Nocardiosis is a rare bacterial infection caused by Nocardia spp., a partially acid-fast, aerobic gram-positive bacillus. It belongs to the Actinomyces genus and is ubiquitous in the environment.1

Nocardia spp. are able to cause localized or disseminated disease, usually affecting immunocompromised patients such as Solid Organ Transplant (SOT) or Hematopoietic Stem Cell Transplantation (HSCT) recipients, patients treated with immunotherapies and/or corticosteroids, with neoplastic disease, Human Immunodeficiency Virus (HIV) infection and structural and functional lung diseases (Cystic fibrosis, Chronic Obstructive Pulmonary Disease [COPD]). Although being generally considered to be an opportunistic pathogen, immunocompetent patients comprise up to one-third of all cases.1

Additionally, despite being considered a rare disease, an increasing incidence has been described, possibly due to increasing number of immunocompromised patients, better awareness and optimization of diagnostic methods. Concurrently, mortality rates are also increasing and can be as high as 50%.1

However, due to the rarity of the disease, data on the prognosis and distribution are still scarce and essential. Therefore, we aim to describe the local epidemiology, clinical characteristics, antibiotic susceptibility patterns and outcomes of patients with infection due to Nocardia spp.

Nocardiosis is an uncommon but emerging disease in both immunocompetent and immunocompromised patients. It may be caused by exogenous inhalation or by direct invasion by injured skin. Therefore, the lung and skin are the most susceptible organs. Ocular and joint infections are rare but have been described.1

The present study provides important information on the risk factors, epidemiological and microbiological characteristics of this disease over a 4-year period. Early recognition and prompt treatment are essential to improve the outcome in this population.

In our study, males were affected more frequently than females, similar to most of the published reports.2-4 The reason for this distribution could be related to men's distinct lifestyle and agriculture-related professions (which increases exposure to Nocardia), hormonal effects on the virulence or growth of this bacteria.2,5

The incidence of nocardiosis is thought to be increasing due to increased awareness and an increased number of immunocompromised patients, such as the growing number of SOT and HSCT recipients.2,6

Among our patients, COPD was the second most common comorbidity (33.3%). Structural modifications of the bronchial architecture, impaired ciliary motility and epithelial damage all lead to impaired local immune defense which may facilitate the presence of Nocardia species.2 Inhaled corticosteroids used for COPD treatment may also increase the risk of Nocardiosis as do shorter courses of systemic corticosteroids during acute exacerbations.7-9

However, it is believed that Nocardia may also colonize the respiratory tract. Therefore, the isolation of Nocardia in sputum should be interpreted carefully. The challenge lies in trying not to routinely initiate antibiotics, but to combine clinical signs, symptoms and chest CT findings to guide this decision.6,10

In agreement with the literature, we also found chronic use of CST to be common in patients with nocardiosis.11,12 However, other factors causing impaired cell-mediated immunity may also contribute to nocardiosis. T-cell mediated immunity is the main protective immune response to nocardiosis explaining the higher rates of nocardiosis in patients with solid organ and HSCT, Acquired Immunodeficiency Syndrome (AIDS), autoimmune diseases and those with lymphoreticular malignancy, with more than 60% of reported cases being associated with one of these conditions.13-15

Evaluation of CD4+ count is helpful in understanding pathogenesis in cases of nocardiosis without comorbidities. The association of idiopathic CD4 lymphocytopenia and nocardiosis is less studied but was already described.16 Moreover, in a recent retrospective multicenter cohort study who aimed to identify the factors associated with Nocardia spp. dissemination, lymphopenia was an independent risk factor for DN and correlates with a worst prognosis.17 In fact, the lower absolute lymphocyte count could imply a more pronounced immunological disfunction, making it a useful index on the evaluation of disease severity.18

In our study, 5 of the 7 patients presenting with lymphopenia had DN and worse outcomes. Hence, CD4+ count should be determined in patients with nocardiosis to evaluate the possible presence of idiopathic CD4+ lymphocytopenia, predicting disease dissemination, a poorer prognosis, and the need for further prophylaxis.

With regard to the site of involvement, pulmonary nocardiosis was the most common type of clinical infection, which is consistent others reports.19-22 However, contrarily to previous reports in which Nocardia farcinica and Nocardia cyriacigeorgica were the most prevalent species worldwide,23 in our report, Nocardia nova/africana was the most frequently isolated Nocardia species. This finding has been described in reports from Australia, but not in studies performed in Europe.24-25

An interesting finding in our study were three cases of disease caused by Nocardia pseudobrasisilensis, which is a rare but emerging species that has been reported in association with more invasive and disseminated disease and higher mortality rates. Moreover, this species is thought to be associated with a less favorable antibiotic susceptibility pattern, which was also described in our analysis.26-28 Although some authors recommend ciprofloxacin as the antibiotic of choice in patients suspected of nocardiosis by this species, we found an isolate resistant to ciprofloxacin, which lead to the inadequate empiric treatment of this patient, and possibly contributed to a worse outcome.29 It is noteworthy that DN resulted in substantial mortality, as 80% of deaths were observed in this group, with Nocardia pseudobrasilliensis being responsible for 40% of deaths in DN.

Antimicrobial susceptibility testing is currently recommended for all Nocardia spp. isolates before initiating antimicrobials, as susceptibilities are often difficult to predict, and patients may not tolerate first line treatments.30-32

Cotrimoxazole, imipenem, linezolid and amikacin, which are recommended as initial treatment for nocardiosis, were the most frequently used antibiotics in our study and the ones with most favorable susceptibility patterns.23,32 Cotrimoxazole is considered the first-line therapy for nocardiosis as most studies have shown high susceptibility rates to this drug, although increasing numbers of cotrimoxazole-resistant Nocardia are being reported.4,33,34

We found high resistance rates to imipenem, ciprofloxacin and amoxicillin-clavulanate, when compared to some of the previous studies, although ceftriaxone resistance was lower than in other reports.35-39

Although we do not use NAAT for the diagnosis of nocardiosis, it may be used in some institutions, and without a culturable specimen, treatment of nocardiosis may be difficult.

Even though most clinical Nocardia isolates are susceptible to cotrimoxazole, linezolid and amikacin, prolonged treatments with these drugs may be challenging. Furthermore, many of the susceptible antibiotics do not have oral formulations, which may lead to increased length of stays in the hospital and decreased quality-of-life.40-43

In our study, treatment-related severe adverse events leading to drug discontinuation occurred in 27.8% of the patients, with acute kidney injury, vomiting and anemia being the most common. All these patients had age >65-years-old. These considerations reveal the difficulty and challenge to manage this condition particularly in elderly patients and in the ambulatory setting. Moreover, they alert to the difficulty of acceptance in home care programs and therefore could lead to prolonged hospital admission – none of our patients could be integrated in these programs.

Nocardiosis is a rare and challenging infectious disease, with a miscellaneous clinical spectrum. The diagnosis is frequently difficult to establish, from suspicion to bacteriological documentation and long-term antimicrobial therapy is often required. This review, the largest Portuguese series so far, demonstrated not only that nocardiosis is responsible for morbidity in Portuguese patients but and also the most frequent and susceptibility patterns of Nocardia species.

We also reported the antimicrobial susceptibility patterns of the first-line and second-line drugs used for this infection.

These findings suggest the need to understand the microbiology of nocardiosis better so that antimicrobial therapy can be optimized, and appropriate surgical intervention be performed, if necessary, to prevent unfavorable outcomes.

All authors contributed to the conception of the Review.

BB: Data analysis, collection and interpretation, writing, review, and approval of the manuscript. DC, JF, CF, SS, CA, TT, AS, GA and LM: reviewed the literature and drafted the manuscript.

The authors declare having followed the protocols in use at their working center regarding patients’ data publication.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

The authors declare that the procedures were followed according to the regulations established by the Clinical Re-search and Ethics Committee and to the Helsinki Declaration of the World Medical Association updated in 2013.