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