A 79-year-old male patient with a 5-year history of chronic obstructive pulmonary disease (COPD), well-controlled with regular inhalation of budesonide-formoterol, presented with a 10-day history of productive cough and exacerbation of exertional dyspnea following cold air exposure. He denied having fever, hemoptysis, chest pain, or a recent travel history prior to admission.

On admission, his oxygen saturation was approximately 90% while receiving 2 L/min of supplemental oxygen. Laboratory tests revealed elevated inflammatory markers: D-dimer increased to 13.31 mg/L (normal range: 0.00–0.55 mg/L), fibrinogen rose to 8.40 g/L (normal range: 1.8–3.5 g/L), and IL-6 levels were markedly elevated to 227.50 pg/ml (normal range: 0–6.6 pg/ml). Additionally, total protein and serum albumin were significantly reduced (Table 1). The elevated CYFRA 21–1 level reported in Table 1 may be attributed to ongoing alveolar epithelial injury and repair associated with the patient’s COPD (Heo et al., 2021). Bedside echocardiography showed normal ventricular systolic function, and Doppler ultrasound of the lower extremities detected an intermuscular venous thrombosis in the right calf (Figure 1).

Computed tomography pulmonary angiography (CTPA) revealed a small, patchy filling defect in the subsegmental pulmonary artery of the posterior basal segment of the left lower lobe. In the right lower lobe, bronchial narrowing and occlusion were identified, surrounded by irregular soft tissue with heterogeneous contrast enhancement, raising suspicion for a malignant process. Additionally, multiple nodules of varying sizes with heterogeneous enhancement were present in both lungs, suggesting the possibility of metastatic disease (Figure 2).

The patient was hospitalized for a total of 17 days. Empirical antibiotic therapy with piperacillin–tazobactam was initiated on the first day of admission, accompanied by inhaled ipratropium bromide and expectorants to relieve symptoms. Given the diagnosis of pulmonary embolism, subcutaneous enoxaparin (4,000 IU every 12 hours) was administered. The patient’s cough and dyspnea improved, but intermittent low-grade fever developed after admission and has persisted since.

To further clarify the diagnosis, flexible bronchoscopy was performed the day after admission, revealing extrinsic compression and luminal narrowing of the bronchus in the right lower lobe (Figure 3). At the same time, tissue samples obtained via transbronchial biopsy and bronchoalveolar lavage (BAL) were submitted for histopathological examination and mNGS, respectively. Histological analysis demonstrated abundant ciliated columnar epithelial cells with inflammatory infiltration, without evidence of malignancy (Figure 4).

A CT-guided percutaneous lung biopsy was subsequently scheduled. However, repeat imaging showed a marked reduction in the previously observed soft tissue density, a finding inconsistent with neoplastic pathology and more indicative of an infectious process. In light of these findings, the planned invasive procedure was cancelled.

On the fourth day after admission, mNGS of the bronchoalveolar lavage fluid identified Nocardia saintgeorgesii (Figure 5), consistent with the patient’s clinical presentation. Simultaneously, sputum culture (including routine bacterial culture and Haemophilus influenzae culture) was performed over two days, with no pathogenic bacteria growth observed in the routine culture and negative results for Haemophilus influenzae culture. Based on this finding, the antimicrobial regimen was adjusted to ceftriaxone in combination with oral trimethoprim-sulfamethoxazole. The patient showed gradual clinical improvement, with marked relief of respiratory symptoms including cough, sputum production, and dyspnea (Figure 6).

Follow-up laboratory tests two week later demonstrated significant improvement: white blood cell count was 3.39 × 109/L, neutrophil count 1.96 × 10⁹/L (58%), C-reactive protein (CRP) decreased to 5.16 mg/L, procalcitonin (PCT) to 0.042 ng/mL, and interleukin-6 (IL-6) to 12.79 pg/mL. Chest computed tomography (CT) revealed substantial resolution of the pulmonary lesions (Figure 7).

At the time of discharge, the patient was afebrile, breathing comfortably, and ambulating without signs of respiratory distress, indicating a stable clinical condition. A follow-up plan was arranged to monitor ongoing recovery and evaluate long-term treatment outcomes.

PN remains a diagnostic challenge due to its nonspecific clinical manifestations. In particular, cases presenting with cavitary lesions or mass-like consolidations are frequently misdiagnosed as lung cancer (Restrepo and Clark, 2019; Thakur et al., 2020). In this case, chest imaging showed signs that strongly resembled malignancy, including bronchial obstruction, thickening of the tissue surrounding the bronchi, and multiple nodules with uneven contrast enhancement. These findings initially led clinicians to suspect lung cancer. However, standard diagnostic procedures—such as sputum cultures and bronchoscopic biopsies—provided relatively limited information. Since Nocardia species grow slowly and require specific culture conditions, they are sometimes missed by routine microbiological tests. In this patient, histopathological analysis of the bronchoscopic biopsy revealed only chronic inflammation, with no evidence of cancer or identifiable pathogens. This inconclusive result created a diagnostic inconvenience and led to consideration of a more invasive percutaneous biopsy for further clarification.

mNGS has emerged as a transformative tool for etiological diagnosis in infectious diseases. The broad-spectrum detection capability of mNGS allows for comprehensive pathogen identification, which is particularly beneficial in cases involving fastidious anaerobes, patients who have received empirical antibiotic therapy prior to sample collection, or complex infections where conventional tests fail to identify the causative agent (Chiu and Miller, 2019).

To identify the causative pathogen, metagenomic next-generation sequencing (mNGS) was performed on the bronchoalveolar lavage fluid using the Miniseq platform. The analysis exclusively detected Nocardia saintgeorgesii (sequence count: 6564), cytomegalovirus (sequence count: 12), and human orthopneumovirus (sequence count: 8) (Figure 5). The MetaCAP targeted pathogen sequencing technology can specifically capture 1,292 bacterial species, 517 fungal species, 1,380 viral species, 210 parasitic species, 2,627 resistance subtypes corresponding to 86 antimicrobial resistance genes, and 74 virulence genes. In the report, Nocardia saintgeorgesii was listed in the primary table with a high sequence count of 6564 RPM and a confidence level of 99%. Combined with its high relative abundance (accounting for 17.97% of bacterial sequences), it was identified as the primary pathogenic bacterium.

In this patient, mNGS analysis of BALF rapidly identified Nocardia saintgeorgesii as the causative pathogen. Combined with clinical correlation, this confirmed the diagnosis of PN, enabling prompt initiation of ceftriaxone and TMP-SMX therapy. The patient subsequently achieved significant symptomatic improvement and successful discharge.

Traditionally considered an opportunistic infection (Wilson, 2012; Wang et al., 2022), PN primarily affects individuals with impaired cell-mediated immunity, including those receiving long-term corticosteroid therapy, solid organ transplant recipients, and chemotherapy patients. However, emerging evidence demonstrates increasing case reports among immunocompetent hosts (Langmaid et al., 2021; Ye et al., 2023; Zhang et al., 2023; Bove et al., 2024; Daniel et al., 2024). In a review of 1,000 cases of nocardiosis over 40 years, 38% of patients studied were neither immunocompromised nor had a risk factor (Duggal and Chugh, 2020).

Chronic structural lung diseases, including COPD and bronchiectasis, are now recognized as significant risk factors for PN, even in the absence of systemic immunodeficiency (Aggarwal et al., 2015; Steinbrink et al., 2018; Anand et al., 2025). These conditions disrupt local mucosal defenses, impair mucociliary clearance, and alter the pulmonary microbiota, creating a microenvironment conducive to opportunistic infections (Sze et al., 2014; Richardson et al., 2019). Additionally, subclinical immune dysfunction—such as impaired neutrophil function or defective alveolar macrophage activity—may compromise innate host defenses, particularly in elderly or chronically ill individuals (Berenson et al., 2013; Effah et al., 2021). Environmental exposure to Nocardia-contaminated soil or water, whether through occupational or regional contact, may also contribute to disease development in otherwise healthy hosts (Lam et al., 2022).

Notably, certain Nocardia species possess enhanced virulence factors that may contribute to rapid disease progression and increased mortality (Liu et al., 2017; Ott et al., 2019; Lepe-Balsalobre et al., 2021). These observations underscore the importance of maintaining a high index of clinical suspicion for nocardiosis, regardless of the patient’s immune status.

A growing body of literature has reported an unexpectedly high incidence of DVT in patients with PN (Liu et al., 2017; Viscuse and Mohabbat, 2019; Douedi et al., 2020; Raslan et al., 2021; Pérez Ramos et al., 2024), suggesting a possible yet underappreciated link between Nocardia infection and thrombotic complications. In this case, the patient was found to have DVT during the first examination after admission, with no prior history of DVT or symptoms suggestive of venous thromboembolism before hospitalization. The patient regularly engaged in physical labor, had no history of malignancy, autoimmune diseases, trauma, recent surgery, or personal or family history of thromboembolic events. Although the patient had COPD, it was well controlled with regular medication. The concurrent occurrence of pulmonary embolism in the absence of traditional risk factors increases the possibility that the Nocardia infection itself may have created a prothrombotic environment.

While direct causal evidence remains lacking, the proposed link between Nocardia infection and thrombosis is biologically plausible. It is well documented that systemic infections can induce a prothrombotic state through complex crosstalk between inflammatory and coagulation pathways. As observed in other infectious diseases such as tuberculosis, Nocardia infection may similarly promote endothelial activation, upregulation of tissue factor, and release of pro-inflammatory cytokines including IL-6 and tumor necrosis factor-alpha (TNF-α), ultimately enhancing thrombin generation and suppressing fibrinolysis (Solis-Soto et al., 2008; Rosas-Taraco et al., 2012; Trevino-Villarreal et al., 2012).

In this case, the markedly elevated levels of inflammatory markers—CRP, PCT, and IL-6—were indicative of a strong systemic inflammatory response, which may have contributed to a procoagulant milieu and the development of pulmonary embolism.

Furthermore, the possibility of direct vascular involvement by Nocardia organisms cannot be entirely ruled out. Although uncommon, several reports have described vascular complications in disseminated nocardiosis, including cerebral vasculitis, retinal vasculopathy, and vascular invasion in soft tissues (Cheung et al., 1994; Ravage and Singerman, 2009; Lally et al., 2014). These observations raise the possibility that Nocardia may exhibit a degree of vascular tropism in certain hosts or under specific immunological conditions. The typical pathological manifestation of Nocardia infection is chronic suppurative granulomatous inflammation. Chronic granulomatous infectious foci serve as persistent and intense local inflammatory stimuli, representing one of the primary drivers of endothelial dysfunction. The markedly elevated inflammatory markers such as IL-6 and CRP in the patient act as key mediators that drive endothelial cell activation, compromise vascular integrity, and create a procoagulant microenvironment (Szmitko et al., 2003). Ultimately, the activated and dysfunctional endothelial cells lose their natural antithrombotic properties. Instead, they begin to express procoagulant substances such as tissue factor, promote the adhesion of platelets and leukocytes, and actively establish a local microenvironment conducive to thrombus formation (Prakash et al., 2022; Donadini et al., 2025). While the mechanism remains speculative, such endothelial or vascular wall involvement could locally disrupt vascular integrity, promote endothelial activation, and create a microenvironment conducive to thrombosis. In the context of pulmonary involvement, this may potentially contribute to in situ thrombus formation or exacerbate existing prothrombotic processes.

Given emerging evidence and biological plausibility, clinicians should maintain a high index of suspicion for thromboembolic events in patients with PN, particularly those exhibiting elevated D-dimer levels or unexplained respiratory deterioration. Further studies are warranted to elucidate the prevalence, pathophysiological mechanisms, and prognostic implications of thrombosis in the setting of Nocardia infection (Fu et al., 2017).

Although a connection between Nocardia infection and thromboembolic complications seems possible, the study has clear limitations. Most notably, we lack direct proof of Nocardia in the thrombotic tissue and do not have serial data on relevant coagulation and fibrinolysis markers. This is indeed the major constraint for clinical interpretation. Still, as noted earlier, localized inflammation from Nocardia could promote endothelial damage. In this case, the activated endothelium, alongside the patient’s elevated inflammatory markers, might have established conditions favorable to clotting. Thus, we believe Nocardia could have played a role in thrombus development.

Though direct microscopy is a traditional method for the rapid diagnosis of nocardiosis, in this case, lung cancer was initially highly suspected, so the diagnostic focus was first placed on histopathological evaluation. Upon admission, we ran routine tests such as a sputum culture and sputum smear before starting antibiotic treatment. Due to elevated inflammatory markers and the need to consider infectious etiologies in the differential diagnosis, mNGS was also conducted. Since the sputum smear result was negative and malignancy was highly suspected at the time, infectious diseases were not prioritized in the diagnostic workup. Therefore, direct microscopic examination was not performed, which indeed reflects an oversight in our clinical consideration.

The patient initially received empirical antibiotic therapy with piperacillin–tazobactam. Although CRP levels showed a downward trend, low-grade fever persisted. Following the identification of Nocardia species, the regimen was switched to ceftriaxone combined with trimethoprim–sulfamethoxazole (TMP–SMX), leading to rapid defervescence and marked clinical improvement. TMP–SMX remains the cornerstone of Nocardia treatment due to its broad-spectrum activity against most species. In our case, combination therapy resulted in prompt resolution of respiratory symptoms, normalization of inflammatory markers, and significant radiographic improvement, ultimately leading to a favorable clinical outcome.

Early identification of the causative pathogen not only facilitates targeted therapy but also minimizes unnecessary exposure to broad-spectrum antibiotics.