Nocardia is an opportunistic, non-commensal bacterium that typically invades the body via the skin and mucous membranes, bloodstream, or respiratory tract, leading to localized or systemic infections that are either pyogenic or granulomatous (4). The lungs are the most frequently affected organ, accounting for approximately 60%−70% of all human Nocardia infections (5), primarily resulting from inhalation of spores or bacterial fragments (6). In addition to pulmonary involvement, Nocardia can infect various organs, including the skin and brain, and can result in systemic dissemination and sepsis, which may be life-threatening (7). The prognosis for Nocardiosis is poor, and the literature indicates that 54 of the 119 validly named Nocardia spp. are associated with human infections, with the most frequent isolates, including Nocardia brasiliensis, Nocardia farcinica, Nocardia abscessus complex, Nocardia nova complex, Nocardia cyriacigeorgica and Nocardia transvalensis complex (8). Wang reported that N. otitidiscaviarum accounted for 5.9% of the 441 Nocardia infection cases (8). N. otitidiscaviarum was originally isolated by Snijders in 1924 from the diseased middle ear of guinea pigs or Sumatran house mice (9). The first documented human infection was not reported until the 1960s, involving two cases of disseminated infection that ultimately resulted in death (10). Although Nocardia infections are gradually being recognized, N. otitidiscaviarum has a lower incidence rate than other species of the Nocardia genus, primarily due to factors, such as reduced virulence and slower growth in soil environments. Reports on this species are relatively rare; however, its mortality rate remains relatively high (7), with a mortality rate of approximately 27%, as presented in Table 2. Conversely, this significant mortality risk has not been sufficiently emphasized, making accurate diagnosis and treatment even more challenging (11). Clinically, N. otitidiscaviarum infections can be categorized based on the site of infection, such as pulmonary, central nervous system, skin, subcutaneous, or disseminated infection (12). In our review of the literature (Table 2), although no significant differences in disease outcomes were observed between sexes, the total number of infected individuals showed a clear male predominance (38 males vs. 18 females), consistent with the findings summarized by Rawat et al. (13), this may be related to hormonal effects on Nocardia virulence or growth. Notably, 37 of the 56 cases (66%) included in our review were published in the past 15 years, suggesting a growing clinical awareness and concern regarding N. otitidiscaviarum as a pathogen of emerging clinical significance.

Most individuals infected with N. otitidiscaviarum have underlying structural lung diseases or immunodeficiency conditions, including long-term use of immunosuppressants or glucocorticoids, stem cell and solid organ transplantation, chronic kidney disease, malignant tumors, chronic lung disease, smoking and alcoholism (14). However, up to 15% of Nocardia-associated infections occur in immunocompetent individuals (15). Among the 56 cases summarized in Table 2, 48 cases (85.7%) had clearly defined risk factors or immunosuppressive conditions. Respiratory comorbidities ranged from common conditions (e.g., chronic obstructive pulmonary disease, asthma and bronchiectasis) to less common ones (e.g., tuberculosis, cystic fibrosis, and chronic thromboembolic pulmonary hypertension). Non-respiratory diseases included underlying malignancies, organ transplantation, autoimmune diseases, diabetes, long-term dialysis, and HIV infection. Notably, 8 (14.2%) cases in Table 2 involved immunocompetent individuals with no underlying disease. Nocardiosis primarily affects immunocompromised patients with impaired T cell-mediated immunity (16). However, animal models have identified immune factors contributing to Nocardia susceptibility and their underlying mechanisms, while the immunological characteristics of nocardiosis in humans remain largely unelucidated (17), necessitating further research. NK cells play a crucial role in innate immunity, recognizing and attacking viruses and bacteria. Severe infections are associated with significantly lower NK cell counts (18). Persistent NK cell dysfunction contributes to infection-induced immunosuppression, increasing susceptibility to secondary infections or reactivation of latent viruses, which can lead to poor prognosis (19). Various primary immunodeficiency diseases can involve NK cells, resulting in NK cell defects, which lead to susceptibility to pathogenic bacteria. In this case, the patient had an open toe fracture 1 year prior, which developed suppurative complications and had remained unhealed before working outdoors for approximately 6 months. The infection pathway may have involved contact with contaminated soil or water sources. Susceptibility factors were considered after the patient was admitted to the hospital: laboratory tests revealed high blood glucose levels, immunological results showed a reduced T-lymphocyte subpopulation, and repeated laboratory tests confirmed a reduced NK cell proportion. Despite no history of HIV, repeated retests were not abnormal; however, the patient exhibited deficiencies in both NK cell-mediated innate and CD4⁺ T lymphocyte-mediated acquired immunity. These findings indicate that the patient had multiple predisposing factors, which increased susceptibility to N. otitidiscaviarum infection. However, the possibility of an underlying immunodeficiency disease warrants further follow-up and long-term monitoring.

Previous studies have indicated that N. otitidiscaviarum is primarily transmitted by inhaling mycelial fragments into the respiratory tract or direct invasion through the skin and mucous membranes. No documented cases of human or animal-to-human transmission exist (4). Among the 56 cases analyzed in our review (Table 2), 7 (12.5%) involved skin or mucosal breaks due to trauma, intravenous drug use, or Peripherally Inserted Central Catheter (PICC) placement, increasing susceptibility to infection. N. otitidiscaviarum is commonly found in decaying organic matter, garden soil, house dust, beach sand, and swimming pools (20). Individuals who work in various outdoor occupations or participate in recreational activities are at a high risk of exposure. Given the patient's history of outdoor work, environmental contact may be a risk factor for infection. Most cases summarized in Table 2 were from Asia, Europe, and North America (n = 54, 96.4%), which may be due to shared Mediterranean climate conditions, as reported by Shen et al. (21). Asia has the highest prevalence due to more agricultural and soil-related work. Tropical regions, including Southeast Asia, are exposed to decaying soil and organic matter, further increasing the risk of infection (22).

N. otitidiscaviarum infections pose a diagnostic challenge due to their lack of specific clinical and imaging features, which can easily lead to misdiagnoses. Pulmonary infection symptoms include fever, cough, sputum, and shortness of breath. Laboratory findings included elevated leukocyte counts, CRP, and other indicators of infection, as well as decreased lymphocyte counts and hypoalbuminemia (23). From an imaging perspective, pulmonary infections caused by N. otitidiscaviarum frequently manifest as consolidation, nodules, and cavitary lesions. Less commonly, lung abscesses and pyothorax may be observed. Several studies have suggested that pleural involvement occurs due to direct extension from the chest wall and the lung parenchyma, leading to these lesions (24). Additionally, hilar lymphadenopathy or combinations of these radiological patterns can make it challenging to distinguish N. otitidiscaviarum infections from other diseases, including bacterial, fungal, and tuberculosis-related infections, as well as non-infectious diseases such as lung tumors (25).

Early identification of N. otitidiscaviarum is crucial for accurate diagnosis; however, current methods face significant challenges. No serological tests exist for rapid detection, making microbiological tests, including smear and culture of sputum specimens, abscesses, wound drainage, or bronchial lavage fluid, the primary diagnostic tools. Microscopic visualization of gram-positive branching filaments remains a key diagnostic indicator (26). However, due to its slow growth, the traditional culture methods may take 1 week or longer (27) and biochemically differ from other Nocardia species in their ability to hydrolyze hypoxanthine and xanthine, further complicating routine clinical diagnosis (28). Additionally, the pathogen's routine biochemical reactions are non-specific, and its staining and culture characteristics are similar to those of to Mycobacterium tuberculosis, making traditional microbiological detection methods less effective. Futhermore, most hosts of nocardiosis may have received antibiotic treatment before sample collection, which reduces the sensitivity of microbial culture, thereby increasing the risk of clinical underdiagnosis, misdiagnosis, and delayed treatment. N. otitidiscaviarum is associated with low morbidity but high mortality in infected individuals and can cause rapidly progressive infections; Deepa reported a case of a 14-year-old patient with N. otitidiscaviarum pneumonia who died before the diagnosis was made (24). Moreover, it has been documented that N. otitidiscaviarum is susceptible to mixed infections with other pathogens (29, 30). Therefore, it is important to be cautious to this infection and implement targeted strategies for early detection to prevent diagnostic errors and ensure timely treatment. Among the 56 cases summarized in Table 2, traditional microbiological testing was used in 31 cases (55.3%), while molecular testing methods (e.g., gene sequencing, mass spectrometry) were used in 25 cases (44.6%). Currently, molecular techniques, such as mass spectrometry, gene sequencing, and NGS, offer improved accuracy. However, polymerase chain reaction (PCR)-based genetic testing requires the design of specific primers or probes, which poses challenges for detecting unknown pathogens or those with genetic mutations. Simultaneously detecting multiple pathogens using this approach is difficult, making it potentially less suitable for cases of mixed infections. Although NGS is widely used in clinical practice, particularly for infectious diseases-due to its high efficiency and accuracy (31)-it also increases healthcare costs. The slow-growing nature of Nocardia also prevents timely culture of target colonies, resulting in a prolonged reporting timeframe. Traditional microbial morphological testing remains indispensable, as it enables immediate sample collection from the infection site and rapid provision of pathogenic evidence, such as smear staining, in the shortest possible time, suggesting that traditional microbial morphology testing remains indispensable. Therefore, in clinical practice, the combination of traditional microbial morphology testing and NGS is required for a rapid, comprehensive, and accurate early diagnosis.

Accurate identification of Nocardia species is the first step in treatment, as antibiotic resistance varies significantly among strains (8). Therefore, species identification and antimicrobial susceptibility testing are required before initiating antimicrobial therapy. The choice of anti-infectious drugs against Nocardia is relatively limited. N. otitidiscaviarum is resistant to β-lactam antibiotics such as ampicillin and amoxicillin-clavulanic acid, and TMP-SMZ remains the first-line treatment for N. otitidiscaviarum (32). However, some differences exist in the drug sensitivity of various bacterial strains, and a gradual increase in drug resistance has been reported (3). Antimicrobial susceptibility testing was performed in 41 of the 56 included cases (73.2%; Table 2). Of these 41 cases, 30 (73.1%) were susceptible to TMP-SMZ and 11 (26.9%) were resistant to sulfonamides. Other agents, including aminoglycosides (e.g., amikacin), linezolid, quinolones, and minocycline, have been used as second-line treatments (14). A study investigating Nocardia infections in China from 2009 to 2021 revealed that all isolated Nocardia strains were susceptible to linezolid, followed by amikacin (99.3% susceptibility) and TMP-SMZ (99.1% susceptibility);among the strains resistant to TMP-SMZ, all were N. otitidiscaviarum (8). However, an increased risk of abnormal hematologic markers after 4 weeks of linezolid administration has been reported in the literature (33), therefore, further attention is required. Additionally, β-lactams such as imipenem are sometimes used as an alternative treatment to TMP-SMZ. However, imipenem has shown different in vitro activities against various Nocardia spp. in numerous studies. Therefore, drug sensitivity testing is necessary.

Current treatment guidelines for N. otitidiscaviarum infections recommend monotherapy for cutaneous infections, stable pulmonary disease and patients with mild illness. However, for severe infections (e.g., severe pulmonary infection, central nervous system involvement, and disseminated disease), especially in immunosuppressed patients, at least two agents are recommended as initial therapy (34). Common regimens include TMP-SMZ + amikacin + minocycline or imipenem, administered for at least 3–4 weeks, followed by sequential monotherapy (35). The literature suggests that linezolid, either alone or in combination with sulfonamides, can be effective in treating moderate to severe nocardiosis (36). Amikacin is rarely used as monotherapy due to its limited penetration into certain infection sites (such as the central nervous system) and some potential toxicities. In this case, because of laboratory limitations, antimicrobial susceptibility testing was not performed. After diagnosis to avoid delaying treatment, empirical initial therapy with cotrimoxazole, linezolid and imipenem-cilastatin sodium was based on literature evidence. Following clinical improvement, the patient was discharged and switched to oral linezolid tablets and TMP-SMZ. In addition to oral or intravenous antimicrobial therapy, adjunctive treatments-including abscess incision and drainage, intrathecal antibiotic injection, surgical resection of lesions, and improvement of the immunization regimen-should be considered in combination when necessary (37).

Treatment for Nocardia should be thorough due to the high recurrence rate (35). While the optimal duration for treating N. otitidiscaviarum infections remains uncertain, most literature recommended that at least 6 weeks of therapy for localized infections in immunocompetent patients. Some experts have reported that recurrence is rare in individuals who have received treatment for more than 3 months (38). In Table 2, 82.9% of the patients who showed clinical improvement had received treatment for more than 3 months. At least 6 months of treatment is recommended for disseminated infections, and at least 1 year of treatment is recommended for immunocompromised patients and those with central nervous system infections (39). Ensuring complete resolution of the lesion via imaging before discontinuing antimicrobial therapy. Treatment for nocardiosis should be initated as early as possible. In patients with a high clinical suspicion of Nocardia infection, particularly in immunocompromised individuals such as organ transplant recipients, empirical therapy should be initiated promptly before susceptibility testing results are available (34), and the need for prolonged therapy or prophylaxis should be determined based on the patient's underlying condition and immune status.

Clinical outcomes of patients with N. otitidiscaviarum infections are influenced by multiple factors. Among the cases included in our literature review (see Supplementary Table S1), 15 deaths were reported (accounting for 26.7% of the 56 included cases). Further analysis identified several factors associated with poor prognosis, including delayed diagnosis (n = 1), co-infection with other pathogens (n = 1), severe underlying diseases (n = 5), and failure to perform timely antimicrobial susceptibility testing or sulfonamide resistance leading to inappropriate treatment (n = 8). There were two cases of recurrence, one was due to disseminated infection plus delayed testing, and the other was due to an insufficient antimicrobial regimen. Therefore, high clinical severity, secondary infections, high-risk clinical severity, secondary infections, presence of risk factors and comorbidities, and delay in diagnosis and treatment were positively associated with poor prognosis (3).