Nocardia Bloodstream Infection: A Retrospective Clinical Analysis of Seven Cases in a Single Centre

Objective: Nocardiosis is a rare opportunistic infection caused by the Nocardia species. Nocardia bacteremia is a life-threatening presentation of disseminated nocardiosis that presents diagnostic and therapeutic challenges. We performed this retrospective analysis in a Chinese hospital from 2010 to 2019 to describe the characteristics of this rare bloodstream infection. Methods: We searched the database of the real-time nosocomial infection surveillance system and identified patients whose blood cultures showed Nocardia bacteria growth. The medical records of these patients were extracted and analyzed by two independent researchers. The data included age, gender, complicating disease, duration from blood drawing to reporting, clinical signs and symptoms, blood routine and C-reactive protein results, radiological examinations, sites of involvement, antibiotic treatments, and outcomes. Results: Seven patients with Nocardia bacteremia were found. There were four male and three female patients, whose ages ranged from 41 to 75 years. Six (85.7%) patients had predisposing conditions and were administrated corticosteroids for various reasons before the identification of Nocardia infection. The most common symptom was fever (100%). Five patients presented with lung or skin involvement; meanwhile, three patients presented with brain involvement. One patient presented with pelvic and peritoneum involvement, respectively. The most common findings of chest CT imaging were consolidation, followed by nodules and cavitations. Trimethoprim/sulfamethoxazole was prescribed to all patients after the diagnosis of Nocardia bacteremia. Six patients recovered, and one patient ultimately died. Conclusions: Nocardia bacteremia is a rare bloodstream infection that usually occurs in immunocompromised patients. Clinical manifestations of patients are nonspecific. It often causes multiple organ involvement, and early diagnosis and prompt aggressive interventions are important to improve the outcome of this disease.


Introduction
Nocardiosis is a granulomatous disease caused by Nocardia species, aerobic environmental Gram-positive actinomycetes. It predominantly occurs in immunocompromised patients, including those with solid-organ or hematopoietic stem cell transplant, malignancies, human 1 2 2 2 immunodeficiency virus infection, and those receiving long-term treatment with steroids or immunosuppressants [1][2][3][4]. Nocardia infection primarily manifests as pulmonary involvement because inhalation is the primary route of bacterial exposure. Extrapulmonary nocardiosis is also common and is characterized by abscess formation, which can occur in skin, pleura, peritoneum, pericardium, and mediastinum. The central nervous system (CNS) is the most common extrapulmonary location for nocardiosis. Nocardia bacteremia is less often encountered and has rarely been reported so far [5][6][7].
In this study, we retrospectively collected the detailed clinical data of all patients with Nocardia bacteremia in a large tertiary-level healthcare facility in Beijing, China, during a 10-year period. This study aims to share our clinical experience on this specific infection.

Study design and data collection
We retrospectively reviewed the clinical information of the patients with Nocardia spp. isolated from blood cultures from January The patients were identified by searching the real-time nosocomial infection surveillance system, the database of the Department of Infection Management and Disease Control of the First Medical Centre of Chinese PLAGH. Patients' data were collected from electronic medical records. We recorded the data including age, gender, complicating disease, duration from blood drawing to reporting, clinical signs and symptoms, blood routine and C-reactive protein results, radiological examinations, sites of involvement, antibiotic treatments, and outcomes. All records were analyzed by two independent reviewers.

Definitions
The diagnosis of Nocardia bacteremia was defined as isolation of Nocardia spp. from one or more blood cultures. The time of diagnosis was defined as the date when the blood culture positive result report was obtained. Disseminated Nocardia infection was defined as Nocardia spp. bloodstream infection or involvement of two or more noncontiguous sites in the setting of clinical and radiographic evidence of organ involvement (e.g., lung, skin, pleura, peritoneum, or brain lesions).

Nocardia species' identification
Blood culture and species identification was accomplished in the microbiology centre of PLAGH. Nocardia spp. identification was based on colony morphology on routine media and microscopic examination, and species were further identified using a battery of biochemical tests.

Characteristics of the patients
Through searching the real-time nosocomial infection surveillance system, we found seven patients with Nocardia bacteremia during the 10-year period in our centre. Characteristics of patients with Nocardia bacteremia are shown in Table 1.

TABLE 1: Demographic and clinical characteristics of patients with Nocardia bacteremia
The age of patients ranged from 41 to 75 years. Four (57.1%) patients were male. Among the seven total patients, six (85.7%) were immunocompromised, receiving high-dose corticosteroid or immunosuppressant treatment due to underlying conditions. Accompanying diseases included primary nephrotic syndrome, acute myelogenous leukemia, thrombocytopenic purpura, sarcoidosis, and pemphigus vulgaris. One patient had a cerebral infarction. All patients were HIV-negative. Fever (100%) was the most common symptom in these patients.
Other common symptoms included cough/expectoration (71.4%), chills (42.9%), and headache (42.9%). One (14.3%) patient experienced nausea/vomiting, confusion, seizure, and septic shock. The mean white blood cell count of patients was 10.39 ± 2.0 × 10 9 /L. The mean percentage of neutrophils was 75.35 ± 0.26. The mean C-reactive protein concentration was 4.21 ± 1.8 mg/dL, which was slightly beyond the normal range (0-0.8 mg/dL). The mean procalcitonin concentration was 0.32 ± 0.21 ng/mL, which was in the normal range (0-0.5 ng/mL). Five patients presented with lung or skin involvement, while three patients presented with brain involvement. The most common findings of chest CT imaging were consolidation (100%), followed by nodules (80%) and cavitations (80%). The CT imaging of one case presented as mass; pleural effusion was observed in another case ( Figure 1).  One patient presented with pelvic and peritoneum involvement. Polymicrobial bloodstream infection with Nocardia and Enterococcus faecium occurred in one (14.3%) patient. The interval of diagnosis was 15.7 ± 6.05 days, and the interval of blood culture report was 7.43 ± 1.59 days.

Nocardia species' identification
Nocardia species were seen microscopically as beaded Gram-positive, thin, branching filamentous bacilli, with modified acid-fast stains. Seven isolates grew well on both blood agar and Löwenstein-Jensen media.

Treatment and outcomes
Most patients were treated with empirical antibiotics for infections before positive culture of Nocardia. Trimethoprim/sulfamethoxazole (TMP/SMZ) was prescribed to all patients after diagnosis of Nocardia bacteremia. Two patients were administered only one medication, which was TMP/SMZ, while the other patients were treated with two or more antibiotics, including levofloxacin, meropenem, ceftriaxone, and linezolid. The daily therapeutic dose of TMP/SMZ ranged from 640 to 1280 mg of trimethoprim and 3200 to 6400 mg of sulfamethoxazole, and the mean duration of treatment was 13.6 ± 4.1 months (range, 5-18 months). Three patients had renal damage, and two patients had hepatic damage during treatment. The blood urea nitrogen, creatinine, glutamate-oxaloacetate transaminase, and glutamate-pyruvate transaminase levels of these patients remained stable after kidney and liver function-protecting treatment. The median follow-up period was 26.4 ± 10.4 months (range, 5-36 months). Six patients recovered, while one patient ultimately died, who was elderly and had been treated with steroids and ciclosporin A because of his primary nephrotic syndrome. He had disseminated nocardiosis with lung, peritoneum, and skin involvement. The patient also had coronary heart disease and had percutaneous coronary intervention stent implantation four years ago. He was intubated shortly after admission to the intensive care unit and died of multiple organ failure five months later. Details of patients with Nocardia bacteremia are shown in Table 2.

Discussion
Nocardia is a Gram-positive bacterium that grows aerobically. It usually causes opportunistic infection especially in immunocompromised hosts, with the most common sites of infection being lung, brain, and skin. Nocardia bacteremia occurs less often and rarely has been reported.
Here, we presented retrospectively the clinical characteristics of seven patients with Nocardia bacteremia. It is the first study of Nocardia bacteremia reported in China.
As a rare pattern of nocardiosis, Nocardia bacteremia mostly developed in patients with depressed cell-mediated immunity. In our study, six (85.7%) patients had predisposing conditions and were treated with corticosteroids for various reasons before identification of Nocardia infection. It was noteworthy that one Nocardia bacteremia patient with cerebral infarction was apparently immunocompetent in this study. Recent studies showed that nocardiosis occurs in immunocompetent patients with increasing rates [4,8]. The underlying mechanism of susceptibility of this cohort remains unknown. It is worth mentioning that regardless of a patient's immunologic status, the isolation of Nocardia from the respiratory tract or other body site should not be considered as a contaminating or colonizing organism.
The symptoms of Nocardia bacteremia were usually nonspecific. They were sometimes confused with manifestations of primary disease, which increased the difficulty of diagnosis for clinicians. Fever was found in all seven patients with Nocardia bacteremia. The other common symptoms included cough/expectoration and chills. CNS is the most common extrapulmonary location for nocardiosis. The clinical manifestations of CNS involvement presented as headache, nausea/vomiting, confusion, and seizure. In this study, three (42.9%) patients with CNS involvement presented typical symptoms of headache, and one patient presented with nausea/vomiting, confusion, and seizure. Four (57.1%) patients presented with skin involvement and one presented with knee joint involvement. Extrapulmonary nocardiosis is characterized by abscess formation histopathologically. It represents a pyogenic bacterial process or develops into a chronic granulomatous lesion or mixed progressive inflammatory mass.
Ninety-two Nocardia species have been reported to date, and 54 have been recognized as having clinical significance [9,10]. The most commonly isolated species in humans include N. asteroides, N. farcinica, N. cyriacigeorgica, N. nova, and N. brasiliensis [11][12][13]. No effective serological method has been developed for diagnosis of nocardiosis so far. A definitive diagnosis of nocardiosis is only made by the separation and identification of Nocardia species using the culture method that usually requires several days to several weeks [14,15]. A bacterial 16S rRNA sequence analysis has recently become the gold standard for the identification of Nocardia species [15]. It is with regret that it was not carried out in our centre, and we did not perform further identification of these species.
Nocardia bacteremia is an extremely severe form of disseminated nocardiosis with a higher mortality rate of approximately 60% [16]. Early diagnosis and treatment of Nocardia bacteremia are highly important to patients' prognosis. TMP-SMZ is widely used as the mainstay drug in the treatment of nocardiosis [16][17][18]. Carbapenems, levofloxacin, amikacin, minocycline, ceftriaxone, and linezolid also have activity against Nocardia [10,17,18]. In the present study, TMP-SMZ was administered to each patient after the diagnosis of Nocardia bacteremia. Five patients received the combination of TMP-SMZ with carbapenems, levofloxacin, ceftriaxone, or linezolid. As for a disseminated refractory infectious disease, treatment of longer duration is needed for Nocardia bacteremia. The mean duration of treatment in our study was 13.6 ± 4.1 months. The common adverse reactions of high-dose TMP-SMZ include renal insufficiency, hepatotoxicity, and myelosuppression. In this study, discontinuations due to drug adverse reactions were not identified. TMP-SMZ is active against most Nocardia species; however, increasing resistance of Nocardia species to TMP-SMZ has been problematic, with resistance rates reported to be as high as 42% [19]. Combination therapy with TMP-SMZ and other alternative effective antimicrobial agents may provide enhanced activity while reducing the side effects of drugs. Therefore, combination therapy with quinolones, carbapenems, amikacin, or a third-generation cephalosporin and TMP-SMZ should be considered in severe cases [18,20]. In our study, six patients improved after treatment, and one patient ultimately died. We thought that this death was related to his multiple organ failure rather than just due to Nocardia infection.

Conclusions
This study described the clinical presentations of Nocardia bacteremia in a tertiary hospital in Beijing, China. This rare infection usually occurs in immunocompromised patients. The diagnosis of Nocardia bacteremia is often delayed due to its nonspecific clinical manifestation and the absence of specific serological diagnostic methods of nocardiosis. The diagnosis of Nocardia bacteremia should be considered early in immunocompromised patients especially with multiple organ involvement. Prompt aggressive interventions are important to improve the outcome of patients. However, it is difficult to draw conclusions about the overall epidemiology and microbiology of Nocardia bacteremia due to the small sample size of the current study. Hence, studies involving larger sample sizes are needed to provide more information on Nocardia bacteremia.

Additional Information Disclosures
Human subjects: Consent was obtained by all participants in this study. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.