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PEDIATRICS Vol. 104 No. 4 October 1999, pp. 961-964
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ABSTRACT |
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Top
Abstract
Introduction
Discussion
References
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Infection with Nocardia poses a diagnostic challenge in patients with chronic granulomatous disease (CGD) because the signs and symptoms are often nonspecific, delay in diagnosis is common, and invasive procedures are frequently required to obtain appropriate tissue specimens. We present the first reported case of N farcinica pneumonia in an adolescent with X-linked CGD. Differentiation of N farcinica from other members of N asteroides complex is important because of its propensity for causing disseminated infection and antimicrobial resistance. Physicians caring for patients with CGD should maintain a high index of suspicion for nocardiosis, especially in those receiving chronic steroid therapy. Early diagnosis remains critical for decreased morbidity and occasional mortality.
Key words: Nocardia farcinica, chronic granulomatous disease, pneumonia.
Chronic granulomatous disease (CGD) is a rare inherited
disorder of the nicotinamide adenine dinucleotide
phosphate-oxidase complex in which phagocytes fail to generate
superoxide and toxic oxygen metabolites, which are key elements in host
defense against a variety of microbes.1 As a result, CGD
patients are susceptible to recurrent, severe infections at an early
age with catalase-positive organisms such as Staphylococcus,
Burkholderia cepacia, Aspergillus, and
Nocardia.1 Two thirds of patients inherit CGD
in an X-linked pattern attributable to mutations in the gene encoding
the membrane-bound cytochrome b558 gp91-phox subunit of the nicotinamide adenine dinucleotide
phosphate-oxidase. One third follow an autosomal recessive
pattern attributable to gene mutations encoding the remaining three
oxidase components: p47-phox, p67-phox, and
p22-phox.2
Nocardia species (spp) are ubiquitous soil-borne aerobic
actinomycetes usually causing invasive disease in patients with
immunodeficiency such as those receiving corticosteroids or
antineoplastic chemotherapy, solid-organ transplant recipients, and
patients with CGD and lymphoreticular malignancies.3,4 The
most common pathogenic Nocardia species are the
Nocardia asteroides complex (comprising three species:
N asteroides sensu stricto, N farcinica, and
N nova) followed by N brasilensis, N
otitidiscavarium (also known as N caviae), and N
transvaliensis.5,6 Reports of nocardosis in pediatric
patients with CGD have been few.7-20 Infection
attributable to N farcinica has been reported recently in a
adult patient with CGD.21 We describe the first case of
N farcinica pneumonia in an adolescent with CGD and review the clinical characteristics of nocardiosis in children with CGD.
A 15-year-old white male with X-linked CGD was admitted to the
hospital with a 5-day history of fever to 40°C, intermittent chills,
and malaise, and a 2-day history of nonproductive cough and right
shoulder pain with deep inspiration. Ten days before admission, he had
completed a 4-week course of oral prednisone (10 mg every other day)
for severe dysuria secondary to bladder granulomatous disease. Review
of systems was negative for hemoptysis, dyspnea, weight loss or
exposure to tuberculosis. There was no history of recent travel or
exposure to pets.
He was diagnosed with CGD at 9 months of age after persistent vomiting
and failure to thrive attributable to gastric outlet obstruction
secondary to biopsy-proven granulomas. CGD was confirmed by the
inability of his granulocytes to reduce nitroblue tetrazolium dye and
to kill Staphylococcus aureus. Past history was also notable for disseminated Aspergillus fumigatus infection
(pneumonia, osteomyelitis and central nervous system lesions) at age 13 years requiring 6 months of liposomal amphotericn B therapy. He had
been maintained on antibacterial and antifungal prophylaxis with
trimethoprim/sulfamethaxazole (TMP-SMX), itraconazole, and recombinant
interferon- Physical examination at admission revealed an alert, comfortable
adolescent with no signs of respiratory distress or increased respiratory effort. Temperature was 38.3°C; heart rate, 90 beats per
minute; respiratory rate, 18 breaths per minute; blood pressure, 130/65
mm Hg; weight, 51.6 kg (25%), height, 160.5 cm (10% to 25%). Chest
examination was remarkable for decreased breath sounds over the
distribution of the right middle lobe. The remainder of the physical
examination was normal.
Laboratory evaluation revealed hemoglobin of 11.6 g/dL, platelets of
325 000/mm3, white blood cell count of
8900/mm3 with 82% neutrophils, 13% lymphocytes, 4%
monocytes, and 1% basophils. A chest radiograph showed a round opacity
in the middle lobe of the right lung and a left upper lobe infiltrate.
Computed tomography scan of the chest confirmed a large right
middle lobe mass, peripherally abutting the pleura without chest wall
invasion, and left upper lobe consolidation. A head magnetic resonance
imaging scan and an ultrasound of the abdomen was unremarkable. An
ophthalmologic evaluation was normal.
The patient was treated with intravenous nafcillin (1 g 4 times daily)
and ciprofloxacin (400 mg twice daily). Fever and shoulder pain
persisted, and on hospital day 2 he underwent computer
tomography-guided percutaneous needle lung biopsy of the right
mass. Gram stain and acid-fast stains did not reveal any
microorganisms. On hospital day 5, biopsy specimen culture was positive
for N asteroides complex. Aerobic, anaerobic, fungal,
and mycobacterial cultures were negative. Histology of the lung tissue
was unrevealing. Treatment with high-dose oral TMP-SMX (20 mg/kg/d of
trimethoprim) and minocycline (100 mg twice daily) was begun on
hospital day 5. The initial antibiotics were discontinued. Blood and
urine cultures obtained at presentation were sterile. Clinical
improvement was noted with resolution of fever and shoulder pain, and
on hospital day 7 he was discharged to home on TMP-SMX and minocycline.
Two weeks after discharge, the Nocardia species was
identified as N farcinica at the Mycobacteria
Nocardia Research Laboratory at Tyler, Texas. The pathogen was
susceptible to sulfamethaxazole, TMP-SMX, amikacin, and ciprofloxacin,
and showed intermediate susceptibility to minocycline, augmentin, and
imipenem. At this point, minocycline was discontinued, and oral
ciprofloxacin (500 mg twice daily) was prescribed. One month after
discharge, he was asymptomatic. Repeat chest radiograph showed
significant resolution of the bilateral pulmonary infiltrates. His
white blood cell counts and liver function tests have remained
stable. The patient is currently receiving TMP-SMX (15 mg/kg of
trimethoprim) and ciprofloxacin which we plan to continue for 12 months.
Pulmonary disease in a patient with underlying
immunosuppression is the most common presentation of nocardiosis in the
United States.22 Infection is acquired via inhalation of
nocardial cells into the lungs.3 The clinical spectrum of
pulmonary nocardiosis is highly variable. Patients may present with
acute or chronic pulmonary infection, including pneumonia, abscess
formation, or both.23 The diverse chest radiographic
findings, including single or multiple abscess cavities, various
degrees of infiltration, and pleural empyema, may mimic more common
lung infections such as staphylococcal, mycobacterial, or fungal
pneumonia.24 If the organism is not contained in the
parenchyma of the lung, dissemination may occur to one or several other
organ systems by hematogenous spread. The most common sites of
extrapulmonary involvement include the brain, skin and subcutaneous
tissues.3
Nocardiosis in children with CGD is rare. Ballenger and
Goldring25 reported the first case of Nocardia
spp (species) infection in a child with presumed CGD in 1957. To
date, 17 cases have been reported in the English language
literature.7-20 The clinical features, treatment, and
outcome of 14 cases (including the present case) are summarized in
Table 1. Three additional cases were
excluded from this Table because limited clinical information was
available.8,10 There were 11 males and 4 females, ranging
from 1 month to 15 years of age. Species identification included
N asteroides (7 cases), N caviae (1 case),
N transvaleinsis (1 case), and N farcinica (1 case); species was not specified in 4 cases. Several clinical
manifestations of Nocardia infection in patients with CGD
are noteworthy. The primary focus of infection was pneumonia in 12 cases, cutaneous abscess in 1 case, and lymphadenitis in 1 case. The
disease disseminated to the bone (3 cases), brain (2 cases), skin/soft
tissue (2 cases), lymph nodes (1 case), and liver (1 case). Extension
of pulmonary nocardiosis to the adjacent pleura and chest wall occurred
in 1 case. The diagnosis of nocardiosis was established by lung biopsy
in 8 patients, lymph node biopsy in 2, bone biopsy in 2, bronchoalveolar lavage in 1 and skin biopsy in 1. The isolation of
Nocardia spp lead to the diagnosis of CGD in 8 cases.7,9,11,12,1518-20 Of the 6 children with
established diagnosis of CGD, 2 were receiving prophylactic TMP-SMX at
the time of Nocardia infection (cases 9 and 15). Concurrent
fungal infection (Aspergillus spp) was present in
1.17 All cases were treated with a sulfa-containing regimen; duration of therapy has ranged from 3 months to 1 year. Surgical intervention was required in 6 cases (bone debridement in 3, lung segment resection in 1, open lung biopsy in 1, and drainage of
adenitis in 1). One patient died secondary to disseminated disease.
TABLE 1
CASE REPORT
(rIFN-).
DISCUSSION
Top
Abstract
Introduction
Discussion
References
Clinical Profile of Nocardia spp Infections in Children With
Chronic Granulomatous Disease
Neutrophils are critical to the initial containment of infection
with Nocardia spp, but infection progresses until the
appearance of cell-mediated immunity, triggered by activated
macrophages and induction of a T cell population capable of
direct lymphocyte-mediated toxicity to N asteroides; both of
these cells kill nocardiae in vitro.4 Suppression of
cellular immunity appears to play a key role in the establishment of
Nocardia infections.3,4 Corticosteroid therapy
is a well-recognized risk factor for the development of invasive
nocardial infections. Chronic steroid treatment for dysuria caused by
obstructive granulomatous disease of bladder26 was
undoubtedly a cofactor for the development of pulmonary nocardiosis in
our patient. Although no controlled trial has been done, extensive
clinical experience has shown that antibiotic prophylaxis in patients
with CGD reduced the incidence of infections and prolongs patients'
survival.27 Notably, our patient had been maintained on
TMP-SMX prophylaxis, which did not prevent infection with
Nocardia. It is possible that the chronic steroid therapy
overwhelmed any beneficial effect of this antibiotic. Nocardiosis may
be accompanied by concomitant fungal infection.17
rIFN- at 0.05 mg/m2/dose given subcutaneously 3 times a week has shown efficacy in preventing both bacterial and fungal
infections.28 IFN-, a cytokine secreted by T
lymphocytes, enhances both oxygen-dependent (respiratory burst) and
oxygen-independent antimicrobial phagocytosis.29
Recently accepted as an important human pathogen,30 N farcinica infection occurs more frequently than previously recognized.31 A wide spectrum of clinical presentations, including cerebral abscess, pulmonary and cutaneous disease, and postoperative wound infections have been described.31,32 Less commonly, the paranasal sinuses, the oral palate, and the eyes (especially the retina) have been involved.31 Underlying immunosuppressive conditions (such as therapies or leukemia, lymphoma, or human immunodeficiency virus infection) are noted in about one third of these cases.31
Isolation and precise species identification within the genus Nocardia is difficult.3 However, distinguishing between N farcinica and other members of N asteroides complex is important. Compared with other N asteroides complex organisms, N farcinica has a greater risk of disseminated infection, antimicrobial resistance, and mortality. Mice pathogencity studies demonstrate that N farcinica is more virulent than N asteroides.33 N farcinica is differentiated from the N asteroides complex by growth at 45°C for 3 days, cefotaxime resistance, acid production from L-rhamnose, and positive results for one of two additional tests (hydrolysis of acetamide and resistance to cefamandole and tobramycin).34
Therapy for N farcinica infections is currently problematic, because clinical isolates of this unusual species often demonstrate an unusually high level of resistance to the cephalosporins, ampicillin, aminoglycosides other than amikacin, and erythromycin but is usually susceptible to amikacin, ciprofloxacin, imipenem, and sulfamethoxazole.34 Many experts recommend in vitro susceptibility testing of Nocardia species35; however, results of such testing have not been well-correlated with clinical outcomes. Sulfonamides (with or without trimethoprim) are the therapy of choice for N farcinica.33,36 Good therapeutic results with monotherapy or various combinations with of imipenem, amikacin, amoxicillin plus clavulanic acid, and minocycline have also been reported.33,36 Data comparing the efficacy of various treatment regimens are not currently available for N farcinica infections.
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ACKNOWLEDGMENTS |
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We thank Richard J. Wallace, Jr, MD, Mycobacteria Nocardia Research Laboratory at Tyler, Texas, for confirming the isolate as N farcinica and performing antibiotic susceptibility testing, and Ross Dehovitz, MD, from Palo Alto Medical Clinic, Palo Alto, California, for referring the patient.
Department of Pediatrics
Stanford University School of Medicine and
Lucile Salter Packard Children's Hospital at Stanford
Stanford, CA 94040
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FOOTNOTES |
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Received for publication Jan 11, 1999; accepted Apr 5, 1999.
Address correspondence to Kathleen M. Gutierrez, MD, Pediatric Infectious Diseases, Rm G312, Stanford University School of Medicine 300 Pasteur Drive, Stanford, CA 94040. E-mail: md.gutka{at}lpch.stanford.edu
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ABBREVIATIONS |
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CGD, chronic granulomatous disease;
spp, species;
TMP-SMX, trimethoprim/sulfamethaxazole;
rIFN-, recombinant
human interferon gamma.
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REFERENCES |
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Top
Abstract
Introduction
Discussion
References
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This article has been cited by other articles:
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  T. Andrews and K. E. Sullivan Infections in Patients with Inherited Defects in Phagocytic Function Clin. Microbiol. Rev., October 1, 2003; 16(4): 597 - 621. [Abstract] [Full Text] [PDF]
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 A. Gaafar, M. J. Unzaga, R. Cisterna, M. V. Leal, V. Bustamante, J. M. Tirapu, and J. A. Crespo Separate Nocardia Infections in a Patient with Chronic Granulomatous Disease J. Clin. Microbiol., August 1, 2001; 39(8): 3015 - 3016. [Full Text] [PDF]
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