Comparison of Clinical Characteristics and Treatment Outcome Between Localized and Disseminated Nocardiosis in a Tertiary Hospital in China

Introduction

Nocardia is a Gram-positive aerobic bacterium characterized by hyphae-like branching. It is a common pathogen in the environment, often found in soil, decomposing vegetation and other organic matter, as well as in fresh and salt water.¹ So far, more than 100 of species of Nocardia have been identified, among which over 40 species have been shown to be clinically relevant.² Notably, Nocardia is often regarded as an “opportunistic infection agent” and most infections usually occur in immunosuppressed individuals under chemotherapy, organ transplants or with immunodeficiency diseases. Nocardia was first reported in 1988, and it was reported that the annual incidence of Nocardia infection/colonization increased from 0.33 (1997–1998) to 0.87 (2007–2008) per 100,000 inhabitants in Quebec, Canada.³ Pulmonary nocardiosis is the most common type of infection, and the main symptoms are fever, cough, shortness of breath, weight loss and night sweats. Additionally, extrapulmonary nocardiosis is also relatively common and can spread to the pleura, pericardium, mediastinum, and vena cava through hematogenous dissemination or continuous spread of necrotizing pneumonia. Disseminated nocardiosis may lead to the involvement of diverse systems, such as the central nervous system (CNS), soft tissue, blood, and lymph nodes.⁴ The mortality rate for nocardiosis ranges from 7% to 44%, but is further increased in cases of disseminated bacteremia or cerebral abscesses.⁵

Based on the enormous heterogeneity of the genomes of diverse Nocardia species, their virulence and antibiotic susceptibility also vary.^6,7 Consequently, this may pose a serious challenge for treatment. It is worth noting that trimethoprim-sulfamethoxazole (TMP-SMX) appears to be a useful antibiotic for the control of Nocardia infections.⁶ Unfortunately, resistance to TMP-SMX has already emerged. A multicenter survey in the USA retrospectively included 552 clinical Nocardia isolates and found that approximately 0.5% (3/552 isolates) of the strains were resistant to TMP-SMX.⁸ Thus, based on the rare and aggressive nature of Nocardia infections, a comprehensive understanding of its clinical features, antibiotic drug susceptibility and therapeutic efficacy is desirable.

In China, due to the large population, infections caused by Nocardia may not be as rare. Unfortunately, there is still inadequate knowledge of the clinical impact caused by Nocardia. Currently, few studies have systematically examined the clinical features of localized and disseminated nocardiosis, despite the numerous variations that may exist in their clinical presentation and treatment. This may make it difficult for patients to benefit from current treatment regimens. Thus, we conducted a retrospective study to compare the clinical characteristics of patients diagnosed with localized and disseminated Nocardia infection in a tertiary hospital in Beijing.

Materials and Methods

Patients

In this study, we retrospectively analyzed the clinical characteristics, laboratory and imaging examinations, treatment and prognosis of patients diagnosed with nocardiosis at Peking Union Medical College Hospital from July 2011 to July 2021. The identification of Nocardia is based on the combination of matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and traditional biochemical methods. The diagnosis of nocardiosis is based on the isolation and culture of Nocardia from suspected sites (bronchoalveolar lavage, blood, pleural fluid, cerebrospinal fluid, pus, conjunctival sac secretions, etc.) and/or tissue (lung biopsy, skin biopsy) on the premise of exclusion of contamination or colonization.⁹

Clinical Data Collection

Patients’ demographics and medical records were retrieved using the Hospital Information System (HIS) and the Laboratory Information System (LIS). Specifically, clinical, imaging, and microbiological data were collected among the 54 patients including risk factors, clinical characteristics, laboratory tests, imaging features, microbiological findings, treatment regimens, and outcomes.

Definition of Localized and Disseminated Nocardiosis

The definitions of localized and disseminated nocardiosis are referred to in previous reports.^9,10 In detail, the presence of Nocardia infection confirmed by microbiology and/or imaging in 2 or more non-contiguous organs is considered as disseminated nocardiosis. Pulmonary infections related to localized organs or systems are classified as localized nocardiosis. Nocardia was considered a colonizer if all 4 of the following conditions were met simultaneously:¹¹ (1) Nocardia was isolated from a nonsterile site; (2) either the patient had no clinical symptoms consistent with Nocardia infection or an alternative diagnosis was present to explain the initial symptoms; (3) patient did not receive antibiotic treatment at a dose and duration (at least 4 months) recommended for invasive nocardiosis; and (4) the clinical presentation did not change during the follow-up period to warrant a revised diagnosis of invasive nocardiosis. In the present study, cases meeting the above criteria for colonization have been excluded.

Statistical Analysis

Excel 2019 was used to manage all the data, and statistical analysis was conducted using SPSS 25.0 (SPSS Inc., Chicago, United States) software. Regarding comparisons between groups, the Student’s t-test or Wilcoxon test was used for analysis of continuous data, while the chi-square test or Fisher’s exact probability for analysis of categorical data. P<0.05 was deemed to be statistically significant.

Results

Baseline Characteristics

After screening, a total of 77 cases were involved and 23 cases were then excluded due to lack of information, finally 54 cases were included in this study. Of the total 54 enrolled patients, 34 were identified as localized nocardiosis, while the remaining 20 were identified as disseminated nocardiosis, according to the criteria. The baseline characteristics of the patients were displayed in Table 1. The mean age of the localized nocardiosis group was 54.0 years, with 55.9% (19/34) males and 44.1% (15/34) females, whilst the mean age of the disseminated nocardiosis group was 44.2 years, with 65.0% (13/20) males and 35.0% (7/20) females. Notably, patients with disseminated infections were more prone to receive long-term glucocorticoids and/or immunosuppressants than the localized nocardiosis group (P=0.027). Furthermore, the proportion of patients with chronic structural lung disease was higher in the localized infection group (P=0.010).

Table 1 The Difference of Clinical Characteristics and Treatment Outcomes Between Localized and Disseminated Nocardiosis

Clinical Manifestations

The prevalent infection sites in the localized nocardiosis group were lung and skin soft tissue, while the prevalent infection sites were lung, central nervous system, and soft skin tissue for disseminated nocardiosis group. Remarkably, disseminated infections were more likely to invade the central nervous system (P<0.001), soft skin tissues (P=0.019), and bone tissues (P=0.030) compared to localized infections (Table 1). Fever, cough, and expectoration were common symptoms of nocardiosis in both groups. However, patients with disseminated infections were more likely to suffer from headache (P=0.001), impaired neurological function (eg, blurred vision, altered visual field, unfavorable speech, limb weakness, etc., P=0.001), and soft tissue skin lesions (P=0.019).

Radiological Features

In the present study, we revealed that pulmonary nodules were prominent features of chest imaging changes in patients with disseminated infections (P=0.027) whereas bronchial dilatation was more common in patients with localized infections (P=0.025). In addition, we also found that when Nocardia infection affected the central nervous system (CNS), the most common cranial MRI or CT manifestations were brain abscesses: multiple brain abscesses in 53.8% (7/13), single brain abscesses in 23.1% (3/13) and abnormal signals in 23.1% (3/13) of the patients.

Identification and Distribution of Nocardia Species

All the cases included in this study had positive culture results for Nocardia species. In localized nocardiosis, 13 specimens were positive for both weakly acid-fast staining and culture and 21 were positive for culture only, whereas in disseminated nocardiosis, 12 specimens were positive for both weakly acid-fast staining and culture and 8 were positive for culture only. In terms of species distribution, the most frequent isolates were Nocardia farcinica and Nocardia brasiliensis, regardless of localized or disseminated infections (Figure 1). Nevertheless, for localized infections, Nocardia is mostly isolated from alveolar lavage fluid (16/34, 47.1%), whereas for disseminated infections, Nocardia is most seen in soft skin tissue (11/20, 55.0%, Figure 2).

Figure 1 The identification results of Nocardia species in this study.

Figure 2 Sample distribution of Nocardia species in this study.

Treatment and Prognosis

All 54 patients were given anti-Nocardia treatment after etiological diagnosis. Among patients with localized infection, 29.4% (10/34) were treated with monotherapy and 70.6% (24/34) with combination therapy, of which 66.6% (16/24) included TMP-SMX. In terms of prognosis, 90.3% (28/31) of the patients recovered, 3 died in hospital and 3 abandoned treatments. For the localized infection group, TMP-SMX is often used in combination with carbapenems, quinolones, minocycline, ceftazidime, amikacin, and linezolid. Notably, combination therapy was used in all the patients with disseminated nocardiosis (20/20), of which 85.0% (17/20) were treated based on TMP-SMX in combination with 1–2 other antibiotics such as carbapenems, quinolones, tetracyclines, cephalosporins, aminoglycosides and oxazolidinones. Eventually, 95.0% (19/20) of the patients recovered and 1 patient was discharged spontaneously. It is worth noting that the average hospitalization days were significantly longer for those with disseminated infection (32.5 days) than those with localized infection (20.0 days, P=0.016, Table 1).

Discussion

An important finding of this study is that disseminated nocardiosis was more common in hosts on long-term glucocorticoid and/or immunosuppressive agents, with the most common species being Nocardia farcinica. The role of disseminated nocardiosis in populations with immunosuppressed conditions has been extensively explored. Soueges et al also demonstrated that hosts with autoimmune diseases, high doses of corticosteroid therapy, lymphopenia or Nocardia farcinica infection were more likely to develop disseminated infections.¹⁰ In the study by Zachary A Yetmar et al, all 33 solid organ transplant recipients had pulmonary involvement, and the majority of patients had central nervous system involvement.¹² They also revealed that 24.2% (8/33) patients with disseminated infection died within 12 months of diagnosis compared to 14.1% (13/92) of patients without disseminated infection. An autopsy study in West Africa showed that 10 of 247 adult HIV cadavers had pulmonary nocardiosis, of which 6 showed disseminated disease.¹³ Thus, we hypothesize that immunosuppressed populations are more likely to develop disseminated disease due to their lowered immunity. Meanwhile, this group needs to be given adequate attention due to the risk of potential poor outcomes. We also found that patients with chronic structural lung disease were mainly associated with localized nocardiosis. For patients with chronic structural lung disease, altered ciliary motility and epithelial damage in the lower respiratory tract may facilitate the survival of Nocardia.

The lung was the most common infection site in this study for both disseminated and localized nocardiosis. In particular, localized infections primarily appear in populations with chronic structural lung disease, and disseminated infections involving the lung mostly occur in patients taking long-term glucocorticoids and/or immunosuppressive agents. The clinical manifestations of pulmonary nocardiosis are mainly fever, cough and expectoration, shortness of breath, and imaging changes may show patchy, nodular, cavernous, or bronchial dilatation, etc. From this perspective, the clinical presentation and imaging changes of nocardiosis were not specific and could easily lead to misdiagnosis. Hence, in patients presenting with unexplained pulmonary symptoms, pathogenic testing for Nocardia is necessary to rule out misdiagnosis and delayed treatments. This study revealed that when Nocardia infection involved the CNS, both brain abscesses and abnormal signals were observed. CNS involvement predominantly occurs in immunocompromised populations and the most common imaging presentation is brain abscess.¹⁴ Primary cutaneous nocardiosis has been reported to be more common in immunocompetent individuals.¹⁵ The clinical presentation of cutaneous nocardiosis is similar to that of other skin infections and may present as skin nodules, subcutaneous abscesses, cellulitis and cutaneous lymph vascular syndrome, making it difficult to differentiate between sporotrichosis, tuberculosis, non-tuberculous mycobacteriosis, leishmaniasis and syphilis.¹⁶ We recommend that immunocompromised patients presenting with the above skin lesions could be screened for cutaneous nocardiosis and undergo a skin biopsy.

The most common strains isolated in this study were Nocardia farcinica and Nocardia brasiliensis, both in disseminated and localized infections. Wang et al analyzed 441 strains of Nocardia from 21 provinces/cities in China and revealed that the common strains were Nocardia farcinica (39.9%) and Nocardia cyriacigeorgica (28.6%).¹⁷ Another study derived from a tertiary hospital in Hunan province showed that the most prevalent species of Nocardia isolated in 2018–2019 were Nocardia farcinica (81.8%) and Nocardia nova (11.4%).¹⁸ In combination with our findings, Nocardia farcinica is still predominant, although the distribution of other Nocardia species varies from region to region. Nocardia farcinica is thought to be closely associated with multiloculated cerebral abscesses, which may lead to significant mortality.¹⁹ Additionally, Nocardia farcinica is prone to complications in patients with underlying malignancies or autoimmune diseases, further increasing its aggressiveness.²⁰ Patients with confirmed Nocardia farcinica infection should be given focused attention and prompt antimicrobial susceptibility testing to select appropriate antibiotics, which may help minimize mortality. The most frequent sample types for localized and disseminated infections were alveolar lavage fluid and skin and soft tissue, respectively. Inhalation of dust containing Nocardia in the lung or direct inoculation through injury may be an important route of infection for Nocardia, especially in immunocompromised individuals.²¹ It has also been reported that 32% of recipients of solid organ transplants with nocardiosis have skin lesions.²² For this reason, pathogenic diagnosis can be applied to alveolar lavage fluid or skin lesion tissue in patients with suspected nocardiosis.

In a retrospective study conducted by Ercibengoa et al, it was confirmed that there was no statistical difference in 1-year mortality between patients with pulmonary nocardiosis receiving TMP-SMX monotherapy (35%, 8/23) and those receiving other regimens (TMP-SMX-based combination) (41%, 13/32).²³ Margalit et al suggested monotherapy for most patients with localized infections, such as primary cutaneous nocardiosis or non-severe pulmonary nocardiosis whist a combination regimen for severe nocardiosis.¹⁵ As for drug selection, TMP-SMX is the first choice for Nocardia. Alternative options such as carbapenems, quinolones, and minocycline are available for patients who are allergic, resistant, or contraindicated to TMP-SMX. Wang et al studied the resistance profile of Nocardia from 2009 to 2021 in China and found that all Nocardia strains were susceptible to linezolid, followed by amikacin (99.3%) and TMP-SMX (99.1%), with resistance to other antibiotics varying greatly among Nocardia species.¹⁷ Given that the resistance rate of Nocardia may be increasing, it is advised to perform strain identification and antimicrobial susceptibility testing before using antibiotics in clinical practice. In the localized group, 10 individuals were prescribed monotherapy, while 24 were given combined therapy. All monotherapy-treated patients survived, most of them (6/10) with soft-tissue skin infections. For the combination group, 3 of the 24 patients eventually died. Reports on treatment options for patients with localized nocardiosis are limited. Nso et al reported a case of localized pulmonary Nocardia farcinica infection in a 37-year-old male HIV patient, and trimethoprim-sulfamethoxazole was started for pulmonary infection, in addition to antiretroviral therapy.²⁴ Kogure et al reported a 60-year-old Japanese woman with refractory localized pulmonary nocardiosis caused by Nocardia mexicana, and the combination of multi-drug medication and surgery was effective for treating the nocardiosis.²⁵ Consequently, for localized nocardiosis, various regimes should be selected and adapted to the patient’s individual condition to obtain the best therapeutic outcomes. In addition, our study showed that the overall morbidity and mortality rate was not statistically significant in the disseminated infection group compared to the localized infection group possibly because combined and extended anti-infective treatment (TMP-SMX-based combined with 1 to 2 intravenous doses) were applied in the former group.

This study also has some limitations. As a retrospective study, the data collected may have underestimated morbidity and mortality, particularly in patients presenting as mild symptoms and those who did not have a comprehensive examination. Moreover, the limited sample size in this study may hinder the validity of the findings. Future collaborative multi-center studies would help to fully understand the current prevalence, diagnosis, and treatment of nocardiosis in China. Moreover, since this study was a retrospective study with a long-time span, much detailed information could not be given, such as the application of antibiotics after hospital discharge and treatment date. And we were only able to perform a cursory follow-up analysis of the patients through their medical records.

In summary, there were differences in the clinical profiles between patients with localized and disseminated nocardiosis in terms of clinical presentation, infection site, radiological features, treatment, and prognosis. We found that patients with disseminated infections were more prone to receive long-term glucocorticoids and/or immunosuppressants than the localized nocardiosis group. In addition, the disseminated group had longer average hospitalization days relative to the localized group, but there was no significant difference in mortality between them. These findings may provide references for the management and treatment of patients with nocardiosis.