Nocardia/Nocardiosis

Classification

General Characteristics

Nocardia

• General characteristics:
  • Structure:
    • Branching, filamentous rods
    • Filaments fragment readily into coccobacillary forms.
  • Gram stain: gram positive
  • Other stain(s): weakly acid fast due to mycolic acids in the cell wall
  • Enzyme produced: urease positive, catalase positive
  • Spore formation: non-spore forming
  • Oxygen requirement: obligate aerobe
• Culture medium: grows on most ordinary laboratory media (such as blood agar) 
• Nocardiosis (disease caused):
  • Frequently an opportunistic infection, manifesting as a pulmonary or disseminated disease.
  • Localized disease occurs, and usually presents as a cutaneous syndrome.

Clinically relevant species

• Nocardia asteroides (N. asteroides) has been divided based antimicrobial susceptibility patterns:
  • N. abscessus complex
  • N. brevicatena-paucivorans complex
  • N. nova complex
  • N. transvalensis complex
  • N. farcinica
  • N. cyriacigeorgica
• Nocardia brasiliensis (N. brasiliensis)

Epidemiology

• Incidence of nocardiosis: 500–1,000 cases per year in the United States
• Infection affects men > women
• All ages are susceptible to infection.

Pathogenesis

Reservoir and transmission

• Reservoir(s): soil, decaying organic matter, water
• Transmission:
  • Inhalation:
    • Primary route of exposure
    • Mainly with N. asteroides, causing pulmonary disease
  • Environmental exposure through trauma or wound contamination:
    • Mainly with N. brasiliensis 
    • Infections affect the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin and lymph nodes.

Virulence

• Mechanisms of Nocardia spp:
  • Resistance to phagocytosis: when bacterial growth is in log phase
  • Resistance to hydrolysis: If phagocytosis occurs, the fusion of the phagosome and lysosome is stopped.
  • Resistance to antimicrobial action of neutrophils:
    • Superoxide dismutase from the cell surface
    • Increased catalase 
• N. farcinica:
  • More virulent than other species
  • With antimicrobial resistance
  • Associated with disseminated infection
• L forms:
  • Microbial variants without a structurally intact cell wall
  • Found to persist in animal models (in cerebrospinal fluid)
  • Believed to be related to relapse or development of neurologic signs even after treatment

Disease process

• Nocardia is introduced after a local injury to the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin and infection occurs:
  • In immunocompetent patients: remains localized
  • In immunocompromised patients: with potential to spread to other organs
• Pleuropulmonary nocardiosis: 
  • Infection follows after inhalation of contaminated aerosolized droplets. 
  • Majority of patients are immunocompromised.

Host risk factors

• Frequently the immunocompromised, particularly with impaired cell-mediated immunity:
  • Human immunodeficiency virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview (HIV) syndrome: usually in patients with < 250 CD4+ T lymphocytes T lymphocytes T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells/μL
  • Transplant recipients 
  • Chronic glucocorticoid use
  • Chronic immunosuppression
  • Malignancy
• Others:
  • Alcoholism
  • Diabetes
  • Chronic obstructive pulmonary disease Chronic obstructive pulmonary disease Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD)
  • Inflammatory bowel disease

Clinical Presentation

Pulmonary nocardiosis

• Predominant clinical presentation
• Presents with fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, night sweats, dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea, weight loss, cough, chest pain Chest Pain Chest pain is one of the most common and challenging complaints that may present in an inpatient and outpatient setting. The differential diagnosis of chest pain is large and includes cardiac, gastrointestinal, pulmonary, musculoskeletal, and psychiatric etiologies. Chest Pain, weight loss 
• Seen mostly in the immunocompromised
• Chest X-ray/computed tomography (CT) scan: infiltrates, cavitary lesions, abscess, or pleural effusion Pleural Effusion Pleural effusion refers to the accumulation of fluid between the layers of the parietal and visceral pleura. Common causes of this condition include infection, malignancy, autoimmune disorders, or volume overload. Clinical manifestations include chest pain, cough, and dyspnea. Pleural Effusion
• May mimic tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis but with negative purified protein derivative (PPD) test

Disseminated nocardiosis

• 2 or more non-contiguous sites are affected.
• Infections may spread to the central nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System (CNS), causing brain abscesses.
• Slow-growing mass(es) causing headaches, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, and neurologic deficits
• Signs of meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis may be present.

Cutaneous nocardiosis

• Commonly from N. brasiliensis
• Occurs after trauma (gardening, surgery, animal bite)
• Affects even the immunocompetent
• Chronic, slowly progressing lesions
• Presentation:
  • Primary cutaneous infection: 
    • Cellulitis Cellulitis Cellulitis is a common infection caused by bacteria that affects the dermis and subcutaneous tissue of the skin. It is frequently caused by Staphylococcus aureus and Streptococcus pyogenes. The skin infection presents as an erythematous and edematous area with warmth and tenderness. Cellulitis or a single/multiple erythematous nodule(s) at the site of trauma
    • May drain purulent material
  • Lymphocutaneous nocardiosis: 
    • Cutaneous infection with lymphadenitis, possibly ulcerating and/or draining purulent material 
    • Similar to how Sporothrix schenckii infection presents (thus also called “sporotrichoid nocardiosis”)
  • Mycetoma: 
    • Progressive and chronic deep skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin infection 
    • May extend to the fascia, muscle, and bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones
    • May cause deformities and sinus tracts
    • May be a form of disseminated infection in immunocompromised patients

Diagnosis and Management

Diagnosis

• Culture: 
  • Grows on ordinary laboratory media after 3 to 5 days incubation in air
  • Specimens: sputum, pus, spinal fluid, or biopsy material
• Microscopic examination: filamentous rods, with beading and branching morphology
• Imaging studies are dictated by the clinical presentation:
  • Chest X-ray/CT scan of the chest: in pulmonary nocardiosis
  • CT scan of the brain/MRI: in patients with neurologic symptoms

Management

• Trimethoprim-sulfamethoxazole
• Newer β-lactams (imipenem, meropenem, cefotaxime) may be effective.
• Surgical drainage for abscess

Comparisons

Actinomyces Actinomyces Actinomyces is an anaerobic, gram-positive, branching, filamentous rod. Actinomyces israelii is the most common species involved in human disease. The organism is commonly found as part of the normal flora in the oral cavity, gastrointestinal tract, and reproductive tract. Actinomyces/Actinomycosis and Nocardia

Mycobacterium Mycobacterium Mycobacterium is a genus of the family Mycobacteriaceae in the phylum Actinobacteria. Mycobacteria comprise more than 150 species of facultative intracellular bacilli that are mostly obligate aerobes. Mycobacteria are responsible for multiple human infections including serious diseases, such as tuberculosis (M. tuberculosis), leprosy (M. leprae), and M. avium complex infections. Mycobacterium and Nocardia

Differential Diagnosis

• Sporotrichosis: infection caused by Sporothrix schenckii. Lymphocutaneous infection is the most common form and presents like cutaneous nocardiosis (inoculation of soil through the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin with erythematous, nodular lesion(s) along lymphatic channels). Culture of aspirated material helps distinguish the organisms.
• Mycobacterial infection: pulmonary infection from Mycobacterium Mycobacterium Mycobacterium is a genus of the family Mycobacteriaceae in the phylum Actinobacteria. Mycobacteria comprise more than 150 species of facultative intracellular bacilli that are mostly obligate aerobes. Mycobacteria are responsible for multiple human infections including serious diseases, such as tuberculosis (M. tuberculosis), leprosy (M. leprae), and M. avium complex infections. Mycobacterium tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis (M. tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis) also presents with fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, night sweats, weight loss, cough, hemoptysis Hemoptysis Hemoptysis is defined as the expectoration of blood originating in the lower respiratory tract. Hemoptysis is a consequence of another disease process and can be classified as either life threatening or non-life threatening. Hemoptysis can result in significant morbidity and mortality due to both drowning (reduced gas exchange as the lungs fill with blood) and hemorrhagic shock. Hemoptysis, and dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea. Both are acid-fast organisms, but Nocardia is only partially acid fast and is seen as a branching rod (resembling fungal hyphae). Recent infection with M. tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis results in a positive PPD test.
• Brain metastasis: Both brain metastasis and CNS nocardiosis present insidiously and imaging may show multiple lesions in one or both cerebral hemispheres. History helps in diagnosing these conditions; disseminated nocardiosis usually comes from a lung infection. Pulmonary investigation with imaging and cultures also help differentiate nocardiosis.