Pulmonary tuberculosis occurring during the diagnosis and treatment of sarcoidosis complicated by chylothorax: A case report 

Introduction

Sarcoidosis is an idiopathic systemic granulomatous disease that predominantly affects the lungs and lymphatic system. According to the latest data, there were 390,000 incident cases of sarcoidosis globally in 2021, with >43 million prevalent cases and 1.88 million sarcoidosis-related deaths (1). The incidence of sarcoidosis exhibits marked geographic, sex and racial disparities. Nordic countries report the highest incidence rates (10-15 cases per 100,000 population), whereas the incidence is lower among Asian populations (1-5 cases per 100,000 population) (2). Although many patients follow an indolent clinical course with spontaneous remission, 10-30% of patients progress to chronic progressive disease, resulting in persistent organ damage (3). Chylothorax is a rare complication of sarcoidosis and accounts for a very small proportion of cases with pleural involvement. It is generally considered to arise from thoracic duct obstruction secondary to mediastinal granulomatous lymphadenopathy, which leads to abnormal accumulation of lymphatic fluid within the pleural cavity. Persistent chylothorax may trigger progressive malnutrition, hypoalbuminemia, lymphopenia and deterioration of immune function. Without timely management, it further increases the risk of secondary bacterial, fungal and mycobacterial infections, and contributes to poorer clinical outcomes (4).

In terms of diagnosis, the disease is characterized by overlapping clinical, imaging and histopathological features between pulmonary tuberculosis and sarcoidosis, thus leading to a relatively high risk of misdiagnosis (5,6). Currently, the main treatment approach used to treat sarcoidosis consists of glucocorticoids combined with dietary modifications, whereas drainage or surgical interventions can be considered in particular cases (7,8). For patients with progressive sarcoidosis, hormones combined with immunosuppressive drugs are commonly used as the main treatment strategy. However, this treatment approach can notably increase the risk of opportunistic infections, including active pulmonary tuberculosis, thereby posing additional challenges to clinical management (9,10).

In the present study, a rare case of sarcoidosis-associated chylothorax in a patient who developed new-onset active pulmonary tuberculosis during immunosuppressive therapy with prednisone and methotrexate was reported. In addition, the differential diagnostic workflow, therapeutic adjustments and long-term clinical outcomes were summarized to provide a clinical reference for the treatment of similar rare cases.

Case report

A 48-year-old female patient was admitted to Weifang No. 2 People's Hospital (Weifang, China) in May 2018 with worsening chest tightness superimposed on a 6-month history of intermittent cough, fever and chest discomfort. Physical examination revealed dullness to percussion over the bilateral lower lung zones, with no bilateral expiratory wheezes. The patient's vital signs remained stable. Arterial blood gas analysis revealed a partial pressure of carbon dioxide (PCO2) of 31 mmHg (reference range, 35-45 mmHg), base excess of -5.6 mmol/l (reference range, -2-3 mmol/l) and an alveolar-arterial oxygen partial pressure gradient (A-aDO2) of 28 mmHg (reference range, <15 mmHg) (Table I). The reduced PCO2, negative base excess and elevated A-aDO2 gradient reflected hyperventilation-induced respiratory alkalosis, tissue hypoxia-related metabolic acidosis and impaired oxygen diffusion, respectively.

Table I Admission physical examination data.

Table I

Admission physical examination data.

Parameter	Value	Reference range
General clinical examination
Body temperature, ˚C	36.2	36.3-37.2
Heart rate, beats/min	102	60-100
Respiratory rate, breaths/min	21	15-20
Blood pressure, mmHg	70/106	90/60-120/80
Arterial blood gas analysis
PCO2, mmHg	31	35-45
PO2, mmHg	88	80-100
HCO3, mmol/l	19.2	18-23
TCO2, mmol/l	20.2	22-28
%SO2c	97	95-98
Alveolar-arterial oxygen difference, mmHg	28	<15
Base excess, mmol/l	-5.6	-2.0-3.0

[i] PCO₂, partial pressure of carbon dioxide; PO₂, partial pressure of oxygen; HCO₃, bicarbonate ion; TCO₂, total carbon dioxide; %SO₂C, percent oxygen saturation.

High-resolution chest computed tomography (CT) revealed multiple soft tissue density shadows in the bilateral hilar and mediastinal regions, accompanied by bilateral hilar lymph node enlargement and pleural effusion (Fig. 1A and B). These findings indicated several differential diagnoses, including tuberculosis, lung cancer and sarcoidosis. Regarding the diagnosis of sarcoidosis, the patient was a middle-aged woman with a prolonged disease course (>6 months). The patient presented with cough, fever and chest tightness accompanied by multisystem lymphadenopathy, which was consistent with the pattern of systemic involvement characteristic of sarcoidosis (Table I). Furthermore, enlarged superficial lymph nodes in the cervical, supraclavicular and retroperitoneal regions were identified by ultrasonography (Fig. 1C and D). The clinical manifestations of multisystem lymph node involvement (hilar, mediastinal, cervical and retroperitoneal) were typical of sarcoidosis. Bronchoscopy revealed diffuse bronchial mucosal hyperemia and scattered micronodules within the left bronchus, suggesting local granulomatous or proliferative lesions (Fig. 1E and F). The proportion of neutrophils in the bronchoalveolar lavage fluid (BALF) was markedly elevated (81.60%), which is not a typical feature of uncomplicated sarcoidosis (Fig. 1G). This finding may indicate infection, severe airway or alveolar inflammation or other concurrent pathological processes. On hospital day 10, transbronchial lung biopsy and cervical lymph node biopsy specimens were obtained for pathological staining. The biopsy tissues were fixed in 10% neutral-buffered formalin at room temperature for 24 h and embedded in paraffin. Sections were cut at a thickness of 5 µm. Routine hematoxylin-eosin staining was performed: Sections were stained with hematoxylin at room temperature for 5 min, followed by eosin staining for 2 min. The slides were examined under an Olympus BX53 light microscope (Olympus Corporation). The results revealed non-caseating epithelioid granulomatous inflammation, a histological feature seen in granulomatous diseases such as tuberculosis and sarcoidosis (Fig. 1H and I). The pleural fluid adenosine deaminase (ADA) concentration was 13.4 U/l (reference range, 0-25 U/l), which differed from the marked elevation typically observed in patients with tuberculous pleuritis. The serum angiotensin-converting enzyme concentration was 51.8 U/l (reference range, 5-52 U/l), which was within the upper limit of the normal reference range, providing limited diagnostic evidence for active sarcoidosis (Table II). To further distinguish sarcoidosis from primary lung cancer, serum tumor markers, including carcinoembryonic antigen, carbohydrate antigen (CA)15-3, CA19-9, CA72-4 and α-fetoprotein, were all within normal ranges. The neuron-specific enolase (25.9 ng/ml) and CA125 (241.6 U/ml) concentrations were increased above the reference ranges. These markers can be elevated in both malignant tumors and benign inflammatory pulmonary disorders and therefore have limited diagnostic specificity for lung cancer (Table II). Chest CT revealed no typical radiological signs of primary lung cancer, such as solitary spiculated masses, lobulation, pleural indentation or unilateral/asymmetric metastatic lymphadenopathy (Fig. 1A and B). Transbronchial and cervical lymph node biopsies demonstrated only granulomatous inflammation without malignant epithelial cells, cellular atypia or carcinomatous infiltration, thereby excluding primary lung cancer (Fig. 1H and I). Regarding differentiation from pulmonary tuberculosis, the patient presented with chronic cough and intermittent fever, with clinical manifestations overlapping with those of tuberculosis (Table I). Chest CT showed pulmonary nodules and pleural effusion but lacked characteristic features of tuberculosis, including upper-lobe-predominant infiltrates, cavitation, calcification and unilateral hilar lymphadenopathy. Furthermore, granulomatous inflammation was detected in both lung and lymph node biopsy specimens, yet caseous necrosis, the pathological hallmark of tuberculous granulomas, was absent Please ensure it is clear which figure subpart is for which statement. Microbiological and laboratory tests (Xpert MTB/RIF assay kit; catalog no. GXMTB/RIF-50; Cepheid) were negative for Mycobacterium tuberculosis DNA using the Xpert MTB/RIF assay in multiple specimens, including pleural effusion, sputum, BALF and pathological tissue. Mycobacterial culture using the BD BACTEC MGIT 960 system was also negative for all samples. An interferon-γ release assay (QuantiFERON-TB Gold In-Tube kit, catalog no. 0597-0403; Qiagen GmbH) was performed on pleural effusion and was likewise negative (Table II). Collectively, these multidisciplinary diagnostic findings did not support a diagnosis of pulmonary tuberculosis.

Figure 1 Baseline imaging, bronchoscopic, and pathological biopsy findings at admission. (A and B) Chest computed tomography images demonstrating multiple soft-tissue densities in the bilateral hilar and mediastinal regions accompanied by bilateral pleural effusion. No tuberculous cavities, upper-lobe predominant infiltrates or calcified lesions were observed. (C and D) Ultrasonography of the superficial cervical and retroperitoneal lymph nodes revealed multiple enlarged lymph nodes, consistent with systemic lymphatic involvement. The bronchoscopic view demonstrates (E) diffuse hyperemia of the left bronchial mucosa with scattered tiny nodules and (F) diffuse hyperemia of the right bronchial mucosa. (G) Cytological analysis of bronchoalveolar lavage fluid revealed a markedly elevated neutrophil proportion, indicating active inflammation in the alveoli and airways. Scale bar, 100 µm. (H) Histopathology from the transbronchial lung biopsy of the left bronchus; (I) histopathology from the cervical lymph node biopsy. Both panels show typical non-caseating epithelioid granulomatous inflammation. No focal caseous necrosis and malignant epithelial cell infiltration were observed. Scale bar, 50 µm.

Table II Laboratory results for tumor and pathogen-related tests.

Table II

Laboratory results for tumor and pathogen-related tests.

Parameter	Results	Reference range
Angiotensin-converting enzyme, U/l	51.8	5.0-52.0
Tumor markers
NSE test, ng/ml	25.95	0-20.30
CEA test, µl/ml	2.00	0-10.00
CA125 test, U/ml	241.6	0-35.0
CA15-3 test, IU/ml	10.08	0-25.00
CA 9-9 test, U/ml	8.37	0-27.00
CA72-4 test, U\ml	0.76	0-6.90
AFP test, ng/l	2.39	0-20.00
Mycobacterium tuberculosis examination
Pleural effusion Adenosine deaminase, U/l	13.4	0-25.0
Pleural effusion TB-DNA test, copies/ml	<5.0x102	<5.0x102
Sputum TB-DNA test, copies/ml	<5.0x102	<5.0x102
Bronchoalveolar lavage (BAL)TB-DNA test, copies/ml	<5.0x102	<5.0x102
Tissue TB-DNA test, copies/ml	<5.0x102	<5.0x102
(Pleural effusion) Mycobacterium tuberculosis culture test	Negative	Negative
(Sputum) Mycobacterium tuberculosis culture test	Negative	Negative
(BAL) Mycobacterium tuberculosis culture test	Negative	Negative
T-cell tuberculosis assay (pleural effusion)	Negative	Negative

[i] NSE, Neuron-Specific Enolase; CEA, carcinoembryonic antigen; CA, carbohydrate antigen; TB-DNA, tuberculosis DNA; BAL, bronchoalveolar lavage.

On hospital day 17, given the complexity of the patient's clinical presentation, the Department of Respiratory and Critical Care Medicine of Weifang No. 2 People's Hospital conducted a remote multidisciplinary consultation with specialists from the Department of Pathology, China-Japan Friendship Hospital (Beijing, China). Based on molecular, pathological and radiological findings, malignancy and tuberculous infection were excluded. The final diagnosis of sarcoidosis complicated by pleural effusion was established, and the patient continued inpatient management and treatment at Weifang No. 2 People's Hospital. According to the clinical practice guidelines for sarcoidosis, systemic glucocorticoids represent the first-line therapy for active sarcoidosis with organ involvement (7). Therefore, prednisone (50 mg/day) combined with therapeutic thoracentesis and closed pleural drainage was initiated to relieve the patient's respiratory symptoms.

On hospital day 22, 5 days after the initiation of glucocorticoid therapy, milky white fluid was drained from the right thoracic cavity, which differed in appearance from that on the left thoracic cavity (pale-yellow and clear, without chylous turbidity) (Fig. S1). The pleural fluid triglyceride and cholesterol concentrations reached 5.09 mmol/l (reference range, 0-1.24 mmol/l) and 2.13 mmol/l (reference range, 2.32-5.56 mmol/l), respectively, which were consistent with true chylothorax. The lactate dehydrogenase concentration was 95.5 U/l (reference range, 120-250 U/l), which was slightly below the lower limit of the reference range and distinguished this effusion from malignant pleural effusions. The ADA concentration was 13.4 U/l (reference range, 0-25 U/l), which was within the normal range and differed from the markedly elevated ADA levels typically observed in tuberculous pleuritis. The total protein level of the right-sided pleural fluid was 35.3 g/l, suggestive of an exudative effusion. Mycobacterial culture of pleural fluid was negative. Pleural fluid cytology demonstrated a total cell count of 370x104/l (reference range, <50x104/l), with 1.2% neutrophils and 92.80% lymphocytes (Fig. S2). The total cell count was markedly elevated with a marked predominance of lymphocytes, consistent with an exudative effusion. Combined with clinical findings and laboratory results, a final diagnosis of secondary chylothorax was ultimately established. The subsequent treatment plan included continued glucocorticoid therapy combined with a low-fat diet.

On hospital day 42, 20 days after the initiation of prednisone and a low-fat diet, the chylothorax did not notably improve. There was no appreciable reduction in the daily drainage volume of chylous fluid, and the patient's chest-tightness symptoms remained incompletely resolved. Laboratory testing revealed a lymphocyte count of 0.72x109/l (reference range, 0.8-4x109/l), total protein of 55.3 g/l (reference range, 65-85 g/l) and albumin of 32.3 g/l (reference range, 40-55 g/l). Persistent chyle loss confers elevated risks of malnutrition, lymphopenia and impaired immune function, which could further worsen the patient's clinical status. Following multidisciplinary consultation, methotrexate (10 mg/week) was added as adjuvant therapy to control sarcoidosis activity. On hospital day 49, 7 days after the initiation of combination therapy, chest CT revealed notable improvement in the pulmonary nodules, hilar lymphadenopathy and pleural effusion, and the patient was discharged from Weifang No. 2 People's Hospital with oral medications (Fig. 2A and B). After discharge, the patient continued treatment with 35 mg/day prednisone and 10 mg/week methotrexate. At the 3-month follow-up at Weifang No. 2 People's Hospital, examination of the pleural effusion revealed that the triglyceride concentration had decreased to 2.77 mmol/l, compared with 5.09 mmol/l prior to treatment initiation. Color Doppler ultrasound examination revealed complete resolution of the bilateral pleural effusions (Fig. 2C-E). The patient continued treatment with prednisone (35 mg/day) and methotrexate (10 mg/week) as consolidation therapy.

Figure 2 Evaluation of the therapeutic efficacy of combined prednisone and methotrexate treatment. (A and B) Chest computed tomography on hospital day 49 revealed that the diffuse bilateral pulmonary nodules and pleural effusion were markedly reduced, and the bilateral hilar and mediastinal lymph nodes were markedly reduced in size, indicating effective treatment response. (C-E) Bilateral thoracic color Doppler ultrasonography at the 3-month follow-up showed no notable anechoic areas in either thoracic cavity, suggesting complete resolution of the pleural effusion.

At the 4-month follow-up at Weifang No. 2 People's Hospital, chest CT revealed marked improvement of the hilar and mediastinal lymph nodes (Fig. 3A and B). However, a new lesion was identified in the basal segment of the left lower lobe of the lung, manifesting as an infiltrative shadow with unilateral hilar lymphadenopathy. At the 6-month follow-up at Weifang No. 2 People's Hospital, subsequent chest CT revealed progression of the lesion in the basal segment of the left lower lung lobe, with cavitation and unilateral hilar lymphadenopathy, a typical characteristic of pulmonary tuberculosis (Fig. 3C and D). Given the patient's prolonged exposure to glucocorticoids and immunosuppressive agents, active tuberculosis was suspected; however, the diagnostic evidence remained insufficient at this stage. Therefore, the patient was readmitted for comprehensive tuberculosis testing. The tuberculosis infection T-cell detection assay yielded a positive result. In addition, bronchoscopy revealed scattered white nodules on the bronchial mucosa of the left lower lobe of the lung (Fig. 3E). Subsequently, biopsy demonstrated granulomatous inflammation accompanied by focal necrosis (Fig. 3F), while mycobacterial culture of the BALF was positive for the Mycobacterium tuberculosis complex. Mycobacterial identification and quantitative drug susceptibility analyses using BALF verified the presence of Mycobacterium tuberculosis complex, which was sensitive to streptomycin, isoniazid, rifampicin and ethambutol. Overall, the CT findings, pathological and laboratory test results established the diagnosis of pulmonary tuberculosis. Standard anti-tuberculosis therapy was initiated, consisting of 0.45 g/day rifampin, 0.75 g/day ethambutol, 0.3 g/day isoniazid and 150 mg/day diammonium glycyrrhizinate enteric soft capsules. During standard anti-tuberculosis therapy, an individualized treatment regimen for sarcoidosis was formulated to balance the suppression of sarcoidosis activity with the prevention of tuberculosis progression. Prednisone was gradually tapered from the initial 35 mg/day by 5 mg reduction every 2 weeks and was ultimately maintained at the minimum effective dosage of 10 mg/day to sustain sarcoidosis remission. Methotrexate was discontinued immediately after the diagnosis of active tuberculosis to reduce the risk of tuberculosis dissemination caused by immunosuppression, and to avoid interference with the clearance of Mycobacterium tuberculosis. Regular follow-up examinations were performed following the patient's discharge, with detailed information shown in the following text and Table III.

Figure 3 Follow-up examinations at 4 and 6 months after discharge showing newly developed tuberculosis. (A and B) Chest CT at the 4-month follow-up: Hilar and mediastinal lymphadenopathy was well controlled; however, a new patchy infiltrative opacity was observed in the basal segment of the left lower lobe. (C and D) Chest CT at the 6-month follow-up: The lesion in the basal segment of the left lower lobe expanded, with thin-walled cavitation, suggestive of pulmonary tuberculosis. (E) Bronchoscopy revealed scattered white miliary tuberculous nodules on the bronchial mucosa of the left lower lobe, indicating endobronchial tuberculous involvement. (F) Histopathological examination of a transbronchial lung biopsy (scale bar, 50 µm) showed granulomatous inflammation with focal caseous necrosis, suggestive of tuberculosis. CT, computed tomography.

Table III Clinical timeline of the patient.

Table III

Clinical timeline of the patient.

Time point	Clinical manifestations and examinations	Treatment adjustments
Day 0 of admission (May 2018)	Admission for chronic cough and chest tightness; CT showed pulmonary nodules, bilateral hilar/mediastinal lymphadenopathy and bilateral pleural effusion; full diagnostic workup launched.	Symptomatic supportive treatment.
Day 17 of admission	Multidisciplinary remote consultation; laboratory, pathological and imaging examinations; diagnosis of sarcoidosis confirmed, tuberculosis and malignancy excluded.	Prednisone 50 mg/day initiated.
Day 22 of admission	Milky-white right-sided pleural drainage fluid. Pleural fluid biochemistry confirmed chylothorax.	Maintain prednisone; add low-fat diet.
Day 42 of admission	No notable improvement in chylothorax was observed, and continuous chylous fluid drainage persists. Laboratory tests showed lymphopenia, hypoalbuminemia.	Multidisciplinary team consultation; add methotrexate 10 mg/week as adjuvant escalation therapy.
Day 49 of admission	Chest CT demonstrated marked improvement of pulmonary nodules, lymphadenopathy and pleural effusion; the patient's symptoms were markedly relieved	Discharged; continue prednisone 35 mg/day and methotrexate 10 mg/week
Month 3 (Follow-up)	Stable remission, Color Doppler ultrasonography showed that bilateral pleural effusion had been completely resolved, with no new lesions detected on imaging.	Unchanged immunosuppressive regimen maintained
Month 6 (Follow-up)	New pulmonary infiltrates and cavitary lesions detected on chest CT. Positive T-cell tuberculosis assay; bronchoscopy, biopsy and BAL mycobacterial culture confirmed active pulmonary tuberculosis.	Methotrexate was discontinued, and prednisone was gradually tapered was gradually tapered from 35 mg/day to a maintenance dose of 10 mg/day; start standard anti-tuberculosis treatment
Month 12 (Follow-up)	Chest CT showed partial resolution of tuberculous lesions. Bronchoscopy, mycobacterial culture and MTB-DNA testing of BAL yielded negative results; clinical cure of pulmonary tuberculosis was confirmed.	Extend anti-tuberculosis therapy for another 3 months for consolidation; prednisone maintained at 10 mg/day
Month 25 (Follow-up)	Chest CT and bronchoscopy revealed post-infectious linear opacities; no recurrence of sarcoidosis or tuberculosis	Prednisone tapered by 2.5 mg every 2 months, final maintenance dose 2.5 mg/day
Month 39 (Follow-up)	Chest CT and bronchoscopy showed stable post-infectious fibrotic changes; no recurrence of sarcoidosis or pulmonary tuberculosis was noted, indicating a favorable long-term prognosis.	Prednisone was tapered and. discontinued

[i] CT, computed tomography; BAL, bronchoalveolar lavage; MTB-DNA, Mycobacterium tuberculosis-DNA.

At the 12-month follow-up at Weifang No. 2 People's Hospital, chest CT revealed partial resolution of the lesions in the basal segment of the left lower lobe, with no mediastinal lymphadenopathy or pleural effusion (Fig. 4A and B). Bronchoscopy revealed patent left-sided bronchi without remarkable abnormalities (Fig. 4C). Both mycobacterial culture and MTB-DNA testing of BALF yielded negative results. Following a 6-month standard course of anti-tuberculosis therapy, a clinical cure of pulmonary tuberculosis was confirmed. Anti-tuberculosis therapy was continued for an additional 3 months as consolidation therapy and was then discontinued. Prednisone was maintained at 10 mg/day to control the underlying sarcoidosis.

Figure 4 Serial long-term follow-up imaging examinations after standardized anti-tuberculosis therapy. (A and B) Chest CT and (C) bronchoscopy at the 12-month follow-up revealed partial resolution of the cavitary lesions in the basal segment of the left lower lobe, with no residual mediastinal lymphadenopathy or pleural effusion. The lumen of the left bronchus remained smooth and patent, with no mucosal nodules or hyperemia. (D and E) Chest CT and (F) bronchoscopy at the 25-month follow-up demonstrated only thin linear fibrotic opacities in the left lung. There was no recurrent lymphadenopathy, pleural effusion, or active infectious lesions, and the bronchial mucosa appeared normal, with no tuberculous nodules. (G and H) Chest CT and (I) bronchoscopy at the final 39-month follow-up revealed stable postinfectious linear fibrotic opacities in the left lung. The trachea and bilateral bronchi were well patent, with no signs of recurrent sarcoidosis or tuberculosis. CT, computed tomography.

At the 25-month follow-up at Weifang No. 2 People's Hospital, chest CT and bronchoscopy showed postinfectious linear opacities in the left lung, with no signs of sarcoidosis or tuberculosis recurrence (Fig. 4D-F). Prednisone was gradually tapered by 2.5 mg every 2 months to a final maintenance dose of 2.5 mg/day. At the 39-month follow-up at Weifang No. 2 People's Hospital, there was no evidence of recurrence of either sarcoidosis or pulmonary tuberculosis (Fig. 4G-I). Therefore, prednisone was discontinued, and the patient achieved a favorable long-term outcome. No further follow-up data were available after the complete discontinuation of prednisone. The key clinical events during the patient's admission, diagnosis, treatment adjustments and long-term follow-up are summarized in Table III, illustrating the complete chronological clinical course.

Discussion

Pleural involvement is relatively rare in patients with sarcoidosis, and cohort studies have reported that the incidence of pleural effusion ranges from 1.1 to 3% (11,12). A retrospective study including 195 patients with sarcoidosis revealed that only three patients (1.5%) developed pleural effusion (13). As a rarer subtype of pleural involvement, chylothorax is most commonly secondary to granulomatous inflammation-mediated mediastinal and hilar lymphadenopathy. These enlarged lymph nodes compress or obstruct the thoracic duct, thus resulting in chyle accumulation (14,15). Inflammation and fibrosis can also increase the risk of chyle leakage, and inflammatory granulomas can directly invade the thoracic duct, also resulting in chyle leakage (16). In the present study, the patient presented with bilateral mediastinal and hilar lymphadenopathy, an elevated neutrophil count in BALF and increased pleural fluid triglyceride levels. Based on previous studies, the cause of chylothorax in this patient could have resulted from compression of the thoracic duct by enlarged lymph nodes accompanied by local inflammation (4,17). Persistent chyle loss can further impair immune function, weaken the host defense and lesion repair, and reduce the response to therapy, thereby hindering disease control and overall prognosis (18,19).

Currently, systemic glucocorticoid therapy remains the first-line etiological treatment for sarcoidosis. Regarding patients with sarcoidosis and thoracic complications, including pleural effusion and chylothorax, glucocorticoids are used to treat granulomatous inflammation, shrink enlarged mediastinal lymph nodes, and are combined with thoracic drainage as adjuvant therapy (6,20). In patients with chylothorax, adjuvant therapy also includes a low-fat diet to reduce chyle production (8,21). Immunosuppressive therapy can be administered to patients with progressive disease or inadequate clinical response. As a second-line immunosuppressant agent for sarcoidosis, methotrexate can suppress enhanced immune responses and alleviate granulomatous inflammation, thereby attenuating disease progression and ameliorating the underlying pathogenic mechanisms of chylothorax (9). Ibrahim et al (10) reported the effectiveness of methotrexate combined with methylprednisolone in the treatment of pleural involvement in patients with sarcoidosis. In the current case, following the diagnosis of sarcoidosis-related chylothorax, treatment with a low-fat diet and prednisone did not achieve the expected clinical outcomes, with persistent chyle loss, residual chest tightness, decreased lymphocyte counts and reduced albumin levels. Although current direct evidence supporting the use of methotrexate for the treatment of sarcoidosis-related chylothorax remains limited, adjuvant therapy with methotrexate was initiated given that ongoing chyle loss can rapidly lead to malnutrition, lymphocytopenia and impaired immune function, which further deteriorates the patient's clinical status and increases the risk of infection (4,22).

For patients with pulmonary sarcoidosis who develop severe complications, such as massive persistent chylothorax, and who are at high risk of secondary malnutrition, early escalation to combined immunosuppressive therapy can be considered to accelerate disease control (23). The PREDMETH trial, published in 2025, further provided evidence-based support for this treatment approach. This trial validated the efficacy of methotrexate in sarcoidosis and suggested that methotrexate combined with low-dose glucocorticoids could be administered as first-line therapy in selected patients with pulmonary sarcoidosis (24). However, this strategy requires careful consideration of the potential benefits and the related risk of infection (11,12). Long-term glucocorticoid therapy can suppress cellular immune function. The combined use of immunosuppressants, such as methotrexate, can further impair host defense against pathogens, thus markedly increasing the risk of opportunistic infections (25-27). Among these, Mycobacterium tuberculosis infection is one of the most clinically notable adverse events and requires close monitoring (28,29). Reactivation of latent tuberculosis infection is the most common mechanism underlying immunosuppression-related tuberculosis; however, new-onset tuberculosis infection and exacerbation of previously undetected paucibacillary tuberculosis can also occur. Therefore, patients treated with immunosuppressive therapy should be closely monitored for signs of infection, and prompt therapy should be initiated if tuberculosis is detected. Notably, non-caseating epithelioid granulomas are not specific for sarcoidosis. The initial clinical and radiological manifestations in the present case partially overlapped with those of pulmonary tuberculosis, which precluded definitive identification of the exact cause of tuberculosis in the present patient. Following the diagnosis of active tuberculosis, prednisone was gradually tapered to a maintenance dose, methotrexate was discontinued and standard anti-tuberculosis therapy was initiated. In the present case, this treatment approach effectively balanced the control of sarcoidosis with the treatment of tuberculosis, and the patient achieved a favorable long-term outcome.

The present study has several limitations. This case report lacked a systematic assessment of immunological parameters, such as the CD4+/CD8+ T lymphocyte ratio in the BALF and the serum IL-2R level, which could reduce the completeness of the evidence supporting the differential diagnosis. Overlapping temporal and clinical manifestations of sarcoidosis and tuberculosis precluded definitive identification of the cause of the subsequent tuberculosis infection. Additionally, as a single case report, it was not possible to accurately distinguish the independent therapeutic effect of methotrexate from the delayed onset of glucocorticoid efficacy. For the diagnosis of chylothorax, the lack of chylomicron assay for right-sided chylous fluid and a full panel of matched laboratory data for left-sided pleural effusion partially restricts comparative analysis between bilateral pleural effusions. Furthermore, direct evidence from lymphangiography, lymphatic magnetic resonance imaging or other imaging technics indicating lymphatic obstruction or injury was lacking. Therefore, future multicentre, prospective and large-scale cohort studies are needed. By integrating the advantages of multidisciplinary approaches with emerging technological means, standardized diagnostic and treatment protocols for sarcoidosis-related chylothorax can be established.

In conclusion, the current case report described a rare case of a patient with sarcoidosis complicated by chylothorax and tuberculosis infection during therapy and summarized the process of differential diagnosis and treatment management of this rare clinical presentation. This case highlighted the importance of early differential diagnosis between sarcoidosis and tuberculosis for appropriate disease management. Combination therapy with methotrexate could be effective in treating selected clinical manifestations of sarcoidosis, such as chylothorax. However, the risk of opportunistic infections associated with long-term immunosuppressive therapy should be carefully considered. In conclusion, this case report provided a real-world reference for the diagnosis and management of this rare disease combination.

Supplementary Material

Bilateral pleural drainage fluid samples collected on hospital day 22. (A) Left pleural drainage fluid: Pale yellow, clear exudate without milky turbidity. (B) Right pleural drainage fluid: Homogeneous chylous fluid. R, right; L, left.

Original cytology report of the right-sided chylous pleural effusion after treatment initation. The results demon-strate markedly elevated total cell count and lymphocyte percentage (scale bar, 100 μm).

Acknowledgements

Not applicable.

Funding

Funding: The present study was supported by the Science and Technology Development Plan of Shandong Medical and Health Science (grant no. 202302070979), and the Scientific Project of Weifang Health Commission (grant nos. WFZYY2024-4-065 and WFZYY2025-4-023).

Availability of data and materials

The data generated in the present study may be requested from the corresponding author.

Authors' contributions

XL was the primary care physician of the patient and developed and implemented the treatment regimen. WH, YYZ and YT performed the literature review and analyzed and interpreted the data. HW and YW organized the treatment regimen and analyzed data. YZ and XZ drafted the report and critically revised the intellectual content. MQ and XZ were involved in conceptualization, study design, manuscript editing and funding acquisition. MQ and XZ confirm the authenticity of all the raw data. All the authors have read and approved the final manuscript.

Ethics approval and consent to participate

The present study was reviewed by the Ethics Committee of the Weifang Second People's Hospital (approval no. KY2025-101-01) and was performed in accordance with the Declaration of Helsinki.

Patient consent for publication

The patient provided written informed consent for the publication of the manuscript, including any identifying images or data.

Competing interests

The authors declare that they have no competing interests.

Use of artificial intelligence tools

GPT-4 was used to enhance readability and language quality during manuscript preparation. The final manuscript was professionally edited by the official language-editing service of Spandidos Publications to ensure accuracy and fluency of the language.

References