Essentials of Diagnosis
- Gram-positive, variably acid-fast, branching filaments with aerial hyphae.
- Colonies have characteristic chalky-white or cotton ball appearance.
- Suspect when chronic pulmonary disease is accompanied by CNS or skin lesions.
- No specific antibody or antigen detection tests.
General Considerations
Epidemiology
Nocardia spp. are strictly aerobic, ubiquitous soil-dwelling organisms that are largely responsible for the decomposition of organic plant material. Infection usually occurs via inhalation of these organisms in airborne dust particles, leading to pulmonary disease.
However, infection can also be acquired via direct percutaneous inoculation by thorns, animal scratches, bites, surgical wounds, and intravenous catheters. Dissemination commonly occurs to the central nervous system (CNS), skin, and subcutaneous tissues.
Nocardiosis is chiefly an opportunistic infection and occurs especially in patients with lymphoma and leukemia and to a lesser extent in patients with solid tumors. It is becoming more frequently recognized in patients with AIDS (~ 10% of all nocardial infections since 1980), those receiving organ transplants (especially renal and heart), and those receiving therapy with cytotoxic agents.
Underlying pulmonary conditions, such as chronic obstructive pulmonary disease and bronchiectasis, also predispose individuals to pulmonary nocardiosis. Children with chronic granulomatous disease are at elevated risk of developing this infection. One-third of patients with nocardiosis, however, have no apparent predisposing factor. The disease affects men approximately threefold as often as it affects women and most often affects men and women between the ages of 30 and 50 years.
Approximately 90% of nocardial infections in the United States are due to Nocardia asteroides (and the related species Nocardia farcinica and Nocardia nova, which together form the N asteroides complex). Other pathogenic species implicated in disease include Nocardia brasiliensis, Nocardia otitidiscaviarum, and Nocardia transvalensis.
While infection with N asteroides is geographically widespread, most cases of N brasiliensis infection in the United States have originated in the southern regions of the United States, especially Texas, southern California, Oklahoma, and Florida. Cases have also been reported from North Carolina.
Microbiology
See earlier introductory comments.
Pathogenesis
Disease occurs after virulent strains of Nocardia successfully evade the bactericidal defenses of the host’s immune response. Nocardia virulence is to a large extent determined by the dynamically changing and complex structure of the bacterial cell envelope. Structural changes result in alterations of cell surface characteristics, of cell-cell interactions, and of specific growth patterns, and all have important effects on Nocardia virulence and host-parasite interactions.
Neutrophils predominate in the early lesions, inhibiting nocardial cell growth, but not killing the organism. N asteroides has the ability to resist intracellular killing by inhibiting phagosome-lysosome fusion, decreasing lysosomal enzyme activity in macrophages, and neutralizing phagosomal acidification. It also resists the oxidative killing mechanism of phagocytes by producing a unique surface-associated and secreted superoxide dismutase.
As a result of this evasive bactericidal response, cell-mediated responses are required for eventual control of this disease. The host mounts a lymphocyte response and releases antibodies and/or lymphocyte signals enabling activated macrophages to kill Nocardia spp. When there is an inadequate cell-mediated immune response, a more indolent infection may ensue, because neutrophils alone are not sufficient to resolve infection.
Clinical Findings
Pulmonary Disease
Pulmonary disease is the most common manifestation of nocardiosis. N asteroides is estimated to cause 80% of pulmonary cases. It may present as a necrotizing pneumonia with or without cavitation, a slowly enlarging pulmonary nodule, or pneumonia with associated empyema. The course of disease ranges from acute to chronic with a tendency to wax and wane.
Pulmonary nocardiosis comprises a constellation of protean and nonspecific findings. Symptoms and signs include fever, night sweats, anorexia, weight loss, productive cough with hemoptysis, and pleural pain. Initial pulmonary parenchymal disease may spread to adjacent lung tissue, progress to form one or more pulmonary abscesses, and spread to pleural surfaces or to distant sites, such as the skin and the brain. Nocardiosis must be suspected when soft-tissue and/or CNS disease develops in conjunction with chronic or subacute pulmonary disease.
Radiographic findings are also variable but most frequently include localized infiltrates, irregular nodules, pleural effusions, and hilar adenopathy. Less common findings include masses, miliary lesions, diffuse alveolar and interstitial infiltrates, and calcified granulomatous lesions suggestive of fungal infection or tuberculosis.
Other respiratory tract manifestations include tracheitis, bronchitis, and pleuropulmonary fistula. Mediastinitis with superior vena cava syndrome and sinusitis have also been reported.
Disseminated Disease
Approximately 50% of all Nocardia infections disseminate, usually from a primary pulmonary infection. Disseminated nocardiosis is defined as disease involving two or more organs of the body. It often occurs late in the course of disease and may be life threatening, especially in severely immunocompromised patients. The CNS is the most frequently affected site, but cutaneous and subcutaneous tissues, eyes (especially the retina), kidneys, joints, bone, and heart tissue can also be involved.
CNS Disease
CNS infections are seen in about one-third of all cases of nocardiosis, usually as part of disseminated disease. Patients with pulmonary or disseminated nocardiosis should have a magnetic resonance imaging (MRI) examination of the head to rule out occult CNS Nocardia infection.
A single Nocardia colony isolated from the cerebrospinal fluid or another normally sterile site with a suggestive clinical picture should not be ignored, because these organisms are rarely laboratory contaminants and are not common members of the normal flora. Of patients with systemic nocardiosis, 45% have CNS infections, with the lung being the most common source of infection. Brain abscess is the most common clinical manifestation.
Rarely, meningitis can also occur. Presentations may vary from an acute, rapidly evolving infection to a more common, insidious onset with infection persisting for months or even years without fever or leukocytosis. Hemiparesis, body tremors, Parkinsonian features, seizures, coma, and ataxia can occur. Bizarre (even psychotic) personality and behavioral presentations dominate certain chronic cases.
Lesions can be found in any anatomic site of the CNS and are often loculated with satellite extensions. CNS nocardiosis is associated with high morbidity and mortality if prompt antimicrobial therapy is not initiated. In compromised hosts, infection is more rapidly progressive and associated with increased mortality.
Cutaneous Disease
Cutaneous nocardiosis, in contrast to invasive pulmonary and disseminated nocardiosis, usually occurs in immunocompetent individuals. Primary disease is often precipitated by local trauma or surgical wound. Secondary cutaneous disease is the result of hematogenous dissemination. N brasiliensis is the predominant agent in primary cutaneous disease.
Localized cutaneous nocardiosis presents as pustules, abscesses, or cellulitis, all of which are usually self-limited. These lesions mimic those of cutaneous Streptococcus or Staphylococcus infection. Nocardia infections tend to be more indolent, however. Frequently, infection spreads to regional lymph nodes, which then suppurate. The resulting lymphocutaneous syndrome is referred to as the sporotrichoid form of cutaneous nocardiosis because it is difficult to distinguish from infection with the fungus Sporothrix schenckii. Thus, an appropriate laboratory diagnostic workup is required for a definitive diagnosis.
Mycetoma is a separate, distinct manifestation of cutaneous and subcutaneous nocardial infection. Other organisms can cause mycetomas, but Nocardia species appear to be the most common cause in the United States. Mycetoma is a chronic, localized, slowly progressive subcutaneous infection that can eventually invade the fascia, muscle, and bone if left untreated. It usually starts as a painless nodule after traumatic inoculation. It may become purulent and necrotic, and suppurate with formation of draining sinus tracts containing granules. Granules are conglomerations of the causal organism whose size, color, and degree of hardness vary by microbial species. Mycetoma is the only clinical form of nocardiosis regularly associated with the presence of such granules. The granules tend to be white, unlike the granules of Actinomyces spp., which are yellow and hence named “sulfur granules.”
Mycetomas can be caused by a number of actinomycetes, in which case they are properly termed actinomycetomas as a group, or they can be caused by fungi, in which case they are referred to as eumycetomas. Microorganisms known to cause actinomycetomas include N brasiliensis, Actinomadura madurae, Actinomadura pelletieri, Streptomyces somaliensis, and, less commonly, N asteroides, N otitidiscaviarum, Nocardiopsis dassonvillei, and N transvalensis. In North America, South America, Mexico, and Australia, N brasiliensis is the chief cause of actinomycetomas, whereas in Africa, it is S somaliensis. Mycetomas tend to be well-delineated infections. Actinomycetomas most often affect persons who live in warm, rural environments. The most common site of infection is the foot, but infections in the leg, arm, hand, face, and neck are also seen.
Ocular Disease
Ocular infections such as keratitis and endophthalmitis with Nocardia spp. have been reported in both immunocompetent and immunocompromised patients. Though rare, these occur after traumatic corneal injury. Nocardia keratitis may mimic noninfectious inflammatory eye conditions and precipitate steroid therapy, which may worsen this (and other) ocular infection(s). Corneal scrapings should be performed on all patients with keratitis for the purpose of diagnosis.
Diagnosis
A Gram stain that shows thin, delicate, variably gram-positive, irregularly stained or beaded branching filaments is suggestive of nocardiosis. The diagnosis must be confirmed by culture. Currently, there is no reliable serodiagnostic test.
This normally elusive organism can usually be detected in pus or abscess drainage from a fistula, which should be submitted in a sterile tube or syringe. Fibers from sterile cotton swabs can interfere with the interpretation of smears, so the use of swabs should be discouraged. Surgical tissues and biopsy material from lung, skin, or brain should be kept moist during transport. When examining sputum specimens, early-morning expectorated samples should be collected on 3 separate days. Single smears and cultures are positive in only one-third of cases, so multiple specimens are encouraged.
Nocardia spp. grow readily on most of the media used for bacterial, fungal, and mycobacterial growth. Their growth can be enhanced if they are incubated at between 32 and 35 °C in the presence of 5-10% carbon dioxide. They are slow growing, so the laboratory should be alerted when Nocardia infection is suspected. Colonies from pure cultures form within 48-72 h, but, with complex specimens such as respiratory samples, other more rapidly growing bacteria can easily obscure small Nocardia colonies. To enhance recovery and inhibit bacterial and fungal overgrowth, a variety of selective media have been used including paraffin agar and buffered charcoal-yeast extract medium (originally designed to isolate Legionella species).
After recovery of a Nocardia isolate, biochemical tests to determine the ability of the isolate to decompose casein, xanthine, hypoxanthine, and tyrosine are performed to distinguish the different Nocardia species. Additional biochemical tests are often necessary for further speciation. Gas chromatography and high-performance liquid chromatography (HPLC) analyses of the mycolic acid composition of nocardiae provide a more rapid technique to distinguish the different species. However, the results must be interpreted cautiously, because the type of culture medium, incubation temperature, and other factors can alter mycolic acid composition. A more rapid and accurate approach to identify different species may be polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis.
Differential Diagnosis
Clinically, pulmonary nocardiosis must be distinguished from other bacterial infections such as mycoplasma infections, actinomycosis, tuberculosis, and fungal infections and carcinomas.
Treatment
Sulfonamides have been the mainstay of therapy for Nocardia infections since the first report of a cure in 1944. Prior to the 1940s, infections with Nocardia spp. were almost always fatal. Today the combination of trimethoprim and sulfamethoxazole (TMP-SMX) is generally the drug of choice despite inadequate in vitro data regarding synergy with this drug combination (Box 2). Between 90 and 95% of pulmonary infections with susceptible strains of N asteroides respond favorably to treatment. Oral or intravenous TMP-SMX is recommended for adults with normal renal function. Sulfonamide levels should be followed initially to ensure that a serum level of between 100 and 150 mg/dL is achieved. Levels should be drawn 2 h after oral ingestion of the drug.
Intolerance of sulfonamides, especially in AIDS patients and in transplant patients, is reported frequently. Rash is a common adverse effect in these patients. TMP-SMX may enhance the nephrotoxicity of cyclosporin A in transplant recipients. Treatment failure has been reported in individuals with CNS infection and/or in immunocompromised individuals. Issues of patient compliance, microbial susceptibility, sequestered pus, and superinfection may have contributed to the poor outcome in these patients.
Other antimicrobial agents have shown in vitro activity against Nocardia spp. There are three oral agents other than sulfonamides which are useful in treating nocardiosis. Minocycline is the only tetracycline with excellent in vitro activity against the majority of pathogenic strains. Amoxicillin-clavulanate is effective, but certain species such as N nova, N otitidiscaviarum, and N transvalensis are resistant to this antibiotic. The fluoroquinolones such as ciprofloxacin and ofloxacin are less consistent in their activity against Nocardia spp., but penetrate most tissues well. Susceptibility studies should guide the choice of therapy.
Useful parenteral agents include imipenem, amikacin, and the third-generation cephalosporins. These drugs can be used alone or in combination with sulfonamides. Although good clinical responses have been achieved with imipenem, drug-induced seizures may deter use in individuals with brain abscesses. Amikacin has variable penetration of the CNS, but has been successfully used to treat CNS infection when the minimum inhibitory concentration (MIC) of the isolate was < 0.12 ug/mL. Third-generation cephalosporins have excellent CNS penetration and low toxicity.
The optimal duration of therapy and the indications for combination therapy remain uncertain, but long-term therapy is the rule, because relapse is common. In the nonimmunosuppressed individual, therapy for pulmonary and systemic nocardiosis should be continued for a minimum of 6-12 months. Complete resolution of primary cutaneous nocardiosis without bone involvement can be achieved with 2-4 months of therapy.
Immunosuppressed patients, regardless of their presentation, should receive a minimum of 12 months of therapy. Parenteral therapy may be necessary for only 3-6 weeks, depending on patient response. The use of immunosuppressive agents should be minimized, especially early in treatment of nocardiosis. Because high failure rates occur in patients with CNS disease and patients who are immunosuppressed, combination parenteral therapy with TMP-SMX and amikacin, imipenem, or a third-generation cephalosporin might be considered. Once a clinical response is achieved, the patient can be switched to single-agent therapy. Individuals with HIV coinfection should probably receive continuous suppressive therapy.
Prevention & Control
Because Nocardia spp. are ubiquitous and nocardiosis is sporadic and dependent on host factors, there are no effective prevention and control measures.
Read more
https://en.wikipedia.org/wiki/Nocardia
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4571773/