Background
Nocardia are weakly gram-positive, filamentous bacteria found worldwide in soils. [1, 2] Human disease from this microbe was first described by Eppinger in 1890, after bovine disease was described by Nocard in 1888. Pathogenic Nocardia are members of the family Nocardiaceae, the aerobic actinomycetes. Nocardia asteroides is the principal cause of systemic nocardiosis in the United States. Nocardia pseudobrasiliensis,Nocardia otitidis-caviarum (formerly Nocardia caviae), Nocardia farcinica,Nocardia nova, and Nocardia transvalensis have also been rarely associated with human systemic disease. [3]
A report of infections with Nocardia carnea, Nocardia elegans, Nocardia paucivorans, Nocardia puris, and Nocardia takedensis has come from Japan. [4] Nocardia brasiliensis is a common cause of localized chronic mycetoma. A total of approximately 30 strains of Nocardia have been associated with human disease.
Two more newly described species have been associated with disease in humans: Nocardia abscessus, from soft-tissue abscesses, [5] and Nocardia africana, from respiratory secretions of patients with pneumonia in the Sudan. [6] Most recently, Nocardia ignorata, a newer agent of human nocardiosis, was isolated from respiratory specimens in Europe and soil samples from Kuwait. [7] Case reports of Nocardia cyriacigeorgica occurring in the United States have been published, with several infections being retrospectively identified from stored samples.
Molecular DNA hybridization techniques (usually involving the 16S ribosomal RNA [rRNA]) have better characterized the Nocardia species; this identification is useful in identifying antibiotic resistance patterns. Several of the species mentioned above (N nova, Nfarcinica, Nabscessus, N cyriacigeorgica) had been considered as N asteroides isolates in some reports. [8]
Nocardiosis is an acute, subacute, or chronic suppurative infection caused by Nocardia. It has a pronounced tendency to remission and exacerbation. Infections are localized or disseminated. Localized cutaneous or lymphocutaneous infections usually occur after contamination of an abrasion, resulting in cutaneous or lymphocutaneous abscess. In children with immunocompetence, systemic spread from the primary skin site is extremely rare.
Disseminated and fulminant disease mainly occurs in immunocompromised hosts (among persons with deficient cell-mediated immunity) with underlying illnesses, such as chronic granulomatous disease or human immunodeficiency virus (HIV) infection, and in children undergoing cytotoxic chemotherapy, bone marrow transplantation, or prolonged glucocorticoid treatment. Nocardiosis has been reported as a secondary infection in patients with coronavirus disease 2019 (COVID-19), including an adolescent with cystic fibrosis and necrotizing N farcinia pneumonia who had been hospitalized for COVID-19. [9, 10, 11]
Nocardiosis has also been associated with pulmonary alveolar proteinosis, tuberculosis and other mycobacterial diseases, and interleukin 12 deficiency. Inhalation of the free-living organism is the likely route of infection. The primary disease occurs in the pulmonary system and may mimic tuberculous, staphylococcal, or mycotic infections. Hematogenous dissemination may occur to all organs of the body. The brain, kidneys, and liver are the most common metastatic sites.
Interestingly, Nocardia species have been found to produce effective antibacterial agents, including one agent (nargencin) that shows promise against methicillin-resistant Staphylococcus aureus. [12] Nocardia lactamdurans has also been found to produce a cephamycin under the right conditions. [13]
Pathophysiology
Introduction of N asteroides via the respiratory tract results in pulmonary lesions that most often manifest as multiple abscesses. Nocardia abscesses are characteristically confluent, with little evidence of encapsulation, which probably accounts for the ready dissemination from the initial pulmonary focus. This organism also evades the host's bactericidal mechanisms. Host neutrophil mobilization can inhibit Nocardia but does not kill them. Cell-mediated immunity triggered by activated macrophages and the induction of a T-cell population capable of direct lymphocyte-mediated cytotoxicity are necessary to kill Nocardia. Infection progresses after the initial inhibition by neutrophils unless antimicrobial therapy or cytotoxic lymphocytes take over.
Nocardia exhibit specific organ tropisms. Log-phase cells of Nocardia, which contain specific cell wall mycolic acids, are more virulent and may influence the ability of nocardiae to localize in certain tissues, such as the brain. Nocardial metastasis manifests as multiple abscesses without granules in different organs. In patients with poor neutrophil activity or impaired cell-mediated immunity, fulminant pulmonary or systemic nocardiosis is an uncommon but opportunistic infection. It is curable but has a high mortality rate (exceeding 50% in some reports), probably because of delayed diagnosis and treatment. A high index of suspicion, followed by aggressive diagnosis and treatment, is necessary for optimal results.
Etiology
Nocardia are usually found in soil and dust, and infection results from inoculation of a wound or inhalation. Person-to-person transmission has not been reported, and Nocardia are not commensal in humans or animals.
Nosocomial cases have been reported. In some cases, N asteroides organisms were detected in the dust and air of the hospital unit.
Epidemiology
United States statistics
Nocardiosis is sporadic and person-to-person spread is not well documented. Rare outbreaks have been associated with contamination of the hospital environment. Incidence estimates vary in immunocompromised populations. In patients who undergo renal transplant, the incidence is 0-20%. In patients who undergo bone marrow transplant, the incidence is 0.3%, and in patients with systemic lupus erythematosus, the incidence is 2.8%.
Higher rates of infection are observed in the hotter, drier states, perhaps because of easier entry of infectious organisms into the lungs from dust blown into the air.
International statistics
Nocardiosis occurs sporadically worldwide.
Race- and age-related demographics
No racial predilection is known. No age predilection is recognized.
Prognosis
Morbidity and mortality are high from fulminant nocardiosis. A high index of suspicion, followed by a rapid diagnosis and treatment, is warranted.
Intensive medical management (surgery, if necessary) and prolonged treatment leads to a cure.
Morbidity/mortality
Death occurs from sepsis, overwhelming pneumonia, or brain abscess, rather than the untreated underlying disease. Mortality is increased in patients with acute infection and in those with disseminated disease involving 2 or more contiguous organs or the CNS. Mortality is also increased in patients taking corticosteroids or antineoplastic agents.
A retrospective study by Yetmar et al found that advanced infection (defined as dissemination, pleural involvement, or cavitary pulmonary infection) is associated with higher mortality than disseminated infection alone. The researchers also reported other factors linked to increased mortality, including a higher burden of comorbidities and N farcinica infection. [14]
