Pediatrics

Nocardiosis

OVERVIEW: What every practitioner needs to know

Are you sure your patient has nocardiosis? What are the typical findings for this disease?

Nocardiosis refers to the disease entities caused by Nocardia species. Nocardia are Gram-positive, partially acid-fast, branched, filamentous environmentally ubiquitous aerobic rods. The most commonly isolated species in the United States are N. nova, N. brasiliensis, and N. farcinica. These species can colonize the skin or upper respiratory tract.

In immunocompetent children, disease is often cutaneous, occurring after direct inoculation of the organism into the skin. In immunocompromised children, disseminated disease can occur; in these instances, the most common sites of infection are the lungs, and hematogenous dissemination to the brain and other distant sites may be seen. Person-to-person transmission of Nocardia does not occur.

Clinical and radiographic findings depend upon host immunological status.

Previously healthy children usually have isolated cutaneous or lymphocutaneous involvement; this is termed primary cutaneous nocardiosis.

Localized cutaneous infection follows skin trauma, ranging from puncture wounds to insect bites. Characteristics of these lesions include the following:

-Abscesses, pustules, and cellulitis

-Shallow ulcers

-Satellite lesions

-Very tender

-More common in the lower extremities in children

Lymphocutaneous: spread to regional lymph nodes:

-Nodules along lymphatic tracts in a linear distribution

Nocardial mycetoma is a chronic infection of the skin and subcutaneous tissues, often with a draining sinus tract. Characteristics include the following:

-Hard painless lump under skin

-Ulcerates from the center, discharging pus with white grains

-Development of sinus tract

-May persist for years and, if untreated, can involve underlying muscle and bone

Systemic signs of inflammation, such as fever, seen in a majority of cases.

If children received trimethoprim-sulfamethoxazole for presumed staphylococcal infection, a clinical response and altered clinical presentation may be seen.

Children with comorbid medical conditions (including solid organ transplant recipients, children with human immunodeficiency virus (HIV) infection or chronic granulomatous disease, and children who are chronic recipients of systemic corticosteroids or tumor necrosis factor-alpha (TNFα) antagonists (see below)) are at risk for disseminated disease:

-Portal of entry is the lungs

-Pulmonary: the most common site of involvement in immunosuppressed children (40%): Signs/Symptoms are decreased appetite, cough (less likely to be productive in young children); older children may complain of pleuritic chest pain and hemoptysis

-Central nervous system: the second most common site of involvement in immunosuppressed children (30%): Signs/Symptoms are fever, headache, vomiting and other signs of increased intracranial pressure, cranial nerve palsies

-Bacteremia: while rarely reported, is usually found in association with an indwelling vascular catheter: Signs/Symptoms are fever, non-specific constitutional symptoms

-Other sites: hematogenous dissemination to a number of sites, including tracheitis, pericarditis, peritonitis, deep tissue abscesses, osteomyelitis, septic arthritis, have been reported.

What other disease/condition shares some of these symptoms?

Previously healthy children:

-Localized cutaneous disease can mimic other pyogenic organisms such as Staphylococcus aureus and Streptococcus pyogenes. Nocardia lesions often are more indolent than pyogenic pathogens.

-Lymphocutaneous disease can mimic sporotrichosis, which cannot be differentiated from Nocardia clinically.

-Nocardial mycetomas can mimic Actinomyces, Aspergillus, Pseudallescheria boydii, chronic osteomyelitis, leprosy, syphilis. Differences in granule colors can help differentiate one from the other.

Children with medical comorbidities:

-Pulmonary and disseminated disease may mimic that caused by tuberculosis, actinomycosis, fungal infection (e.g., Aspergillus).

-Central nervous system due to Nocardia must be distinguished from other causes of brain abscesses (e.g., streptococcal and staphylococcal species, Gram-negative enterics), tuberculosis.

What caused this disease to develop at this time?

Nocardiosis has been associated with a number of medical comorbidities:

Solid organ transplantation: in one study, nocardiosis was seen in 0.6% of adult organ transplant recipients. Receipt of high-dose corticosteroids and history of cytomegalovirus disease were risk factors. Rates of drug-resistant Nocardia isolates were higher in patients who were receiving sulfamethoxazole for Pneumocystis jirovecii prophylaxis.

Chronic granulomatous disease (CGD): in one series of 23 children with CGD, the rate of disseminated nocardiosis was 25%, but higher in patients receiving neither sulfonamide prophylaxis nor interferon-gamma. All episodes involved pulmonary infection.

Human immunodeficiency virus (HIV) infection: in one series of 25 cases of nocardiosis in adults, over three-quarters of adults were HIV-infected. Of these, all had CD4 counts < 100 cells/mm3; over 80% involved the lungs, and approximately one-third were disseminated. Only case reports exist for children with HIV-infection and nocardiosis.

Chronic, systemic corticosteroid therapy: it is estimated that antecedent corticosteroid use was present in over 50% of adults who develop nocardiosis. Case reports exist of children on chronic corticosteroids for solid organ transplantation and rheumatologic conditions developing either pulmonary or disseminated nocardiosis; prevalence figures are unavailable.

TNFα antagonist therapy: case reports exist of patients with inflammatory bowel disease and rheumatologic conditions who received TNFα antagonists (e.g., adalimumab [Humira], etanercept [Enbrel], infliximab [Remicade]) and then developed either localized or disseminated nocardiosis. There is still debate on the safety of restarting these agents in patients who have developed nocardiosis after disease resolution. The role of prophylaxis with cotrimoxazole is controversial.

Nocardia can also be seen in otherwise healthy children who have sustained skin trauma.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Blood cultures should be obtained in any child with suspected nocardiosis. The laboratory should be notified to keep the culture for up to 2-3 weeks, given the indolent growth of the organism.

Cutaneous disease:

-Culture and Gram-stain of the lesion; as with blood cultures, laboratory should be instructed to hold culture for 2-3 weeks

-Acid-fast stain may also be sent, as Nocardia is weakly acid-fast

-Silver stains increase sensitivity of detection of organism in tissue

Pulmonary:

-Sputum for routine Gram stain and culture (while isolates usually grow in 3-5 days, more indolent growth can be seen)

-Consider pulmonary function tests for children with pre-existing lung disease to establish a new baseline

Central nervous system:

-Lumbar puncture for routine studies

-Hearing screen

Baseline laboratories before starting medication:

-Complete blood count

-Serum electrolytes and blood urea nitrogen and creatinine

Serologic studies are not recommended.

Would imaging studies be helpful? If so, which ones?

Cutaneous disease in an otherwise healthy child in whom you do not suspect disseminated disease requires no imaging studies. Magnetic resonance imaging (MRI) may be warranted in a child with a mycetoma to determine the extent (depth) of disease to assist with surgical management.

Pulmonary: Imaging should be performed to assess for the following:

-Lobar infiltrates, pleural effusions

-Abscesses with rim-enhancement

-Cavities are seen in up to one-third of adults; less common in children

-Superinfection of bronchiectatic lung

-Computed tomography (CT) may also demonstrate pulmonary nodules, and a halo of ground-glass opacity surrounding nodule

-Extension through lung into chest wall (empyema necessitatis)

-Intrathoracic lymphadenopathy is not common

Central nervous system (CNS):

-CNS imaging by MRI or CT is recommended for all patients with pulmonary nocardiosis given the frequency of involvement and the way in which the diagnosis alters therapy

-Most common finding is brain abscess, and multiloculated lesions with satellite extensions may be present

-Meningeal enhancement and ventriculitis are less commonly seen, but often associated with parenchymal disease

-Enhancing lesions of the choroid plexus can be seen.

If you are able to confirm that the patient has nocardiosis, what treatment should be initiated?

See Table I. Initiation of Treatment for Nocardiosis

Table I.

Initiation of Treatment for Nocardiosis
Host Site Drug Duration Notes
Immunocompetent Cutaneous Trimethoprim-sulfamethoxazole 6-12 weeks Abscess drainage is beneficial – decreases metastatic lesions
Immunocompromised Pulmonary Trimethoprim-sulfamethoxazole 6-12 months and at least 3 months after apparent cure HIV-infected patients may require a longer duration of therapy for pulmonary or disseminated disease
Central nervous system, disseminated disease, or overwhelming infection Trimethoprim-sulfamethoxazole + amikacin + (ceftriaxone or carbapenem) Trimethoprim-sulfamethoxazole: 6-12 months and at least 3 months after apparent cureAmikacin + ceftriaxone for 1st 4-12 weeks or until clinical improvement Should have serial neuroimaging to monitor response to therapy; hearing screens should be performed at baseline and at least monthly while on an aminoglycosideCentral venous catheter should be removed; risk of recurrence is high if bacteremia treated with line in situ

What are the adverse effects associated with each treatment option?

See Table II. Common Adverse Effects of Medications Used to Treat Nocardiosis.

Table II.

Common Adverse Effects of Medications Used To Treat Nocardiosis
Drug Side effect
Trimethoprim-sulfamethoxazole Rash, bone marrow suppression, hypersensitivity reactions
Carbapenems Decrease seizure threshold
Amoxicillin-clavulanate Bone marrow suppression with chronic therapy, hypersensitivity reaction, diarrhea
Linezolid Optic neuritis, bone marrow suppression
Macrolides Prolongation of QTc
Fluoroquinolones Tendon inflammation/rupture, prolongation of QTc, central nervous system stimulation and confusion; may exacerbate weakness in patients with myasthenia gravis

What are the possible outcomes of nocardiosis?

Cutaneous disease:

-Spontaneous resolution can be seen with localized cutaneous disease in immunocompetent hosts.

-Metastatic disease can be seen from untreated localized cutaneous and lymphocutaneous disease.

-Untreated mycetomas can cause localized tissue destruction and have contiguous spread to surrounding tissues.

Pulmonary and disseminated disease:

-Few pediatric data exist for disseminated and pulmonary nocardiosis; most data are single-center studies in adults, where overall mortality is 20-25% and dependent on the underlying medical comorbidities of the patients studied. One European study reported mortality rates of 41% and 64% for pulmonary and disseminated nocardiosis, respectively.

-There are case reports of HIV-infected persons with nocardiosis who improve after initiation of antiretroviral therapy without specific Nocardia treatment.

What causes this disease and how frequent is it?

Epidemiology: as Nocardia is not a reportable disease in the United States, no national epidemiologic data exist; data are instead from individual centers’ experience or reports of series of patients with similar underlying diagnoses. However, some patterns of disease have emerged:

-Seasonality: most pediatric cases of cutaneous disease occur between April and September

-Cutaneous: Localized cutaneous and lymphocutaneous forms are more common in males, in a bimodal distribution, with peaks seen in children younger than 10 years of age and adults older than 65 years of age; Mycetoma: rare in children; more often seen in young adults

Genetics: Certain inherited conditions include enhanced susceptibility to Nocardia infections. These include the following:

-Chronic granulomatous disease: failure to produce reactive oxygen species decreases killing in macrophages

-Interleukin mutations: defects in interferon-gamma-mediated immunity predispose to intracellular pathogens

How does Nocardia cause disease?

Nocardia causes disease after mucosal barriers have been breached. Penetration of tissue planes is associated with little evidence of organism encapsulation, potentially explaining the ease with which the organism can disseminate.

How can nocardiosis be prevented?

There is no vaccine against Nocardia. Given its ubiquitous environmental presence, it cannot be avoided. There is no person-to-person transmission; standard infection control precautions apply.

What is the Evidence?

Broome Uhde, K, Pathak, S, McCullum, I. "Antimicrobial-resistant Nocardia isolates, United States, 1995-2004". Clin Infect Dis. vol. 51. 2010. pp. 1445.

Fukuda, H, Saotome, A, Usami, N. "Lymphocutaneous type of nocardiosis caused by Nocardia brasiliensis: a case report and review of primary cutaneous nocardiosis caused by N. brasiliensis reported in Japan". J Dermatol. vol. 35. 2008. pp. 346-353.

Fergie, JE, Purcell, K.. "Nocardiosis in South Texas children". Pediatr Infect Dis J. vol. 20. 2001. pp. 711-714.

Arenas, R, Ameen, M.. "Giant grains of Nocardia actinomycetoma". Lancet Infect Dis. vol. 10. 2010. pp. 66.

Goodkin, HP, Harper, MB, Pomeroy, SL.. "Intracerebral abscess in children: historical trends at Children’s Hospital Boston". Pediatrics. vol. 113. 2004. pp. 1765-1770.

Mei-Zahav, M, Livnat, G, Bentur, L. "The spectrum of Nocardia lung disease in cystic fibrosis". Pediatr Infect Dis J. vol. 34. 2015. pp. 909-911.

(Four percent of patients with cystic fibrosis had Nocardia isolated from sputum. One-half of these patients developed parenchymal lung disease.)

McTaggart, LR, Doucet, J, Witkowska, M, Richardson, SE.. "Antimicrobial susceptibility among clinical Nocardia species identified by multilocus sequence analysis". Antimicrob Agents Chemother. vol. 59. 2015. pp. 269-275.

(Isolates were almost uniformly susceptible to trimethoprim-sulfamethoxazole, linezolid, and amikacin. For other antibiotics [e.g., carbapenems, cephalosporins, and fluoroquinolones], there was variation in resistance by Nocardia species.)

Abreu, C, Rocha-Pereira, N, Sarmento, A, Magro, F.. "Nocardia infections among immunomodulated inflammatory bowel disease patients: a review". World J Gastroenterol. vol. 21. 2015. pp. 6491-6498.

(This review of all published cases of Nocardia in patients with inflammatory bowel disease from 1980-2014 identified 11 cases associated with receipt of TNFα antagonists. The sites of disease varied, with some patients having localized cutaneous or pulmonary disease, while others had disseminated disease. The role of prophylactic cotrimoxazole is unclear.)

Peleg, AY, Husain, S, Qureshi, ZA. "Risk factors, clinical characteristics, and outcome of Nocardia infection in organ transplant recipients: a matched case-control study". Clin Infect Dis. vol. 44. 2007. pp. 1307-1314.

Dorman, SE, Guide, SV, Conville, PS. "Nocardia infection in chronic granulomatous disease". Clin Infect Dis. vol. 35. 2002. pp. 390-394.

Castro, JG, Espinoza, L.. "Nocardia species infections in a large county hospital in Miami: 6 years experience". J Infect. vol. 54. 2007. pp. 358-361.

Minero, MV, Marin, M, Cercenado, E. "Nocardiosis at the turn of the century". Medicine (Baltimore). vol. 88. 2009. pp. 250-261.

Rinaldi, S, D’Argenio, P, Fiscarelli, E. "Fatal disseminated Nocardia farcinica infection in a renal transplant recipient". Pediatr Nephrol. vol. 14. 2000. pp. 111-113.

Wang, SM, Liu, CC, Chen, CT. "Pulmonary nocardiosis in a child with systemic lupus erythematosus: report of a case". J Formos Med Assoc. vol. 94. 1995. pp. 506-508.

Klein-Gitelman, MS, Szer, IS.. "Disseminated Nocardia brasiliensis infection: an unusual complication of immunosuppressive treatment for childhood dermatomyositis". J Rheumatol. vol. 18. 1991. pp. 1243-1246.

Kanne, JP, Yandow, DR, Mohammed, T-L H. "CT findings in pulmonary nocardiosis". AJR Am J Roentgenol. vol. 197. 2011. pp. W266-W272.

Ambrosioni, J, Lew, D, Garbino, J.. "Nocardiosis: updated clinical review and experience at a tertiary center". Infection. vol. 38. 2010. pp. 89-97.

Hagiwara, E, Nath, J.. "Choroid plexitis in a case of systemic nocardiosis". Emerg Radiol. vol. 14. 2007. pp. 337-343.

Pickering, LK, Baker, CJ, Kimberlin, DW, Long, SS. "Nocardiosis". Red Book: 2009 Report of the Committee on Infectious Diseases. American Academy of Pediatrics. 2009. pp. 475-476.

Freeman, AF, Marciano, BE, Anderson, VL. "Corticosteroids in the treatment of severe Nocardia pneumonia in chronic granulomatous disease". Pediatr Infect Dis J. vol. 30. 2011. pp. 806-808.

Hardak, E, Yigla, M, Berger, G. "Clinical spectrum and outcome of Nocardia infection: experience of 15-year period from a single tertiary medical center". Am J Med Sci. 2011.

Martinez-Tomas, R, Menendez Villanueva, R, Reyes Calzada, S. "Pulmonary nocardiosis: risk factors and outcomes". Respirology. vol. 12. 2007. pp. 394-400.

King, AS, Castro, JG, Dow, GC.. "Nocardia farcinica lung abscess presenting in the context of advanced HIV infection: spontaneous resolution in response to highly active antiretroviral therapy alone". Can J Infect Dis Med Microbiol. vol. 20. 2009. pp. e103-106.

Luangwedchakarn, V, Jirapongsaranuruk, O, NiemeLa, JE. "A novel mutation of the IL12RB1 gene in a child with nocardiosis, recurrent salmonellosis, and neurofibromatosis type 1: first case report from Thailand". Asian Pac J Allergy Immunol. vol. 27. 2009. pp. 161-165.

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