INTRODUCTION — Nocardiosis is an uncommon gram-positive bacterial infection caused by aerobic actinomycetes in the genus Nocardia. Nocardia spp have the ability to cause localized or systemic suppurative disease in humans and animals [1-5]. Nocardiosis is typically regarded as an opportunistic infection, but approximately one-third of infected patients are immunocompetent [4]. (See 'Immunocompromise' below.)
Two characteristics of nocardiosis are its ability to disseminate to virtually any organ, particularly the central nervous system, and its tendency to relapse or progress despite appropriate therapy.
The microbiology, taxonomy, epidemiology, and pathogenesis of nocardiosis will be reviewed here. The clinical manifestations, complications, diagnosis, and treatment are discussed separately. (See "Clinical manifestations and diagnosis of nocardiosis" and "Treatment of nocardiosis".)
MICROBIOLOGY — Actinomycetes are a group of aerobic and anaerobic bacteria in the order Actinomycetales. These organisms are phylogenetically diverse but morphologically similar, exhibiting characteristic filamentous branching with fragmentation into bacillary or coccoid forms [6]. Aerobic actinomyces that cause human and veterinary disease include Nocardia, Gordona, Tsukamurella, Streptomyces, Rhodococcus, Mycobacteria, and Corynebacteria. Anaerobic genera of medical importance include Actinomyces, Arachnia, Rothia, and Bifidobacterium.
Nocardia typically appear as delicate filamentous gram-positive branching rods (picture 1) that appear similar to Actinomyces species. Nocardia can usually be differentiated from Actinomyces by acid-fast staining, as Nocardia typically exhibit varying degrees of acid fastness due to the mycolic acid content of the cell wall (picture 2). Another useful clue is that Nocardia grow under aerobic conditions, whereas Actinomyces grow under anaerobic conditions.
In the laboratory, Nocardia can display both aerial branching and substrate branching into the media or along its surface. These organisms were once considered fungi because of their hyphal-like appearance, but molecular analysis of their cell wall has confirmed their classification as bacteria [5,6].
Formal species identification is best done using molecular techniques (see 'Taxonomy' below).
TAXONOMY — The genus Nocardia includes more than 90 species, at least 54 of which cause disease in humans [1,4,7,8]. Nocardia species were originally classified based upon biochemical properties. However, molecular techniques are now the preferred methods for speciation. (See "Clinical manifestations and diagnosis of nocardiosis", section on 'Speciation'.)
Molecular methods including gene sequencing [9] and multilocus sequence analysis (MLSA) [10,11] have led to reclassification and renaming of many Nocardia isolates. For example, isolates that in the past had been identified as N. asteroides complex have now been renamed to other or new species. Because of this, N. asteroides, once a common species, is now rarely seen [12]. Also, molecular studies indicate that N. brasiliensis, N. otitidiscaviarum, and N. transvalensis, once thought to be fairly homogeneous genera, also exhibit diverse characteristics, and it is anticipated that new species will continue to emerge [13-15].
EPIDEMIOLOGY — Nocardia species are not members of normal human flora. Nocardia species are found worldwide in soil, decaying vegetable matter, and aquatic environments and can become airborne, particularly on dust particles [16]. Inhalation of the organism is considered to be the most common mode of entry, which is supported by the observation that the majority of infections involve the lung.
A number of other modes of entry may be important in selected cases:
●Ingestion of contaminated food may produce disease via the gastrointestinal tract [5].
●Cutaneous disease usually occurs by direct inoculation of the organism as a result of trauma (including puncture by a thorn or splinter or an animal scratch or bite), surgery, a vascular catheter, intralesional infection, or an insect bite [3,5,17]. An outbreak of N. cyriacigeorgica soft tissue infection involving eight individuals was linked to the use of unlicensed cosmetic injections [18]. Cutaneous disease may also occur secondary to hematogenous dissemination. In such cases, lesions are typically multiple and widespread.
●Reports of case clusters support nosocomial transmission [19-21]. As an example, a cluster of nosocomial cases of postoperative sternal wound infection with N. farcinica was caused by an isolate that was identical to one cultured from the hands and home of a healthy healthcare worker [21].
In the early 1970s, the incidence of nocardiosis in the United States was estimated to be approximately 500 to 1000 new cases per year [22]. This probably represented an underestimate since nocardiosis is not a reportable disease and infection is difficult to diagnose. The current incidence is likely to be much higher, as the United States population has increased substantially since then and the proportion of individuals at risk for nocardiosis has greatly increased (eg, transplant recipients and HIV-infected patients). Some authors now regard nocardiosis to be an emerging and increasing infectious disease [23].
Species prevalence and distribution — Up to 54 Nocardia species have been shown to cause disease in humans [1,4,6,8] with variation in the frequency of species with geographical region [12,24]. This has not been well characterized due to changes in taxonomy, difficulty in routine identification of Nocardia strains at the species level, and, perhaps, referral and reporting biases.
Among 765 isolates submitted to the United States Centers for Disease Control and Prevention (CDC) between 1995 and 2004, the following species were identified most commonly [25]:
●N. nova complex (28 percent)
●N. brasiliensis (14 percent)
●N. farcinica (14 percent)
●N. cyriacigeorgica (13 percent)
●N. brevicatena (7 percent)
●N. abscessus (6 percent)
A somewhat different distribution of Nocardia spp was noted in a review of 1119 isolates from Spain collected between 2005 and 2014 [12]:
●N. cyriacigeorgica (25 percent)
●N. nova (15 percent)
●N. abscessus (13 percent)
●N. farcinica (11 percent)
●N. carnea (4 percent)
N. farcinica was also the most common species in studies from Belgium [26], France [27], and China [10], whereas N. brasiliensis was the most common species in a study from Taiwan [28]. N. nova was the most common species in two series from Australia [9,29].
For unclear reasons, males have predominated in most cases series of nocardial infection. Although it has been postulated that this male predominance may be related to occupation, there is in vitro evidence that estrogen might be protective. For example, in a murine model of N. brasiliensis–induced actinomycetoma, estradiol limited mycetoma lesions [30].
PATHOGENESIS — Nocardia spp possess multiple mechanisms to overcome the immune response of the host. The ability to combat host resistance to infection appears to vary with the strain and growth phase of the bacteria [31]. Bacteria that are in log-phase exhibit filamentous growth and are resistant to phagocytosis. When phagocytosis does occur, inhibition of phagosome-lysosome fusion has been observed with some nocardial strains, thereby avoiding hydrolysis by the host cell. The production of a bacterial cell surface–associated superoxide dismutase and possibly increased production of catalase may be involved in resistance to human neutrophils [32].
L-forms are cell wall–deficient variants of some bacterial species, including Nocardia. L-forms have been recovered from cerebrospinal fluid (CSF) in human nocardiosis and cause disease in animal models. Lifelong persistence of L-forms has been demonstrated in murine models, and it has been postulated that L-forms may be related to the tendency of nocardiosis to relapse and to recur years after successful initial antimicrobial therapy [5].
Some species have enhanced virulence. N. farcinica appears to be more virulent than some other species, since infection with this species is more likely to result in disseminated disease and tends to be more resistant to antimicrobials [33-35]. (See "Treatment of nocardiosis", section on 'Antibiotic susceptibility'.)
Host defenses — The interplay between host defenses and nocardial infections has been studied extensively both in vivo and in vitro. Although not all mechanisms are fully understood, it is clear that cell-mediated immunity is crucial in containing Nocardia spp infection.
The initial host response to nocardiosis involves neutrophils and local macrophages, which inhibit but do not kill the bacteria [36,37]. This inhibition helps to limit the spread of infection until a specific cell-mediated response can occur. A population of immune-primed T cells enhances phagocytosis, stimulates cellular response, and may be capable of direct cytotoxicity to the bacteria [5,38].
Gamma delta T lymphocytes may play a crucial role in the host defenses against Nocardia spp. In a murine model, gamma delta T cell–deficient mice died within 14 days after inoculation with N. asteroides at a dose that was not lethal to control mice [39]. Lung tissue from these mice showed severe damage and growth of the organism compared with a neutrophil response and clearance of the bacteria in the control animals.
The role of humoral immunity in nocardiosis is unknown. Murine models indicate that humoral immunity is not as critical as cell-mediated immunity [40,41], but antibody has been demonstrated to enhance phagocytosis and the microbicidal activity of activated macrophages in a rabbit model [42]. There is no evidence that B cells directly influence host defenses in nocardial infections [43].
RISK FACTORS
Immunocompromise — The majority of patients with nocardial infection are immunocompromised, most often with cell-mediated abnormalities [3,4,44]. In a review of 1050 cases, for example, 64 percent were immunocompromised [5]. The most common causes are glucocorticoid therapy, malignancy, organ and hematopoietic stem cell transplantation, and HIV infection.
Glucocorticoid therapy — Virtually every illness that requires prolonged glucocorticoid therapy has been associated with nocardiosis [3,45-48]. (See "Major side effects of systemic glucocorticoids", section on 'Immune system effects'.)
Malignancy — Solid tumors and hematologic malignancies accounted for 17 percent of cases of nocardiosis in the series of 1050 cases cited above [5]. In another series, hematologic malignancies were present in 64 percent of cases; almost one-half had undergone hematopoietic stem cell transplantation [45]. Risk factors in such patients include recent chemotherapy, glucocorticoid administration, and antirejection drugs.
Organ transplant recipients — The risk of nocardiosis is highest in the first year following organ transplantation, presumably due to greater immunosuppression to prevent rejection [3]. Studies in transplant recipients treated with steroid-sparing regimens, such as cyclosporine, have found significantly reduced rates of nocardial infections: 2.6 to 0.7 percent in renal transplant recipients [46] and 13 to ≤4 percent in later series in heart transplant recipients [3,47].
The clinical features of and risk factors for Nocardia infection in organ transplant recipients was evaluated in a matched case-control study of 5126 organ transplant recipients, 35 of whom (0.6 percent) developed Nocardia infection [48]. The following findings were noted:
●The rate of Nocardia infection was highest in lung and heart transplant recipients (3.5 and 2.5 percent) and lowest in liver and kidney transplant recipients (0.1 and 0.2 percent). Most patients (69 percent) were receiving trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis when they developed nocardiosis.
●N. nova and N. farcinica accounted for 77 percent of the infections. Most patients had only pulmonary infection, but 20 percent had disseminated disease. (See "Clinical manifestations and diagnosis of nocardiosis".)
●When the patients were matched to 70 uninfected controls, independent risk factors for Nocardia infection were high-dose glucocorticoids (odds ratio 27), cytomegalovirus disease in the preceding six months (odds ratio 6.9), and high median serum calcineurin inhibitor concentrations in the preceding 30 days (odds ratio 5.8).
In a separate case-control study of solid organ transplant recipients, multivariable analysis identified the following risk factors for nocardial infection following transplant: high calcineurin inhibitor trough levels (odds ratio 6.11), use of tacrolimus (odds ratio 2.65), increasing glucocorticoid dose at the time of diagnosis (odds ratio 1.12), increasing patient age (odds ratio 1.04), and length of stay in the intensive unit (odds ratio 1.04) [24].
HIV infection — Nocardiosis is uncommon in HIV-infected patients, occurring in 0.2 to 2 percent of patients. Most HIV-infected patients with nocardiosis are severely immunocompromised (median CD4 count of 35 cells/microL) [49]. TMP-SMX prophylaxis for Nocardia infection to date has not shown a benefit in patients with AIDS. Reasons for this are multifactorial and may include the low frequency of disease, the increasing use of antiretroviral therapy, and/or misdiagnosis with other pulmonary infections such as tuberculosis or bacterial pneumonia [3,49,50]. However, support for TMP-SMX prophylaxis was noted in a study that documented that most cases of nocardiosis occurred in AIDS patients who had not been receiving sulfonamide prophylaxis for other infections [50]. Since the use of TMP-SMX prophylaxis to prevent Pneumocystis jirovecii pneumonia is routine for AIDS patients with CD4 counts <200 cells/mm3, most high-risk AIDS patients receive concurrent prophylaxis for nocardiosis. (See "Bacterial pulmonary infections in patients with HIV".)
Other risk factors — Other conditions that have been associated with nocardiosis include diabetes mellitus, alcoholism, chronic granulomatous disease, alveolar proteinosis, structural lung disease, tumor necrosis factor-alpha inhibitor (eg, infliximab) therapy, inflammatory bowel disease [51], chronic obstructive pulmonary disease, and tuberculosis [3-5,29,44,52]. (See "Epidemiology of pulmonary infections in immunocompromised patients" and "Causes, clinical manifestations, and diagnosis of pulmonary alveolar proteinosis in adults".)
SUMMARY
●Nocardiosis is caused by aerobic actinomycetes in the genus Nocardia, an unusual gram-positive bacteria. (See 'Microbiology' above.)
●Nocardia typically appear as delicate filamentous gram-positive branching rods that appear similar to Actinomyces species. Nocardia spp can be differentiated from Actinomyces by acid-fast staining and their ability to grow under aerobic conditions, neither of which is a characteristic of Actinomyces. (See 'Taxonomy' above.)
●The genus Nocardia includes more than 90 species, at least 54 of which cause disease in humans. (See 'Taxonomy' above.)
●Nocardia species are found worldwide in soil, decaying vegetable matter, and aquatic environments. Modes of entry include inhalation, ingestion, and direct inoculation through the skin. Inhalation is the most common route of entry. (See 'Epidemiology' above.)
●The most common Nocardia species to cause disease in the United States are members of the N. nova complex, N. brasiliensis, N. farcinica, and N. cyriacigeorgica. The species prevalence has varied in studies from different geographic regions. (See 'Species prevalence and distribution' above.)
●Nocardia spp possess multiple mechanisms to overcome the immune response of the host. (See 'Pathogenesis' above.)
●Cell-mediated immunity is crucial in containing Nocardia spp infection. (See 'Host defenses' above.)
●The majority of patients with nocardial infection are immunocompromised, most often with cell-mediated abnormalities. The most common causes are glucocorticoid therapy, malignancy, organ and hematopoietic stem cell transplantation, and HIV infection. (See 'Immunocompromise' above.)
