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By Omneya Magdy Omar Assistant Lecturer Pediatrics

Atypical mycobacteria
Nontuberculous mycobacteria (NTM) mycobacteria other than tuberculosis (MOTT) More than 130 species are known. The majority of NTM are not pathogenic for humans,but almost all can behave as opportunists and be responsible for disease in the presence of predisposing conditions.

Environmental organisms
(isolated from water,soil, dust and plants) contact with contaminated environments may occasionally be responsible for infection

No evidence of animal-to-human or human-tohuman transmission of NTM.

The most common forms of diseases


Cervical adenopathy in children Skin and soft tissue infections Chronic pulmonary disease resembling TB (mainly in adults) Disseminated disease in immunocompromised persons

Classification of Nontuberculous Mycobacteria The Runyon system of classification Growth rate Production of yellow pigment whether this pigment was produced in the dark or only after exposure to light

The Runyon system of classification Growth rate

Groups I, II, and III Slow growing (>7 days to detect growth)

Group IV
Rapid growing (<7 days to detect growth).

Rapid and slow growers differ in their antimicrobial susceptibility Slow growers are most often responsible for pulmonary and lymphonodal diseases, Rapid growers prevalently affect skin,bones and joints

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The Runyon system of classification


Production of yellow pigment
I
Photochromogens II Scotochromogens III
Nonphotochromogens

M. marinum
Develop pigment following exposure to light M. kansasii

M. simiae M. xenopi M. szulgai M. intracellulare


M. malmoense M. ulcerans

Develop pigment in the dark or light Nonpigmented regardless of whether they are grown in the dark or light

IV Rapid growers

M. fortuitum M. abscessus

Epidemiology
The increased frequency of NTM is due to :
Prevalence of (TB) declines in the developed world, the proportion of mycobacterial lung disease due to (NTM) is increasing Advances in the diagnostic procedures Association of NTM infection with AIDS

Lymphadenitis
In the USA, M. avium complex with its two major species M. avium & M. intracellulare accounts for approximately 80% of NTM lymphadenitis in children

Site
Commonly,Superior anterior cervical or submandibular Occasionally, posterior cervical, axillary and inguinal

Age:1-5 yr
Lack constitutional symptoms Unilateral subacute and slowly enlarging , >1.5 cm Firm, painless, freely movable, and not erythematous The involved nodes occasionally resolve without treatment Most undergo rapid suppuration after several weeks

Lymphadenitis
NTM lymphadenitis usually have a tuberculin skin test reaction of <15 mm unilateral anterior cervical node involvement Normal chest xray No history of exposure to adult TB

D.D bacterial lymphadenitis Tuberculosis cat scratch dis mononucleosis toxoplasmosis Brucellosis tularemia malignancies (lymphomas)

Cutaneous infections

Swimming pool (or fish tank) granuloma by Mycobacterium marinum

Buruli ulcer by

Mycobacterium ulcerans

Swimming pool or (fish tank) granuloma


Rare in children At site of minor abrasions on the elbows, knees, or feet (swimming pool granuloma) or on the hands & fingers of fish tank owners (fish tank granuloma) Within 2-6 wk after exposure Lesion : Nontender erythematous papule that enlarge over 3-5 wk to form violaceous plaques. Nodules or pustules can develop, and occasionally these lesions ulcerate, resulting in a serosanguineous discharge. Although most infections remain localized to skin, penetrating infections can result in tenosynovitis, bursitis, osteomyelitis, or arthritis Sporotrichoid forms is characterized by small nodules along lymphatic ducts Lymphadenopathy is usually absent.

M. marinum is a photochromogenic species with optimal growth at 32C The standard incubation at 37C may be responsible for growth failure. Clinical suspicion is therefore a major prerequisite for a successful microbiological diagnosis.

Swimming pool granuloma

Fish tank granuloma

Buruli ulcer

Third most common mycobacterial disease after tuberculosis and leprosy it is particularly frequent in Africa and Australia

Buruli ulcer
Caused by M. ulcerans
produces immunosuppressive toxin called mycolactone which is directly toxic to cells Infection follows percutaneous inoculation from minor trauma (pricks and cuts from plants or insect bites).

IP: 3 m
Constitutional symptoms are unusual , lesions are typically painless
Erythematous, Firm , non-tender movable nodule or small papule commonly on legs or arms central necrosis and ulceration (Buruli ulcer )

(undermined edge, expands over several weeks and can result in deep soft tissue destruction or bone involvement )

Growth in culture requires incubation at temperatures lower than 32C

Buruli ulcer

Cutaneous infections
Many rapid growers are often involved in post-traumatic or postsurgical infections; include M. fortuitum, M. chelonae and M. abscessus Outbreaks of cutaneous mycobacterioses are increasingly reported worldwide. The infectious agent is accidentally introduced into the host by injection (multidose vaccines, local anaesthetic) or because of the use of contaminated disinfectants

Catheter-related infections
Most common nosocomial NTM infections Caused by: rapid growers such M. fortuitum, M. chelonae and M. abscessus Patients with long-term central intravenous catheters , peritoneal and shunt catheters. Local catheter site drainage, tunnel infections and mycobacteremia.

Pulmonary infections

Most common form of NTM illness in adults but are rare in children.

Pulmonary infections
In normal children ,M. avium complex is the most commonly organisms capable of causing acute pneumonitis, chronic cough, or wheezing associated with paratracheal or peribronchial lymphadenitis and airway compression Constitutional symptoms such as fever, anorexia and weight loss occur in 60% of these children. Chest x ray: are very similar to those for primary TB with unilateral infiltrates and hilar lymphadenopathy Pleural effusion is uncommon.

Pulmonary infections
In adults with underlying chronic lung disease. The onset is insidious and consists of cough and fatigue, progressing to weight loss, night sweats, low-grade fever, and generalized malaise in severe cases. Chest x ray :thin-walled cavities with minimal surrounding parenchymal infiltrates are characteristic, but radiographic findings can resemble those of TB A separate disease manifestation occurs in postmenopausal women and is radiologically characterized by bronchiectasis and nodular lesions, often affecting the middle lobe and lingula.

Pulmonary infections
Clinical suspicion and staining and culture of respiratory specimens for mycobacteria are the first steps in the diagnosis of NTM lung disease Whenever mycobacterial disease is considered, it is important to rule out pulmonary TB. In patients without HIV infection, those with pulmonary TB are more likely to have systemic symptoms, such as fever, night sweats, and weight loss, but patients with more advanced NTM lung disease may have similar symptoms. Features that suggest TB History of +v TB skin test & history of residence in an endemic area and it is less likely if patients were treated for latent TB Upper-lobe disease and cavitation, are not helpful in distinguishing TB from NTM lung disease

Chronic pulmonary infections and cystic fibrosis


M. abscessus affects children M. avium complex affects adults

PF: underlying structural airway disease and altered mucociliary


clearance . Diagnosis can be quite difficult due to Overlapping symptoms and radiographic changes due to the underlying CF. It can be difficult to exclude the frequent presence of other organisms such as P. aeruginosa and Staphylococcus

Recommendations:
Adult and adolescent patients with CF should have periodic at least yearly, screening cultures for NTM. During periods of clinical decline while unresponsive to treatment for nonNTM pathogens, all patients with CF, including children, should be evaluated for NTM

Isolation of NTM from the respiratory tract does not, per se, indicate NTM disease. Therefore, the American Thoracic Society (ATS) has established diagnostic criteria to help to distinguish between contamination and true NTM disease

Diagnostic criteria of the American and British Thoracic Societies


Criteria take into consideration clinical features and radiologic, pathologic, and microbiologic findings. The hallmark of these criteria is the need for multiple positive cultures yielding the same NTM species to make a definitive diagnosis of pulmonary NTM disease. In children:Definitive diagnosis often requires invasive procedures such as bronchoscopy and pulmonary or endobronchial biopsy In cystic fibrosis : More-aggressive sample pretreatment is necessary to prevent overgrowth by other species, especially Pseudomonas spp

Diagnostic criteria of the American and British Thoracic Societies

Diagnostic criteria of the American and British Thoracic Societies


Clinical (both required) 1. Pulmonary symptoms,
nodular or cavitary opacities on chest radiograph

or
a high-resolution CTscan that shows multifocal bronchiectasis with multiple small nodules

2. Appropriate exclusion of other diagnoses

Diagnostic criteria of the American and British Thoracic Societies


Microbiological
1. Positive culture results from at least two separate expectorated sputum samples; if the results from one are nondiagnostic, repeating sputum smears and cultures should be considered or 2. Positive culture result from at least one bronchial wash or lavage or 3. Transbronchial or other lung biopsy with mycobacterial histopathological features (granulomatous inflammation or acid fast bacilli) and positive culture for NTM or biopsy showing mycobacterial histopathological features (granulomatous inflammation or acid fast bacilli) and one or more sputum or bronchial washings that are culture positive for NTM

Diagnostic criteria of the American and British Thoracic Societies


4.

Expert consultation should be obtained when NTM are recovered that are either infrequently encountered or that usually represent environmental contamination

5. Patients who are suspected of having NTM lung disease but do not meet the diagnostic criteria should be followed until the diagnosis is firmly established or excluded 6. Making the diagnosis of NTM lung disease does not, per se, necessitate the institution of therapy, which is a decision based on the potential risks and benefits of therapy for individual patients

Disseminated disease

Persons with mutations in genes coding for the IFN- receptor (IFNGR) or the IL-12 receptor or for IL-12 production

patients with AIDS usually appears when CD4 <50 cells/mm3; younger children (especially <2 yr) these infections occur at higher CD4 cell count

Immunosuppression established to prevent the rejection of transplanted organs. ( kidney and B.M)

M. avium complex infection

Disseminated disease
Continuous high-grade bacteremia L.N, liver, spleen, B.M, GIT, Thyroid, pancreas, adrenal gland, kidney, muscle& brain Signs & symptoms : fever, night sweats, chills, anorexia, weight loss, wasting, weakness,abd pain , generalized lymphadenopathy, HSM, Jaundice Lab: ALP & LDH, albumin, anemia, and neutropenia

Otomastoiditis
Affects children with tympanostomy tubes and a history of topical antibiotic or steroid use.

M. abscessus is the most common causative agent, followed by M. avium complex


Patients present with painless, chronic otorrhea resistant to antibiotic therapy. CT imaging can reveal destruction of the mastoid bone with mucosal swelling Delayed or unsuccessful treatment can result in permanent hearing loss

Diagnosis
LN, skin, bone, and soft tissues
Isolation of the causative NTM bacteria by culture with histologic confirmation of granulomatous inflammation. Growth is best achieved using selective mycobacterial media (Lowenstein-Jensen medium)

Disseminated disease:
Blood cultures are 90-95% sensitive in AIDS patients Histiocytes containing numerous acid-fast bacilli from BM and other biopsy tissues. Development of nucleic acid amplification and DNA probes allow more rapid diagnosis of mycobacterial disease and the quicker differentiation of NTM from TB

Treatment
The treatment is almost always more complicated than the treatment of TB The drugs, frequency of administration, and duration of therapy will vary depending on the species of NTM causing the disease, site of infection, and extent of disease

Therapy involves medical, surgical, or combined treatment

Treatment
NTM lymphadenitis : complete surgical excision 3-6 mo trial of chemotherapy clarithromycin or azithromycin combined with rifabutin or ethambutol
If the surgery cannot be performed Removal of infected tissue is incomplete Recurrence or chronic drainage develops

M. marinum :
Rrifampin, amikacin, ethambutol, sulfonamides, trimethoprimsulfamethoxazole, and tetracycline. Therapy with a combination of these drugs, particularly rifampin and ethambutol may be given for 3-4 mo. Buruli ulcer Rifampicin and streptomycin Surgery to remove necrotic tissue, cover skin defects, and correct deformities.

Treatment
Pulmonary infections
should be treated initially with isoniazid, rifampin, ethambutol, and pyrazinamide pending culture identification and drug susceptibility testing.

Slow-growing NTM, a combination of rifampin or rifabutin, ethambutol, and clarithromycin Rapidly growing NTM, a combination of macrolides, fluoroquinolones, aminoglycosides, cefoxitin, and carbapenems is the optimal therapy Three or four-drug regimens are selected on the basis of drug susceptibility testing results. In CF, there may be a role for inhaled antibiotics.

Treatment
Disseminated M. avium complex and IL-12 pathway defects or IFNGR deficiency : Clarithromycin or azithromycin combined with rifampin or rifabutin and ethambutol for at least 12 mo . Once the clinical illness has resolved, lifelong daily prophylaxis with azithromycin or clarithromycin is advisable to prevent recurrent disease. The use of interferon adjunctive therapy is determined by the specific genetic defect.

Prophylaxis in HIV-infected children


Azithromycin or clarithromycin is indicated to prevent infection with MAC. Indication:
significant immune deficiency as defined by the CD4 count
6 yr: <50 cells/mm3 2-6 yr, <75 cells/mm3; 1-2 yr, <500 cells/mm3; <1 yr, <750 cells/mm3. Prophylaxis may be safely discontinued in children aged >2 yr receiving stable HAART for >6 mo and experiencing sustained (>3 mo) normal CD4 cell For children <2 yr of age, no specific recommendations for discontinuing MAC prophylaxis exist.