on 06-Mar-2023 (Mon)

Nocardia spp are aerobic gram-positive bacteria that can cause localized or systemic disease in humans [1-5]. Nocardial infections are typically regarded as opportunistic infections, but approximately one-third of infections occur in immunocompetent individuals [5].

Geographic distribution and prevalence – Nocardia species are found worldwide in both temperate and tropical climates, and infections in humans have been reported on all continents except Antarctica [6-10]. A review published in 2020 found that the United States, India, and Mexico had the most cases reported in the literature [10].

Due to lack of systematic surveillance, the true prevalence of nocardial infections is unknown. In the early 1970s, the incidence in the United States was estimated to be approximately 500 to 1000 new cases per year [11].

Reservoir – The bacteria's natural habitat is soil, decaying vegetation, and salt- and fresh-water aquatic environments [12].

Transmission – Nocardia is usually transmitted to humans via one of two routes: inhalation or inoculation into the skin.

• Inhalation of contaminated dust is thought to be the most common mode of entry [3,5].

• Skin inoculation occurs via penetrating trauma from a contaminated source (eg, puncture by a contaminated thorn) or exposure of a pre-existing wound to contaminated dust, soil, or water [3,5,14,15].

Human-to-human transmission has not been documented except for one report of nosocomial transmission from a health care worker, as described below [16,17].

Immunocompromising conditions — Data suggest that approximately two-thirds of nocardial infections occur in immunocompromised individuals, particularly those with cell-mediated immunosuppression [3-5,18-25].

Glucocorticoids and other immunosuppressive medications – Treatment with glucocorticoids is the most frequently reported risk factor for nocardial infection [3,20,22-28]. In a case-control study of 70 infected individuals, glucocorticoid therapy conferred almost a five-fold increase in infection risk (odds ratio [OR] 4.69; 95% CI, 2.45-8.99) [25].

The dosage of glucocorticoid therapy that predisposes to infection is unclear; some data suggest that higher dosages and prolonged courses (eg, ≥20 mg of prednisone for ≥1 month) confer greater risk [20,25,29]

Other immunosuppressive medications associated with Nocardia infection include calcineurin inhibitors (eg, tacrolimus, cyclosporine), chemotherapy for malignancy, and monoclonal antibodies to B-cells, T-cells, and tumor necrosis factor-alpha (eg, rituximab, alemtuzumab, infliximab) [20,29-37].

Organ transplant recipients – Observational data suggest that organ transplant recipients represent up to half of all infections, most likely due to the immunosuppressive medications used to prevent rejection [3,20,25,27-29,36-40].

Transplant recipients are most at risk in the first year post-transplant and during episodes of organ rejection, as discussed elsewhere [3,20,29,39].

Prophylactic trimethoprim-sulfamethoxazole (TMP-SMX) is not protective against Nocardia in organ transplant recipients, based on available data [20,29,39]. Failure of prophylaxis does not appear to be due to TMP-SMX resistance.

Other risk factors specific to organ transplant recipients include cytomegalovirus infection in the preceding six months and length of stay in the intensive care unit after transplantation [20,25,29]. The type of organ transplanted (eg, kidney, lung) does not appear to affect risk.

Malignancy – Solid-tumor and hematologic malignancies, including those treated with hematopoietic cell transplantation, have been associated with nocardial infection [5,25,26]. Like organ transplant recipients, the risk is primarily due to the immunosuppressive medications used to treat malignancy rather than the malignancy itself. Neutropenia has not been found to be a significant risk factor.

HIV infection – Since the advent of highly effective antiretroviral therapy, individuals with HIV no longer represent a large proportion of reported cases [8,9,22,23,41-44]. Most patients with human immunodeficiency virus (HIV) and Nocardia with nocardial infection are severely immunocompromised; in case series, the mean CD4 count is between 20 and 40 cells/microL [22,41]. Nocardial infections have been reported in patients with HIV on typical doses of prophylactic TMP-SMX used to prevent Pneumocystis infection [3,41,42].

Primary immune deficiencies – Certain primary immune deficiencies, such as chronic granulomatous disease, idiopathic CD4 lymphopenia, interleukin-12 p40 deficiency, and anti-granulocyte macrophage colony-stimulating factor (GM-CSF) autoantibodies, have been associated with nocardial infections [10,45,46].

Other risk factors — Other conditions that have been associated with nocardial infections include chronic lung disease (eg, alveolar proteinosis, chronic obstructive pulmonary disease), diabetes mellitus, alcoholism, injection drug use disorder, cigarette smoking, and tuberculosis [3,5,19,23,30,31,38,41,65]. Male sex has also been identified as a risk factor.

Course of illness — Patients with nocardial infections typically have an insidious onset of symptoms with a subacute course that progresses over several weeks [9]. Systemic indicators of infection, such as fever or leukocytosis, may or may not be present. As the disease progresses, focal symptoms develop related to the anatomic site or sites of infection.

Anatomic sites of infection — Most often, Nocardia causes localized disease at the portal of entry (ie, lungs or skin) [2,5,10,29,65-67]. However, it can disseminate to other organs via the bloodstream or spread to adjacent tissues by contiguous invasion.

Disseminated disease, defined as infection at two or more noncontiguous sites, has been estimated to occur in 20 to 50 percent of infections and is more common in immunocompromised individuals [2,65,68]. The most common site of dissemination is the brain [2,5,9,10,12].

Lungs — The lungs are the primary site of infection in approximately 80 percent of cases in immunocompromised individuals and up to half of cases in nonimmunocompromised individuals [3,20,38,65,69]. Among nonimmunocompromised individuals, reported risk factors include cigarette smoking, chronic obstructive pulmonary disease (COPD), bronchiectasis, and other chronic lung diseases [23,38,65].

Clinical features – The onset of pulmonary infection may be acute, subacute, or chronic. Fever and cough are the most frequently reported symptoms; night sweats, fatigue, anorexia, weight loss, hemoptysis, dyspnea, and pleuritic chest pain have also been described [2-4,23,67,70]. In patients with chronic lung disease (eg, COPD, sarcoidosis), diagnostic delays may occur because the clinical presentation can mimic an exacerbation of the underlying lung condition [71,72].

More than half of all pulmonary infections disseminate hematogenously, most often to the brain [10,29,67]. Both immunocompromised and nonimmunocompromised individuals can have disseminated infection.

Imaging findings – Radiographs (plain x-rays) and computed tomography (CT) of the lungs may reveal a broad range of findings. The most common finding is unilateral or bilateral nodular disease; the nodules may be cavitary, especially in immunocompromised individuals [65]. Other imaging findings include lung masses, consolidation, pleural effusion, reticulonodular infiltrates, interstitial infiltrates, and subpleural plaques (image 1 and image 2) [5,43,76-78].

In a review of 400 published cases of nocardial infection in nonimmunocompromised individuals, approximately 3 to 8 percent of patients with cutaneous infection had dissemination to the central nervous system (CNS; eg, brain) compared with 28 to 35 percent of patients with pulmonary infection [10].

Dissemination to the skin from another site of infection – Rarely, disseminated infection presents with cutaneous skin lesions due to hematogenous spread from another site of infection. The lesions typically appear as rounded cellulitic lesions about 1 to 5 cm in diameter, and multiple lesions in a widespread distribution may occur (picture 1) [24,67,89-92].

Primary cutaneous disease presents as one of three syndromes:

• Localized infection – Localized infection typically presents with one or more progressively painful skin lesions at the site of an injury or pre-existing wound. Lesions usually appear as nodules or ulcerations, although papules, pustules, cellulitis, and subcutaneous abscesses may occur, with or without purulent drainage [79-81].

Localized infection may spread to muscle, bone, or joint via contiguous spread [1,4].

• Nodular lymphangitis (ie, sporotrichoid lymphocutaneous disease) – Patients with this infection complain of a slowly enlarging skin lesion on an extremity with subsequent progression in a linear fashion up the extremity. Exam reveals either a nodular or ulcerative primary lesion with erythematous nodules extending up the extremity. This syndrome has been termed "sporotrichoid nocardiosis" due to its similar presentation to sporotrichosis [82-85].

• Mycetoma – A mycetoma is a chronic cutaneous infection that initially begins with one or more painless, slow-growing indurated nodules that eventually coalesce to form large tumors with necrotic abscesses and draining sinus tracts. The most common location is a foot or leg, but mycetomas can occur in other areas as well. The enlarging mass can remain localized or can spread contiguously to adjacent muscles and bone [67,86-88].

Mycetomas can also be caused by fungi and other bacteria. Further details regarding the microbiology and clinical features of mycetoma are found elsewhere.

Central nervous system — Central nervous system (CNS) infection is the most common site of disseminated infection and has been reported to occur in 20 to 58 percent of patients with nocardial infections [5,10,12,24,44,67,93]. Most cases of CNS infection are reported in immunocompromised individuals.

Brain abscess – Brain abscess is the most common form of CNS infection. Infection can cause single or multiple abscesses in any region of the brain [5,24,43,67,69,94-98]. Patients may present with acute or subacute focal neurologic deficits (eg, hemiparesis, cranial nerve palsy), headache, altered mental status, seizure, or ataxia; systemic signs of infection, such as fever, are often absent. The clinical manifestations of brain abscess are discussed in further detail elsewhere. (See "Pathogenesis, clinical manifestations, and diagnosis of brain abscess", section on 'Clinical manifestations'.)

Many patients with nocardial brain abscess have no symptoms or signs of brain involvement; in an observational study including 30 organ transplant recipients with CNS infection, 13 (43 percent) had no neurologic symptoms or abnormalities on exam [29]. For some patients with confirmed nocardial infection outside the CNS, brain imaging is performed to detect asymptomatic disease, as discussed below.

Meningitis – Rarely, patients present with meningitis, with or without an associated brain abscess [24,67,99,100]. In a case series of 28 individuals with nocardial meningitis, the typical presentation was subacute or chronic meningitis characterized by fever (68 percent), meningismus (64 percent), and headache (55 percent); brain abscess was present in 43 percent [100]. The cerebrospinal fluid (CSF) demonstrated neutrophilic pleocytosis, hypoglycorrhachia, and elevated protein concentration, findings that are characteristic of bacterial meningitis. CSF analysis is discussed in more detail elsewhere.

Imaging findings – Brain imaging reveals ring-enhancing lesions in over 90 percent of individuals with CNS disease, and approximately half have multiple lesions [24,101]. Surrounding edema (with or without mass effect) is present in 40 to 50 percent.

Primary cutaneous infections can invade adjacent bone, muscle, and lymph nodes, and pulmonary infections can invade the pleural space, mediastinum, pericardium, and superior vena cava, as described above

When to suspect nocardial infection — Clinical suspicion for nocardial infection varies depending on the anatomic site or sites of involvement.

● Cutaneous infection – Nocardial skin infection should be suspected in any individual with a subacute presentation of nodular lymphangitis, mycetoma, or wound infection following exposure to soil or water. Skin infections that fail to respond to usual antibiotic therapy should further prompt consideration of Nocardia. (See 'Skin' above.)

● Lung nodules – Nocardial infection should be suspected in any patient with cell-mediated immune deficiency (eg, corticosteroid use) and/or chronic lung disease who has new pulmonary nodules. (See 'Lungs' above.)

● Brain abscess – Ring-enhancing brain lesions in a patient with cell-mediated immune deficiency (eg, corticosteroid use) should prompt consideration of Nocardia. (See 'Central nervous system' above.)

Obtaining samples for testing — Prior to obtaining specimens for testing, laboratory personnel should be notified that Nocardia is suspected so they can take special measures to optimize results. Most microbiology and pathology labs have specific protocols for detection of Nocardia, as discussed elsewhere.

Gram stain – Nocardia spp usually appear as delicate, branching, filamentous, sometimes beaded gram-positive bacilli on Gram stain (picture 2 and picture 3) [1].

In a study of 80 individuals with nocardial infections, the overall sensitivity of Gram stains performed on direct clinical specimens was 64 percent, and the sensitivity for sputum was 78 percent [21].

Modified acid-fast stain – This stain should be performed on any sample that shows organisms consistent with Nocardia on Gram stain: among the various branching gram-positive bacilli, only Nocardia spp will stain positive by modified acid-fast staining [67,134].

However, the sensitivity is suboptimal; in a study of 50 patients with confirmed nocardial infection who had positive Gram stains, only 26 (51 percent) were positive by modified acid-fast staining.

Culture – Recovery of Nocardia in cultures can be difficult, so the microbiology laboratory should be notified so they can take measures to optimize growth (eg, prolonging incubation time, using special growth media) [1-3,5,67,135,136].

The overall sensitivity of culture for respiratory or tissue specimens ranges between 85 and 95 percent in most studies [21,67]. Yield from blood cultures is low, even in disseminated disease [61,68].

Once Nocardia grows in culture, we suggest that the isolate be sent to a reference laboratory for susceptibility testing and species identification. In general, reference laboratories have more extensive and accurate tests that can help guide antimicrobial therapy. Further information regarding susceptibility testing, including specific reference laboratories in the United States, is found below.

Molecular tests – Molecular tests for Nocardia spp, such as polymerase chain reaction (PCR) or whole genome sequencing, are not widely available in clinical laboratories. When no pathogen has been identified using traditional microbiologic testing and clinical suspicion remains for Nocardia, PCR or whole genome sequencing at reference laboratories may identify the organism.

Histopathology — There are no pathognomonic histopathologic findings specific for Nocardia in biopsied tissue, but visualization of the organism in stained tissue is highly suggestive. Microscopic evaluation of infected tissue most often reveals necrosis with abscess (including microabscess) formation [137-139]. There may be a mixed cellular infiltrate of polymorphonuclear leucocytes, lymphocytes, plasma cells, and hemosiderin-laden macrophages [139-141]. Granulomas with central necrosis mimicking tuberculosis have been described in lung and pleural tissue, but these findings occur infrequently [139,140].

Infectious causes of lung nodules – Each of these conditions is differentiated from Nocardia by microbiologic tests discussed in this topic and elsewhere (see 'Microbiologic tests' above and "Nocardia infections: Clinical microbiology and pathogenesis", section on 'Specific microbiologic tests'). Like Nocardia, many of the infections below occur primarily in immunocompromised individuals.

• Fungal infections – These include mold infections (eg, Aspergillus spp, Mucorales), Cryptococcus spp, and endemic mycoses (eg, histoplasmosis, blastomycosis, coccidioidomycosis). (See "Epidemiology and clinical manifestations of invasive aspergillosis", section on 'Pulmonary aspergillosis' and "Diagnosis of invasive aspergillosis".)

• Mycobacterial infections – Tuberculosis and nontuberculous mycobacteria (eg, Mycobacterium avium complex, M. kansasii) can cause lung lesions similar in appearance to Nocardia. Misdiagnosis of nocardial infection as mycobacteria has been reported on microbiologic staining as well [2]. (See "Clinical manifestations and complications of pulmonary tuberculosis", section on 'Clinical manifestations' and "Diagnosis of pulmonary tuberculosis in adults" and "Diagnosis of nontuberculous mycobacterial infections of the lungs".)

• Bacterial infection – Bacterial infections may mimic nocardiosis, including Rhodococcus equi and gram-negative bacilli such as Pseudomonas aeruginosa and Klebsiella pneumoniae. Septic pulmonary emboli from endocarditis and other intravascular infections (eg, Lemierre syndrome) can cause nodular infiltrates but typically have positive blood cultures. Actinomyces spp can mimic Nocardia, except Actinomyces pulmonary infections have a propensity to cross lung fissures and invade the chest wall. Actinomyces and Rhodococcus can have a similar appearance to Nocardia on microbio

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Noninfectious causes of lung nodules – Noninfectious considerations include malignancy (eg, primary lung cancer, pulmonary metastases), sarcoidosis, and ANCA-associated vasculitides and other autoimmune diseases (eg, rheumatoid arthritis).

Infectious causes of ring-enhancing brain abscesses – Infectious causes of brain abscess are numerous and are discussed in detail elsewhere (see "Pathogenesis, clinical manifestations, and diagnosis of brain abscess"). Listed below are some etiologies likely to mimic CNS nocardial infection.

• Bacterial infection – Brain abscess is most frequently caused by bacteria such as anaerobes, streptococci, Staphylococcus aureus, and aerobic gram-negative bacilli. Multiple brain abscesses may be due to septic emboli from endocarditis, which is usually accompanied by positive blood cultures. Rhodococcus can also cause brain abscess. (See "Pathogenesis, clinical manifestations, and diagnosis of brain abscess".)

• Fungal infection – Mold infections (eg, Aspergillus spp, Mucorales) and Cryptococcus spp can cause ring-enhancing brain abscesses. Most, but not all, cases of intracerebral Mucorales infection have rhino-orbital involvement, a finding that would be unusual for nocardiosis. (See "Clinical manifestations and diagnosis of Cryptococcus neoformans meningoencephalitis in patients without HIV" and "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV" and "Epidemiology and clinical manifestations of invasive aspergillosis", section on 'Central nervous system infection'.)

• M. tuberculosis – Tuberculosis can cause ring-enhancing lesions in the brain known as tuberculomas. (See "Central nervous system tuberculosis: An overview", section on 'Tuberculoma'.)

• Parasitic infection – T. gondii and Taenia solium (the causative agent of neurocysticercosis) both cause ring-enhancing lesions of the brain. CNS toxoplasmosis is most common in patients with advanced HIV disease, whereas neurocysticercosis often occurs in nonimmunocompromised individuals. (See "Toxoplasmosis in patients with HIV", section on 'Serology' and

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Noninfectious causes of ring-enhancing brain lesions – Brain tumors (malignant or benign primary brain tumors, CNS lymphoma, or metastatic disease), sarcoidosis, and multiple sclerosis can all cause ring-enhancing lesions. Tissue biopsy is necessary to diagnosis brain tumors, whereas the diagnosis of neurologic sarcoid and multiple sclerosis can be elusive and requires thorough clinical evaluation.

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