Version May 2024
INTRODUCTION — Nocardia spp are aerobic gram-positive bacteria that can cause localized or systemic disease in humans [1-5]. Nocardial infections are typically regarded as opportunistic infections, but approximately one-third of infections occur in immunocompetent individuals [5].
This topic will review the epidemiology, clinical manifestations, and diagnosis of nocardial infections. The microbiology, pathogenesis, and treatment of nocardial infections are discussed separately. (See "Nocardia infections: Clinical microbiology and pathogenesis" and "Treatment of nocardiosis".)
EPIDEMIOLOGY
●Geographic distribution and prevalence – Nocardia species are found worldwide in both temperate and tropical climates, and infections in humans have been reported on all continents except Antarctica [6-10]. A review published in 2020 found that the United States, India, and Mexico had the most cases reported in the literature [10].
Due to lack of systematic surveillance, the true prevalence of nocardial infections is unknown. In the early 1970s, the incidence in the United States was estimated to be approximately 500 to 1000 new cases per year [11]. The current incidence is likely to be higher because the overall United States population has increased, as has the proportion of individuals at risk for nocardiosis.
●Reservoir – The bacteria's natural habitat is soil, decaying vegetation, and salt- and fresh-water aquatic environments [12]. It has been isolated from common sources, such as house dust, swimming pools, tap water, waste water, beach sand, compost, and manure [2,13]. It has also been isolated on dust particles obtained from air samples.
●Transmission – Nocardia is usually transmitted to humans via one of two routes: inhalation or inoculation into the skin.
•Inhalation of contaminated dust is thought to be the most common mode of entry [3,5].
•Skin inoculation occurs via penetrating trauma from a contaminated source (eg, puncture by a contaminated thorn) or exposure of a pre-existing wound to contaminated dust, soil, or water [3,5,14,15].
Human-to-human transmission has not been documented except for one report of nosocomial transmission from a health care worker, as described below [16,17]. (See 'Environmental exposures' below.)
RISK FACTORS — The most common risk factors for nocardial infection relate to patients' comorbidities, although specific environmental exposures can also predispose to infection.
Immunocompromising conditions — Data suggest that approximately two-thirds of nocardial infections occur in immunocompromised individuals, particularly those with cell-mediated immunosuppression [3-5,18-25].
●Glucocorticoids and other immunosuppressive medications – Treatment with glucocorticoids is the most frequently reported risk factor for nocardial infection [3,20,22-28]. In a case-control study of 70 infected individuals, glucocorticoid therapy conferred almost a five-fold increase in infection risk (odds ratio [OR] 4.69; 95% CI, 2.45-8.99) [25].
The dosage of glucocorticoid therapy that predisposes to infection is unclear; some data suggest that higher dosages and prolonged courses (eg, ≥20 mg of prednisone for ≥1 month) confer greater risk [20,25,29]. Immune-related side effects from glucocorticoid therapy are discussed in further detail elsewhere. (See "Major adverse effects of systemic glucocorticoids", section on 'Immune system effects'.)
Other immunosuppressive medications associated with Nocardia infection include calcineurin inhibitors (eg, tacrolimus, cyclosporine), chemotherapy for malignancy, and monoclonal antibodies to B-cells, T-cells, and tumor necrosis factor-alpha (eg, rituximab, alemtuzumab, infliximab) [20,29-37]. The immunosuppressive action of these agents is discussed in further detail elsewhere. (See "Secondary immunodeficiency induced by biologic therapies" and "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections" and "Infection in the solid organ transplant recipient".)
●Organ transplant recipients – Observational data suggest that organ transplant recipients represent up to half of all infections, most likely due to the immunosuppressive medications used to prevent rejection [3,20,25,27-29,36-40].
Transplant recipients are most at risk in the first year post-transplant and during episodes of organ rejection, as discussed elsewhere [3,20,29,39]. (See "Infection in the solid organ transplant recipient", section on 'Timing of infection post-transplantation'.)
Prophylactic trimethoprim-sulfamethoxazole (TMP-SMX) is not protective against Nocardia in organ transplant recipients, based on available data [20,29,39]. Failure of prophylaxis does not appear to be due to TMP-SMX resistance.
Other risk factors specific to organ transplant recipients include cytomegalovirus infection in the preceding six months and length of stay in the intensive care unit after transplantation [20,25,29]. The type of organ transplanted (eg, kidney, lung) does not appear to affect risk.
●Malignancy – Solid-tumor and hematologic malignancies, including those treated with hematopoietic cell transplantation, have been associated with nocardial infection [5,25,26]. Like organ transplant recipients, the risk is primarily due to the immunosuppressive medications used to treat malignancy rather than the malignancy itself. Neutropenia has not been found to be a significant risk factor.
●HIV infection – Since the advent of highly effective antiretroviral therapy, individuals with HIV no longer represent a large proportion of reported cases [8,9,22,23,41-44]. Most patients with human immunodeficiency virus (HIV) and Nocardia with nocardial infection are severely immunocompromised; in case series, the mean CD4 count is between 20 and 40 cells/microL [22,41]. Nocardial infections have been reported in patients with HIV on typical doses of prophylactic TMP-SMX used to prevent Pneumocystis infection [3,41,42].
●Primary immune deficiencies – Certain primary immune deficiencies, such as chronic granulomatous disease, idiopathic CD4 lymphopenia, interleukin-12 p40 deficiency, and anti-granulocyte macrophage colony-stimulating factor (GM-CSF) autoantibodies, have been associated with nocardial infections [10,45,46]. Primary immune deficiencies are discussed in detail elsewhere. (See "Inborn errors of immunity (primary immunodeficiencies): Classification".)
Environmental exposures — In some cases, especially cutaneous infections, specific environmental exposures prior to onset of symptoms can be identified.
●Outdoor exposure – Cutaneous infection has been associated with many outdoor exposures, such as gardening, farming, insect bites, skin trauma from motor vehicle accidents ("road rash"), and puncture wounds from thorns or splinters [3,5,47-54].
●Health care exposure – Health care-associated infections have been reported, including surgical site infections, catheter-related bloodstream infections, implantable defibrillator pocket infections, and infections following cutaneous injection of corticosteroids or contaminated cosmetic solutions [12,14,16,55-64]. Outbreaks within hospitals can occur, as described in an outbreak of 18 surgical site infections and three pulmonary infections caused by a single strain of Nocardia found in the air of patient rooms [16,55,56]. In another example, a cluster of nosocomial postoperative sternal wound infections was caused by a nocardial isolate that was identical to one cultured from the hands and home of a healthy anesthesiologist who had cared for the patients during surgery [16].
Further details regarding environmental sources of infection are discussed elsewhere. (See 'Epidemiology' above.)
Other risk factors — Other conditions that have been associated with nocardial infections include chronic lung disease (eg, alveolar proteinosis, chronic obstructive pulmonary disease), diabetes mellitus, alcoholism, injection drug use disorder, cigarette smoking, and tuberculosis [3,5,19,23,30,31,38,41,65]. Male sex has also been identified as a risk factor.
CLINICAL MANIFESTATIONS
Course of illness — Patients with nocardial infections typically have an insidious onset of symptoms with a subacute course that progresses over several weeks [9]. Systemic indicators of infection, such as fever or leukocytosis, may or may not be present. As the disease progresses, focal symptoms develop related to the anatomic site or sites of infection.
Anatomic sites of infection — Most often, Nocardia causes localized disease at the portal of entry (ie, lungs or skin) [2,5,10,29,65-67]. However, it can disseminate to other organs via the bloodstream or spread to adjacent tissues by contiguous invasion.
Disseminated disease, defined as infection at two or more noncontiguous sites, has been estimated to occur in 20 to 50 percent of infections and is more common in immunocompromised individuals [2,65,68]. The most common site of dissemination is the brain [2,5,9,10,12].
Lungs — The lungs are the primary site of infection in approximately 80 percent of cases in immunocompromised individuals and up to half of cases in nonimmunocompromised individuals [3,20,38,65,69]. Among nonimmunocompromised individuals, reported risk factors include cigarette smoking, chronic obstructive pulmonary disease (COPD), bronchiectasis, and other chronic lung diseases [23,38,65].
●Clinical features – The onset of pulmonary infection may be acute, subacute, or chronic. Fever and cough are the most frequently reported symptoms; night sweats, fatigue, anorexia, weight loss, hemoptysis, dyspnea, and pleuritic chest pain have also been described [2-4,23,67,70]. In patients with chronic lung disease (eg, COPD, sarcoidosis), diagnostic delays may occur because the clinical presentation can mimic an exacerbation of the underlying lung condition [71,72].
More than half of all pulmonary infections disseminate hematogenously, most often to the brain [10,29,67]. Both immunocompromised and nonimmunocompromised individuals can have disseminated infection.
Nocardia spp can also spread contiguously from the lungs to adjacent structures, causing complications such as empyema, mediastinitis, pericarditis, and superior vena cava syndrome [73-75]. The clinical presentation of these conditions is discussed separately. (See "Epidemiology, clinical presentation, and diagnostic evaluation of parapneumonic effusion and empyema in adults", section on 'Clinical features' and "Mediastinal granuloma and fibrosing mediastinitis", section on 'Clinical presentation' and "Acute pericarditis: Clinical presentation and diagnosis", section on 'Clinical features' and "Clinical features, diagnosis, and classification of thoracic central venous obstruction", section on 'Clinical features'.)
●Imaging findings – Radiographs (plain x-rays) and computed tomography (CT) of the lungs may reveal a broad range of findings. The most common finding is unilateral or bilateral nodular disease; the nodules may be cavitary, especially in immunocompromised individuals [65]. Other imaging findings include lung masses, consolidation, pleural effusion, reticulonodular infiltrates, interstitial infiltrates, and subpleural plaques (image 1 and image 2) [5,43,76-78].
Skin — Cutaneous disease results from direct inoculation of the skin (primary cutaneous disease) or dissemination to the skin from another site of infection.
●Primary cutaneous disease – The most common cause of cutaneous disease is penetrating trauma from a contaminated object (eg, thorn) or exposure of a pre-existing wound to contaminated dust, soil, or water [3,5,14,15].
Primary cutaneous disease is more likely than other forms of nocardial infection to occur in nonimmunocompromised individuals and is less likely to disseminate hematogenously to remote locations throughout the body. In a review of 400 published cases of nocardial infection in nonimmunocompromised individuals, approximately 3 to 8 percent of patients with cutaneous infection had dissemination to the central nervous system (CNS; eg, brain) compared with 28 to 35 percent of patients with pulmonary infection [10].
Primary cutaneous disease presents as one of three syndromes:
•Localized infection – Localized infection typically presents with one or more progressively painful skin lesions at the site of an injury or pre-existing wound. Lesions usually appear as nodules or ulcerations, although papules, pustules, cellulitis, and subcutaneous abscesses may occur, with or without purulent drainage [79-81].
Localized infection may spread to muscle, bone, or joint via contiguous spread [1,4].
•Nodular lymphangitis (ie, sporotrichoid lymphocutaneous disease) – Patients with this infection complain of a slowly enlarging skin lesion on an extremity with subsequent progression in a linear fashion up the extremity. Exam reveals either a nodular or ulcerative primary lesion with erythematous nodules extending up the extremity. This syndrome has been termed "sporotrichoid nocardiosis" due to its similar presentation to sporotrichosis [82-85].
•Mycetoma – A mycetoma is a chronic cutaneous infection that initially begins with one or more painless, slow-growing indurated nodules that eventually coalesce to form large tumors with necrotic abscesses and draining sinus tracts. The most common location is a foot or leg, but mycetomas can occur in other areas as well. The enlarging mass can remain localized or can spread contiguously to adjacent muscles and bone (picture 1) [67,86-88].
Mycetomas can also be caused by fungi and other bacteria. Further details regarding the microbiology and clinical features of mycetoma are found elsewhere. (See "Eumycetoma".)
●Dissemination to the skin from another site of infection – Rarely, disseminated infection presents with cutaneous skin lesions due to hematogenous spread from another site of infection. The lesions typically appear as rounded cellulitic lesions about 1 to 5 cm in diameter, and multiple lesions in a widespread distribution may occur (picture 2) [24,67,89-92].
Cutaneous infections associated with antecedent wounds or trauma, nodular lymphangitis, and mycetoma are unlikely to be due to dissemination.
Central nervous system — Central nervous system (CNS) infection is the most common site of disseminated infection and has been reported to occur in 20 to 58 percent of patients with nocardial infections [5,10,12,24,44,67,93]. Most cases of CNS infection are reported in immunocompromised individuals.
The presumed mechanism of CNS infection is hematogenous spread from a distant focus of infection, usually the lungs. Many patients have coexistent pulmonary infection at the time of diagnosis. Others have only isolated CNS infection presumed to have been caused by prior transient pulmonary or cutaneous infection [5,24,44,67].
●Clinical features
•Brain abscess – Brain abscess is the most common form of CNS infection. Infection can cause single or multiple abscesses in any region of the brain [5,24,43,67,69,94-98]. Patients may present with acute or subacute focal neurologic deficits (eg, hemiparesis, cranial nerve palsy), headache, altered mental status, seizure, or ataxia; systemic signs of infection, such as fever, are often absent. The clinical manifestations of brain abscess are discussed in further detail elsewhere. (See "Pathogenesis, clinical manifestations, and diagnosis of brain abscess", section on 'Clinical manifestations'.)
Many patients with nocardial brain abscess have no symptoms or signs of brain involvement; in an observational study including 30 organ transplant recipients with CNS infection, 13 (43 percent) had no neurologic symptoms or abnormalities on exam [29]. For some patients with confirmed nocardial infection outside the CNS, brain imaging is performed to detect asymptomatic disease, as discussed below. (See 'Evaluating for disseminated disease' below.)
•Meningitis – Rarely, patients present with meningitis, with or without an associated brain abscess [24,67,99,100]. In a case series of 28 individuals with nocardial meningitis, the typical presentation was subacute or chronic meningitis characterized by fever (68 percent), meningismus (64 percent), and headache (55 percent); brain abscess was present in 43 percent [100]. The cerebrospinal fluid (CSF) demonstrated neutrophilic pleocytosis, hypoglycorrhachia, and elevated protein concentration, findings that are characteristic of bacterial meningitis. CSF analysis is discussed in more detail elsewhere. (See "Cerebrospinal fluid: Physiology and utility of an examination in disease states".)
●Imaging findings – Brain imaging reveals ring-enhancing lesions in over 90 percent of individuals with CNS disease, and approximately half have multiple lesions [24,101]. Surrounding edema (with or without mass effect) is present in 40 to 50 percent (image 3 and image 4).
Other sites of infection
●Eye – Nocardial ocular infections almost always occur in eyes that have been damaged from trauma, ophthalmologic surgery, or contact lens-associated corneal abrasions [9,10,21,67,102-111]. Rarely, Nocardia can disseminate to the eye from other sites of infection and cause endophthalmitis [24,111].
Symptoms of infection include pain, photophobia, visual impairment, or floaters in the affected eye. Examination may reveal red eye, corneal opacity, purulent discharge, hypopyon, retinal abnormalities, decreased visual acuity, and other signs of ocular infection, as described elsewhere (picture 3). (See "The red eye: Evaluation and management", section on 'Bacterial keratitis' and "Bacterial endophthalmitis".)
Available data suggest that immunocompromised individuals do not have increased risk for ocular infection, and ocular infections rarely spread contiguously or hematogenously to other anatomic sites [10,65]. In a review of 400 published cases of nocardial infection in nonimmunocompromised individuals, approximately 2 percent of patients with keratitis had dissemination to the central nervous system (eg, brain) [10].
●Bloodstream – Nocardial bacteremia is a rare occurrence, even in individuals with disseminated disease. Most patients with bacteremia have concomitant pulmonary infection and are immunocompromised. Endocarditis has been reported in individuals with bacteremia; in a systematic review of 25 case series, endocarditis was present in 15 (11 percent) of 138 individuals with nocardial bacteremia [61]. In some cases, endovascular foreign bodies (eg, intravascular catheters or stents, prosthetic heart valves) are the only identifiable cause of bacteremia [57,68,112].
●Rare sites of infection – Because Nocardia can disseminate hematogenously, infections have been reported throughout the body, including in joints, kidneys, liver, spleen, adrenal glands, pancreas, thyroid gland, psoas muscle, spinal epidural space, retroperitoneum, urinary tract, prostate, and testicles [2,3,5,16,61-64,67,102-104,113-123]. When the original focus of infection cannot be identified, the patient is presumed to have had prior unrecognized pulmonary or cutaneous disease.
Primary cutaneous infections can invade adjacent bone, muscle, and lymph nodes, and pulmonary infections can invade the pleural space, mediastinum, pericardium, and superior vena cava, as described above (see 'Skin' above and 'Lungs' above). Nocardial sinusitis, believed to be caused by nasal inhalation of nocardial organisms, is rare and can invade into bone, muscle, cavernous sinuses, meninges, and brain [104,114,124-127].
COINFECTIONS WITH OTHER ORGANISMS — Coinfections with other pathogens are not uncommon, occurring in up to 20 percent of infected individuals in some case series [20,24,39,67,69,128]. Most often, both organisms grow in cultures from the lungs, but brain coinfections have been reported as well. Molds (primarily Aspergillus), Mycobacterium tuberculosis, and nontuberculous mycobacteria are the most common causes of coinfections.
DIAGNOSIS
When to suspect nocardial infection — Clinical suspicion for nocardial infection varies depending on the anatomic site or sites of involvement.
●Cutaneous infection – Nocardial skin infection should be suspected in any individual with a subacute presentation of nodular lymphangitis, mycetoma, or wound infection following exposure to soil or water. Skin infections that fail to respond to usual antibiotic therapy should further prompt consideration of Nocardia. (See 'Skin' above.)
●Lung nodules – Nocardial infection should be suspected in any patient with cell-mediated immune deficiency (eg, corticosteroid use) and/or chronic lung disease who has new pulmonary nodules. (See 'Lungs' above.)
●Brain abscess – Ring-enhancing brain lesions in a patient with cell-mediated immune deficiency (eg, corticosteroid use) should prompt consideration of Nocardia. (See 'Central nervous system' above.)
Clinical suspicion for nocardial infection should be particularly high in individuals who have both lung nodules and brain abscess. (See 'Disseminated infection' below.)
Confirming the diagnosis — The diagnosis of nocardial infection is confirmed by microbiologic identification of the organism in a clinical specimen from any suspected site of infection.
Nocardial colonization of the lungs without infection is considered uncommon [129,130]. In our experience, 7 of our 67 patients (10 percent) fit this category. All had a chronic lung condition but without evidence of new clinical disease. Such patients need regular ongoing clinical review [38].
Obtaining samples for testing — Prior to obtaining specimens for testing, laboratory personnel should be notified that Nocardia is suspected so they can take special measures to optimize results. Most microbiology and pathology labs have specific protocols for detection of Nocardia, as discussed elsewhere. (See "Nocardia infections: Clinical microbiology and pathogenesis", section on 'Specific microbiologic tests'.)
●Pulmonary infection – Sputum or bronchoalveolar lavage (BAL) samples are usually adequate to diagnose pulmonary nocardial infection. In an observational study of individuals with pulmonary infection, expectorated sputum was diagnostic in 45 (88 percent) of 51 individuals who submitted sputum [21].
●Infections outside the lungs – For patients suspected of nonpulmonary nocardial infection, biopsy of affected tissue is typically necessary to make the diagnosis. Tissue specimens should be sent to the microbiology lab as well as to the pathology lab for microscopic evaluation.
●Multiple sites of infection – For patients who have multiple suspected sites of infection, we usually sample the site that is easiest to access. However, in certain situations, obtaining samples from each suspected site may be indicated, as discussed below. (See 'Evaluating for disseminated disease' below.)
Despite their low sensitivity, we also submit two sets of routine blood cultures on every patient suspected of having nocardial infection. Positive results can confirm the diagnosis or identify an alternative organism or coinfection.
Microbiologic tests — Nocardia spp can be identified by microbiologic stains (eg, Gram stain), culture, or molecular testing.
We request stains and cultures specific for Nocardia when we send the samples to the microbiology and pathology laboratories. In addition, we typically order routine bacterial, fungal, and mycobacterial stains and cultures of the specimens to detect other infections that are clinically indistinguishable from nocardial infection.
●Microbiologic stains – In individuals with compatible syndromes, a rapid diagnosis of nocardial infection can be made by visualizing the organisms in clinical specimens (picture 4 and picture 5 and picture 6). The value of direct microscopy of stained specimens cannot be overemphasized [131-133].
•Gram stain – Nocardia spp usually appear as delicate, branching, filamentous, sometimes beaded gram-positive bacilli on Gram stain (picture 4 and picture 5) [1].
In a study of 80 individuals with nocardial infections, the overall sensitivity of Gram stains performed on direct clinical specimens was 64 percent, and the sensitivity for sputum was 78 percent [21].
•Modified acid-fast stain – This stain should be performed on any sample that shows organisms consistent with Nocardia on Gram stain: among the various branching gram-positive bacilli, only Nocardia spp will stain positive by modified acid-fast staining [67,134].
However, the sensitivity is suboptimal; in a study of 50 patients with confirmed nocardial infection who had positive Gram stains, only 26 (51 percent) were positive by modified acid-fast staining.
●Culture – Recovery of Nocardia in cultures can be difficult, so the microbiology laboratory should be notified so they can take measures to optimize growth (eg, prolonging incubation time, using special growth media) [1-3,5,67,135,136].
The overall sensitivity of culture for respiratory or tissue specimens ranges between 85 and 95 percent in most studies [21,67]. Yield from blood cultures is low, even in disseminated disease [61,68].
Once Nocardia grows in culture, we suggest that the isolate be sent to a reference laboratory for susceptibility testing and species identification. In general, reference laboratories have more extensive and accurate tests that can help guide antimicrobial therapy. Further information regarding susceptibility testing, including specific reference laboratories in the United States, is found below. (See 'Antimicrobial susceptibility testing' below.)
●Molecular tests – Molecular tests for Nocardia spp, such as polymerase chain reaction (PCR) or whole genome sequencing, are not widely available in clinical laboratories. When no pathogen has been identified using traditional microbiologic testing and clinical suspicion remains for Nocardia, PCR or whole genome sequencing at reference laboratories may identify the organism.
Details regarding laboratory techniques for staining of Nocardia spp are found elsewhere. (See "Nocardia infections: Clinical microbiology and pathogenesis", section on 'Specific microbiologic tests'.)
Histopathology — There are no pathognomonic histopathologic findings specific for Nocardia in biopsied tissue, but visualization of the organism in stained tissue is highly suggestive. Microscopic evaluation of infected tissue most often reveals necrosis with abscess (including microabscess) formation [137-139]. There may be a mixed cellular infiltrate of polymorphonuclear leucocytes, lymphocytes, plasma cells, and hemosiderin-laden macrophages [139-141]. Granulomas with central necrosis mimicking tuberculosis have been described in lung and pleural tissue, but these findings occur infrequently [139,140].
Laboratory tests — There are no laboratory tests that are specific for nocardial infection. However, we often send lab tests that can indicate or rule out other potential diagnoses, such as those included in the differential diagnoses outlined elsewhere. (See 'Differential diagnosis' below.)
POST-DIAGNOSIS EVALUATION — Once the diagnosis of nocardial infection has been confirmed by microbiologic testing of a clinical specimen, additional evaluation is often performed to guide therapy, assess the extent of infection, and identify underlying predisposing conditions.
Antimicrobial susceptibility testing — As soon as growth has been achieved in the microbiology lab, we ask our microbiology laboratory to send samples of the isolate to specific reference laboratories to obtain more reliable susceptibility testing and species identification. Antimicrobial susceptibility profiles vary markedly among different species of Nocardia and standard susceptibility testing may produce inaccurate results.
In the United States, reference laboratories that provide such testing include the following:
●University of Utah
●The Mycobacteria/Nocardia Research Laboratory, University of Texas Health Sciences Center
Antibiotic susceptibility patterns of different species of Nocardia spp and microbiologic techniques are discussed separately. (See "Treatment of nocardiosis", section on 'Antibiotic susceptibility' and "Nocardia infections: Clinical microbiology and pathogenesis", section on 'Antimicrobial susceptibility testing'.)
Evaluating for disseminated disease — Once nocardial infection has been confirmed in one anatomic site, the value of further testing to detect other sites of infection (ie, disseminated disease) is unclear.
●Brain and lung imaging – For most patients with nocardial infection, we obtain brain magnetic resonance imaging (MRI) and chest CT (if not already performed) to evaluate for brain or lung involvement. The exception is nonimmunocompromised individuals with primary cutaneous disease or keratitis.
Our rationale for performing brain imaging is that brain abscesses are potentially fatal illnesses that usually require neurosurgical intervention, and patients with nocardial brain abscesses can be asymptomatic with normal neurologic exams. We obtain chest imaging because the lungs are the most common source of hematogenous spread, and asymptomatic lung infection may alter treatment plans. We may exclude individuals with primary cutaneous disease or keratitis because these conditions rarely disseminate hematogenously, except, perhaps, in patients who are immunocompromised. Further discussion of the risk of dissemination is found elsewhere. (See 'Anatomic sites of infection' above.)
The value of such screening has not been formally assessed. Typical imaging findings are discussed elsewhere. (See 'Lungs' above and 'Central nervous system' above.)
●Microbiologic testing of multiple sites of infection – Once the diagnosis has been microbiologically confirmed at one site, additional specimens from other suspected sites of infection are generally unnecessary (ie, we presume that the other sites are also due to Nocardia).
However, in select situations, we seek microbiologic confirmation of disseminated infection. For example, because primary cutaneous disease and keratitis infrequently disseminate, we obtain specimens from other sites where infection is suspected (eg, lung, brain). Other exceptions may include patients with malignancy and nocardial infection with clinical features that could be due to either illness or patients with coinfection (eg, pulmonary Nocardia and Aspergillus) who have brain lesions that could be due to either organism. Coinfections are further discussed elsewhere. (See 'Coinfections with other organisms' above.)
●Limited role of echocardiography – Due to the rarity of endocarditis, we do not perform echocardiography in most patients with nocardial infection, even those with disseminated disease. However, we do initiate workup for endocarditis in patients with underlying cardiac valve abnormality, nocardial bacteremia, or other symptoms and signs of endocarditis. The clinical manifestations and diagnosis of endocarditis are discussed separately. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis" and "Prosthetic valve endocarditis: Epidemiology, clinical manifestations, and diagnosis".)
Assessing for underlying immune deficiency — The role of evaluating the immune system in individuals with nocardial infection who have no identifiable immunocompromising condition is unclear [3,10,45].
Nevertheless, we check all patients for HIV and perform a thorough clinical history to assess for evidence of frequent or past unusual infections, findings that would warrant further workup by an immunologist. The threshold for evaluating the immune system in children should be lower, and referral to an immunologist is advised. (See "Laboratory evaluation of the immune system" and "Inborn errors of immunity (primary immunodeficiencies): Classification".)
DIFFERENTIAL DIAGNOSIS — The differential diagnosis for nocardial infections is broad and varies with the site of involvement. Noninfectious and infectious diseases can mimic Nocardia as outlined in the table (table 1).
Pulmonary infection — Nodular pulmonary disease with or without cavitation is the most common radiographic finding of nocardial infection. (See 'Lungs' above.)
●Infectious causes of lung nodules – Each of these conditions is differentiated from Nocardia by microbiologic tests discussed in this topic and elsewhere (see 'Microbiologic tests' above and "Nocardia infections: Clinical microbiology and pathogenesis", section on 'Specific microbiologic tests'). Like Nocardia, many of the infections below occur primarily in immunocompromised individuals.
•Fungal infections – These include mold infections (eg, Aspergillus spp, Mucorales), Cryptococcus spp, and endemic mycoses (eg, histoplasmosis, blastomycosis, coccidioidomycosis). (See "Epidemiology and clinical manifestations of invasive aspergillosis", section on 'Pulmonary aspergillosis' and "Diagnosis of invasive aspergillosis".)
•Mycobacterial infections – Tuberculosis and nontuberculous mycobacteria (eg, Mycobacterium avium complex, M. kansasii) can cause lung lesions similar in appearance to Nocardia. Misdiagnosis of nocardial infection as mycobacteria has been reported on microbiologic staining as well [2]. (See "Pulmonary tuberculosis: Clinical manifestations and complications", section on 'Clinical manifestations' and "Diagnosis of pulmonary tuberculosis in adults" and "Diagnosis of nontuberculous mycobacterial infections of the lungs".)
•Bacterial infection – Bacterial infections may mimic nocardiosis, including Rhodococcus equi and gram-negative bacilli such as Pseudomonas aeruginosa and Klebsiella pneumoniae. Septic pulmonary emboli from endocarditis and other intravascular infections (eg, Lemierre syndrome) can cause nodular infiltrates but typically have positive blood cultures. Actinomyces spp can mimic Nocardia, except Actinomyces pulmonary infections have a propensity to cross lung fissures and invade the chest wall. Actinomyces and Rhodococcus can have a similar appearance to Nocardia on microbiologic staining. (See "Clinical features, diagnosis, therapy, and prevention of Rhodococcus equi infections", section on 'Clinical features' and "Clinical features, diagnosis, therapy, and prevention of Rhodococcus equi infections", section on 'Diagnosis'.)
•Parasitic infection – Toxoplasma gondii occasionally causes nodular and cavitary lung disease. (See "Diagnostic testing for toxoplasmosis infection", section on 'Diagnosing acute infection'.)
●Noninfectious causes of lung nodules – Noninfectious considerations include malignancy (eg, primary lung cancer, pulmonary metastases), sarcoidosis, and ANCA-associated vasculitides and other autoimmune diseases (eg, rheumatoid arthritis). Tissue biopsy is often necessary to make these diagnoses, and serologic tests can be of value for the vasculitides and other autoimmune diseases. (See "Overview of the initial evaluation, diagnosis, and staging of patients with suspected lung cancer" and "Clinical manifestations and diagnosis of sarcoidosis" and "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis".)
For non-nodular pulmonary disease, the differential is even broader. (See "Approach to the immunocompromised patient with fever and pulmonary infiltrates".)
CNS infection — Ring-enhancing brain abscesses are the most frequent finding of central nervous system (CNS) nocardial infection. The differential diagnosis is broad, and tissue samples are usually required to differentiate these conditions. Like CNS nocardial infections, many of these conditions most often occur in immunocompromised individuals.
●Infectious causes of ring-enhancing brain abscesses – Infectious causes of brain abscess are numerous and are discussed in detail elsewhere (see "Pathogenesis, clinical manifestations, and diagnosis of brain abscess"). Listed below are some etiologies likely to mimic CNS nocardial infection.
•Bacterial infection – Brain abscess is most frequently caused by bacteria such as anaerobes, streptococci, Staphylococcus aureus, and aerobic gram-negative bacilli. Multiple brain abscesses may be due to septic emboli from endocarditis, which is usually accompanied by positive blood cultures. Rhodococcus can also cause brain abscess. (See "Pathogenesis, clinical manifestations, and diagnosis of brain abscess".)
•Fungal infection – Mold infections (eg, Aspergillus spp, Mucorales) and Cryptococcus spp can cause ring-enhancing brain abscesses. Most, but not all, cases of intracerebral Mucorales infection have rhino-orbital involvement, a finding that would be unusual for nocardiosis. (See "Clinical manifestations and diagnosis of Cryptococcus neoformans meningoencephalitis in patients without HIV" and "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV" and "Epidemiology and clinical manifestations of invasive aspergillosis", section on 'Central nervous system infection'.)
•M. tuberculosis – Tuberculosis can cause ring-enhancing lesions in the brain known as tuberculomas. (See "Central nervous system tuberculosis: An overview", section on 'Tuberculoma'.)
•Parasitic infection – T. gondii and Taenia solium (the causative agent of neurocysticercosis) both cause ring-enhancing lesions of the brain. CNS toxoplasmosis is most common in patients with advanced HIV disease, whereas neurocysticercosis often occurs in nonimmunocompromised individuals. (See "Toxoplasmosis in patients with HIV", section on 'Serology' and "Cysticercosis: Clinical manifestations and diagnosis", section on 'Serology'.)
●Noninfectious causes of ring-enhancing brain lesions – Brain tumors (malignant or benign primary brain tumors, CNS lymphoma, or metastatic disease), sarcoidosis, and multiple sclerosis can all cause ring-enhancing lesions. Tissue biopsy is necessary to diagnosis brain tumors, whereas the diagnosis of neurologic sarcoid and multiple sclerosis can be elusive and requires thorough clinical evaluation. (See "Overview of the clinical features and diagnosis of brain tumors in adults" and "Clinical manifestations and diagnosis of central nervous system tumors in children" and "Neurologic sarcoidosis" and "Evaluation and diagnosis of multiple sclerosis in adults", section on 'Active versus chronic lesions' and "Evaluation and diagnosis of multiple sclerosis in adults", section on 'Tumefactive demyelination'.)
Cutaneous infection — The differential diagnosis of cutaneous nocardiosis is broad and can be categorized based on the clinical presentation. Tissue biopsy and culture are necessary to differentiate most of these syndromes.
●Localized infection – There are innumerable alternative etiologies for localized skin infection. For cellulitis, the differential includes any cause of cellulitis, such as streptococci and staphylococci.
Papular, pustular, nodular, and ulcerative infection can also be due to Pseudomonas spp (ie, ecthyma gangrenosum), mycobacteria, fungi (eg, Cryptococcus spp, molds, endemic mycoses [eg, histoplasmosis, blastomycosis, coccidioidomycosis]), and Burkholderia pseudomallei (melioidosis).
Noninfectious etiologies include acne vulgaris, hidradenitis suppurative, pyoderma gangrenosum, Sweet syndrome, and others. (See "Cellulitis and skin abscess: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Microbiology' and "Approach to the patient with pustular skin lesions".)
Localized infections can also be caused by any of the organisms that cause nodular lymphangitis, listed below.
●Nodular lymphangitis – Organisms known to cause this syndrome include Bartonella henselae (cat scratch disease), nontuberculous mycobacteria (primarily M. marinum), Sporothrix schenckii, Erysipelothrix rhusiopathiae, Leishmania spp, Francisella tularensis, and Scedosporium. Clinical suspicion for these infections is often based on environmental exposures (eg, soil or thorn exposures for Nocardia and sporotrichosis, aquarium or fish exposure for M. marinum, fish or hunting exposure for Erysipelothrix, living or traveling to endemic areas for Leishmania). (See "Lymphangitis", section on 'Nodular lymphangitis'.)
●Mycetoma – Botryomycosis, chromoblastomycosis, and mycetoma due to non-nocardial organisms may mimic nocardial mycetoma. Organisms other than Nocardia that cause mycetoma include fungi (eumycetoma) and members of the Actinomycetales order other than Nocardia, including Actinomyces and Streptomyces. The causative organisms are typically identified by culture and histopathologic examination of tissue and extracted grains. (See "Eumycetoma".)
Disseminated infection — There is significant overlap in the differential diagnosis of pulmonary, CNS, and cutaneous nocardiosis. When patients present with a combination of manifestations, the differential diagnosis can be narrowed to organisms that can infect those specific anatomic sites as depicted in the table (table 1). (See 'Pulmonary infection' above and 'CNS infection' above and 'Cutaneous infection' above.)
SUMMARY AND RECOMMENDATIONS
●Epidemiology – Nocardial infections occur worldwide. The organism's natural environment is soil and aquatic environments, and the two main modes of transmission to humans are inhalation and skin inoculation. (See 'Epidemiology' above.)
●Risk factors – The main risk factor for cutaneous disease is puncture wounds from soil-contaminated objects (eg, thorns). For all other forms of disease, the primary risk factor is immunocompromising conditions, especially the use of glucocorticoids and other immunosuppressive medications. (See 'Risk factors' above.)
●Clinical manifestations – Illness usually has a subacute course over a few weeks. The organism can disseminate hematogenously to almost anywhere in the body, and symptoms are primarily related to the site of infection. (See 'Clinical manifestations' above.)
•Lungs – The lungs are the most common site of infection. Symptoms include fever and cough, and the most common radiographic finding is lung nodules with or without cavitation. (See 'Lungs' above.)
•Skin – Cutaneous infection may manifest as many different types of skin lesions. Nodular and ulcerative lesions are most common, and nodular lymphangitis may occur. Mycetoma can occur as well. Skin disease infrequently disseminates. (See 'Skin' above.)
•Brain – Brain abscesses are the most common site of dissemination, and may be asymptomatic. The brain may be the only site of infection at the time of diagnosis. MRI typically reveals one or more ring-enhancing lesions with or without surrounding edema. (See 'Central nervous system' above.)
•Other sites of infection – Due to Nocardia's ability to disseminate, infections have been reported in almost every organ. Infectious keratitis can occur due to eye injury. (See 'Other sites of infection' above.)
●Coinfections – Coinfections with molds (eg, Aspergillus spp) and mycobacteria are not uncommon, especially in the lungs. (See 'Coinfections with other organisms' above.)
●Diagnostic evaluation – Clinical suspicion for nocardial infection varies depending on the anatomic site or sites of involvement. (See 'When to suspect nocardial infection' above.)
•Microbiologic testing – The diagnosis is confirmed by identifying the organism by culture, microbiologic staining (eg, Gram stain), or molecular testing of samples obtained from a suspected site of infection. The diagnosis usually requires tissue biopsy, except sputum samples are often adequate for lung infection. The microbiology lab personnel should be notified if Nocardia is suspected so they can take special measures to optimize results. (See 'Microbiologic tests' above.)
●Evaluating for disseminated disease – To rule out asymptomatic brain abscess and lung disease, we typically obtain brain MRI and chest CT. Once the diagnosis has been microbiologically confirmed at one site, additional specimens from other suspected sites of infection are generally unnecessary. (See 'Evaluating for disseminated disease' above.)
●Differential diagnosis – The differential diagnosis depends on the suspected site(s) of infection. Diseases that can affect the lungs, brain, and skin include infections due to fungi (eg, Aspergillus, Cryptococcus) or mycobacteria (eg, tuberculosis) as well as malignancies and sarcoidosis (table 1). (See 'Differential diagnosis' above.)
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