Nocardia and actinomyces

Epidemiology and risk factors

Nocardia species are a heterogeneous group of ubiquitous aerobic, gram-positive filamentous organisms that reside in soil and decaying organic matter and are associated with an array of infections in both immunocompetent and immunocompromised hosts. First described by Edmond Nocard in 1888, Nocardia infections are associated with a range of illnesses, from localized suppurative skin lesions and chronic mycetomas, to invasive pulmonary infections, bacteremia and central nervous system (CNS) infection. Although nocardiosis remains a relatively rare infection overall, with an estimated 500 to 1000 cases diagnosed annually in the United States; immunocompromised hosts, particularly those with impaired T-cell immunity, are at significant risk for infection, with prevalence rates as high as 2.0% to 3.5% in select populations. ^, Geographically, Nocardia infections occur throughout the world, with variations in local incidence and Nocardia subspecies attributable to differences in climate and geography. Within the United States, dry, warmer climates (such as in the Southwest) are associated with higher rates of Nocardia infection, potentially caused by increased aerosolization of pathogens with dust, or contamination of wounds with dirt. Among children, 60% to 70% of cases occur in the setting of underlying immune deficiency (e.g., systemic lupus erythematosus, solid organ transplant [SOT], bone marrow transplant (BMT), chronic granulomatous disease, or cancer), with pulmonary infection the most common manifestation, followed by central nervous system (CNS) infection, disseminated bacteremia, and skin and soft tissue disease. In contrast, approximately 30% of pediatric cases occur in otherwise immunocompetent children and typically present as lymphocutaneous disease, orbital cellulitis, arthritis, or pneumonia. Outcomes in this setting are almost uniformly good and rarely fatal. In the largest single-center study of pediatric nocardiosis to date, 31 cases of Nocardia brasiliensis infection were identified among healthy children in south Texas over a 5-year period; all presented with lymphocutaneous disease, with no noted episodes of dissemination and no reported deaths. In contrast, mortality rates among SOT and BMT recipients have been reported to be as high as 60% to 70%.

Microbiology of Nocardia

The recent advent of molecular diagnostic tools such as gene sequencing and matrix-assisted laser desorption ionization/time-of-flight mass spectrometry has led to significant changes in the classification of Nocardia species. Although classic methods of identification previously relegated most pathogenic species to a relatively limited number of Nocardia groups or complexes, ( N. asteroides complex, N. brasiliensis and N. otitidiscaviarium ), the use of molecular diagnostics has led to the discovery of more than 50 distinct pathogenic Nocardia species previously classified within these groups. As a result, the complex previously known as N. asteroides complex, once considered the most pathogenic of Nocardia complexes, has in recent years been reclassified into six distinct taxa, each of which demonstrates unique antimicrobial susceptibility patterns; these include N. nova, N. abscessus, N. transvallensis, N. brevicatena/N. paucivorans, N. cyriacigeorgica, and N. farcinica complexes. Other important pathogenic Nocardia species include N. brasiliensis, N. otitidiscaviarium, and N. pseudobrasiliensis . As a result of these classification changes, in recent years, the majority of Nocardia infections in the U.S. have been attributable to these species, specifically N. nova , N. abscessus, N. farcinica , and N. cyriacigeorgica .

Given the unique pathogenic characteristics and antimicrobial susceptibility patterns of various Nocardia species, identification of Nocardia infections to the species level is recommended. Given the recognized limits of classic phenotypic testing, current guidelines recommend the use of molecular methods to identify Nocardia isolates in cases of suspected infection. ^,

Nocardiosis in solid organ transplant recipients

SOT recipients are at increased risk for nocardiosis, with high rates of associated morbidity and mortality. Although estimates vary based on the type of organ transplanted, immunosuppressive regimen, and geographic region, the frequency of Nocardia infection among kidney, heart, and lung transplant recipients has been reported to be between 0.6% and 3.5%, with incidence estimates in transplant recipients suggesting a 100- to 3000-fold greater risk for Nocardia infection than in the general population. ^, As can be expected from an environmental pathogen that primarily enters the host via inhalation, lung transplant recipients are likely to be uniquely susceptible to nocardiosis. Among North American SOT recipients, lung transplant recipients are at greatest risk for Nocardia infection (3.5%), followed by heart transplant recipients (2.5%) and multivisceral transplant recipients (1.3%). Infection risk among liver and kidney transplant recipients is low, with less than 1% diagnosed with nocardiosis in most studies. Potential donor-derived Nocardia transmission is another consideration in the SOT population. Although there are no published reports of donor-derived nocardiosis in pediatrics, it is listed a single time as a potential donor-derived transmission from the ad hoc Disease Transmission Advisory Committee based on the 2005-2009 Organ Procurement and Transplant Network reports. ^, Geography and environment are also likely to affect risk of infection among SOT recipients, with individuals residing in warm dry climates at increased risk of nocardiosis. In a study of more than 2000 SOT recipients in the American Southwest, the risk of infection was noted to be between 2 and 3 times higher across all SOT groups, compared with other regions. In this setting, lung transplant recipients remained at greatest risk (9.28%), with heart transplant (4.57%), kidney transplant (1.13%), and liver transplant recipients (0.45%) following, respectively.

Nocardia infection is associated with significant morbidity and mortality among SOT recipients, with an overall estimated 10-fold increase in 1-year mortality risk over noninfected individuals. Risk factors for infection among SOT recipients include receipt of high-dose steroids, cytomegalovirus disease in the preceding 6 months, use of tacrolimus, and high median calcineurin inhibitor levels in the preceding 30 days. ^, The majority of infections occur between 1 month and 1 year after, with a range of clinical presentations from predominately isolated pulmonary infections (∼70%) in North American studies to higher rates of disseminated disease (∼40%) and CNS infection (25%) in European studies.

Nocardiosis in hematologic malignancy and stem cell transplant

Hematology/oncology patients and recipients of hematopoietic stem cell transplant (HSCT) are also at increased risk for morbidity and mortality owing to nocardiosis. Incidence estimates from a systematic review between 1966 and 2004 reported 13 cases/1000 person-years among BMT recipients, 300 times greater than the estimated risk in the general population. Other more recent (2008 to 2013) retrospective studies in HSCT recipients found an incidence rate of 2.4 cases/1000 patients. Depending on the type of HSCT, such as autologous versus allogeneic, other reported incidence rates vary from 0.4% to 3.6%. Predisposing risk factors for nocardiosis in the HSCT population include high prednisone doses (≥20 mg of prednisone per day), lymphopenia, concurrent opportunistic infections (e.g., cytomegalovirus), CD4 ⁺ T cells <100 cells/μL and active graft-versus-host disease. ^, Sites of infection in adult HSCT and oncology patients are similar to those seen in SOT with pulmonary infection the most common (70% to 87%), followed by CNS/disseminated infection (47% to 50%), and skin (6% to 8%). Nocardia infection-related mortality in HSCT and oncology patients remains high with reports ranging from 60% to 70% mortality and one report of approximately 25% survival at 300 days after diagnosis of Nocardia.