CONTENTS

• Epidemiology
• Clinical presentation
  • CNS involvement
• Diagnosis
  • Laboratory diagnosis
  • Chest imaging
  • Nocardia vs. actinomyces ➡️
• Treatment
• Questions & discussion

abbreviations used in the pulmonary section: 3

• ABPA: Allergic bronchopulmonary aspergillosis 📖
• AE-ILD: Acute exacerbation of ILD 📖
• AEP: Acute eosinophilic pneumonia 📖
• AFB: Acid Fast Bacilli
• AIP: Acute interstitial pneumonia (Hamman-Rich syndrome) 📖
• ANA: Antinuclear antibody 📖
• ANCA: Antineutrophil cytoplasmic antibodies 📖
• ARDS: Acute respiratory distress syndrome 📖
• ASS: Antisynthetase Syndrome 📖
• BAL: Bronchoalveolar lavage 📖
• BiPAP: Bilevel positive airway pressure 📖
• CEP: Chronic eosinophilic pneumonia 📖
• CF: Cystic fibrosis 📖
• COP: Cryptogenic organizing pneumonia 📖
• CPAP: Continuous positive airway pressure 📖
• CPFE: Combined pulmonary fibrosis and emphysema 📖
• CTD-ILD: Connective tissue disease associated interstitial lung disease 📖
• CTEPH: Chronic thromboembolic pulmonary hypertension 📖
• DAD: Diffuse alveolar damage 📖
• DAH: Diffuse alveolar hemorrhage 📖
• DIP: Desquamative interstitial pneumonia 📖
• DLCO: Diffusing capacity for carbon monoxide 📖
• DRESS: Drug reaction with eosinophilia and systemic symptoms 📖
• EGPA: Eosinophilic granulomatosis with polyangiitis 📖
• FEV1: Forced expiratory volume in 1 second 📖
• FVC: Forced vital capacity 📖
• GGO: Ground glass opacity 📖
• GLILD: Granulomatous and lymphocytic interstitial lung disease 📖
• HFNC: High flow nasal cannula 📖
• HP: Hypersensitivity pneumonitis 📖
• IPAF: Interstitial pneumonia with autoimmune features 📖
• IPF: Idiopathic pulmonary fibrosis 📖
• IVIG: Intravenous immunoglobulin 📖
• LAM: Lymphangioleiomyomatosis 📖
• LIP: Lymphocytic interstitial pneumonia 📖
• MAC: Mycobacterium Avium complex 📖
• MCTD: Mixed connective tissue disease 📖
• NIV: Noninvasive ventilation (including CPAP or BiPAP) 📖
• NSIP: Nonspecific interstitial pneumonia 📖
• NTM: Non-tuberculous mycobacteria 📖
• OP: Organizing pneumonia 📖
• PAP: Pulmonary alveolar proteinosis 📖
• PE: Pulmonary embolism 📖
• PFT: Pulmonary function test 📖
• PLCH: Pulmonary Langerhans Cell Histiocytosis 📖
• PPFE: Pleuroparenchymal fibroelastosis 📖
• PPF: Progressive pulmonary fibrosis 📖
• PVOD/PCH Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis 📖
• RB-ILD: Respiratory bronchiolitis-associated interstitial lung disease 📖
• RP-ILD: Rapidly progressive interstitial lung disease 📖
• TNF: tumor necrosis factor
• UIP: Usual Interstitial Pneumonia 📖

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epidemiology

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risk factors for Nocardia infection

• Transplantation:
  • Risk depends on the organ transplanted: (36314911, 33376366)
    • Heart or lung: 1-3.5% risk.
    • Kidney or liver: <1% risk.
  • Additional risk factors for Nocardia infection in this population:
    • High trough levels of calcineurin inhibitor.
    • High steroid dose.
    • CMV infection within the preceding six months.
  • The risk of infection is greatest soon after transplant, but ~15% of infections might occur >5 years after transplantation. (36314911)
  • Note that prophylactic use of trimethoprim-sulfamethoxazole does not reliably prevent nocardiosis. (32629491)
• Therapeutic immunosuppression:
  • Chronic steroid use (even doses as low as 10-15 mg/day prednisone increase risk). (Fishman 2023)
  • TNF-alpha antagonists.
  • Tocilizumab. (32629491)
• Malignancy:
  • The risk for Nocardia infection seems to result from treatments for cancer (e.g., chemotherapy, steroid, stem cell therapy). Effects of alemtuzumab or purine analogs can persist for months to a few years after administration. (36314911)
  • Malignancy itself (without therapy) doesn't seem to be a substantial risk for nocardiosis. (33376366)
• Uncontrolled HIV:
  • Nocardia infection mostly occurs with CD4 counts <100-200/uL.
  • Nocardia may be associated with HIV in the context of IVDU (intravenous drug use).
  • Due to improved treatments for HIV, HIV now accounts for <10% of Nocardia infection. (33418019)
• Rare immunodeficiencies:
  • Chronic granulomatous disease.
  • Antibodies against GM-CSF (granulocyte macrophage colony stimulating factor).
  • Ectopic secretion of ACTH (adrenocorticotropic hormone). (33418019)
  • Idiopathic CD4 lymphopenia.
  • IL-12 receptor deficiency, or IL-12 deficiency.
• Structural lung disease (especially if patients are using oral or inhaled steroid): (32629491; 33376366)
  • Bronchiectasis.
  • Advanced COPD.
  • Silicosis.
  • Pulmonary fibrosis.
• Apparently healthy patients (~0-20% of patients):
  • Patients without known risk factors may develop Nocardia infection.
  • Thorough evaluation of such patients will usually reveal an underlying immunodeficiency (as listed above).

source and mode of entry

• Nocardia is a ubiquitous gram-positive rod found in soil, house dust, and decaying plant matter. Exposure may be more likely among people with agricultural or outdoor occupations. (32629491)
• Transmission usually results from inhalation into the lungs. However, other modes include inoculation into the skin due to abrasions or penetrating trauma. (32629491)
• Human-to-human transmission is extremely rare, but may occur iatrogenically during surgery. (32629491)
• Nosocomial acquisition of Nocardia is rare but well documented, for example: (36314911)
  • During surgical procedures.
  • Outbreak in a renal unit related to air duct contamination.
  • Central line-associated Nocardia infection.

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clinical presentation

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pneumonia is usually subacute

• Course is usually subacute over weeks (but may be acute among immunosuppressed patients).
  • The diagnosis of nocardiosis is reached an average of 42 days after symptom onset, although disease is recognized more rapidly among immunosuppressed patients. (36314911)
• Cough typically produces sputum, occasionally with blood streaking.
• Constitutional symptoms are common (e.g., night sweats, anorexia, weight loss, fever, and malaise).

local spread in the thorax

• Empyema occurs in about a third of patients with pneumonia.
• Pericarditis, mediastinitis, osteomyelitis, and/or superior vena cava syndrome may occur.

metastatic spread of infection

• Statistics:
  • Roughly 1/3 of patients with clinical pulmonary infection will also have metastatic spread to other organs.
  • Among patients with disseminated disease, 80% will have clinically apparent lung disease. (Primary cutaneous infection is also possible, due to direct inoculation into the skin.)
  • Dissemination is more likely in the context of immunosuppression.
• Brain abscess is the most notable form of metastatic infection, occurring in 25% of patients with pulmonary nocardiosis (more on this below).
• Almost any organ can be involved, with other sites of involvement including:
  • Skin, bone, muscle, and/or joints (e.g., multiple subcutaneous abscesses with or without sinus tracts, multiple pustules, nodules). (Murray 2022)
  • Kidneys.
  • Heart: Endocarditis, purulent pericarditis, and pericardial tamponade.
  • Retinal involvement.

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CNS involvement

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clinical presentation of CNS involvement

• Brain involvement occurs in ~25-50% of patients with pulmonary nocardiosis. However, 38% of patients with CNS infection lack infection elsewhere. (33549266)
• CNS involvement usually consists of one or more indolent abscesses. Symptoms may include headache, focal neurologic abnormalities, fever, altered mental status, or seizures. (34623105) 
• Meningitis is uncommon, but can occur if an abscess ruptures into the subarachnoid space.

diagnosis

• CSF is generally unhelpful (although rare cases involving nocardial meningitis may cause a bacterial-type CSF profile and may grow Nocardia in culture). (34623105) 
• Brain abscess aspiration is highly sensitive.
• 💡 Neuroimaging should generally be performed in any patient with Nocardia infection to evaluate for occult CNS involvement (since this may affect antibiotic selection and radiologic follow-up).

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laboratory diagnosis

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staining

• Staining may be extremely helpful to provide rapid information (before cultures have time to grow).
• Nocardia are weakly gram-positive aerobic rods which form delicate, branching filamentous forms.
• Nocardia are often weakly positive on acid-fast staining. Actinomyces may appear similar to Nocardia on gram staining, but Actinomyces are not acid-fast staining.
• ⚠️ A specific stain and culture for Nocardia should be requested from the laboratory. Routine gram stain and culture will not detect acid-fast bacilli.

culture

• 💡 Communicate with the pathology laboratory if you suspect nocardia infection, as this may require extended incubation with special growth media. At some hospitals this may be ordered separately as a Nocardia culture/smear.
  • Growth usually occurs after 3-5 days, but it may require 2-4 weeks.
• Sensitivity from various sites:
  • Sputum may have a sensitivity of ~1/3 among patients with Nocardia pneumonia.
  • Abscess drainage or tissue biopsy may have high sensitivity.
  • Blood cultures are usually negative (unless infection involves an intravascular catheter or heart valve).
• Nocardia can represent colonization:
  • In general, a positive culture should usually be interpreted as indicating invasive disease.
  • However, ~20% of isolates may represent airway colonization. (36314911) Colonization may be more likely to occur in the context of bronchiectasis. (32629491) For an immunocompetent patient with bronchiectasis, identifying Nocardia rarely reflects a systemic infection. (35947710) 
• Identification of the Nocardia species and antibiotic sensitivity may be helpful in designing prolonged antibiotic regimens.

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chest imaging

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Nocardia may take on a variety of forms, which may occur together in different parts of the lung. In some cases, CT scan may help suggest the diagnosis of an unusual form of pneumonia. 

lung nodules (~66%)

• Nodules are the most common radiographic finding: (Fishman 2023)
  • Usually multiple nodules are present.
  • Size usually ranges from 0.5 – 3 cm. (29518379)
  • Borders may be well-defined or irregular. (Rosado-de-Christenson 2022)
• Mass-like appearance can mimic malignancy. (Fishman 2023)

consolidation (~33%)

• Areas of consolidated lung may be rather dense and well-demarcated.
• Consolidation may be unifocal or multifocal, with size ranging from lobar to segmental.
• Margins of consolidation are often indistinct. (Rosado-de-Christenson 2022)

cavitation (~33%)

• Cavitation may occur in about a third of patients with pulmonary nocardiosis. (33376366)
• Cavitation is more likely among immunosuppressed patients. (32629491)

effusion/empyema (~33%)

• Pleural thickening may be notable on CT scan.
• Empyema necessitans: The empyema may invade the chest wall and drain out of the skin.
• Bronchopleural fistula formation can occur.

other findings

• Mediastinal lymphadenopathy is frequent. (Shepard 2019)
• Mediastinitis, pericardial effusion.

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treatment

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general comments

• Treatment is difficult. Nocardiosis has a tendency to relapse or progress, even despite appropriate therapy.
• Brain imaging should be performed to evaluate for occult CNS involvement. CNS involvement may require a broader antimicrobial regimen and also neurosurgical drainage. Imaging should include either contrast-enhanced CT scan or MRI.
• Immunosuppressive agents should be reduced, as possible. For an immunocompromised patient with severe Nocardia infection, following completion of therapy it may be reasonable to utilize secondary prophylaxis with ongoing trimethoprim-sulfamethoxazole to reduce the risk of recurrence. (30424889) 
• Speciation and antimicrobial susceptibility should always be performed, but this may not be available for several weeks.
• Sensitivity of more common species of Nocardia to various agents is listed below.

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commonly used antimicrobial agents

The following five classes of antibiotics may be utilized for initial therapy of Nocardia (prior to obtaining antibiotic susceptibility testing). Once antibiotic susceptibility results are returned, a broader range of agents may be utilized. (33376366)

trimethoprim-sulfamethoxazole

• Trimethoprim-sulfamethoxazole is generally considered the front-line agent for Nocardia.
• Nearly all strains of Nocardia are susceptible.
• CNS penetration is reasonable (~50%). (33376366)
• The dose is 10-20 mg/kg daily divided in 3-4 doses. (33376366)
• For patients with sulfa allergy, desensitization is recommended (oral trimethoprim-sulfamethoxazole may be a very useful maintenance therapy).

linezolid

• Linezolid is broadly effective against various strains in vitro. The clinical efficacy of linezolid has been supported by a retrospective study. (32258209)
• Dosing is the same as for other infections (600 mg BID, either PO/IV).
• One advantage of linezolid is excellent CNS penetration (~80%). (33376366) There are some reports of good clinical response, even among patients with CNS involvement or prior treatment failure. (32629491)
• Linezolid toxicity accumulates with prolonged therapy (>2 weeks), so linezolid often needs to be discontinued eventually (often due to thrombocytopenia). However, linezolid may be a useful agent, especially for initial therapy (before sensitivity data is available).

carbapenems

• Imipenem and meropenem are optimal for different Nocardia species.
• Side effects of note: imipenem reduces seizure threshold.
• (Ertapenem has less activity and shouldn't be used.) (32629491)

third-generation cephalosporins (e.g., ceftriaxone)

• These have variable activity against different Nocardia species.
• They are well tolerated, with good CNS penetration.
• They may be useful, especially after speciation and sensitivity data are available.

amikacin

• Amikacin may be used in more serious nocardiosis.
• Dosing: 20-30 mg/kg/day as a once-daily aminoglycoside administration. (33376366) Management requires close monitoring of levels.
• CNS penetration is only ~10%. (33376366) However, an amikacin dose of 30 mg/kg may achieve a peak serum level of ~60-80 mg/L, which may allow a Peak/MIC ratio of >10 in the CNS (since amikacin has a MIC90 value of 0.5-1 mg/L for most Nocardia species). (33418019)
• In vitro antagonism has been observed between linezolid and amikacin. (33418019)

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commonly utilized initial regimens

There are no guidelines and little high-quality evidence regarding treatment. The regimens below are based on recent reviews. (33418019, 33376366) 

some comments on combining agents

• Once susceptibility is known, a single antibiotic is generally sufficient (even for CNS Nocardia). (33418019)
• Multidrug regimens are conventionally recommended and utilized as initial empiric therapy. However, there is no high-quality evidence that a multidrug regimen is superior to a single-drug regimen. The evidence supporting trimethoprim-sulfamethoxazole monotherapy is substantial. (33376366)

skin

• Monotherapy: Trimethoprim-sulfamethoxazole OR linezolid.
• Duration of therapy: 3 months.

pneumonia, non-severe

• Monotherapy: Trimethoprim-sulfamethoxazole OR linezolid.
• Duration of therapy: 4-6 months.

pneumonia, severe

• Dual therapy using two agents chosen from the above (including trimethoprim-sulfamethoxazole and/or linezolid).
• Duration: 4-6 months.

CNS infection

• Two or three drugs are chosen initially.
• Therapy should probably include trimethoprim-sulfamethoxazole and/or linezolid (given that these agents have high CNS penetration and broad activity against Nocardia).
• Duration of therapy: 12 months (3-6 weeks of intravenous therapy, followed by oral therapy).

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causes of treatment failure may include: 

• Need for surgical drainage of an abscess or empyema.
• Antibiotic underdosing, poor penetration of the infected site, or drug-drug interactions.
• Poor adherence to therapy.
• Resistance of Nocardia to antibiotic(s) utilized.
• Coinfection is not infrequently a problem (given that patients are generally immunocompromised). Coinfection will depend on the intensity of immunosuppression, but may involve such pathogens as CMV, endemic fungi, Cryptococcus neoformans, or tuberculosis.
• Paradoxical reaction to therapy (rare). (33376366)

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questions & discussion

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