Nocardia Species

Molecular Identification and Taxonomy

Molecular techniques are now preferred for accurate species determination. In addition, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) has proven useful for identification of clinically relevant Nocardia spp.

The application of molecular methods has greatly expanded the spectrum of pathogenic nocardiae and has led to significant taxonomic changes and species reassignment within the genus. This is particularly evident among isolates formerly assigned to the Nocardia asteroides complex. More than 100 Nocardia spp. have now been identified (National Center for Biotechnology Information—taxonomy for Nocardia: www.ncbi.nlm.nih.gov/Taxonomy/ , and www.bacterio.net/nocardia.html ), many of which have been implicated in human disease ( Table 253.1 ). The nomenclature of isolates formerly in the N. asteroides complex is summarized in Table 253.2 and includes Nocardia cyriacigeorgica, Nocardia abscessus, the Nocardia nova complex, and the Nocardia transvalensis complex. Other major human pathogens include Nocardia otitidiscaviarum, Nocardia farcinica, and Nocardia brasiliensis. Some more recently described or reclassified species have been reported to cause human infection. They include Nocardia paucivorans ( Nocardia brevicatena/paucivorans complex ), Nocardia africana, Nocardia veterana ( N. nova complex ), Nocardia wallacei , and Nocardia blacklockiae ( N. transvalensis complex). The terminology “ N. asteroides spp. complex” is no longer used because it encompasses such a heterogenous group of organisms.

Immune Response to Nocardia Infection

After IV inoculation into mice, virulent Nocardia are cleared from the blood within a few hours and localize in a number of organs (lung, brain, kidneys, liver, and spleen). Innate immune function is important in the initial response to infection. In an intranasal mouse model of pulmonary nocardiosis, effective clearance was dependent on early neutrophil recruitment initiated by interleukin-17 (IL-17) production by γδT lymphocytes. Early neutrophil mobilization appears to retard the process until lymphocyte-mediated cytotoxicity and activated macrophages effect a definitive response. In human infection Nocardia -induced granulocyte-macrophage colony-stimulating factor (GM-CSF) production may also be a key cytokine response mediator. Protective immune responses to Nocardia spp. are primarily T-cell–mediated. Nocardiosis is more problematic in patients with impaired cell-mediated immunity, eliciting little in the way of an effective humoral response. Healing is associated with strong, sustained rises in interferon-γ (IFN-γ) in animal models, and IFN-γ may have a therapeutic role in humans with chronic granulomatous disease.

Specific Virulence Determinants

The nocardial envelope of the Corynebacterineae suborder, which includes Mycobacterium spp. and Nocardia spp., is an asymmetrical bilayer composed of inner-leaflet mycolic acids and assorted noncovalently bound outer-layer glycolipids. A substantial proportion of the cell wall mass is composed of peptidoglycan. Mycolic acid polymers are found in many actinomycetes, including Nocardia spp., and are associated with virulence. Outer-layer lipids induce production of proinflammatory cytokines IL-1β and IL-6 by macrophages and are likely to be responsible for the powerful granulomatous reaction to N. brasiliensisis infection , but they are also implicated in the immunosuppressive microenvironment generated later.

Nocardia spp. contain no cell wall lipopolysaccharide, exopolysaccharide capsule, or surface fimbriae. Strain-dependent specific adhesins and invasive properties influence the outcome of infection in animal models. Specific toxins, including hemolysins and proteases, have been identified, but these are not thought to be widespread or particularly significant virulence factors. Highly pathogenic members of the N. asteroides complex secrete superoxide dismutase into growth media, whereas nonpathogenic Nocardia spp. do not. Catalases, superoxide dismutase, and two types of putative determinants of mammalian cell entry, secreted siderophores and toxins, are present in the genomes of pathogenic Nocardia .

Host Cell– Nocardia Interactions

Virulent strains of N. asteroides are relatively resistant to neutrophil-mediated killing. Patients with specific defects in the phagocyte oxidative burst (e.g., chronic granulomatous disease) or with anti–GM-CSF neutralizing antibodies in their serum may be more vulnerable to this infection.

Virulent Nocardia inhibit phagosome-lysosome fusion more successfully in vitro, giving rise to cell wall–deficient forms (L-forms) that persist within macrophages. Such forms (“filterable Nocardia ”) are readily cultured from in vitro broth filtrates, especially when supplemented with erythrocytes, and L-forms have been isolated from animal infections.

Ciliated epithelia appear relatively resistant to invasion by Nocardia spp. However, a range of susceptible lung- and airway-associated cell types has been observed in rat models. Tropism for cerebral tissue is evident experimentally, but neuroinvasiveness and macrophage penetration vary significantly between strains. Electron microscopic studies of infected macrophage and astrocytoma-derived or astrocytoma-related cell lines suggest that the penetration competence of invasive N. asteroides spp. complex is localized to the bacterial apex. Specific lectins have been shown to determine site specificity in the murine brain, intrinsic differences in expression of which may contribute to variations in host susceptibility.

Biofilms

Although IV catheter–associated bloodstream infections are rare in clinical practice, nocardiae promote heavy growth of biofilms, both on the surface of central venous catheter segments in vitro and in a biofilm model. When embedded in such a matrix, the organisms are resistant to antimicrobial drugs unless exposed to very high local concentrations, such as can be achieved with intraluminal antimicrobial lock therapy.

Nocardia Species and Disease Associations

Members of the former N. asteroides spp. complex are responsible for about 80% of noncutaneous invasive disease and for most systemic and central nervous system (CNS) disease. N. farcinica is also an important pathogen, notable for its relatively greater resistance to antibiotics. There is also evidence from mouse models that it may be more virulent than other Nocardia spp. N. brasiliensis is the most often reported cause of cutaneous and lymphocutaneous disease, particularly in tropical areas. N. pseudobrasiliensis, a species now separated from N. brasiliensis, appears to be associated with disseminated, including CNS, infections. Pulmonary disease is the most frequent presentation of nocardiosis caused by the less common pathogens N. transvalensis and N. otitidiscavarum, although both may cause severe cutaneous infection. Superficial nocardiosis after implantation is not necessarily associated with compromised cell-mediated immunity but may progress to disseminated disease in that setting.

Immunocompromise as a Risk Factor for Nocardiosis

Immunocompromise is a well-established risk factor for nocardiosis. Nocardia spp. may therefore be considered as opportunistic pathogens, which cause serious and disseminated disease in settings such as organ transplantation and lymphoreticular neoplasia. The relative risk for progressive disease reflects the level of immunosuppression. A compilation of more than 1000 randomly selected cases from the literature in the early 1990s showed that greater than 60% of all reported cases of nocardiosis were associated with preexisting immune compromise, ranging from alcoholism and diabetes to chronic granulomatous disease, organ transplantation, and acquired immunodeficiency syndrome (AIDS). In a recent northern Australian study, greater than one-third (36%) of patients with nocardiosis were immuncompromised. Among recipients of solid-organ transplants with nocardiosis, significant risk factors include receipt of high-dose corticosteroids at time of onset, cytomegalovirus disease within the preceding 6 months, high serum trough levels of calcineurin inhibitors within the preceding 30 days, use of tacrolimus, patient age, and length of stay in the intensive care unit postoperatively. Use of low-dose trimethoprim-sulfamethoxazole (TMP-SMX) for Pneumocystis prophylaxis, such as one double-strength tablet twice a week, did not prevent nocardiosis in either solid-organ or hematopoietic stem cell transplant (HSCT) recipients. Breakthrough nocardiosis remains susceptible to TMP-SMX. The use of anti–tumor necrosis factor-α agents has been associated with disseminated nocardial infections. Although cases of nocardiosis have been described in patients with AIDS, the overall incidence is low and not fully explained by the use of sulfonamide prophylaxis against Pneumocystis jirovecii pneumonia.

Chronic Lung Disease as a Risk Factor for Nocardiosis

Persons with chronic lung disorders, such as pulmonary alveolar proteinosis, and almost any condition requiring long-term corticosteroid use are also at risk. Other chronic airway conditions that may predispose to colonization with Nocardia, with the potential, albeit low, for subsequent infection include cystic fibrosis (CF) and non-CF bronchiectasis. In one study the incidence of nocardiosis among patients with bronchiectasis rose significantly between 1996 and 2013.

Primary Cutaneous Nocardiosis

Primary cutaneous nocardiosis may manifest as superficial cellulitis or abscess, lymphocutaneous (spirotrichoid) infection, or mycetoma. Unlike other forms of nocardiosis, this usually develops in immunocompetent hosts. Superficial infection often follows relatively trivial inoculation injuries ( Fig. 253.2 ), which may vary from insect and animal bites to puncture wounds and contaminated abrasions. The lymphocutaneous form includes a rare variant, cervicofacial nocardiosis, which is associated with prominent localized lymphadenitis. Members of the former N. asteroides complex more commonly cause superficial infections, whereas N. brasiliensis is the most common cause of progressive cutaneous and lymphocutaneous disease. Because the initial response to Nocardia is pyogenic, localized skin lesions may initially be treated as staphylococcal or streptococcal in origin; however, nocardial disease is usually more indolent. In advanced disease a mycetoma can develop with sinus tract formation. Mycetomas are a chronically progressive, destructive disease, occurring days to months after inoculation, and are typically located distally on the limbs. Eumycetoma (of fungal etiology) and actinomycetoma (due to actinomycetes) are equally prominent in the literature, the epidemiology varying with geographic location (see Chapter 261 ). Overall, Streptomyces and Actinomadura spp. appear to be of equal or greater importance than Nocardia spp. as causative agents of actinomycetoma. Suppurative granulomas, progressive fibrosis and necrosis, sinus formation with destruction of adjacent structures, and macroscopically visible infective granules (grains) are regular features of nocardial mycetoma.

Pulmonary Disease

Pulmonary disease is the predominant clinical presentation of nocardiosis and is acquired through inhalation of organisms from the environment. Any species may cause lung infection, although the most common are N. cyriacigeorgica , N. nova, and N. farcinica . Onset of symptoms may be subacute or chronic and include one or more of productive or nonproductive cough, dyspnea, hemoptysis, and fever and other systemic symptoms. In patients with malignancy, radiologically evident pulmonary infiltrates commonly herald the presence of nocardiosis. Established infection may include endobronchial inflammatory masses, pneumonia, lung abscess, and cavitary disease with contiguous extension to surface and deep structures, including effusion and empyema.

Radiologic Manifestations of Pulmonary Nocardiosis

These include irregular nodules (usually cavitating when large), reticulonodular or diffuse pneumonic infiltrates, and pleural effusions ( Fig. 253.3 ). High-resolution computed tomography (CT) of pulmonary lesions most often shows them to be dense, well-circumscribed nodules or masses, often with central cavitation. Interlobar septal thickening around the lesion or ground-glass infiltrates may also be seen. The “halo sign,” considered characteristic of aspergillosis in neutropenic patients, has been described. Progressive fibrotic disease may develop in the immunocompetent host, and diagnosis is often difficult. Pulmonary nocardiosis may occasionally complicate advanced human immunodeficiency virus (HIV) infection (most commonly when the CD4 count is <200/mm ³ ), where it often presents with alveolar infiltrates that progress during therapy rather than as cavitary disease.

Central Nervous System Nocardiosis

CNS involvement was recognized in greater than 44% of cases of all systemic nocardiosis in an early survey compared with 4% to 33% in more recent series. Clinical manifestations usually result from local effects of granulomas or abscesses in the brain and, less commonly, the spinal cord or meninges ( Fig. 253.4 ). These include headache, focal neurologic signs, seizures, confusion, and depressed consciousness. Multiple brain lesions are common. CNS nocardiosis should always be considered in patients with pulmonary or disseminated disease. Indeed, clinically silent brain abscess is sufficiently common that cerebral imaging, preferably magnetic resonance imaging (MRI), should be performed routinely in such cases. Isolated CNS disease can also occur. Insidious presentations are often mistaken for neoplasia because of the paucity of clinical and laboratory signs of inflammation; silent invasion and persistence make diagnosis and management more difficult. Tissue diagnosis of a cerebral mass in the setting of proven pulmonary nocardiosis is not always necessary. However, cerebral biopsy or aspiration should be considered early in the immunocompromised patient because of the higher incidence of serious coexisting pathology and a more aggressive course than that ascribed traditionally to cerebral nocardiosis. N. farcinica has a particular association with CNS (and skin) disease.