Nontuberculous Mycobacterial Infections in Children Jyotsna Bhattacharya, MD,* Sindhu Mohandas, MBBS,* David L. Goldman, MD† *Department of Pediatric Infectious Diseases and †Department of Pediatrics and Microbiology and Immunology, Children’s Hospital at Montefiore/Albert Einstein College of Medicine, Bronx, NY Education Gaps 1. Outbreaks of nontuberculous mycobacterial infections have been increasingly reported following cosmetic procedures performed abroad. Failure to recognize this association can lead to inappropriate or delayed therapy. (1) 2. The emergence of drug resistance in specificspeciesofnontuberculous mycobacteria infections (especially Mycobacterium abscessus) complicates medical therapy. Appropriate treatment of these infections involves the identification of a specific species and drug resistance testing. (2) Objectives After completing this article, readers should be able to: 1. Recognize the major clinical features associated with nontuberculous AUTHOR DISCLOSURE Drs Bhattacharya, mycobacteria (NTM) infections in children. Mohandas, and Goldman have disclosed 2. Recognize that NTM infections are a potential risk related to medical no financial relationships relevant to this article. This commentary does not contain a tourism for cosmetic surgery. discussion of an unapproved/investigative use of a commercial product/device. 3. Understand the strengths and weaknesses of currently available diagnostic methods. ABBREVIATIONS AFB acid-fast bacillus 4. Plan the appropriate management of NTM infections based on the CF cystic fibrosis specific clinical presentation and mycobacterial species. HAART highly active antiretroviral therapy HIV human immunodeficiency virus INTRODUCTION IFN-g interferon-g IGRA interferon-g release assay Nontuberculous mycobacteria (NTM) include all mycobacteria other than IRIS immune reconstitution inflammatory syndrome Mycobacterium tuberculosis, Mycobacterium bovis, and Mycobacterium leprae. MAC Mycobacterium avium complex Children are constantly exposed to NTM, yet clinical signs of infection are MALDI-TOF matrix-assisted laser unusual. NTM exist primarily in the environment, causing human disease as – desorption/ionization time of opportunistic pathogens in the appropriate clinical context. Lymphadenitis is far flight and away the most common manifestation of NTM disease in children. Other, NTM nontuberculous mycobacteria RGM rapidly growing mycobacteria less common, manifestations include skin and soft tissue infections (SSTIs), SGM slowly growing mycobacteria lung infections, and disseminated disease. Since the last review of NTM disease SSTI skin and soft tissue infection in Pediatrics in Review, (3) several important developments have occurred, Vol. 40 No. 4 APRIL 2019 179 Downloaded from http://pedsinreview.aappublications.org/ at Stony Brook University on June 3, 2020 including changes in the epidemiology and treatment, to grow. (10) The NTM species commonly implicated in which are reviewed herein. human disease are listed in Tables 1 and 2. Growth char- acteristics along with colony pigmentation are used to sort NTM into groups using the Runyon classification system. MICROBIOLOGY AND CLASSIFICATION Definitive speciation of NTM isolates using standard Currently there are more than 170 recognized NTM species, microbiological techniques is often not possible. As a result, although a limited number of species cause human disease. species with similar phenotypic characteristics have his- It survives inside amoeba, and the traits that promote this torically been grouped into complexes (ie, Mycobacterium process may also allow for successful macrophage infection. avium and Mycobacterium abscessus complex). Newer (4) Several characteristics promote both persistence in the molecular assays (see later herein) have led to improved environment and human disease. The lipid mycolic acid discrimination of NTM at the species and subspecies outer membrane is responsible for the acid-fast bacillus levels. (AFB) staining feature of NTM (Fig 1). It confers a hydro- phobic nature to the organism, which has been linked to EPIDEMIOLOGY changes in organism aggregation and enhanced aerosoliza- tion. (5) The hydrophobic NTM membrane also promotes NTM are found in a wide range of environmental sites, and surface adherence and helps restrict entry of antibiotics and disease is acquired primarily through exposure to these disinfectants into the cell. NTM form biofilms that promote sites, including soil and water (ie, drinking water, household surface attachment and persistence of the organism in water plumbing, drainage waters, and natural waters). (6)(11) systems (ie, pipes, showerheads) and catheters. (6) Other These organisms are easily aerosolized in droplets and also traits that have been linked with the NTM persistence in the survive in dust particles, both of which serve as a source for environment include the ability to grow in a variety of hos- pulmonary infection. Aerosols containing high densities of tile conditions, such as low oxygen concentrations, low or- NTM are found around areas with splashing water, includ- ganic matter concentrations, high temperatures, and low ing sinks and showers. Human-to-human and animal-to- pH. (7)(8)(9) human transmissions are thought not to occur or to occur Typically, NTM are categorized by their growth charac- rarely. A recent whole genome sequencing study of respi- teristics into 2 categories: slowly growing (SGM) and ratory NTM isolates indicates the possibility of human-to- rapidly growing (RGM) mycobacteria species. RGM dem- human transmission, although more study is needed in onstrate visible growth in culture media within 7 days, this area. (12) Health-care–associated transmission can whereas SGM take weeks to exhibit growth. Certain species also occur after dental, surgical, and cosmetic procedures. are particularly slow growers (eg, Mycobacterium ulcerans (13)(14) and Mycobacterium genavense) and may take 8 to 12 weeks Pediatric studies during the past decade show NTM disease incidence rates ranging from 0.84 per 100,000 in Australia to 3.1 per 100,000 in Germany. (15)(16) Many but not all studies report an increasing incidence of NTM disease, although it is unclear whether this reflects a true increase in disease or a result of improved diagnostics. (17)(18)(19) An increase in the number of susceptible children due to new immunomodulatory therapies may have also contributed to this increased incidence. Seasonal variation in the incidence of NTM lymphadenitis and SSTIs with a higher incidence in the late winter and early spring has been reported. (20) Outbreaks of NTM disease can occur in both cystic fibrosis (CF) centers and in the context of contaminated medical equipment. (14)(21) Severe NTM disease occurs with immunodeficiency and chronic lung disease. In immunocompromised Figure 1. Acid-fast bacillus stain of tissue from a patient that subsequently grew Mycobacterium chelonae. (Image provided by children, NTM infections may present in both local- Dr Michael Levi [Montefiore Hospital, Bronx, NY]). ized and nonlocalized forms. Effective immunity against 180 Pediatrics in Review Downloaded from http://pedsinreview.aappublications.org/ at Stony Brook University on June 3, 2020 TABLE 1. Slowly Growing Mycobacteria SPECIES PULMONARY DISEASE SSTI PHYSICAL EXAMINATION Mycobacterium • Frequently isolated in patients with • Most common cause of cervical • Nodules, pustules, or plaques avium complex cystic fibrosis adenitis • Sinus tract and abscess formation Mycobacterium • More frequent in patients with HIV • Infrequent • Nodules, pustules, ulcers, and kansasii and older individuals with COPD abscesses • Similar to Mycobacterium tuberculosis • May resemble sporotrichosis disease • In the United States, more frequent in the South and Midwest Mycobacterium • Exposure to fresh or salt water • Solitary, red to violaceous papule or marinum and marine animals nodule that progresses to a shallow • Swimming pool granuloma ulceration • Occasionally in a sporotrichotic distribution • Delay in diagnosis can lead to tenosynovitis, septic arthritis, and osteomyelitis Mycobacterium • Buruli ulcer • Chronic ulcerative skin disease ulcerans • Endemic in Africa, Southeast Asia, Australia, and South and Central America COPD¼chronic obstructive pulmonary disease; HIV¼human immunodeficiency virus; SSTI¼skin and soft tissue infection. NTM involves a coordinated response among Tcells, natural infections has been observed in both hematopoietic killer cells, and macrophages. Macrophage infection with stem cell and solid organ transplant recipients. Lung NTM results in interleukin-12 production that stimulates transplant recipients are disproportionately affected by interferon-g (IFN-g) by T cells and natural killer cells. In NTM-associated pneumonia, presumably due to previous turn, IFN-g activates macrophages to limit organism colonization of the donor lung and augmented immuno- growth. Children with defects in T-cell immunity (ie, AIDS) suppression. Similar to M tuberculosis infections, tumor or the interleukin-12/IFN-g pathway are, therefore, at risk necrosis factor–blocking agents seem to increase the risk for severe disease. (22) An increased incidence of NTM of NTM infections, although additional studies are needed TABLE 2. Rapidly Growing Mycobacteria SPECIES PULMONARY SSTI PHYSICAL EXAMINATION OTHER Mycobacterium • Severe pneumonia in • Commonly • Multiple lesions that may be • Three subspecies with different abscessus children with cystic fibrosis implicated purple, persistent-drainage