Authors: Liliana Fernandez-Trujillo, Eliana I. Morales, Daniela Arias, Valeria Zúñiga-Restrepo, Luz F. Sua
Categories: Case Report, Bronchoscopy, Case report, Organizing pneumonia, Sjögren syndrome, Transbronchial biopsy
Source: Respiratory Medicine Case Reports
Authors: Liliana Fernandez-Trujillo, Eliana I. Morales, Daniela Arias, Valeria Zúñiga-Restrepo, Luz F. Sua
Sjögren's Syndrome (SS) is an autoimmune inflammatory disease, characterized by lymphocytic infiltration of exocrine glands. Approximately 10% of patients with SS have pulmonary involvement as the first manifestation of their disease, the most common being non-specific interstitial pneumonia.
We present the case of a 51-year-old man with organizing pneumonia as the presenting feature of primary SS.
Pulmonary involvement as the presenting feature of SS is uncommon, especially when the pattern on CT-scan is that of organized pneumonia. Initial management includes steroids and other immunosuppressants agents, with a better response in organized pneumonia secondary SS cases.
Sjögren's syndrome (SS) is an autoimmune, slowly progressive inflammatory disease characterized by lymphocytic infiltration of exocrine glands. SS can be primary with a prevalence of 1%, or more commonly secondary to another autoimmune disease with a prevalence of up to 30%. It can affect multiple organs and extraglandular systems including skin, lung, heart, kidney, nervous and hematopoietic system [1].
Pulmonary affection in SS is defined as the presence of symptoms and alteration in structural or functional pulmonary tests. Its prevalence lies between 9 and 22%, and in subclinical disease this prevalence is increased up to 50% [2]. Approximately 10% of patients with SS have pulmonary involvement as the first manifestation of their disease; the most frequent symptoms are dyspnea and cough. On physical examination, it is common to find basal crackles, and pulmonary function tests characteristically show a restrictive pattern and marked decrease of carbon monoxide diffusing capacity (DLCO) [3].
The most common radiological finding is non-specific interstitial pneumonia, followed by that of usual interstitial pneumonia, lymphoid interstitial pneumonia and less commonly organizing pneumonia [4]. We present the case of a 51-year-old man with pulmonary involvement as the presenting feature of primary SS, with a transbronchial biopsy showing an organizing pneumonia pattern.
51-year-old male, with no significant personal history, non-smoker, no known allergies, no occupational exposures, no history of traveling six months prior to consultation, and no pet owner. He consulted with two-week asthenia, adynamia, malaise, rhinorrhea, and dyspnea (modified Medical Research Council) mMRC1, that worsened with exposure to air conditioning. Additionally, he presented with xerostomia and weight loss of 3 kg in 3 months. Physical examination showed normal vital signs, oropharynx erythema without lesions of the oral mucosa, no neck masses nor jugular engorgement, crackles at the end of inspiration in lung bases at auscultation. The rest of the physical examination was unremarkable.
Chest radiograph showed basal reticular opacities, without consolidation areas. Chest CT-scan showed thickening of inter and intralobular septa, grounded glass areas predominantly in the bases with multiple consolidation areas (Fig. 1). Blood count showed leukocytosis and neutrophilia, hemoglobin of 14 g/dL, C-reactive protein of 5, normal lactate dehydrogenase (LDH), creatinine and liver tests. Sputum bacilloscopic (BK) was negative. With these findings, multilobes community acquired pneumonia was suspected, IV antibiotics were initiated, with gradual improvement, until the patient was finally discharged.Fig. 1High-resolution chest CT-scan showing thickening of inter and intralobular septa associated with grounded glass opacities predominantly in lung bases. Multiple foci of multilobes consolidation areas, bronchiolectasias without evidence of honeycomb, suggestive of unspecified interstitial pneumonia.Fig. 1
One month after discharge, he consulted at the outpatient clinic due to persistent cough and worsening of dyspnea (mMRC2). Chest radiograph showed persistence of bilateral basal interstitial infiltrates, severe DLCO decrease up to 29% of predicted, non-interpretable spirometry due to non-toleration of the procedure. ANAs were found in 320 (speckled pattern), positive ENAs Anti Ro/SSA of 100 U/mL, Anti La/SSA of 60 U/mL, Anti-Smith (Sm) of 2.4 U/mL, Anti RNP (antinuclear ribonucleoprotein antibodies) of 2.3 U/mL (Table 1). Physical examination revealed persistence of crackles at the end of inspiration, predominantly in the bases, with adequate oxygen saturation at rest. These findings were considered secondary to an interstitial lung disease. He was admitted for a rheumatology assessment with the suspicion of pulmonary affection as the presenting feature of SS, with a European League Against Rheumatism-Sjögren's Syndrome (EULAR-SS) disease activity index (ESSDAI) score at diagnosis of 15 points.Table 1Laboratory results.Table 1ResultsReference valuesWBC count8370/μL4230–9070Neutrophils5970/μL1780–5380Lynphocytes1280/μL1320–3570Monocytes870/μL30–820Eosinophils180/μL40–540Basophils40/μL10–80Hemoglobin14.8 gr/dL13.7–17.5Hematocrit45.9%40.1–51Platelet count257.000/μL163.000–337.000Serum creatinine1.01 mg/dL0.67 - 1.17BUN17.2 mg/dL6–20C-reactive protein0.6 mg/dL0–0.5TSH0.81 uUI/mL0.27–4.2C3117.8 mg/dL90–180C422.9 mg/dL10–40Anti-SCL 700.6 U/mL<15Anti-DNA5.3 U/mL<20ANAs1:320 (speckled pattern)PositiveENAsRo: 156.4 U/mL<15La: 25.8 U/mL<15Sm: 0.7 U/mLRNP: 0 U/mLAnti-neutrophil cytoplasmic antibodiesAnti-proteinase 1.7 U/mL<5Anti-myeloperoxidase: 1.3 U/mLBUN: blood urea nitrogen, TSH: thyroid stimulating hormone, C3: complement component C3, C4: complement component C4, Anti-DNA: anti-DNA antibodies, ANAS: antinuclear antibodies, ENAS: extractable nuclear antigen antibodies.
Upon admission blood workup was completed finding a normal blood, negative c-reactive protein, normal complement, negative anti cardiolipin synthase (anti-CLS), negative anti deoxyribonucleic acid (anti-DNA), negative antineutrophil cytoplasmic antibodies (ANCAs), positive ANAs, ENAs, Anti Ro and Anti La (Table 1). Bronchoscopy with transbronchial biopsies was performed along with bronchoalveolar lavage (Fig. 2). Direct microscopic examination and cultures for bacteria, fungi and mycobacteria and Gen-Expert for tuberculosis were all negative. Histological sections showed pulmonary parenchyma with altered architecture given by the presence of collagen foci and young fibroblasts that in some places protrude towards the alveolar spaces. In some alveolar septa there is lymphoplasmacytic cellularity without acute inflammation. This was considered compatible with organizing pneumonia (Fig. 3).Fig. 2Bronchoscopy showing pale mucosa, without evidence of endobronchial lesions or abnormal secretions.Fig. 2Fig. 3A. H&E 10x (low magnification). Bronchial mucosa shows no abnormalities in the lining epithelium. Pulmonary parenchyma with alteration of the architecture is observed due to the presence of collagen foci and young fibroblasts that in some places protrude towards the alveolar spaces. B. H&E 20x. At higher magnification, fibroblasts with protrusion towards the alveoli become more evident. In some alveolar septa there is lymphoplasmacytic cellularity without acute inflammation. C. Movat 10x (low magnification). Fibroblastic foci are identified, causing thickening of the alveolar septa. D. Movat 20x. At higher magnification, the alternation between green and yellow hue of young fibroblasts is observed. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)Fig. 3
Treatment with methylprednisolone pulses was initiated for three days along with intravenous cyclophosphamide 500 mg/m2. Improvement of symptoms such as cough and dyspnea were seen, as well as of the basal crackles. Given the clinical improvement, the patient was discharged with oral steroids and cyclophosphamide with outpatient control with pulmonology and rheumatology. Although Schirmer's test was not performed, a salivary gland biopsy was done without histological alterations. The patient fulfilled 3 points of the EULAR criteria with positive anti-SSA. Despite the above, the patient still considered to have primary SS, since all etiologies of secondary SS were ruled out.
Pulmonary involvement in SS is defined as the presence of symptoms with altered pulmonary function tests or pulmonary architecture. Risk factors include male gender, smoking, late onset and latent disease. Patients who have pulmonary disease have a lower quality of life and physical performance and a higher risk of death. It has been described that only 10% of patients have pulmonary involvement as the first manifestation of SS, and are mainly associated with systemic manifestations, hypergammaglobulinemia, positive anti Ro, anti La and ANAs [3].
Generally, clinical manifestations of pulmonary disease in primary SS are nonspecific, such as dyspnea (62%), cough (54%), sputum production (14%), chest pain (11%) and/or fever (7%), as was seen in this report. Almost three-fourths of the patients have positive anti Ro antibodies and one third has positive anti La antibodies (1). On physical examination it is common to find inspiratory crackles (67%), but up to 28% of patients may have normal pulmonary auscultation. Regarding pulmonary function tests, a restrictive pattern is found in most cases with reduced DLCO, as seen in this report, especially if there is interstitial pulmonary affection [5]. When the airway is mainly affected, the spirometry pattern can be obstructive or mixed [6]. The use of bronchoalveolar lavage is not yet clearly established for this disease, but generally shows an increase in inflammatory cells, specifically in lymphocytes [4].
Diagnostic images, mainly high-resolution chest CT-scan, allow visualization of airway changes due to active chronic inflammation with lymphoplasmacytic infiltration and associated fibrotic changes such as bronchial wall thickening, bronchiectasis, and air entrapment. Mosaic attenuation or grounded glass opacities can also be found; pleural involvement is rare [7,8]. On chest radiograph, findings are nonspecific, with bilateral interstitial infiltrates in up to 56% of patients and alveolar and nodular infiltrates in a smaller percentage [9]. In a study by Koyama et al., it was found that the most common CT-scan findings in pulmonary disease due to primary SS were grounded glass opacities (92%), followed by small subpleural nodules (78%), non-septal linear opacities (75%), interlobular septal thickening (55%), bronchiectasis (38%) and cysts (30%) [10].
Regarding histopathological examination, chronic active inflammation with lymphoplasmacytic infiltration affecting the central and peripheral bronchi and bronchiole is described. Cellular bronchiolitis, follicular bronchitis, peri bronchial and peri bronquiolar fibrosis and bronchiectasis are commonly observed [11]. The pattern of non-specific interstitial pneumonia (NSIP) is more common in this entity, followed by usual interstitial pneumonia (UIP), lymphoid interstitial pneumonia (LIP) and finally organizing pneumonia (OP) [12]. The latter is rare in primary SS and only a few cases have been reported [13]. In this case, organizing pneumonia, an interstitial pneumonia with unique clinical and pathological characteristics was seen, which generally responds well to steroids and has a good prognosis if treated on time. However, compared to cryptogenic organizing pneumonia, secondary organizing pneumonia has a worse prognosis; recovery is slower and has higher recurrence rates [14].
Treatment depends on each type of manifestation. Corticosteroids, immunosuppressants such as azathioprine, mycophenolate, cyclophosphamide and monoclonal antibodies such as rituximab have been studied in interstitial lung disease due to connective tissue diseases but there are not yet large clinical trials assessing the effectiveness of this therapy in the treatment of patients with primary SS with interstitial lung disease. Studies are currently being carried out for patients with severe pulmonary disease, using belimumab (human monoclonal antibody that inhibits B-cell activating factor) [1]. In cases of refractory disease, tocilizumab has been described to be promising, but additional studies are required [15]. As mentioned above, due to the lower quality of life and lower survival rates in these cases, patients should undergo close follow-up [16,17].
Even though patients may present with SSA antibodies, it is important to look for SS since up to 20–33% of patients with pulmonary involvement can have negative antibodies [18]. The latest consensus guidelines establish that in those patients with SS and acute or subacute pulmonary manifestations who require hospitalization, initial management with rituximab or cyclophosphamide associated with steroid pulses should be considered [19], as we did with our patient who received cyclophosphamide.
In conclusion, this case is rare given the pulmonary involvement as the presenting feature of SS in a male patient. Additionally, organizing pneumonia occupies the fourth place in frequency of interstitial pneumonias in this entity, which makes it very unique. Initial treatment with steroids has been shown to be successful, especially when SS is secondary, even though higher recurrence rates are expected in this setting.
This report was prepared in accordance with the ethical standards of the institutional ethics committee and with the 1964 Helsinki Declaration. We have approval letter of Ethics Committee in biomedical research IRB/EC No. 207–2020 of the Fundación Valle del Lili to publish this manuscript.
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
All data and material are available for sharing if needed.
No funding sources were used.
All authors have read and approved the manuscript, and significantly contributed to this paper. LFT: Conception and design, literature review, manuscript writing and correction, final approval of the manuscript. EIM: Conception and design, literature review, manuscript writing and correction, final approval of the manuscript. DA: Conception and design, literature review, manuscript writing and correction, final approval of the manuscript. VZR: Literature review, manuscript writing and correction, final approval of the manuscript, LFS: Conception and design, literature review, manuscript writing and correction, final approval of the manuscript.
We have no conflicts of interest to disclose. This manuscript has not been published and is not under consideration for publication elsewhere. Additionally, all of the authors have approved the contents of this paper and have agreed to the journal's submission policies.