
==== Front
BMC Pulm Med
BMC Pulm Med
BMC Pulmonary Medicine
1471-2466
BioMed Central London

39251945
3217
10.1186/s12890-024-03217-0
Systematic Review
Clinical features and outcomes of persons with cystic fibrosis and nocardia isolation: a systematic review
Terlizzi Vito 1
Ballerini Tommaso 2
Castaldo Alice 23
Dolce Daniela 1
Campana Silvia 1
Taccetti Giovanni 1
Chiappini Elena elena.chiappini@unifi.it

45
1 https://ror.org/01n2xwm51 grid.413181.e 0000 0004 1757 8562 Department of Paediatric Medicine, IRCCS, Cystic Fibrosis Regional Reference Center, Meyer Children’s Hospital, Florence, Italy
2 https://ror.org/04jr1s763 grid.8404.8 0000 0004 1757 2304 Department of Health Sciences, Pediatric resident, Meyer Children’s University Hospital IRCCS, University of Florence, Florence, Italy
3 SC di Pneumologia e UTSIR, AORN Santobono-Pausilipon, Naples, Italy
4 grid.413181.e 0000 0004 1757 8562 Infectious Diseases Unit, Meyer Children’s Hospital IRCCS, Florence, Italy
5 https://ror.org/04jr1s763 grid.8404.8 0000 0004 1757 2304 Department of Health Sciences, University of Florence, Meyer Children’s Hospital IRCCS, Viale Pieraccini, Florence, 24 - 50139 Italy
9 9 2024
9 9 2024
2024
24 44030 3 2024
14 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Background

Recurrent respiratory infections are a leading cause of morbidity and mortality in persons with Cystic Fibrosis (pwCF). Recently, the emergence of Nocardia species as a potential pathogen in CF has raised questions about its role and management, as its clinical significance and the optimal patient management remain unclear in current clinical practice. This review explores the clinical implications of Nocardia species in patients with Cystic Fibrosis (pwCF) through a comprehensive literature review. Key objectives include assessing its impact on lung function, identifying colonization risk factors, and evaluating an appropriate treatment.

Methods

The literature review, conducted until June 30, 2023, from databases like MEDLINE, PubMed, Embase, and Cochrane, included 16 articles involving 89 pwCF with Nocardia species isolation according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline recommendations. Articles reporting Nocardia prevalence and symptoms based on original data in adult and paediatric pwCF were included. All the retrieved studies were observational ones, thus, they were categorized by study type as case report and case series.

Results

Overall 89 pwCF and Nocardia species isolation were included: 42 children and 47 adults. Where reported, we found these main following bacterial species: Nocardia asteroides (35%, 23/64), Nocardia farcinica (21%, 14/64), Nocardia tranvalensis (13%, 8/64) and Nocardia cyriacigeorgica (11%, 7/64). A co-infection was reported in 85% of patients (61/72). Of patients whose lung function was reported before and after Nocardia isolation, 23% (16/68) showed a decline in FEV1. Above all, 82 patients were treated at least once after isolation of Nocardia strain. In 93% (77/82) of cases, treatment was started immediately upon isolation. Antibiotic treatment was performed per os or intravenously depending on the clinical condition of the individual patient. Nocardia eradication was attempted in only 32 cases out of 82, and 78% (25/32) of these patients were successfully eradicated after one or more courses of antibiotics. Death was reported in 3 patients, 2 of which were children.

Conclusion

In general the isolation of the bacteria does not necessarily imply therapy, but patients need to be monitored closely to assess the possible occurrence of active infection. The treatment seems to be indicated in patients showing lung involvement with the possible appearance of pneumonia, pleural effusion, fever, cough, or a decrease in FEV1, as in the case that we described, or in patients undergoing pulmonary transplantation.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12890-024-03217-0.

Strengths and limitations of this study

• A strength of this study is that it provides an updated systematic review on the management of Nocardia’s isolation in patients with Cystic Fibrosis. By synthesising findings across all included studies we propose a therapeutic management algorithm.

• This systematic review protocol follows the Joanna Briggs Institute, mixed-method systematic review protocol.

• Limitations of the study is the paucity of randomised controlled trials and the heterogeneity among available publications.

• There is potential for heterogeneity of published data, which may limit the conclusions that can be drawn from this study.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12890-024-03217-0.

Keywords

FEV1
Lung transplantation
Therapy
Eradication
Children
issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
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pmcIntroduction

Cystic fibrosis (CF) is a common autosomal recessive disorder resulting from variants in the CF transmembrane conductance regulator (CFTR) gene. Multiple systems are affected, however, respiratory tract infections are one leading cause of morbidity and mortality [1].

The adaption of 16s rDNA community sequencing technologies and more extensive culturing approaches [2] have enabled the identification of bacterial strains in the pulmonary microbiota only recently considered to potentially have a pathogenic role including members of the genera Bacteroides, Gemella, Prevotella, Sphingobacterium and Nocardia spp [9–15].

Specifically for Nocardia, a large number of species have been recognized with different geographic prevalences, pathogenic traits, and antimicrobial susceptibility patterns [5]. Therefore, the identification of Nocardia isolates to the species level might provide physicians with useful information but only limited laboratories have the necessary facilities [5]. Nocardia spp are a gram-positive aerobic filamentous bacteria, ubiquitous in soil and aquatic habitats and worldwide spread. Transmission occurs mainly by inhalation of organisms contained in the dust, but also, more rarely, by skin inoculation directly through a wound [3–6].

Nocardial infection may be associated to lung or skin disease and, especially in immunocompromised patients, it may disseminate and virtually involve any body site, including the central nervous system (CNS) where brain abscesses may occur, while meningitis is rarely seen [4, 6].

Pulmonary nocardiosis can manifest as acute, subacute, or chronic disease. Symptoms of nocardiosis are unspecific and may include fever, dyspnea, chest pain, increased respiratory secretions and night sweats [4, 6]. X-ray shows multiple lung infiltrates, rarely associated with necrotizing pneumonia. Chest radiograph can demonstrate areas of consolidation, mild diffuse infiltrates, reticulonodular patterns, or cavitation [6]. According to some experts“opinion, if Nocardia species are identified in CF sputum, his clinical significance and the optimal patient management remain unclear [9–19]. Determining the difference between Nocardia infection versus colonization is extremely challenging in CF patients due to several reasons: the inconsistency of patient’s clinical symptoms, the absence of pathognomonic radiological features, the difficulty in identifying this slow-growing microorganism on common culture media (although nowadays the use of non-culture methods such as NGS (Next-Generation Sequencing) and PCR (Polymerase Chain Reaction), where applicable, have resolved this issue), the lack of understanding of its role in the microbiota of the lung in a patient with CF. Furthermore, Nocardia species are often found alongside other microorganisms. Moreover, to complicate the picture, adverse events to antibiotic therapy may occur and appropriate duration of therapy in these patients is under debate [8–10, 15].

With this systematic review, our aim is to examine the current understanding of the clinical implications of Nocardia species in individuals with CF, starting from the presentation of a clinical case. Moreover, a systematic literature review was performed in order to evaluate the management of Nocardia isolation and outcomes in patients with CF. Finally, we attempt to address some of the questions that clinicians might face when encountering this unconventional bacterium in the respiratory tracts of pwCF.

Review questions

Do Nocardia species have a pathogenic role in patients with CF?

What are the risk factors for nocardiosis in pwCF?

Does Nocardia affect lung function in pwCF?

Should pwCF with Nocardia-positive sputum always be treated?

What antibiotic regimen should be used in pwCF?

How long should the antibiotic treatment for Nocardia last in pwCF?

Inclusion and exclusion criteria

Articles reporting Nocardia prevalence and symptoms based on original data in adult and paediatric pwCF were included. Commentaries, editorials and letters to the author with no original data were excluded as well as studies concerning Nocardia’s infection in persons who did not have CF. No restrictions on language of publication were applied.

Methods and analysis

We performed a systematic review of the literature, according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline recommendations.

Search strategy

We searched the MEDLINE by PubMed, Embase and Cochrane databases for articles available up to 30 June 2023. Search terms for the MEDLINE and EMBASE database were: (“Nocardiosis” [All Fields] OR “Cystic Fibrosis” [All Fields] OR “Nocardiosis isolation” [All Fields] OR “Nocardiosis treatment” [All Fields] OR “Nocardiosis prognosis” [All Fields] OR “Infections in pwCF” [All Fields].

Study selection

At first, we screened titles and abstracts to discover eligible studies, and then we analyzed all full texts for the final evaluation. Two investigators (TB, AC) independently reviewed and evaluated every study. Studies were limited to human participants and of any follow-up duration and timepoints. The quality of the eligible studies was evaluated by two authors independently (TB, AC), using different methods according to the study design: The Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case Reports [16] and the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case Series [17]. We planned to use the Newcastle-Ottawa Quality Assessment Form for the analytic observational studies [18], however, we did not identify articles that properly fitted this definition.

Data extraction

From each study, we selected information regarding study design, date of publication, country of origin, age at first Nocardia’s isolation, Nocardia’s species, co-infections, reported symptoms, deaths related to Nocardiosis, patients for whom FEV1 has worsened, type of treatment and the number of eradicated patients. All key extracted data were reviewed and quality checked at the end of the data extraction phase by the same two researchers. All the retrieved studies were observational ones, thus, they were categorized by study type as case report and case series.

Results

Literature review

Included studies

The process of selecting included studies is shown in the Fig. 1.

Fig. 1 flow chart of the study selection

Overall, 41 articles were initially retrieved; a total of 16 articles were eligible according to our criteria and were included in the review: 9 case reports and 7 case series.

Characteristics of the included studies are reported in Table 1.

Table 1 Literature reviews’s results

	Patient, sex, mean age at first isolation of Nocardia species (years)	Species	Other microorganisms isolated	Clinical symptoms	Worsening FEV1 after Nocardia species isolation
(Death †)	Antibiotics prescribed	Nocardia eradication	
Yagupsky et al., 1994, Case report, Israel	M, 6 yy	N. Asteroides	Pseudomonas Aeruginosa,

S. Aureus

	Fever

Cough

Hypoxia

	Not reported	Trimetoprim-sulfometoxazole	Not reported	
Lumb et al., [8], Case series,

Australia

	3 patients, 2 M, 1 F, 25.3 yy	N. Asteroides (3/3)	P. Aeruginosa (2/3)	Exacerbation of respiratory symptoms (1/3)

Asymptomatic (2/3)

	Yes (1/3)

† (1)

	Trimetoprim-sulfometoxazole (3/3)	Yes (2/3)	
Petersen et al., [9], Case report, USA	5, M, 8 yy	N. Farcinica	S. aureus, A. fumigatus	Fever,

cough

	Not reported	Trimetoprim-sulfometoxazole	No	
Barrio et al., [10], Case series, Spain	9 patients, 1 M, 8 F, 16.6 yy	N. Asiatica (1/9)

N. Asteroides (2/9)

N. elegans (1/9)

N. farcinica (1/9)

N. transvalensis (1/9)

Not reported (3/9)

	P. Aeruginosa (7/9),

S. Aureus (5/9)

S. Maltophila (2/9)

H. Influenzae (3/9)

C. Albicans (1/9)

A. Fumigatus (2/9), Achromobacter xylosoxidans (1/9)

	Fever, dyspnea, chest pain, hemoptysis, cough

Asymptomatic (3/9)

	Not reported	Trimetoprim-sulfometoxazole (6/9)

Aminoglycosides (1/9)

Tetracyclines (2/9)

Carbapenems (1/9)

No treatment (2/9)

	Yes (9/9)	
Thorn et al., [11], Case series,

USA

	17 patients, 6 F, 11 M, 24,7 yy	N. Asteroides (14/17),

N farcinica (1/17),

N cyriacigeorgica (1/17),

N. otitidiscavariaum (1/17)

	Unknown	Unknown	No	Trimetoprim-sulfometoxazole (13/17)

Tetracyclines (3/17)

No treatment

(1/17)

	Not reported	
Beucher et al., 2009, case report, France	M, 20 yy	N. Farcinica	None	Fever, dyspnea, skin nodular eruption	Yes

†

	Trimetoprim-sulfometoxazole

Aminoglycosides

	No	
Bittar et al., [13], case report, France	M, 15 yy	N. Farcinica	S. Aureus

H. Influenzae

	Fever (39 °C), fatigue, haemoptysis, bronchial syndrome, and respiratory decompensation	Not reported	Trimetoprim-sulfometoxazole

Aminoglycosides

Ciprofloxacine

	Not reported	
Aravantagi et al., [14], case report, USA	M, 19 yy	N. Transvalensis	P. Aeruginosa	Respiratory decompensation	Yes	Trimetoprim-sulfometoxazole

Linezolid

	Yes	
Rodriguez-Nava et al., [15], Case series, France	16 patients, 11 M, 5 F, 22.6 yy	N. Cyriacigeorgica (8/16)

N. Farcinica (3/16)

N. abscessus (3/16)

N. veterana (1/16)

N. wallacei (1/16)

Not reported (1/16)

	S. aureus (8/16)

S. maltophila (3/16)

H.influenzae (1/16)

S.pneumoniae (1/16)

P. Aeruginosa (3/16)

Candida Albicans (2/16)

A. fumigatus (5/16)

None (6/16)

	Cough Weight loss

Dyspnea

Fever

Asthenia

Chest pain

Asymptomatic (3/16)

	Yes (5/16)	Trimetoprim-sulfometoxazole

(6/16)

Aminoglycosides (3/16)

Penicillines (5/16)

Cephalosporins (2/16)

Ciprofloxacine (2/16)

Linezolid (3/16)

	Not reported	
Chacon et al., [19], case report, Spain	F, 26 yy	N. farcinica	A. Fumigatus	15 dd after lung transplantation: respiratory decompensation	Not reported	Trimetoprim-sulfometoxazole

Aminoglycosides

Carbapenems

Ciprofloxacine

Linezolid

	Yes	
Schoen et al., [20], case report, USA	F, 9 yy	N. transvalensis	None	Respiratory decompensation	Yes	Trimetoprim-sulfometoxazole

Penicillines

Cephalosporins

Linezolid

	Yes	
Meir Mei-Zahav et al., [21], Case series, Israel	8 patients, 5 M, 3 F, 17.6 yy	N. Asteroides (2/8)

N. Cyriacigeorgica (1/8)

N. Miyunesis (1/8)

Not reported (3/8)

N. Farcinica (1/8)

	Pseudomonas Aeruginosa (5/8)

S. Maltophila (1/8)

None (2/8)

A.Fumigatus (1/8)

	Fever

Cough

Weight loss

Recurrent febril episodes, respiratory decompensation

Asymptomatic (1/8)

	Yes (7/8)	Trimetoprim-sulfometoxazole (5/8)

Aminoglycosides (2/8)

Carbapenems

(4/8)

Penicillines (1/8)

Cephalosporins (1/8)

Linezolid (2/8)

	Yes (5/8)	
Adi Dagan et al., [22], Case series, Israel	19 patients, sex unknown, 20.5 yy	Unknown	S. Aureus 7/19,

P.Aeruginosa 15/19,

Aspergillus sp 12/19,

M. abscessus 5/19

	Dyspnea, cough, fever, chest pain, and hemoptysis	No	Trimetoprim-sulfometoxazole (3/19)

Aminoglycosides (7/19)

Tetracyclines (3/19)

Carbapenems (7/19)

Penicillines (7/19)

Cephalosporins (7/19)

Ciprofloxacine (12/19)

	Not reported	
Betran et al., [23], Case series, Spain	8 patients, 2 M, 6 F, 14.8 yy	N. Farcinica (3/8)

N. transvalensis (2/8)

N. Veterana (1/8)

N. Pneumoniae (1/8)

N. Wallacei (1/8)

	S. Aureus (6/8)

H. Influenzae (1/8)

P. Aeruginosa (6/8)

S. apiospermum (2/8)

A.Fumigatus (1/8)

	Respiratory decompensation (2/8)

Asymptomatic (6/8)

	Not reported

† (1)

	Trimetoprim-sulfometoxazole (5/8)

Penicillines (2/8)

Aminoglycosides (2/8)

No treatment (2/8)

	Yes (5/8)	
Eyboglu et al., [24], case report, Turkey	M, 7 yy	Unknown	None	Fever

Cough

Dyspnea

Evolution to macrophage activation syndrome

	Not reported	Penicillines

Trimetoprim-sulfometoxazole

Aminoglycosides

Carbapenems

	Yes	
Driscoll et al., [25], case report, United Kingdom	M, 16 yy	N. Farcinica	SARS-CoV2

P. Aeruginosa

	Fever, dyspnea, lethargy, hypoxia	Not reported	Trimetoprim-sulfometoxazole

Carbapenems

Cephalosporins

Ciprofloxacine

	No	

Quality assessment

The quality assessment of the studies is reported in Figs. 2 and 3.

Quality assessment of the included studies. Figure 2: The Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case Reports; Fig. 3: The Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case Series.

Fig. 2 Quality assessment of the included studies: the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case Reports

Fig. 3 Quality assessment of the included studies: the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case Series

Outcomes

Overall, 89 pwCF and Nocardia species isolation were included: 42 children and 47 adults. Among the 71 patients whose sex was specified, 32 were female (45%) and 39 were male (55%). Where reported, we found the following bacterial species: Nocardia asteroides (35%, 23/64), Nocardia farcinica (21%, 14/64), Nocardia tranvalensis (13%, 8/64), Nocardia cyriacigeorgica (11%, 7/64), Nocardia abscessus (5%, 3/64), Nocardia veterana (3%, 2/64), Nocardia wallacei (3%, 2/64), Nocardia miyunesis (1%, 1/64), Nocardia pneumoniae (1%, 1/64), Nocardia asiatica (1%, 1/64), Nocardia elegans (1%, 1/64), Nocardia otitidiscavarium (1%, 1/64). A co-infection was reported in 85% of patients (61/72). In 17 patients the possible presence of other microorganisms in sputum was not mentioned.

Of patients whose lung function was reported before and after Nocardia isolation, 23% (16/68) showed a decline in FEV1.

Above all, 82 patients were treated at least once after isolation of Nocardia strain. In 93% (77/82) of cases, treatment was started immediately upon isolation.

Antibiotic treatment was performed per os or intravenously depending on the clinical condition of the individual patient. The following antibiotics were prescribed in the 16 selected articles: trimethoprim-sulfamethoxazole (52/82, 63%), ciprofloxacin (17/82, 20%), penicillins (16/82, 18%), aminoglycosides (12/82, 14%), cephalosporins (11/82, 13%), carbapenems (10/82, 12%), tetracyclines (8/82, 10%), linezolid (7/82, 9%). For 30 out of 89 patients (33%), hospitalization and intravenous antibiotic therapy were required. Death was reported in 3 patients, 2 of which were children, with severe lung disease or Pa and Mycobacterium avium complex co-infection.

Nocardia eradication was attempted in only 32 cases out of 82, and 78% (25/32) of these patients were successfully eradicated from Nocardia after one or more courses of antibiotics.

The results of the studies have been reported in the Table 1.

Discussion

Do Nocardia species have a pathogenic role in patients with CF?

The pathogenic role of Nocardia in pwCF is still unclear [10, 15]. In 2002, Lumb et al., in a retrospective study on 3 pwCF, firstly discussed the role of Nocardia as a possible pathogen in CF, concluding that the isolation of this bacteria does not always mean active infection. Therefore, the treatment must be considered in the clinical context of each patient and a careful follow-up is mandatory, particularly in patients in therapy with steroids due to their immunosuppressive effect [8]. This view was confirmed by subsequent studies. In 2009 Thorn et al., in a retrospective study on 17 pwCF, concluded that Nocardia frequently acts as a colonizer, not resulting in active infection with symptoms or impaired respiratory function [10]. Our study confirms this variability in the pathogenicity of Nocardia across various studies and suggests a clinically guided approach based on imaging and lung function.

What are the risk factors for nocardiosis?

In the previously mentioned study by Lumb et al., the authors associate nocardiosis with cell-mediated immunosuppression, potentially facilitated by corticosteroid oral treatment or a history of transplantation [8, 9, 13, 19]. Others link nocardiosis to the co-colonization of Nocardia species and Pa [10], although this observation is strictly clinical and contradicted by other case series studies [15, 22], or highlight a history of bronchopulmonary aspergillosis (ABPA) as a high risk to develop lung disease in CF patients with Nocardia species [21]. Similarly, Nocardia can be damaging in patients undergoing lung transplantation, resulting in rapid failure of respiratory function, as described by Chacon et al. in 2014 [19]. Some authors correlate the subspecies of Nocardia transvalensis with a greater symptom burden than the more prevalent Nocardia asteroides subspecies [20]. Nocardia isolations are typically uncommon in the general pediatric population, and advanced age is recognized as a risk factor for nocardia’s infections. However, our analysis reveals that children contract these infections at a similar rate to adults. These findings might indicate that, in addition to age, CF should be regarded as an additional risk factor [15]. Finally, a recent case report link necrotizing pneumonia to co-infection of Nocardia and Covid-19 in pwCF [25].

Does Nocardia affect lung function?

In 2015, a longitudinal study examined pulmonary function tests (PFT) in pwCF before and after Nocardia isolation not reporting statistically significant difference between patients with a single episode and those with recurrent isolation, nor between patients that underwent antibiotic therapy and those who did not receive treatment. However, pwCF affected by nocardiosis showed a small trend to faster decline in PFTs compared to similar status CF patients without isolation of this microorganism in their sputum [11, 22]. Other authors noticed Nocardia species positive sputum culture may be followed by lung function deterioration and may promote the onset of other infections [21]. Our review demonstrates that only a few patients exhibit a deterioration in lung function following the isolation of Nocardia. However, data on lung function trends in these patients are weak in the literature and deserve further investigation.

Should patients with Nocardia-positive sputum always be treated?

At the present there are no guidelines for treatment of Nocardia in pwCF and the most prudent strategy seems to be the one suggested by Barrio et al. in a retrospective study in 2008: the isolation of Nocardia does not necessarily imply therapy and patients need to be monitored closely to assess the possible occurrence of active infection and subjects to be treated should be selected on an individual basis [10].

A proposal for a therapeutic management algorithm is reported in Supplemental Figure S1. Antibiotic treatment should always be administered when Nocardia species are isolated in patients before undergoing lung transplantation [13, 15, 19]. Otherwise the majority of authors agree to treat Nocardia species when, even though initially categorized as a colonizer, they are isolated in presence of : worsening of clinical status, radiological features or lung function or in cases where there is a concurrent infection with more common bacterial species in pwCF, such as Pa, and the patient does not improve despite broad antibiotic coverage [8, 10, 14, 15, 20, 21]. However, the eradication of Nocardia species is difficult to obtain [19]. In any case, most studies performed so far describe few cases of Nocardia infection in pwCF, and it is possible that the occurrence of such infection is underestimated due to its limited recognition and research in laboratories [9, 15, 23].

In conclusion, our study shows that, although in a few cases the isolation of Nocardia is directly associated with a deterioration in lung function, various cystic fibrosis centers around the world prefer to treat it immediately.

What antibiotic regimen should be used?

Antibiogram should drive the selection of the most effective therapy [11, 23]. Interestingly, the species that more frequently infect pwCF seem to not show difference in the pattern of susceptibility [15, 23] even if the identification of the species is rather difficult using conventional cultural and biochemical methods, and misclassifications may occur [4]. In most studies, trimethoprim-sulfamethoxazole was used as first-line treatment, followed by minocycline or amikacin in more severe forms [7–12, 14, 15, 19, 21, 23]. Linezolid, to which Nocardia is almost always susceptible, may be an alternative [14–21]. In case of worsening general clinical conditions, hospitalization is necessary along with the initiation of intravenous antibiotic therapy using at least two antibiotics chosen based on the antibiogram [14, 15, 21]. When combination therapy is required, drugs included can be third- generation cephalosporins, amikacin and imipenem [12, 13, 15, 19–23].

How long should the antibiotic treatment for Nocardia last?

It should be continued based on the severity of the pulmonary condition and the progression of antimicrobial susceptibility [3, 14, 15, 20, 21]. In the literature, treatments from 6 to 12 months are recommended for serious lung infections or in patients with strong immunosuppression. If symptoms are few, treatment could be reduced to 1–3 months [15].

Conclusions

Nocardia species are a complex group of organisms which can be isolated in pwCF. Of the validly described species, not all strains have been shown to be pathogenic in humans. Several species have been implicated as the cause of serious infections, especially in immunocompromised patients such as pwCF, but the identification of the specific Nocardia spp complex and expensive techniques available only in few laboratories. The picture is further complicated by the fact that Nocardia is not included in dedicated CF registries, so the care of these patients relies on individual experiences reported by centers located around the world and related reviews.

Several studies suggest that Nocardia acts mainly as a colonizer rather than a pathogen, not resulting in active infection, while other studies illustrate how Nocardia species could cause lung deterioration and promote the onset of other bacterial infections. In particular, patients with history of ABPA, those undergone lung transplantation or in therapy with steroids or immunosuppressor, are at a higher risk of clinically active Nocardiosis.

Management of nocardia isolation has no protocols validated by evidence-based medicine approach and under these circumstances our center, as well as others reported in this review, has chosen a pro-active approach and attempted eradication in the absence of symptoms as is done with other pathogens in pwCF.

In general the isolation of the bacteria does not necessarily imply therapy, but patients need to be monitored closely to assess the possible occurrence of active infection. On the contrary, the treatment is indicated in patients showing lung involvement with the possible appearance of pneumonia, pleural effusion, fever, cough, or a decrease in FEV1, or in patients undergoing pulmonary transplantation. However, the eradication of Nocardia is difficult to obtain. The complexity of Nocardia’s role in pwCF underscores the importance of individualized patient care and ongoing clinical monitoring.

Further research is needed to refine treatment strategies, identify definitive risk factors, and elucidate its impact on lung function, as well as defining the role of the lung microbiota on the risk of infection or the impact of new CFTR modulators. The possibility of improvement in CFTR function resulting in enhanced ability to clear pathogens, has attracted considerable attention and literature, in particular for P. Aeruginosa and A. Fumigatus [24, 25], and this possibility could radically change the prognosis of these patients witch Nocardiosis.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Author contributions

All authors contributed to the concept and design of the systematic review for which this protocol has been written. TB and AC wrote the first draft of the manuscript. EC, VT, DD, SC and GT contributed to subsequent drafts. All authors reviewed and approved the final manuscript before submission.

Funding

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Data availability

All data generated or analysed during this study are included in this published article.

Declarations

Ethics approval and consent to participate

was obtained from the Ethical Committee of the CF Center of Florence (on November 14, 2023) and written informed consent for the clinical case publication was obtained by the patient.

Consent for publication

Non applicable.

Patient and public involvement

No patients or members of the public were directly involved in this research study.

Competing interests

The authors declare no competing interests.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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