to normal level with the improved condition and imaging results suggesting the value of interleukin-2 in NSG's prognosis . There is still no clear association of the severity of granulomatous vasculitis and necrosis in correlation to NSG prognosis. However, it was observed that the cases with less severe NSG granulomatous vasculitis or necrosis had better prognosis . In the present case the patient with severe lung granulomatous vasculitis and necrosis had rapid clinical relapse and lethal hemoptysis.
We firstly reported the NSG case with the fatal complication of massive hemoptysis during the flexible bronchoscope endobronchial biopsy. In particular, special attention should be paid to the patients with necrosis-like lesions during bronchoscopic biopsy to avoid lethal hemoptysis. Based on the clinical course and pathological features of our case, we presented the clinical conjecture that NSG cases with severe granulomatous vasculitis and necrosis in pathology would have a poor prognosis. So far, it's still lack of comprehensive and in-depth studies on this disease. Further studies on the etiology and pathogenesis of NSG will pave the way to the understanding of the classification, diagnosis, treatment and prognosis of NSG.