Nocardiosis Brijesh Singh Yadav brijeshbioinfo@gmail.com

Disease Type: Bacterial DiseaseCommon Name: NocardiosisCausative Agent: Nocardia asteroidesDisease Discription: A rare, acute, chronic suppurative infectious disease caused by bacteria Nocardia asteroides which primarily affects the lung but may also involve the brain, soft tissues and other organs . It has a pronounced tendency to remission and exacerbation.

Fig.1. Nocardia skin lesion.2. Filamentous bacteria identified as nocardia asteroides in sputum.

Causes of Disease:Nocardiosis is an infection caused by bacteria (Nocardia) which live in the soil. If inhaled, the bacterial infection causes pneumonia-like symptoms leading to blood poisoning (sepsis) and the spread of nocardiosis to other organs of the body but brain and skin infections are the most common complications.Nocardia may also infect the skin through a cut, puncture wound, or scratch that occurs while working outdoors or gardening. The skin infections, which may take different forms, are called cutaneous nocardiosis. Occupational exposure to soil, as in fieldwork, landscaping, and farming, increases the risk of contracting cutaneous nocardiosis. Pulmonary and disseminated infections occur through inhalation and primary cutaneous disease through soil-contaminated wounds. Rarely, nosocomial postsurgical transmission occurs.

Risk Factors: Having a risk factor for Nocardiosis makes the chances of getting a condition higher but does not always lead to Nocardiosis. Severely immunocompromised persons (e.g., persons with malignancy, connective tissue disorders, bone marrow or solid organ transplantation, high-

dose corticosteroid use, HIV infection, alcoholism or pulmonary alveolar proteinosis, and males (ratio male: female = 3:1).

Causative Agent Description:Pathogen Name: Nocardia Pathogen Description: Nocardia is a genus of Gram-positive, catalase-positive, rod-shaped bacteria. It has total 85 species. Some species are non pathogenic; some species are pathogenic (nocardiosis). Nocardia are found worldwide in soil that is rich with organic matter. Most Nocardia infections are acquired by inhalation of the bacteria or through traumatic introduction. Taxonoimic Classification:

Kingdom BacteriaPhylum ActinobacteriaOrder ActinomycetalesSuborder CorynebacterineaeFamily NocardiaceaeGenus Nocardia

Fig.4 Nocardia filamentous bacteria Other Pathogenic speices: Other pathogenic species include N. farcinica, N. nova, N.transvalensis,N. brasiliensis, and N. pseudobrasiliensis. A recent report of infections with Nocardia cornea, Nocardia elegans, Nocardia paucivorans, Nocardia puris, and Nocardia takedensis has come from Japan. Nocardia brasiliensis is a common cause of localized chronic mycetoma. A total of approximately 30 strains of Nocardia have been associated with human disease.

Morphology and toxin production: The Nocardia do not have complex growth requirements. They grow well on most commonly used routine bacteriologic media. They usually require a minimum of 48 to72 hours before colonies become visible. They may manifest extremely variable colonial morphologies on different culture media. They are dry, chalky, rough, folded, irregular and powdery. Nocardia colonies have a variable appearance, but most species appear to have aerial hyphae when viewed with a dissecting microscope particularly when they have been grown on nutritionally-limiting media. Nocardia grow slowly on non-selective culture media, and are strict aerobes with the ability to grow in a wide temperature range. Some species are partially acid fast(meaning that a less concentrated solution of hydrochloric acid should be used during the staining procedure) due to the presence of intermediate-length mycolic acids in their cell wall. Majority of strains possess the cord factor(trehalose 6-6' dimycolate),an important virulence factor.

History: Nocard, a French microbiologist and veterinary pathologist, first isolated Nocardia in 1888 and described the species Nocardia faraneux, a lymphatic and visceral disease of oxen. Nocardia infections in humans range from chronic skin lesions to a progressive pulmonary disease with documented haematogenous dissemination to virtually any organ in the body.

Epidemiology: Although nocardiosis has been diagnosed in individuals with no detectable deficiency of humoral or cell-mediated immunity, it usually occurs in patients whose immune status has been compromised by post-transplant immunosuppressive therapy, leukemia, lymphoma, dysgammaglobulinemia, pancytopenia, humoral defects, chronic granulomatous disease, or steroid therapy. The male/female ratio in nocardiosis is approximately 2:1, and infections occur from infancy to old age. There is no apparent geographic clustering of cases in the United States, except for cutaneous infection with N brasiliensis, which is more common in the south.

Disease Host: Both normal and immunocompromised humans and animals.

Disease Transmission:

Nocardiosis is sporadic and person-to-person spread is not well documented. Nocardia are parasitic bacteria which grow and reproduce on organic material. Their man habitat is carbon-rich sources such as soils, and plant and animal tissues. In fact, they can be found almost anywhere. One environmental survey found Nocardia in "beach sand, swimming pools, house dust, and garden soil". Upon infection of a plant or animal host, it metabolizes necrotizing tissues for energy and nutrients. Because Nocardia can form endospores, transmission of the bacteria "aerogenically" from one host to another is relatively easy, and the bacteria can survive dormantly when food sources are not present.

As stated, Nocardia infections can be transmitted aerogenically to host respiratory systems or cutaneous wound sites, they can be introduced by innoculation (puncture wounds with the bacteria contaminant), and through fluid contact (ex: case reported of keratitis due to contaminated contact lenses). Infection, once contracted, may spread systemically (dissemination).

Fig. Pathogenesis of Nocardiosis

Mechanism:

Introduction of N. asteroides via the respiratory tract results in pulmonary lesions that most often manifest as multiple abscesses. Nocardia abscesses are characteristically confluent, with little evidence of encapsulation, which probably accounts for the ready dissemination from the initial pulmonary focus. This organism also evades the host's bactericidal mechanisms. Host neutrophil mobilization can inhibit Nocardia but does not kill them. Cell-mediated immunity triggered by activated macrophages and the induction of a T-cell population capable of direct lymphocyte-mediated cytotoxicity are necessary to kill Nocardia. Infection progresses after the initial inhibition by neutrophils unless antimicrobial therapy or cytotoxic lymphocytes take over.

Nocardia exhibit specific organ tropisms. Log-phase cells of Nocardia, which contain specific cell wall mycolic acids, are more virulent and may influence the ability of nocardiae to localize in certain tissues, such as the brain. Nocardial metastasis manifests as multiple abscesses without granules in different organs. In patients with poor neutrophil activity or impaired cell-mediated immunity, fulminant pulmonary or systemic nocardiosis is an uncommon but opportunistic infection. It is curable but has a high mortality rate (exceeding 50% in some reports), probably because of delayed diagnosis and treatment. A high index of suspicion, followed by aggressive diagnosis and treatment, is necessary for optimal results.

Signs and Symptoms of disease:

Symptoms vary and depend on the organs involved.

Lungs (pulmonary nocardiosis): Fevers Night sweats Weight loss Coughing blood Chest pain upon breathing(may occue slowly or suddenly)

Brain (cerebral nocardiosis): Fever Headache Loss of neurological function (may be seen, depending the part of the brain affected) Confusion Disorientation, which means a loss of awareness of people, place, and time Dizziness Nausea Seizures

Skin: Red bump or Ulcer Swollen lymph gland

Diagnosis: Nocardiosis is diagnosed by tests that identify the bacteria. Depending on the site involved this may involve obtaining a tissue sample by way of the following:

Sputum culture Bronchoscopy Lung biopsy Skin biopsy Brain biopsy Generalized infections Chest radiographic findings vary and include fluffy infiltrates, scattered nodules, and

confluent lobar infiltrates progressing to complete consolidation and cavitation. Chest CT scanning is necessary to visualize the extent of disease and to rule out

empyema. CT scanning with contrast or MRI may be necessary to visualize cerebral abscesses. Perform abdominal and/or pelvic sonography and CT scanning to rule out intra-

abdominal, hepatic, splenic, or renal abscesses Use 2-dimensional echocardiography to rule out vegetations Perform CT scanning with contrast or MRI to rule out cerebral abscesses. Because of the high incidence of spread to the brain, all patients with pulmonary

nocardiosis should have a neuroimaging study, even in the absence of CNS symptoms.

Treatment: Individuals with Nocardiosis, either disseminated or cutaneous, require long-term antibiotic treatment (for 6 months) for the infection.

Sulfamethoxazole-trimethoprim (Bactrim) is used most frequently, and can be taken in pill form. Skin lesions may need to be surgically drained or removed. Diseased tissue may need to be removed from mycetomas.

Linezolid has a growing literature in support of its use in combination and even monotherapy for treatment of Nocardia infections. It has good CNS penetration, is available in an oral form, and is the only antibiotic known to be active against all strains of Nocardia.

Other medications for the pediatric age group include extended-spectrum cephalosporins, imipenem/meropenem, ampicillin, and amoxicillin-clavulanate. Tetracycline derivatives used in treatment include minocycline or doxycycline (in a child >8 y with sulfa hypersensitivity)

Patients who are immunocompetent with lymphocutaneous disease are usually treated for 6-12 weeks. Therapy includes incision and drainage of abscesses. Patients with immunocompromising conditions are treated for at least 3 months after clinical cure (usually up to 1 y of therapy

Individuals who are immune compromised, though, may have a more difficult time recovering

Geographical Distribution: Nocardia asteroides, the bacteria that causes nocardiosis, is found worldwide in the natural environment.Nocardiosis in India: Nocardiosis, an uncommon infection of the past, is being increasingly reported in recent years with rise of immunosuppressed patients. In India, very few centers have reported this disease. The present report describes twelve consecutive cases of nocardiosis reported over a period of 26 months (January 2004 to March 2006) from a tertiary care center in north India.

Disease Statistics:

o Incidence (annual) of Nocardiosis: estimated 500-1,000 annual cases in USA (DBMD). An estimated 10%-15% of these patients also have HIV infection.

o Incidence Rate: approx 1 in 544,000 or 0.00% or 500 people in USA o Incidence extrapolations for USA for Nocardiosis: 500 per year, 41 per month, 9

per week, 1 per day, 0 per hour, 0 per minute, 0 per second. o In patients who undergo renal transplant, the incidence rate is 0-20%.o In patients who undergo bone marrow transplant, the incidence rate is 0.3%, and in

patients with systemic lupus erythematosus, the incidence rate is 2.8%.

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Brijesh Singh Yadav