Nocardiosis is an infection caused by bacteria belonging to the genus Nocardia. The taxonomy of the genus Nocardia has undergone numerous revisions over recent years, and greater than 50 species have been characterized. Among these species, approximately 16 have been implicated in human infections.1,2 These soil-borne aerobic bacteria cause disseminated infections that most commonly present as pulmonary disease or cutaneous infections through direct skin inoculation. Although nocardiosis is commonly considered an opportunistic disease, mainly affecting patients with deficiencies in cell-mediated immunity, it can affect immunocompetent patients as well. Due to many non-specific manifestations of nocardiosis, the clinical diagnosis can often be difficult.3
Epidemiology and Pathogenesis
Nocardia species are ubiquitous soil-dwelling organisms first described in 1888 by Edmond Nocard, a French veterinarian and microbiologist, as a bovine pathogen. They were identified as gram-positive, branching, beaded bacilli that are weakly acid-fast staining. The main routes of transmission are inhalation or a penetrating cutaneous injury. The most common species associated with human disease is Nocardia asteroides, a member of the N. asteroides complex, which also includes N nova, N farcinica and N transvalensis. Disseminated nocardiosis is largely considered an opportunistic infection and usually affects immunocompromised individuals, whereas primary cutaneous nocardiosis usually affects immunocompetent individuals. Although the current incidence of nocardiosis is not well defined, an estimated 1,000 cases occur annually in the United States, and infection occurs more commonly in men. This incidence will continue to increase over time as the prevalence of immunocompromised patients increases as a result of advances in oncology, rheumatology and transplant medicine.4 Geographically, N farcinica has been reported more frequently in western European countries, whereas N brasiliensis has been reported more frequently in the southern United States.
An estimated 50% of patients with N asteroides have underlying immunological deficiencies, such as in transplant recipients and in patients with HIV/AIDS. In autopsy series, nocardiosis has been diagnosed in up to 4% of patients with AIDS, and 10.6% of renal transplant recipients who died from infectious causes.4 Transplant patients comprise up to 13% of reported cases of nocardiosis in the United States. The rate of symptomatic nocardial infections is lower in AIDS patients, with an incidence between 0.19%-2.0%.4 Rarely, nocardiosis is seen in the pediatric population, primarily in children with severe underlying pulmonary disease.
Clinical Presentation
The main transmission route is through inhalation; therefore the lungs are the primary site of Nocardia infection in over 66% of cases. Pulmonary nocardiosis typically produces a necrotizing, poorly contained cavitary lesion that tends to affect the upper lobe. Radiographic imaging of the chest can also demonstrate focal or multifocal disease. Pleural effusions develop in up to one-third of patients, and necrotizing pneumonitis can spread into the pleura, pericardium, mediastinum and vena cavum through hematogenous dissemination or contiguous spread. Hematogenous dissemination can lead to widespread involvement of other organs throughout the body. The most common extrapulmonary site for nocardiosis is the central nervous system. Although cerebral nocardiosis typically occurs alongside pulmonary nocardiosis, isolated intracranial disease has been reported.2 Other less common manifestations of disseminated nocardiosis include psoas abscess, cutaneous or subcutaneous nodules, brain abscess, retinitis, septic joint with myositis, catheter tip infection, hepatic abscess, adrenal abscess and multiple intraabdominal abscesses (Table 1).
Primary cutaneous nocardiosis (PCN) comprises up to 5% of cases of nocardiosis, and occurs when the organism enters by direct inoculation through a break in the skin. The risk factors for PCN are soil or sand exposure, gardening, farming, trauma and/or skin abrasions from motor vehicle accidents.4 There are numerous acute manifestations of PCN, which include cellulitis, ulcerative/bullous lesions, linear/keloid-like lesions and nodular-pustular lesions (Figure 1).
Figure 1. Ulcerative, nodular and pustular lesions of primary cutaneous nocardiosis located on the shoulder and back. Source: Graham Library of Digital Images, Wake Forest University Department of Dermatology © 2009 Wake Forest University Dermatology
The acute presentation of cutaneous nocardiosis can resemble the appearance of soft tissue infections produced by Staphylococcus aureus or streptococci infections. After skin inoculation, Nocardia can spread to regional lymph nodes, producing either solitary nodular lesions or a linear chain of lesions. In this form, the infection can resemble that of sporotrichosis, and has been referred to as sporotrichoid nocardiosis.2 PCN can develop into a chronic infection, which may manifest as hyperkeratotic plaques with tumor-like masses and sinus tracts, known as actinomycetomas (Figures 2 and 3).
Figure 2. Nodular, tumor-like lesions of primary cutaneous nocardiosis. Source: Graham Library of Digital Images, Wake Forest University Department of Dermatology © 2009 Wake Forest University Dermatology
Figure 3. Primary cutaneous nocardiosis actinomycetoma with discharging sinuses on the dorsal foot. Source: Graham Library of Digital Images, Wake Forest University Department of Dermatology © 2009 Wake Forest University Dermatology
Although PCN can lay dormant and reactivate over time, primary cutaneous lesions very rarely progress into systemic illness. Among the Nocardia species, N brasiliensis is most often implicated in PCN. Other species that have been identified are N asteroides, N otitidiscaviarum and N nova.
Histopathology
In biopsies of primary cutaneous nocardiosis, dermal fibrosis and suppurative, granulomatous inflammation is commonly seen (Figure 4).
Figure 4. Skin biopsy of an actinomycetoma demonstrating suppurative and granulomatous inflammation that involves the dermis and subcutaneous fat (hematoxylin and eosin, original magnification 50x). Source: Graham Library of Digital Images, Wake Forest University Department of Dermatology © 2009 Wake Forest University Dermatology
Nocardia are also among the various fungal and bacterial infections that can cause in vivo formation of intensely eosinophilic material around the microorganism, known as the Splendore-Hoeppli phenomenon (Figure 5).
Figure 5. Cutaneous nocardiosis demonstrating Splendore-Hoeppli phenomenon. Eosinophilic material composed of antigenantibody complexes, tissue debris and fibrin forming around the bacteria in vivo (hematoxylin and eosin, magnification x160). Source: Graham Library of Digital Images, Wake Forest University Department of Dermatology © 2009 Wake Forest University Dermatology
These peribacterial asteroid bodies are thought to be immunologic reactions, composed of antigen-antibody complexes, tissue debris and fibrin. These may prevent phagocytosis and killing of the organism and can lead to chronicity of infection.5 Additional findings include coccobacillary organisms, fibrinopurulent exudates, monocytic infiltrates, chronic nodular dermatitis, microabscess formation and/or sulfur granules.
The thin filaments of Nocardia species do not stain by hematoxylin and eosin or periodic acid-Schiff stains. However, Gomori methenamine-silver and tissue gram stains can be used to aid in visualization.
Differential Diagnosis
Pulmonary nocardiosis is commonly mistaken for tuberculosis, due its presentation as a cavitary lesion in the upper lobe, and often in immunocompromised patients. Its radiographic appearance also may resemble that of primary or secondary lung malignancies. Other diseases included in the clinical differential diagnosis are fungal infections that affect the lung, including aspergillosis, mucormycosis, histoplasmosis, blastomycosis and actinomycosis infections. (Table 2)
Cutaneous nocardiosis has a wide differential diagnosis based on clinical presentation. PCN has been called a “great imitator” because it can resemble superficial cellulitis caused by a bacterial infection or a lymphocutaneous disease such as sporotrichosis or Mycobacterium marinum. In later stages with the formation of actinomycetoma, the differential diagnosis includes actinomycosis, fungal infections with Pseudallescheria or other molds or other cutaneous diseases such as cutaneous leishmaniasis and Cryptococcus.2
Diagnostic Tests
Nocardia are gram-positive, aerobic, branching bacteria that usually stain with modified (Kinyoun) acid-fast staining and have thin, delicate beaded branching filaments (Figure 6).
Figure 6. Nocardia asteroides seen on gram stain. Gram-positive, filamentous branching rods with irregular, beaded staining patterns. Source: Graham Library of Digital Images, Wake Forest University Department of Dermatology © 2009 Wake Forest University Dermatology
The weakly acid-fast staining property of Nocardia helps distinguish it from actinomycetes. Colonies with aerial filamentous growth often have a rugose (wrinkly) chalky white or cotton-ball appearance on blood agar. These aerial filaments distinguish Nocardia species from other nocardioform gram-positive bacteria, such as Rhodococcus, Corynebacterium, Actinomadura, as well as mycobacteria.6
The laboratory should always be notified when there is clinical suspicion for nocardial infection, as these are slow-growing organisms and can be difficult to recover. The yield in clinical cultures approaches 33%, and thus, multiple clinical specimens from purulent drainage should be obtained. On pure cultures, Nocardia colonies can grow within 2 days, but can take up to weeks when isolated from mixed cultures. Delayed growth can lead to disposal of cultures. Although Nocardia will grow on non -selective media, yield can be increased with use of selective media such as Modified Thayer-Martin medium and buffered charcoal-yeast extract agar.2
Treatment
The mainstay and most studied treatment for nocardiosis are sulfonamides, which include sulfadiazine and sulfisoxazole.2 For disseminated disease, trimethoprim-sulfamethoxazole (TMP-SMX) has been the preferred agent, as it can achieve high tissue concentrations in lung, brain, skin and bone. Antimicrobial susceptibility testing is strongly recommended, as certain strains such as N farcinica and N otitidiscaviarum have been shown to demonstrate high-grade resistance to sulfa-containing regimens.6 Alternatives to TMP-SMX that have been demonstrated in small reports include minocycline, imipenem and ampicillin.2
For cutaneous disease, therapy with sulfonamides for 2 to 4 months is recommended. In cases of large or bulky lesions, surgery as well as antimicrobial therapy may be necessary. Initial debridement before treatment has been reported to shorten the course of antibiotics necessary.4
Key Points
• Nocardiosis is caused by several species of Nocardia, ubiquitous environmental bacteria that are transmitted via inhalation or direct cutaneous inoculation.
• Nocardiosis affects both immunocompromised and immunocompetent patients, leading to disseminated and cutaneous disease, respectively.
• Disseminated disease most commonly presents as pulmonary infections, but also leads to extrapulmonary disease, such as brain abscesses.
• Nocardia are gram-positive, aerobic, branching bacteria with thin, delicate beaded branching filaments that stain with modified (Kinyoun) acid-fast staining.
• Histological examination reveals coccobacillary organisms, granuloma formation, fibrinopurulent exudates and monocytic infiltrates.
• The most studied antimicrobials of choice for nocardiosis are sulfonamides (sulfadiazine and sulfisoxazole). n
Ms. Ahn, is a 4th year medical student at the Center for Dermatology Research, department of dermatology at Wake Forest University School of Medicine in Winston-Salem, NC.
Mr. Al-Dabagh is a 4th year medical student at Case Western Reserve University School of Medicine in Cleveland, OH.
Dr. Feldman is with the Center for Dermatology Research and the Departments of Dermatology, Pathology and Public Health Sciences at Wake Forest University School of Medicine in Winston-Salem, NC.
Disclosures: The Center for Dermatology Research is supported by an unrestricted educational grant from Galderma Laboratories, L.P. Dr. Feldman is a consultant and speaker for Galderma, Stiefel/GlaxoSmithKline, Abbott Labs, Warner Chilcott, Janssen, Amgen, Photomedex, Genentech, BiogenIdec, and Bristol Myers Squibb. Dr. Feldman has received grants from Galderma, Astellas, Abbott Labs, Warner Chilcott, Janssen, Amgen, Photomedex, Genentech, BiogenIdec, Coria/Valeant, Pharmaderm, Ortho Pharmaceuticals, Aventis Pharmaceuticals, Roche Dermatology, 3M, Bristol Myers Squibb, Stiefel/GlaxoSmithKline, Novartis, Medicis, Leo, HanAll Pharmaceuticals, Celgene, Basilea, and Anacor and has received stock options from Photomedex. He is owner of www.DrScore.com and a founder of Causa Research. Ms. Ahn and Mr. Al-Dabagh have no conflicts to disclose.
References
1. Brown-Elliott BA, Brown JM, Conville PS, Wallace RJ Jr. Clinical and laboratory features of the Nocardia spp. based on current molecular taxonomy. Clin Microbiol Rev. 2006;19(2):259-282.
2. Wilson JW. Nocardiosis: updates and clinical overview. Mayo Clin Proc. 2012;87(4):403-407.
3. Muñoz J, Mirelis B, Aragón LM, et al. Clinical and microbiological features of nocardiosis 1997-2003. J Med Microbiol. 2007;56(Pt 4):545-550.
4. Lederman ER, Crum NF. A case series and focused review of nocardiosis: clinical and microbiologic aspects. Medicine (Baltimore). 2004;83(5):300-313.
5. Hussein MR. Mucocutaneous Splendore-Hoeppli phenomenon. J Cutan Pathol. 2008;35(11):979-988.
6. Nocardia infections. Am J Transplant. 2004;4(suppl 10):47-50.
Nocardiosis is an infection caused by bacteria belonging to the genus Nocardia. The taxonomy of the genus Nocardia has undergone numerous revisions over recent years, and greater than 50 species have been characterized. Among these species, approximately 16 have been implicated in human infections.1,2 These soil-borne aerobic bacteria cause disseminated infections that most commonly present as pulmonary disease or cutaneous infections through direct skin inoculation. Although nocardiosis is commonly considered an opportunistic disease, mainly affecting patients with deficiencies in cell-mediated immunity, it can affect immunocompetent patients as well. Due to many non-specific manifestations of nocardiosis, the clinical diagnosis can often be difficult.3
Epidemiology and Pathogenesis
Nocardia species are ubiquitous soil-dwelling organisms first described in 1888 by Edmond Nocard, a French veterinarian and microbiologist, as a bovine pathogen. They were identified as gram-positive, branching, beaded bacilli that are weakly acid-fast staining. The main routes of transmission are inhalation or a penetrating cutaneous injury. The most common species associated with human disease is Nocardia asteroides, a member of the N. asteroides complex, which also includes N nova, N farcinica and N transvalensis. Disseminated nocardiosis is largely considered an opportunistic infection and usually affects immunocompromised individuals, whereas primary cutaneous nocardiosis usually affects immunocompetent individuals. Although the current incidence of nocardiosis is not well defined, an estimated 1,000 cases occur annually in the United States, and infection occurs more commonly in men. This incidence will continue to increase over time as the prevalence of immunocompromised patients increases as a result of advances in oncology, rheumatology and transplant medicine.4 Geographically, N farcinica has been reported more frequently in western European countries, whereas N brasiliensis has been reported more frequently in the southern United States.
An estimated 50% of patients with N asteroides have underlying immunological deficiencies, such as in transplant recipients and in patients with HIV/AIDS. In autopsy series, nocardiosis has been diagnosed in up to 4% of patients with AIDS, and 10.6% of renal transplant recipients who died from infectious causes.4 Transplant patients comprise up to 13% of reported cases of nocardiosis in the United States. The rate of symptomatic nocardial infections is lower in AIDS patients, with an incidence between 0.19%-2.0%.4 Rarely, nocardiosis is seen in the pediatric population, primarily in children with severe underlying pulmonary disease.
Clinical Presentation
The main transmission route is through inhalation; therefore the lungs are the primary site of Nocardia infection in over 66% of cases. Pulmonary nocardiosis typically produces a necrotizing, poorly contained cavitary lesion that tends to affect the upper lobe. Radiographic imaging of the chest can also demonstrate focal or multifocal disease. Pleural effusions develop in up to one-third of patients, and necrotizing pneumonitis can spread into the pleura, pericardium, mediastinum and vena cavum through hematogenous dissemination or contiguous spread. Hematogenous dissemination can lead to widespread involvement of other organs throughout the body. The most common extrapulmonary site for nocardiosis is the central nervous system. Although cerebral nocardiosis typically occurs alongside pulmonary nocardiosis, isolated intracranial disease has been reported.2 Other less common manifestations of disseminated nocardiosis include psoas abscess, cutaneous or subcutaneous nodules, brain abscess, retinitis, septic joint with myositis, catheter tip infection, hepatic abscess, adrenal abscess and multiple intraabdominal abscesses (Table 1).
Primary cutaneous nocardiosis (PCN) comprises up to 5% of cases of nocardiosis, and occurs when the organism enters by direct inoculation through a break in the skin. The risk factors for PCN are soil or sand exposure, gardening, farming, trauma and/or skin abrasions from motor vehicle accidents.4 There are numerous acute manifestations of PCN, which include cellulitis, ulcerative/bullous lesions, linear/keloid-like lesions and nodular-pustular lesions (Figure 1).
Figure 1. Ulcerative, nodular and pustular lesions of primary cutaneous nocardiosis located on the shoulder and back. Source: Graham Library of Digital Images, Wake Forest University Department of Dermatology © 2009 Wake Forest University Dermatology
The acute presentation of cutaneous nocardiosis can resemble the appearance of soft tissue infections produced by Staphylococcus aureus or streptococci infections. After skin inoculation, Nocardia can spread to regional lymph nodes, producing either solitary nodular lesions or a linear chain of lesions. In this form, the infection can resemble that of sporotrichosis, and has been referred to as sporotrichoid nocardiosis.2 PCN can develop into a chronic infection, which may manifest as hyperkeratotic plaques with tumor-like masses and sinus tracts, known as actinomycetomas (Figures 2 and 3).
Figure 2. Nodular, tumor-like lesions of primary cutaneous nocardiosis. Source: Graham Library of Digital Images, Wake Forest University Department of Dermatology © 2009 Wake Forest University Dermatology
Figure 3. Primary cutaneous nocardiosis actinomycetoma with discharging sinuses on the dorsal foot. Source: Graham Library of Digital Images, Wake Forest University Department of Dermatology © 2009 Wake Forest University Dermatology
Although PCN can lay dormant and reactivate over time, primary cutaneous lesions very rarely progress into systemic illness. Among the Nocardia species, N brasiliensis is most often implicated in PCN. Other species that have been identified are N asteroides, N otitidiscaviarum and N nova.
Histopathology
In biopsies of primary cutaneous nocardiosis, dermal fibrosis and suppurative, granulomatous inflammation is commonly seen (Figure 4).
Figure 4. Skin biopsy of an actinomycetoma demonstrating suppurative and granulomatous inflammation that involves the dermis and subcutaneous fat (hematoxylin and eosin, original magnification 50x). Source: Graham Library of Digital Images, Wake Forest University Department of Dermatology © 2009 Wake Forest University Dermatology
Nocardia are also among the various fungal and bacterial infections that can cause in vivo formation of intensely eosinophilic material around the microorganism, known as the Splendore-Hoeppli phenomenon (Figure 5).
Figure 5. Cutaneous nocardiosis demonstrating Splendore-Hoeppli phenomenon. Eosinophilic material composed of antigenantibody complexes, tissue debris and fibrin forming around the bacteria in vivo (hematoxylin and eosin, magnification x160). Source: Graham Library of Digital Images, Wake Forest University Department of Dermatology © 2009 Wake Forest University Dermatology
These peribacterial asteroid bodies are thought to be immunologic reactions, composed of antigen-antibody complexes, tissue debris and fibrin. These may prevent phagocytosis and killing of the organism and can lead to chronicity of infection.5 Additional findings include coccobacillary organisms, fibrinopurulent exudates, monocytic infiltrates, chronic nodular dermatitis, microabscess formation and/or sulfur granules.
The thin filaments of Nocardia species do not stain by hematoxylin and eosin or periodic acid-Schiff stains. However, Gomori methenamine-silver and tissue gram stains can be used to aid in visualization.
Differential Diagnosis
Pulmonary nocardiosis is commonly mistaken for tuberculosis, due its presentation as a cavitary lesion in the upper lobe, and often in immunocompromised patients. Its radiographic appearance also may resemble that of primary or secondary lung malignancies. Other diseases included in the clinical differential diagnosis are fungal infections that affect the lung, including aspergillosis, mucormycosis, histoplasmosis, blastomycosis and actinomycosis infections. (Table 2)
Cutaneous nocardiosis has a wide differential diagnosis based on clinical presentation. PCN has been called a “great imitator” because it can resemble superficial cellulitis caused by a bacterial infection or a lymphocutaneous disease such as sporotrichosis or Mycobacterium marinum. In later stages with the formation of actinomycetoma, the differential diagnosis includes actinomycosis, fungal infections with Pseudallescheria or other molds or other cutaneous diseases such as cutaneous leishmaniasis and Cryptococcus.2
Diagnostic Tests
Nocardia are gram-positive, aerobic, branching bacteria that usually stain with modified (Kinyoun) acid-fast staining and have thin, delicate beaded branching filaments (Figure 6).
Figure 6. Nocardia asteroides seen on gram stain. Gram-positive, filamentous branching rods with irregular, beaded staining patterns. Source: Graham Library of Digital Images, Wake Forest University Department of Dermatology © 2009 Wake Forest University Dermatology
The weakly acid-fast staining property of Nocardia helps distinguish it from actinomycetes. Colonies with aerial filamentous growth often have a rugose (wrinkly) chalky white or cotton-ball appearance on blood agar. These aerial filaments distinguish Nocardia species from other nocardioform gram-positive bacteria, such as Rhodococcus, Corynebacterium, Actinomadura, as well as mycobacteria.6
The laboratory should always be notified when there is clinical suspicion for nocardial infection, as these are slow-growing organisms and can be difficult to recover. The yield in clinical cultures approaches 33%, and thus, multiple clinical specimens from purulent drainage should be obtained. On pure cultures, Nocardia colonies can grow within 2 days, but can take up to weeks when isolated from mixed cultures. Delayed growth can lead to disposal of cultures. Although Nocardia will grow on non -selective media, yield can be increased with use of selective media such as Modified Thayer-Martin medium and buffered charcoal-yeast extract agar.2
Treatment
The mainstay and most studied treatment for nocardiosis are sulfonamides, which include sulfadiazine and sulfisoxazole.2 For disseminated disease, trimethoprim-sulfamethoxazole (TMP-SMX) has been the preferred agent, as it can achieve high tissue concentrations in lung, brain, skin and bone. Antimicrobial susceptibility testing is strongly recommended, as certain strains such as N farcinica and N otitidiscaviarum have been shown to demonstrate high-grade resistance to sulfa-containing regimens.6 Alternatives to TMP-SMX that have been demonstrated in small reports include minocycline, imipenem and ampicillin.2
For cutaneous disease, therapy with sulfonamides for 2 to 4 months is recommended. In cases of large or bulky lesions, surgery as well as antimicrobial therapy may be necessary. Initial debridement before treatment has been reported to shorten the course of antibiotics necessary.4
Key Points
• Nocardiosis is caused by several species of Nocardia, ubiquitous environmental bacteria that are transmitted via inhalation or direct cutaneous inoculation.
• Nocardiosis affects both immunocompromised and immunocompetent patients, leading to disseminated and cutaneous disease, respectively.
• Disseminated disease most commonly presents as pulmonary infections, but also leads to extrapulmonary disease, such as brain abscesses.
• Nocardia are gram-positive, aerobic, branching bacteria with thin, delicate beaded branching filaments that stain with modified (Kinyoun) acid-fast staining.
• Histological examination reveals coccobacillary organisms, granuloma formation, fibrinopurulent exudates and monocytic infiltrates.
• The most studied antimicrobials of choice for nocardiosis are sulfonamides (sulfadiazine and sulfisoxazole). n
Ms. Ahn, is a 4th year medical student at the Center for Dermatology Research, department of dermatology at Wake Forest University School of Medicine in Winston-Salem, NC.
Mr. Al-Dabagh is a 4th year medical student at Case Western Reserve University School of Medicine in Cleveland, OH.
Dr. Feldman is with the Center for Dermatology Research and the Departments of Dermatology, Pathology and Public Health Sciences at Wake Forest University School of Medicine in Winston-Salem, NC.
Disclosures: The Center for Dermatology Research is supported by an unrestricted educational grant from Galderma Laboratories, L.P. Dr. Feldman is a consultant and speaker for Galderma, Stiefel/GlaxoSmithKline, Abbott Labs, Warner Chilcott, Janssen, Amgen, Photomedex, Genentech, BiogenIdec, and Bristol Myers Squibb. Dr. Feldman has received grants from Galderma, Astellas, Abbott Labs, Warner Chilcott, Janssen, Amgen, Photomedex, Genentech, BiogenIdec, Coria/Valeant, Pharmaderm, Ortho Pharmaceuticals, Aventis Pharmaceuticals, Roche Dermatology, 3M, Bristol Myers Squibb, Stiefel/GlaxoSmithKline, Novartis, Medicis, Leo, HanAll Pharmaceuticals, Celgene, Basilea, and Anacor and has received stock options from Photomedex. He is owner of www.DrScore.com and a founder of Causa Research. Ms. Ahn and Mr. Al-Dabagh have no conflicts to disclose.
References
1. Brown-Elliott BA, Brown JM, Conville PS, Wallace RJ Jr. Clinical and laboratory features of the Nocardia spp. based on current molecular taxonomy. Clin Microbiol Rev. 2006;19(2):259-282.
2. Wilson JW. Nocardiosis: updates and clinical overview. Mayo Clin Proc. 2012;87(4):403-407.
3. Muñoz J, Mirelis B, Aragón LM, et al. Clinical and microbiological features of nocardiosis 1997-2003. J Med Microbiol. 2007;56(Pt 4):545-550.
4. Lederman ER, Crum NF. A case series and focused review of nocardiosis: clinical and microbiologic aspects. Medicine (Baltimore). 2004;83(5):300-313.
5. Hussein MR. Mucocutaneous Splendore-Hoeppli phenomenon. J Cutan Pathol. 2008;35(11):979-988.
6. Nocardia infections. Am J Transplant. 2004;4(suppl 10):47-50.
Nocardiosis is an infection caused by bacteria belonging to the genus Nocardia. The taxonomy of the genus Nocardia has undergone numerous revisions over recent years, and greater than 50 species have been characterized. Among these species, approximately 16 have been implicated in human infections.1,2 These soil-borne aerobic bacteria cause disseminated infections that most commonly present as pulmonary disease or cutaneous infections through direct skin inoculation. Although nocardiosis is commonly considered an opportunistic disease, mainly affecting patients with deficiencies in cell-mediated immunity, it can affect immunocompetent patients as well. Due to many non-specific manifestations of nocardiosis, the clinical diagnosis can often be difficult.3
Epidemiology and Pathogenesis
Nocardia species are ubiquitous soil-dwelling organisms first described in 1888 by Edmond Nocard, a French veterinarian and microbiologist, as a bovine pathogen. They were identified as gram-positive, branching, beaded bacilli that are weakly acid-fast staining. The main routes of transmission are inhalation or a penetrating cutaneous injury. The most common species associated with human disease is Nocardia asteroides, a member of the N. asteroides complex, which also includes N nova, N farcinica and N transvalensis. Disseminated nocardiosis is largely considered an opportunistic infection and usually affects immunocompromised individuals, whereas primary cutaneous nocardiosis usually affects immunocompetent individuals. Although the current incidence of nocardiosis is not well defined, an estimated 1,000 cases occur annually in the United States, and infection occurs more commonly in men. This incidence will continue to increase over time as the prevalence of immunocompromised patients increases as a result of advances in oncology, rheumatology and transplant medicine.4 Geographically, N farcinica has been reported more frequently in western European countries, whereas N brasiliensis has been reported more frequently in the southern United States.
An estimated 50% of patients with N asteroides have underlying immunological deficiencies, such as in transplant recipients and in patients with HIV/AIDS. In autopsy series, nocardiosis has been diagnosed in up to 4% of patients with AIDS, and 10.6% of renal transplant recipients who died from infectious causes.4 Transplant patients comprise up to 13% of reported cases of nocardiosis in the United States. The rate of symptomatic nocardial infections is lower in AIDS patients, with an incidence between 0.19%-2.0%.4 Rarely, nocardiosis is seen in the pediatric population, primarily in children with severe underlying pulmonary disease.
Clinical Presentation
The main transmission route is through inhalation; therefore the lungs are the primary site of Nocardia infection in over 66% of cases. Pulmonary nocardiosis typically produces a necrotizing, poorly contained cavitary lesion that tends to affect the upper lobe. Radiographic imaging of the chest can also demonstrate focal or multifocal disease. Pleural effusions develop in up to one-third of patients, and necrotizing pneumonitis can spread into the pleura, pericardium, mediastinum and vena cavum through hematogenous dissemination or contiguous spread. Hematogenous dissemination can lead to widespread involvement of other organs throughout the body. The most common extrapulmonary site for nocardiosis is the central nervous system. Although cerebral nocardiosis typically occurs alongside pulmonary nocardiosis, isolated intracranial disease has been reported.2 Other less common manifestations of disseminated nocardiosis include psoas abscess, cutaneous or subcutaneous nodules, brain abscess, retinitis, septic joint with myositis, catheter tip infection, hepatic abscess, adrenal abscess and multiple intraabdominal abscesses (Table 1).
Primary cutaneous nocardiosis (PCN) comprises up to 5% of cases of nocardiosis, and occurs when the organism enters by direct inoculation through a break in the skin. The risk factors for PCN are soil or sand exposure, gardening, farming, trauma and/or skin abrasions from motor vehicle accidents.4 There are numerous acute manifestations of PCN, which include cellulitis, ulcerative/bullous lesions, linear/keloid-like lesions and nodular-pustular lesions (Figure 1).
Figure 1. Ulcerative, nodular and pustular lesions of primary cutaneous nocardiosis located on the shoulder and back. Source: Graham Library of Digital Images, Wake Forest University Department of Dermatology © 2009 Wake Forest University Dermatology
The acute presentation of cutaneous nocardiosis can resemble the appearance of soft tissue infections produced by Staphylococcus aureus or streptococci infections. After skin inoculation, Nocardia can spread to regional lymph nodes, producing either solitary nodular lesions or a linear chain of lesions. In this form, the infection can resemble that of sporotrichosis, and has been referred to as sporotrichoid nocardiosis.2 PCN can develop into a chronic infection, which may manifest as hyperkeratotic plaques with tumor-like masses and sinus tracts, known as actinomycetomas (Figures 2 and 3).
Figure 2. Nodular, tumor-like lesions of primary cutaneous nocardiosis. Source: Graham Library of Digital Images, Wake Forest University Department of Dermatology © 2009 Wake Forest University Dermatology
Figure 3. Primary cutaneous nocardiosis actinomycetoma with discharging sinuses on the dorsal foot. Source: Graham Library of Digital Images, Wake Forest University Department of Dermatology © 2009 Wake Forest University Dermatology
Although PCN can lay dormant and reactivate over time, primary cutaneous lesions very rarely progress into systemic illness. Among the Nocardia species, N brasiliensis is most often implicated in PCN. Other species that have been identified are N asteroides, N otitidiscaviarum and N nova.
Histopathology
In biopsies of primary cutaneous nocardiosis, dermal fibrosis and suppurative, granulomatous inflammation is commonly seen (Figure 4).
Figure 4. Skin biopsy of an actinomycetoma demonstrating suppurative and granulomatous inflammation that involves the dermis and subcutaneous fat (hematoxylin and eosin, original magnification 50x). Source: Graham Library of Digital Images, Wake Forest University Department of Dermatology © 2009 Wake Forest University Dermatology
Nocardia are also among the various fungal and bacterial infections that can cause in vivo formation of intensely eosinophilic material around the microorganism, known as the Splendore-Hoeppli phenomenon (Figure 5).
Figure 5. Cutaneous nocardiosis demonstrating Splendore-Hoeppli phenomenon. Eosinophilic material composed of antigenantibody complexes, tissue debris and fibrin forming around the bacteria in vivo (hematoxylin and eosin, magnification x160). Source: Graham Library of Digital Images, Wake Forest University Department of Dermatology © 2009 Wake Forest University Dermatology
These peribacterial asteroid bodies are thought to be immunologic reactions, composed of antigen-antibody complexes, tissue debris and fibrin. These may prevent phagocytosis and killing of the organism and can lead to chronicity of infection.5 Additional findings include coccobacillary organisms, fibrinopurulent exudates, monocytic infiltrates, chronic nodular dermatitis, microabscess formation and/or sulfur granules.
The thin filaments of Nocardia species do not stain by hematoxylin and eosin or periodic acid-Schiff stains. However, Gomori methenamine-silver and tissue gram stains can be used to aid in visualization.
Differential Diagnosis
Pulmonary nocardiosis is commonly mistaken for tuberculosis, due its presentation as a cavitary lesion in the upper lobe, and often in immunocompromised patients. Its radiographic appearance also may resemble that of primary or secondary lung malignancies. Other diseases included in the clinical differential diagnosis are fungal infections that affect the lung, including aspergillosis, mucormycosis, histoplasmosis, blastomycosis and actinomycosis infections. (Table 2)
Cutaneous nocardiosis has a wide differential diagnosis based on clinical presentation. PCN has been called a “great imitator” because it can resemble superficial cellulitis caused by a bacterial infection or a lymphocutaneous disease such as sporotrichosis or Mycobacterium marinum. In later stages with the formation of actinomycetoma, the differential diagnosis includes actinomycosis, fungal infections with Pseudallescheria or other molds or other cutaneous diseases such as cutaneous leishmaniasis and Cryptococcus.2
Diagnostic Tests
Nocardia are gram-positive, aerobic, branching bacteria that usually stain with modified (Kinyoun) acid-fast staining and have thin, delicate beaded branching filaments (Figure 6).
Figure 6. Nocardia asteroides seen on gram stain. Gram-positive, filamentous branching rods with irregular, beaded staining patterns. Source: Graham Library of Digital Images, Wake Forest University Department of Dermatology © 2009 Wake Forest University Dermatology
The weakly acid-fast staining property of Nocardia helps distinguish it from actinomycetes. Colonies with aerial filamentous growth often have a rugose (wrinkly) chalky white or cotton-ball appearance on blood agar. These aerial filaments distinguish Nocardia species from other nocardioform gram-positive bacteria, such as Rhodococcus, Corynebacterium, Actinomadura, as well as mycobacteria.6
The laboratory should always be notified when there is clinical suspicion for nocardial infection, as these are slow-growing organisms and can be difficult to recover. The yield in clinical cultures approaches 33%, and thus, multiple clinical specimens from purulent drainage should be obtained. On pure cultures, Nocardia colonies can grow within 2 days, but can take up to weeks when isolated from mixed cultures. Delayed growth can lead to disposal of cultures. Although Nocardia will grow on non -selective media, yield can be increased with use of selective media such as Modified Thayer-Martin medium and buffered charcoal-yeast extract agar.2
Treatment
The mainstay and most studied treatment for nocardiosis are sulfonamides, which include sulfadiazine and sulfisoxazole.2 For disseminated disease, trimethoprim-sulfamethoxazole (TMP-SMX) has been the preferred agent, as it can achieve high tissue concentrations in lung, brain, skin and bone. Antimicrobial susceptibility testing is strongly recommended, as certain strains such as N farcinica and N otitidiscaviarum have been shown to demonstrate high-grade resistance to sulfa-containing regimens.6 Alternatives to TMP-SMX that have been demonstrated in small reports include minocycline, imipenem and ampicillin.2
For cutaneous disease, therapy with sulfonamides for 2 to 4 months is recommended. In cases of large or bulky lesions, surgery as well as antimicrobial therapy may be necessary. Initial debridement before treatment has been reported to shorten the course of antibiotics necessary.4
Key Points
• Nocardiosis is caused by several species of Nocardia, ubiquitous environmental bacteria that are transmitted via inhalation or direct cutaneous inoculation.
• Nocardiosis affects both immunocompromised and immunocompetent patients, leading to disseminated and cutaneous disease, respectively.
• Disseminated disease most commonly presents as pulmonary infections, but also leads to extrapulmonary disease, such as brain abscesses.
• Nocardia are gram-positive, aerobic, branching bacteria with thin, delicate beaded branching filaments that stain with modified (Kinyoun) acid-fast staining.
• Histological examination reveals coccobacillary organisms, granuloma formation, fibrinopurulent exudates and monocytic infiltrates.
• The most studied antimicrobials of choice for nocardiosis are sulfonamides (sulfadiazine and sulfisoxazole). n
Ms. Ahn, is a 4th year medical student at the Center for Dermatology Research, department of dermatology at Wake Forest University School of Medicine in Winston-Salem, NC.
Mr. Al-Dabagh is a 4th year medical student at Case Western Reserve University School of Medicine in Cleveland, OH.
Dr. Feldman is with the Center for Dermatology Research and the Departments of Dermatology, Pathology and Public Health Sciences at Wake Forest University School of Medicine in Winston-Salem, NC.
Disclosures: The Center for Dermatology Research is supported by an unrestricted educational grant from Galderma Laboratories, L.P. Dr. Feldman is a consultant and speaker for Galderma, Stiefel/GlaxoSmithKline, Abbott Labs, Warner Chilcott, Janssen, Amgen, Photomedex, Genentech, BiogenIdec, and Bristol Myers Squibb. Dr. Feldman has received grants from Galderma, Astellas, Abbott Labs, Warner Chilcott, Janssen, Amgen, Photomedex, Genentech, BiogenIdec, Coria/Valeant, Pharmaderm, Ortho Pharmaceuticals, Aventis Pharmaceuticals, Roche Dermatology, 3M, Bristol Myers Squibb, Stiefel/GlaxoSmithKline, Novartis, Medicis, Leo, HanAll Pharmaceuticals, Celgene, Basilea, and Anacor and has received stock options from Photomedex. He is owner of www.DrScore.com and a founder of Causa Research. Ms. Ahn and Mr. Al-Dabagh have no conflicts to disclose.
References
1. Brown-Elliott BA, Brown JM, Conville PS, Wallace RJ Jr. Clinical and laboratory features of the Nocardia spp. based on current molecular taxonomy. Clin Microbiol Rev. 2006;19(2):259-282.
2. Wilson JW. Nocardiosis: updates and clinical overview. Mayo Clin Proc. 2012;87(4):403-407.
3. Muñoz J, Mirelis B, Aragón LM, et al. Clinical and microbiological features of nocardiosis 1997-2003. J Med Microbiol. 2007;56(Pt 4):545-550.
4. Lederman ER, Crum NF. A case series and focused review of nocardiosis: clinical and microbiologic aspects. Medicine (Baltimore). 2004;83(5):300-313.
5. Hussein MR. Mucocutaneous Splendore-Hoeppli phenomenon. J Cutan Pathol. 2008;35(11):979-988.
6. Nocardia infections. Am J Transplant. 2004;4(suppl 10):47-50.
