What is Nocardiosis?

Nocardiosis (synonyms: streptotrichosis, cladotrichosis, atypical actinomycosis; Nocardiose – German; nocardiose – French) – mycosis, characterized by a long progressive course with frequent damage to the lungs, central nervous system. Lethal outcomes are frequent.

Causes of Nocardiosis

Infections due to Nocardia spp. happen both in humans and in animals. Differences in etiology, clinical symptoms, treatment and prognosis allow us to distinguish two subgroups of diseases, namely sensu stricto nocardiosis and actinomycetes. The latter, which may also be called “actinomycotic mycetomas,” are a clinically well-defined nosological form of the disease with a heterogeneous etiology that causes not only Nocardia, but also Actinomadura and Streptomyces spp.

The definition of nocardiosis, although, first of all, etiological, is at the same time both clinical and pathological. Its potential causative agents are Nocardia asteroides, Nocardia farcinica, Nocardia nova, Nocardia brasiliensis, Nocardia pseudobrasiliensis, Nocardia otitidiscaviarum and Nocardia transvalensis. Significant doubts remain regarding the taxonomic status of N. asteroides, N. farcinica, and N. nova, which affects their identification. Until recently, all of these microorganisms were included in N. asteroides, but were then separated from N. asteroides sensu stricto by taxonomic and molecular methods. Thus, it is still difficult to assess the extent to which N. farcinica and N. nova are involved in human infections, although at least the latter can be reliably identified.

Pathogenesis during Nocardiosis

Nocardial lesions can be purulent or granulomatous or both together, which makes their histopathological manifestations very variable. Abscesses and pure granulomas can be detected, but more often the body’s response becomes mixed. Formation of granules – does not characterize any type of nocardiosis, but is common for actinomycetes.

Since pathogenic nocardia grows mainly in the environment, human nocardiosis is always of exogenous origin. Assumptions that noninvasive colonization by nocardia of the respiratory tract may be the cause of endogenous infections are not convincing. Isolation of pathogenic Nocardia spp. from sputum or bronchial secretion in the absence of symptoms of a pulmonary disease, rather indicates a short-term contamination or subclinical infection, rather than a long colonization.

The pathogenicity of the various Nocardia spp. Mentioned above has some distinct differences in species dependence. Pulmonary, systemic, CNS nocardiosis and extrapulmonary nocardiosis in the predominant number of cases are caused by N. asteroides, N. farcinica, less often N. pseudobrasiliensis and, only occasionally, N. nova, N. brasiliensis, N. otitidiscaviarum and N. transvalensis.

There is no complete clarity regarding the clinical importance of N. farcinica. In a literature review, Beaman and Beaman (1994) found only 13 cases of infection due to N. farcinica out of 1,050 cases, while Schaal and Lee (1992) revealed 60.3% of nocardial infections caused by this microorganism. Undoubtedly, problems with the identification of the pathogen could influence the results obtained by Beaman and Beaman (1994), although regional differences can also be responsible for such a discrepancy in the results.

Superficial skin and subcutaneous infections were mainly caused by N. brasiliensis, as well as N. otitidiscaviarum and N. transvalensis. These infections can also sometimes be caused by N. asteroides, N. farcinica, and N. nova. Nocardia brevicatena was isolated from the respiratory tract, but its etiological role in infections in humans has not been established.

The immune response in nocardiosis
The host parasite relationship for nocardial infections has been reviewed by Beaman and Beaman (1994). Attempts have been made to detect antibodies to Nocardia spp. for the purpose of possible use for diagnostic purposes. Very little information is available regarding the diagnostic value of these tests. Kjelstrom and Beaman (1993) investigated the possibilities of various serological tests for the diagnosis of nocardial infection. These studies suggested a correlation between antibody synthesis and nocardial infection, provided that clinical and other factors were also taken into account.

Animal studies have shown that macrophages, T-cells, and cellular immunity play an important role in the body’s resistance to nocardial infection. Macrophages phagocytize nocardial cells and, depending on the virulence of a particular species, kill most of the absorbed organisms. Some less virulent strains can survive as L-forms inside the phagocyte, while more virulent strains propagate inside the macrophage, and nocardial filaments can grow through the cell membrane. T lymphocytes can either activate macrophages and stimulate a cellular immune response, or they can directly effect nocardial killing.

Symptoms of Nocardiosis

In addition to actinomycetomas, 5 main forms of nocardiosis are determined (Beaman 1994):

  1. Pulmonary nocardiosis.
  2. Systemic nocardiosis involving two or more organs.
  3. CNS nocardiosis.
  4. Extrapulmonary nocardiosis.
  5. Cutaneous and lymphococcal nocardiosis.

This unit is more detailed than that proposed by Schaal and Beaman in 1984, but is justified from a clinical, therapeutic and prognostic point of view.

Pulmonary nocardiosis
Nocardial cells, due to their natural habitat in the soil or plant material, can enter the air as fragments of mycelium or be contained in dust particles. Thus, pulmonary infections occur mainly after inhalation of these infected particles. Rare cases of pulmonary nocardiosis have been reported, associated with hematogenous spread from the oral cavity or gastrointestinal tract after eating contaminated food, or after accidentally injecting (e.g. drug addicts) directly into the bloodstream, or introducing the pathogen into the tissue due to injury. Inhalation of reproductive nocardial cells does not always lead to disease. In addition to their transient presence in the airways shortly after inhalation of contaminated dust, it is necessary that pathogenic nocardia can colonize or subclinically infect the airways. It remains unclear how often such colonization or subclinical infection occurs.

In addition to systemic immunosuppression, damage to the local protective mechanisms of the lungs can be predisposed to the development of nocardiosis, which include: chronic bronchitis and emphysema, bronchial asthma, bronchiectasis and alveolar proteinosis, however, an invasive process in the lungs can also occur in patients without local or systemic defects in protection. The clinical presentation of lung nocardiosis is very variable. The most common is subacute or chronic, often necrotic, pneumonia, often associated with the formation of an abscess or cavity. In patients with severe immunosuppression, the disease sometimes manifests itself as acute fulminant necrotic pneumonitis, which can lead to death before a diagnosis is made. Pulmonary nocardiosis can also be presented as slowly developing single or multiple pulmonary nodules or parietal pneumonia with empyema. Common complications include pleural effusion, empyema, pericarditis, mediastenitis, obstruction of the superior vena cava, and sometimes chest wall abscesses. For such cases, hematogenous spread is characteristic, which can lead to systemic nocardiosis, including central nervous system nocardiosis.

Patients with lung nocardiosis usually have the following symptoms: fever, night sweats, weight loss, productive cough, and sometimes hemoptysis. The disease can be preceded or accompanied by empyema of the pleura, in these cases, the main complaint may be pleural pain. X-ray data are usually nonspecific and include limited infiltrates, which appear as wedge-shaped shadows in the right middle zone, nodules, the formation of cavities within the nodules or infiltrates, pleural effusion, and an increase in radical lymph nodes. Multiple nodules, abscesses, miliary lesions, diffuse interstitial infiltration, and subpleural plaques are much less common.

Systemic Nocardiosis
At any site of the lesion, a nocardial infection can enter the bloodstream and metastasize to other organs. Sometimes, microorganisms can be transported with blood after an injury by contaminated materials such as spikes, wooden fragments and bullets, as well as due to accidental ingestion from infected syringes or needles by drug addicts, or after insect or animal bites. By definition, systemic or disseminated nocardiosis is diagnosed in cases where damage is present in two or more parts of the body. Any anatomical formation can be affected, however, the central nervous system and, especially, the brain are the most often involved in pathological extrapulmonary areas. Nocardiosis of the brain, in the form of a specific nocardial brain abscess, is an important cause of volumetric brain formations. Common places that the infection can spread to include kidneys, spleen, liver, subcutaneous tissue, and eyes. The retina is usually affected in the eye. Very rarely, nocardial metastases are found in bones, joints, heart or skin. The formation of an abscess is a common manifestation of disseminated nocardiosis. Thus, the symptoms of the disease depend on the size and location of the abscess and pain due to inflammation and displacement of adjacent tissues.

Nocardiosis of the central nervous system (CNS)
Nocardial lesions of the central nervous system is one of the most frequent localizations in systemic forms and usually follows pulmonary nocardiosis. Among 1050 cases described in the literature analyzed by Beaman and Beaman (1994), the central nervous system was involved in 22.7% of all cases, as well as in 44% of cases in patients with disseminated nocardiosis. In 38.2% of cases of CNS nocardiosis, there were no signs of infection elsewhere. Therefore, CNS nocardiosis can also be considered as a primary infection. In addition, 42% of patients were pre-healthy individuals without obvious predisposing factors. Therefore, Nocardia spp. are the primary pathogens of the central nervous system and especially the brain. The onset of CNS nocardiosis is often insidious, as even large damage may not cause severe symptoms. Such lesions are usually presented as abscesses, less commonly as granulomas, and only in very rare cases, as meningitis. Brain abscesses and granulomas can occur acutely, with rapid spread, but usually the disease progresses slowly over months to years. Since CNS infections alone are often not accompanied by fever or leukocytosis, they are often treated as tumors. Symptoms depend on the location of the lesions. Sometimes, only the spinal cord is affected.

Extrapulmonary nocardiosis
The question of whether extrapulmonary nocardiosis is the same infection as cutaneous, subcutaneous and lymphocutaneous, or how CNS lesions should be considered in a separate category, as suggested by Beaman and Beaman (1994), remains a moot point. Extrapulmonary infections can be detected in the bones, eyes, heart, joints, and kidneys. Retinal nocardial lesions can occur during disseminated nocardiosis. Primary eye infections usually follow trauma or, less commonly, surgery with contamination with pathogenic nocardia, and lead to keratitis and then, ultimately, to endophthalmitis. Inappropriately sterilized soft contact lenses are a less common source of exogenous nocardial eye damage. Nocardial keratitis can resemble non-infectious inflammatory eye diseases, which sometimes leads to serious complications if corticosteroids are prescribed.

Nocardial joint infections are presented as septic arthritis, the frequency of detection of which is constantly increasing. The same applies to nocardial pericarditis and endocarditis. Cases of nocardial endocarditis after aortic valve replacement have been described that have been successfully treated with imipenem, amikacin, and valve replacement surgery.

Limited cutaneous, subcutaneous and lymphocutaneous nocardiosis
In addition to the involvement of skin and subcutaneous tissues during disseminated nocardiosis, it is also possible to encounter primary skin and subcutaneous nocardial lesions. They usually follow the introduction of pathogenic nocardia into the skin through puncture wounds, insect or dog bites, and animal scratches. Since Nocardia spp. usually present in the soil, such infections should, in theory, occur quite often, however, skin nocardiosis is rare, which indicates that these infections often occur subclinically or are not detected, as they can go away without treatment and resemble other skin infections.

The primary response to the introduction of pathogenic nocardia into the skin is panniculitis or pyoderma, from which an abscess can develop. Pustules or slowly expanding nodules may also occur. All these manifestations are similar to infections caused by other purulent bacteria, with the exception that nocardial infections tend to be more painless. Nocardia can spread through the lymphatic paths to regional lymph nodes with a characteristic clinical picture of lymphocytic nocardiosis. An almost identical syndrome can be observed with the defeat of the fungus Sporothrix schenckii (sporotrichosis), in connection with which lymphatic cutaneous nocardial infections are often referred to as sporotrichoid nocardiosis.

Diagnosis of Nocardiosis

A reliable diagnosis of nocardiosis is possible only by isolating the causative agent from the material, including sputum, bronchial swabs, exudate, pus, cerebrospinal fluid, blood, urine, and autopsy or biopsy materials. Although pathogenic nocardia are quite resistant to external influences, research materials must be transported to the laboratory quickly, because nocardia that grow slowly are usually overgrown with contaminating bacteria. Cooling is not desirable because some Nocardia species do not tolerate low temperatures.

When stained, for example, by Gram or silver impregnation, microscopic examination of sputum, pus or tissue samples can detect filiform branching bacteria. Nocardial microscopy has no differences with fermenting and aerobic actinomycetes. Specification is possible only by cultural methods, and, in the future, by molecular methods (PCR).

For blood, cerebrospinal fluid, and empyema exudate to excrete Nocardia spp. any general incubation medium at a temperature of 36 + -1 ° C is suitable. Solid nutrient media should be transparent, such as cerebral – cardiac agar, so that growth can be observed microscopically in the early stages. Selective media should be used to study the material, usually containing the innate microflora of the mucous membranes (e.g., sputum, bronchial secretions, urine, autopsy material), in order to reduce the risk of overgrowing nocardia contaminating microorganisms. Identification of nocardia to a species requires chemotaxonomic, carbon and hydrolysis tests. Reliable identification of N. asteroides sensu stricto, N. farcinica, and N. nova is especially difficult because they are divided into many phenotypic characters. Differences in antibiotic sensitivity may facilitate recognition of these varieties.

Although attempts have been made to create serological diagnostic tests for the recognition of nocardial infections, in no case have the use of any separate or combined tests yielded satisfactory results. Attempts have also been made to use DNA testing to quickly identify suspected N.asteroides isolates. The diagnostic value of such studies is also limited, since N. asteroides is a heterogeneous species that requires a large group of studies to identify all its members. The same applies to PCR methods.

Nocardiosis Treatment

The choice of specific drugs for the treatment of nocardiosis remains controversial due to the problems of studying the sensitivity of these microorganisms and the lack of controlled clinical trials on this issue. Available recommendations are usually based on a limited number of observations. However, data obtained in vitro and in experimental animals with N. asteroides are directly applicable to human infections. Pathogenic nocardia showed significant differences in sensitivity and, in addition, possible geographical differences in susceptibility should be considered; which seems to be relevant to N. asteroides, N. farcinica, and N. nova. As an exception, European samples of N. asteroides and N. farcinica are sensitive to sulfonamides or biseptol. Outside this region, only N. brasiliensis is usually susceptible to these drugs.

Therapy of choice for nocardioses caused by N. asteroides and N. farcinica is high doses of imipenem and amikacin. The daily dose of imipenem should not be less than 4 g, as for amikacin, and these doses should be based on the concentration of the drug in serum. Some species of N. asteroides are also sensitive to amoxicillin plus clavulanic acid and this combination can be used when the culture is poorly sensitive to imipenem. For N. brasiliensis, N. otitidiscaviarum, and N. transvalensis, such therapy is usually not effective due to resistance to either imipenem or to the amoxicillin plus clavulanic acid complex or both. Nevertheless, resistance to amikacin was observed in pathogenic nocardia quite rarely, so this drug should be included as part of therapy. Sulfanilamides, biseptol and tetracyclines, especially minocycline, are also effective drugs against these infections. However, it should be borne in mind that treatment with sulfanilamides, if effective at all, may require 12 months or more with excretion of N. asteroides and N. farcinica, while treatment with imipenem or the amoxicillin-clavulanic acid plus amikacin complex usually leads to an improvement in within a week and recovery within 4-6 weeks. If relapse occurs after antimicrobial therapy, especially in the lungs or with a brain abscess, or valve endocarditis associated with prosthetics, surgical treatment should be considered.

Prevention of Nocardiosis

Preventive measures are recommended as with other deep mycoses. Events in the outbreak are not carried out.