Pulmonary Nocardiosis: Clinical Experience in Ten CasesMari B.a · Montón C.a · Mariscal D.b · Luján M.a · Sala M.c · Domingo C.a
Departments of aPneumology, bMicrobiology and cInternal Medicine, Corporació Sanitària Parc Taulí, Sabadell, Spain Corresponding Author
Background: Pulmonary nocardiosis is an infrequent infection whose incidence seems to be increasing due to a higher degree of clinical suspicion and the increasing number of immunosuppressive factors. Objective: To study the predisposing factors, clinical characteristics, diagnostic procedures, treatment and progress of pulmonary nocardiosis (PN). Methods: Review of 10 patients (9 male, 1 female, mean age 61) with PN in a 600-bed teaching hospital, diagnosed from 1992 to 1999. Results: Associated diseases observed were chronic obstructive pulmonary disease (COPD) in 6 patients, human immunodeficiency virus (HIV) infection in 3 and polymyalgia rheumatica in 1. Four patients had received oral corticotherapy for COPD for over a year (mean dose 13 mg/day of prednisone or equivalent). The main reason for consultation was an increase in dyspnea in the patients with COPD (6/6) and fever in those with HIV (3/3). Mean time between onset of symptoms and diagnosis was 5 weeks. In 8 patients, the infection occurred outside the hospital setting. The infection was restricted to the lung in 9/10; in the remaining case, the central nervous system (CNS) and subcutaneous tissue were affected. Lobar or multilobar consolidation was the most frequent radiographic pattern found (6/10). Sputum culture was positive when performed (8 cases). Diagnosis was made or confirmed by bronchoscopy (bronchoaspirate or protected specimen brush) in 5 patients. Germs isolated were: Nocardia asteroides (8/10), Nocardia farcinica (1/10), Nocardia otitidiscaviarum (1/10). Cotrimoxazole was the most used empirical treatment (6/10). Resolution was achieved in 5 cases. Four subjects died: 1 HIV patient with disseminated nocardiosis, and 3 COPD patients, 2 of whom had received long-term corticotherapy. Illness recurred in only 1 case, due to failure to comply with treatment. Conclusions: (1) In our geographical setting Nocardia presents as a subacute or chronic pulmonary infection, mainly outside the hospital. (2) It tends to affect only the lung. (3) Diagnosis requires a high clinical suspicion, and can be made on the basis of a sputum culture. (4) Nocardia tends to attack patients with underlying COPD, or immunodepressed patients treated with glucocorticoids, or patients with HIV infection. (5) Mortality is high in both COPD and HIV patients. (6) In our area, cotrimoxazole seems to be the most commonly prescribed treatment.
Copyright © 2001 S. Karger AG, Basel
Nocardiosis is a localized or disseminated infection caused by soil-dwelling aerobic actinomycetes, which habitually enter through the respiratory tract. The annual incidence in the US is estimated at between 500 and 1,000 cases , though this figure may not reflect the true rate [2, 3] because of the difficulty of diagnosis and the fact that it is not a reportable disease. Recent reports have shown an increase in the incidence of Nocardia spp. infections in humans, probably due to a higher degree of clinical suspicion, the use of more aggressive diagnostic examinations, the increased use of immunosuppressive treatments (chemotherapy agents and immunosuppression for organ transplantations) [4, 5], and the appearance of the acquired immunodeficiency syndrome (AIDS) .
We review of the predisposing factors, clinical characteristics, diagnostic procedures, treatment and progress of the 10 cases of pulmonary nocardiosis (PN) diagnosed at our center between 1992 and 1999.
patients and methods
We reviewed all patients in whom PN was diagnosed at our center between January 1992 and February 1999. Our institution is a 600-bed teaching hospital which is the AIDS referral center of an area of 350,000 inhabitants. No organ transplantations are performed. In total, 10 diagnoses of PN were made.
We included all patients in whom Nocardia spp. had been isolated in at least one respiratory sample, obtained by sputum culture or bronchoscopy. Data compiled during the study were: underlying disease, previous immunosuppressive treatment, clinical, analytical and radiographic manifestations, mean time between onset of the disease and diagnosis, diagnostic methods, extension to other organs, treatment received, and evolution.
Respiratory samples were cultured on blood agar medium, chocolate agar, colistine-nalidixic acid agar and McConkey agar, with an incubation period of 3–14 days at 35°C. However, when there was clinical suspicion of Nocardia infection or when a gram-positive, branched diphtheroid to filamentous bacterium was visualized on the gram stain, a Sabouraud dextrose agar was also plated. Cultures for mycobacteria were grown on Löwenstein-Jensen and Middlebrook 7H9 at 35°C in a 5% CO2 atmosphere for 8 weeks. Identification was performed according to the methods routinely used by the Microbiology Department at our institution.
Antibiotic sensitivity was studied by the microdilution method (Pasco®). The cut-off points for minimal inhibitory concentrations were those defined by the National Committee for Clinical Laboratory Standards (NCCLS) for fast-growing microorganisms [7, 8, 9].
Nine males and 1 female with PN (mean age 61 years, range 32–84 years) were recruited. Associated diseases are summarized in table 1. Forty percent (4/10) had received immunosuppressive treatment with glucocorticoids, administered orally, for a period of over a year (mean dose 13 mg/day of prednisone or equivalent, range 7.5–25 mg), all for COPD. The patient with polymyalgia rheumatica (1/10) had received treatment with prednisone at a dose of 10 mg/day for the previous 3 weeks. The patients with HIV infection were AIDS category C-3 with a CD4 lymphocyte count below 100 cells/mm3 at the moment of development of the pulmonary infection (table 1).
Table 1. Clinical characteristics
An increase in dyspnea was the main reason for consultation in COPD patients (6/6) either accompanied by other symptoms or not (1/6 hemoptysis, 3/6 cough with purulent expectoration, 3/6 fever). In HIV patients, the reason for consultation was fever in all cases, associated with dyspnea and asthenia. Two of the COPD patients were admitted to the intensive care unit and administered orotracheal intubation and mechanical ventilation for respiratory failure. Mean time between onset of symptoms and diagnosis was 5–6 weeks; there was no significant difference in this parameter between patients with HIV infection, COPD or patients who had received chronic corticosteroid treatment in the last year.
The infection occurred outside the hospital setting in 8/10 of patients. We considered infections detected at admission to be community-acquired infections. In-hospital infection was defined according to the criteria of the American Thoracic Society . Nocardiosis was restricted to the lung in 9/10 cases; in the remaining case, the CNS and subcutaneous tissue were affected. The neurological impairment presented in the form of right hemiparesis and stiffness in the neck, the subcutaneous tissue disorder as a recurrent cutaneous abscess.
The most relevant analytical data were the existence of leukocytosis in patients without HIV infection, with a mean leukocyte count of 19.22 × 109/l (range 9.9–28 leukocytes × 109/l), and leukopenia in patients with HIV infection, mean leukocyte count 3.37 × 109/l (range 1.5– 6.5 leukocytes × 109/l), and a high erythrocyte sedimentation rate, mean 82 mm (range 10–138 mm).
Fig. 1. Lobar consolidation in the left upper lobe, with several nodules in the right lung.
Fig. 2. This computed tomograph of the chest shows several nodules mainly affecting the right lower lobe. The left lower lobe is also affected.
Table 2. Microbiology, treatment and evolution
A cranial computed tomography scan was performed to study disseminated disease in 3 of the 10 patients. Hyperdense nodular images compatible with CNS nocardiosis were found in only 1 case.
PN was diagnosed in all patients on isolation of Nocardia spp. in respiratory samples. Sputum culture, the most frequently used diagnostic test, was positive in the 8 cases in which it was performed. The diagnosis was confirmed or performed by a respiratory sample obtained by fiberoptic bronchoscopy with a bronchoaspirate or a protected specimen brush in 5 patients. In one case, diagnosis was made postmortem, on the basis of the necropsy culture. The germs isolated in the various respiratory samples are shown in table 2: Nocardia asteroides (8/10), Nocardia farcinica (1/10), Nocardia otitidiscaviarum (1/10). The infection was polymicrobial in 3/10 of cases: Pseudomonas aeruginosa (1), Aspergillus fumigatus (1), and Mycobacterium tuberculosis (1). In the case of Aspergillus, the infection was considered and treated as a chronic necrotizing pulmonary aspergillosis. In the case in which Nocardia spp. and Pseudomonas had been previously isolated in a sputum culture before death, only Nocardia spp. was detected. Again PN was recorded as the cause of death. Finally, in 1 case, both M. tuberculosis and Nocardia spp. were isolated. The patient received treatment against M. tuberculosis, and recovered. Nocardia spp. was not considered to have been the infecting agent. Five years later, the patient is alive and in good health.
Cotrimoxazole (trimethoprim-sulfametoxazole; TMP-SMX), with trimethoprim at a dose of 10 mg/kg/day, was the most commonly used empirical treatment (6/10), in 4 cases in association with other antibiotics for the treatment of polymicrobial infection. Imipenem was used in patients with severe disease requiring admission to the intensive care unit (2/10), in 1 case in association with a third-generation cephalosporin.
Ciprofloxacin was used as empirical treatment in 1 patient with bronchiectasis, and it was maintained after the germ’s sensitivity to the antibiotic was confirmed. The patient diagnosed post mortem had received treatment with amoxicillin and clavulanic acid, and subsequently with a third-generation cephalosporin. Significant treatment complication occurred in 3/10 patients (all receiving treatment with TMP-SMX): anemia (1/3), severe hyponatremia (1/3) and renal tubular acidosis (1/3). A change in treatment was only required in the last case, in which minocycline was used as a replacement. An antibiogram was performed in 7/10 patients; the Nocardia spp. isolate was sensitive to TMP-SMX in 6/7 patients and resistant in 1/7 patients. These results are summarized in table 2.
The resolution of the disease was evaluated according to the clinical symptoms (5/10), whether or not accompanied by radiological resolution (2/5). Forty percent of the patients died – 1 HIV and 3 COPD –, 2 of whom had received prolonged glucocorticoid treatment and died due to respiratory failure. The HIV patient refused treatment, and disseminated disease was considered the cause of death. The disease recurred in only 1 case, due to failure to comply with the treatment; after resumption of the medication, the evolution was favorable. The patients’ evolution is shown in table 2.
Nocardia is a gram-positive aerobic bacillus which has been identified as the cause of a wide variety of infections. There are no known cases of person-to-person transmission, and so the acquisition of these infections is considered to be environmental, generally via the respiratory tract . For this reason, PN appears to be a community-acquired infection. However, according to the consensus criteria of the American Thoracic Society  2 of our patients were considered to have became infected in hospital. Nosocomial cases, some in clustered outbreaks, have been described . However, one might reasonably speculate that the infection was in fact acquired outside the hospital, and has become clinically relevant in hospital.
More than half of the patients who present infections due to Nocardia are immunocompromised for different reasons . In our series, as in the review of 10 cases by Menéndez et al. , the predominant underlying disease was COPD, followed by HIV infection. However, none of our patients had underlying neoplastic disease or a history of alcoholism. Steroid and immunosuppressive treatments also favor PN. Although, as stated above, COPD was considered a risk factor, 4 of these 6 patients were also steroid-depenent. Conceivably, therefore, the real risk factor may have been steroid treatment.
Clinical characteristics were relatively nonspecific, in accordance with other reports in the literature . PN tends to present as a subacute pneumonia, the symptoms appearing over the course of several days or weeks . In the series reported by Menéndez et al. , 50% of the PN had dissemination outside the lungs. Hematogenous dissemination is more frequent in the case of N. asteroides (principally into the CNS), and lymphangitic spread or dissemination into contiguous areas in the case of N. brasiliensis . However, in our series only 1 case had disseminated disease (into the CNS). Colonization without infection has been described , though it is infrequent. In our series, Nocardia spp. was only isolated in 1 respiratory sample which was considered a colonization (case 8). The commonest radiographic finding in our series was lobar or multilobar consolidation (6/10), as also reported by others [14, 16]. The presumptive diagnosis is established by Gram’s stain although isolation and identification of the microorganism in a respiratory sample are needed for confirmation. The microbiology laboratory should be informed of the suspicion of PN since the incubation time of the cultures must be prolonged, and the laboratory should also be advised to use concentration and decontamination techniques with the sample. The most frequently isolated Nocardia species in our series of PN was N. asteroides, as also reported by others [1, 14].
The need for multiple antimicrobial treatment in patients with severe Nocardia spp. infections, the variable susceptibility of these microorganisms to antimicrobials, and the problem of patient allergy to sulfamides are all grounds for performing antibiograms in samples in which Nocardia spp. has been isolated . Generally, two or more antibiotics (one of them a sulfamide) are used to treat nocardiosis. Today, cotrimoxazole (TMP-SMX) is the most frequently used drug [15, 18, 19]. The use of this combination is based on the demonstration of its synergic activity in vitro against Nocardia spp. [20, 21]. Its advantages are its excellent penetration into many tissues such as the lung and the CNS, which allows a high concentration, and its good oral absorption. This therapeutic combination was the most frequently used in our series (6/10). Experimental studies using antimicrobial combinations, supported by clinical observations, have demonstrated synergism in vitro with imipenem-amikacin, imipenem-cefotaxime and cefotaxime-amikacin [22, 23]. In these studies, therapy with sulfamides has proved effective in patients with pulmonary or cutaneous nocardiosis, but in seriously immunocompromised patients (e.g. organ transplant patients) and those with disseminated disease this treatment should be initiated in association with imipenem, a third-generation cephalosporin or amikacin. Treatment with a sulfamide alone should only be introduced when clinical improvement has been achieved [14, 24]. Two of our patients required treatment with imipenem alone or associated with a third-generation cephalosporin, after admission to the intensive care unit for severe PN with respiratory failure. Other antibiotics, such as amoxicillin associated with clavulanic acid and minocycline, are effective alternatives in patients intolerant or allergic to oral sulfamides . Minocycline was used in 1 of our patients who developed renal tubular acidosis 15 days after initiating a treatment with sulfamides (case 4). Similarly to fluoroquinolones, ciprofloxacin and ofloxacin have been reported to be active in vitro against Nocardia spp., but there are very few reports of successfully treated cases. Due to their good tissue penetration when administered orally and their activity in vitro, fluoroquinolones may be an effective alternative treatment in some cases, but not in those in which the CNS is affected, due to their limited penetration in the nervous tissue. Ciprofloxacin was used in 1 patient with initial recurrence of disease due to failure to comply with the treatment and the patient achieved full recovery a few months after resuming his treatment and appearing regularly for follow-up. Nocardia spp. infections may recur, and for this reason prolonged treatments of between 6 and 12 months are recommended. In seriously immunodepressed patients, the treatment of pulmonary and systemic nocardiosis should be maintained for a year, and in some cases even longer .
In some cases, the infection can be polymicrobial. One of the opportunistic germs that may invade the lung in the setting of PN is Aspergillus, either acutely  or as a chronic necrosis . In these cases, Nocardia should not be considered routinely as a colonizing agent and should be treated specifically, as in our series.
Forty percent of our patients, died, a figure similar to those reported in other series . Among the prognostic factors related to high mortality perhaps the most important are prior treatment with corticoids and disseminated infection . In our series, one of the patients who died presented disseminated disease, and of the 3 remaining patients 2 had received glucocorticoid treatment.
In summary, Nocadia spp. present as a subacute or chronic pulmonary infection, in which usually only the lung is affected. It occurs mainly outside the hospital setting. Diagnosis requires a high degree of clinical suspicion and can be made on the basis of a sputum culture. Nocardia usually affects patients with underlying COPD, or immunodepressed patients treated with glucocorticoids, or patients with HIV infection. Mortality is high, in both COPD and HIV patients. In our geographical setting, cotrimoxazole remains the most frequently prescribed treatment.
Dr. Ch. Domingo
S. Pneumologia, Corporació Sanitària Parc Taulí
Parc Taulí s/n.
E–08208 Sabadell (Spain)
Tel. +34 937231010, Fax +34 937160646, E-Mail firstname.lastname@example.org
Received: Received: May 18, 2000
Accepted after revision: December 28, 2000
Number of Print Pages : 7
Number of Figures : 2, Number of Tables : 2, Number of References : 28
Respiration (International Review of Thoracic Diseases)
Founded 1944 as ‘Schweizerische Zeitschrift für Tuberkulose und Pneumonologie’ by E. Bachmann, M. Gilbert, F. Häberlin, W. Löffler, P. Steiner and E. Uehlinger, continued 1962–1967 as ‘Medicina Thoracalis’
Vol. 68, No. 4, Year 2001 (Cover Date: July-August 2001)
Journal Editor: C.T. Bolliger, Cape Town
ISSN: 0025–7931 (print), 1423–0356 (Online)
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