Mycobacterium Chelonae

Mycobacterium chelonae is a non-tuberculous mycobacteria (NTM), a group comprised of over 190 organisms and defined as mycobacteria species not categorized within the Mycobacterium tuberculosis complex or as Mycobacterium leprae. ^{[1, 2, 3]}  [Note: some authors will also exclude Mycobacterium ulcerans from the NTM category owing to its distinct clinical presentation.] ^[4]  Traditionally, these organisms were organized into phenotypic groups through the Runyon system of classification, which is based on characteristic colony morphology, growth rate, and pigmentation. ^[5]  This resulted in NTM being broadly categorized into rapid growing mycobacteria (RGM) or slow growing mycobacteria (SGM), based on the presence of growth on solid media either occuring within 7 days, or after 7 days, respectively. ^[3]  Improved molecular diagnostics have led to the identification of a multitude of new species, making the taxonomy of NTM a dynamic field. NTM are typically grouped on the basis of their growth rate (ie, rapid or slow) and then further subcategorized based upon genetic relatedness, most commonly determined by 16s rRNA sequencing, rpoB sequencing (sequencing of a highly conserved subunit of the RNA polymerase), or whole genome sequencing. ^[5]  Based on molecular diagnostics, there are 6 groups or complexes of RGM, which include the Mycobacterium chelonae-abscessus group, M fortuitum group, M smegatis group, M mageritense/M wolinskyi, M mucogenicum group, and the pigmented RGM. ^[6]

The M chelonae-abscessus group (MC-AG) is comprised of at least 11 species and subspecies, including M chelonae and its subspecies, chelonae, bovis, and gwanakae. The latter 2 are of unclear clinical significance in humans. ^[4]  Other notable pathogenic species in the MC-AG include Mycobacterium abscessus and its subspecies abscessus, bolletti, and massiliense, as well as M immunogenum and Mfranklinii. ^[4]  Prior to 1992, M chelonae and M abscessus were considered to be the same species due to their nearly identical biochemical features. ^[7]  Whereas NTM are felt to be of varying human pathogenicity, M chelonae is one species most often recognized as a human pathogen. M chelonae most commonly causes skin and soft tissue infections – both localized and disseminated, but it also has been implicated as a cause of pulmonary infection. ^[8]  Although typically susceptible to macrolides, which are a common backbone in NTM therapy, the resistance patterns of M chelonae species make treatment quite challenging. ^[9]  Because of these differences in antimicrobial susceptibility patterns between NTM species and the often prolonged treatment duration, it is critical to correctly identify the organism, and to establish that M chelonae truly is causing disease. ^[8] Ultimately, optimal therapeutic interventions including surgery and appropriate choice and duration of antimicrobial therapy have not been established for M chelonae infections. Treatment continues to be guided by expert consensus.

The pathophysiology of M chelonae is best explained by the evidence that the overwhelming number of M chelonae infections typically are linked to traumatic inoculation from the environment. NTM including M chelonae commonly are found worldwide, and human infections have been reported from most of the industrialized world. Environmental studies have isolated these organisms from soil (30 to 78% of soil samples in the United States), both natural and treated water sources, and in domestic and wild animal populations. ^{[10, 8]}  Multiple studies have documented the ability of NTM to form and grow in biofilms, leading to growth of RGM in samples from water distribution pipes, faucets, and ice machines, as well as medical equipment cleaned with water from these sources. ^[11]  This prominent feature of their pathophysiology is why potable water supplies are considered important reservoirs for human NTM pathogens, and have been implicated in both community acquired and nosocomial infections. ^{[12, 13]}  M chelonae in particular is one of the NTM species known to be resistant to multiple sterilizing agents (in part because of biofilm formation) including chlorine and glutaraldehyde, which are commonly used as disinfectants in hospital settings. ^{[14, 5]}

When identified in a specimen, NTM isolates can represent colonization, true infection, or pseudoinfection/contamination. TM isolates that are pseudo-infecting or contaminants (ie, isolates without a compatible clinical syndrome) sometimes are linked to pseudo-outbreaks. ^[15]  A pseudo-outbreak is a cluster of pseudoinfections often identified by an increased frequency of NTM isolates in patients without a compatible clinical syndrome. ^[15]  Several studies have identified contamination of automated bronchoscope disinfecting machines as the cause of pseudo-outbreaks of M chelonae. ^{[16, 17]}  M chelonae causes a wide range of clinical syndromes, most commonly skin and soft tissue infections, and can cause disease in both immunocompetent and immunocompromised hosts. Whereas the most common presentation of NTM infection in general is pulmonary disease, M chelonae is unique in that it rarely is thought to be a causative pathogen in pulmonary disease. In a study examining clinical features of pulmonary disease secondary to RGM in 154 patients, only 1 of the 146 isolates was identified as M chelonae. ^[18]

Skin and soft tissue infections secondary to M chelonae typically are categorized as localized cellulitis or abscess, or disseminated. Localized disease more commonly occurs in immunocompetent patients, whereas disseminated disease is more common in immunocompromised patients. Trauma, either surgical or nonsurgical injury, causing inoculation either via soil exposure or contaminated water or equipment is a clear explanation for the pathophysiology of M chelonae infection ^[6]  in the immunocompetent host. Traumatic inoculation also can lead to osteomyelitis. Cutaneous NTM infections have been associated with tattoos, and a study published in 2012 in NEJM detailed an outbreak of M chelonae infections secondary to tattoo ink. ^[19]  Sporadic pedicure-associated furunculosis secondary to M chelonae also has been identified in multiple studies. ^[20]  Immunosuppression (particularly corticosteroid use, organ transplantation, and rheumatoid arthritis), is an important risk factor for disseminated disease. ^[21]

A wide variety of procedures have been implicated as the source of health-care associated M chelonae infections including cosmetic, dermatologic, cardiovascular, orthopedic, and otolaryngologic procedures, among many others. Although rare, interventions involving the injection or placement of foreign material including implantable devices, prosthetic joints, subcutaneous injections, and intravenous catheters have been linked to M chelonae infection. ^{[22, 23]}  Less commonly identified M chelonae infections include sinusitis, otitis media, ocular infections, and bacteremia. Bacteremia typically is thought to be a catheter-associated infection. ^{[9, 15]}  Although M abscessus and M fortuitum more commonly are identified in cases of mycobacteremia, a 2021 study identified M chelonae as the pathogen in 6 of 28 episodes of RGM blood stream infections. ^[24]  M chelonae is one of the most frequently isolated in NTM ocular infections, the risk factors for which include trauma, prior surgery, and the presence of ocular biomaterials. ^[25]

Geographic Distribution

NTM are ubiquitous in the environment. Commonly found in soil and water worldwide, they increasingly are being identified as human pathogens. ^[8]  When examining epidemiology of M chelonae specifically, it is important to take into account that historically, M abscessus and M chelonae were identified as one species and it is therefore possible that M chelonae is under or overrepresented in epidemiology studies. The global epidemiology of pulmonary infection secondary to NTM was reviewed in 2015, and worldwide Mycobacterium avium complex was the most frequently identified cause of NTM-pulmonary disease (PD). ^[26]  Upon review of data from Europe, Central and South America, Asia, Africa, and Australia, M chelonae infrequently is identified as 1 of the top 5 causes of NTM-PD. In Central and South America, only one study identified M chelonae (5.7%) as 1 of the 5 most common organisms to cause NTM-PD. ^[27]  Two other studies from this region identify M abscessus as a common organism, with no mention of M chelonae, and no comment is made with regard to differentiation of these 2 species. ^{[28, 27]}  Three of 12 European studies (ranging 5-9.4% of cases), and 0 studies from the Middle East, South Asia, and Australia identified M chelonae as a cause of NTM-PD. ^[27]  Interestingly, a study from a single medical center in Taiwan identified MC-AG as the second most frequent cause of 30% of NTM-PD; this was the only study out of East Asia that identified MC-AG. Identification of Mycobacterium species in this study was performed using conventional biochemical testing; hence, the inability to differentiate between the species. ^[29]

In North America, Mycobacterium avium complex (64-85%) was the most commonly identified organism in all included studies (64-85%), whereas M abscessus/chelonae (3-13%) frequently was identified as the second most common species. Studies from various states and regions of the United States examining prevalence of individual NTM species have been published. In a study performed in Oregon between 2005 and 2006, the authors reported an annualized prevalence of NTM disease of 7.2 cases per 100,000 persons; these predominately were pulmonary cases (5.6 cases per 100,000 persons), followed by skin and soft tissue infections (0.9 cases per 100,000 persons). In this study, M chelonae prevalence was 0.2 case per 100,000 persons, with the majority of cases isolated from skin and soft tissue infection. In Washington State, Ford et al examined geographic variability of NTM species; M chelonae was identified in all regions except the Olympic peninsula over their study period. ^[30]  Although never the most frequently identified organism, M chelonae or MC-AG organisms continue to be identified throughout the United States, ^{[5, 8]}  with 1 study finding that of 100 M chelonae case isolates, 51% came from either Texas or the southeastern coastal states from Louisiana to Maryland. ^[21]

Age/Sex/Race

The majority of patients worldwide who are diagnosed with NTM-PD tend to be older (mean age of 54-70 years), and except for in Europe, the majority are female. However, these data are for NTM-PD in general, and no clear age or sexual predilection has been identified for M chelonae infection. ^[26]  No clear racial predilection has been identified for M chelonae infection. This is in contrast to NTM-PD in the United States, in which persons classified as “Asian” were found to have relative prevalence rates approximately twice as high as those categorized as “white.” ^[26]

Frequency

Prevalence of NTM infections appears to be increasing worldwide. ^[26]  Although it is unclear why prevalence appears to be increasing, several factors have been identified as possibly contributory, including improved diagnostics, increased numbers of immunocompromised hosts, and longer life expectancies. ^[26]  Neither pulmonary nor extrapulmonary infections are considered nationally reportable conditions in the United States. Additionally, as microbiologic isolation does not necessarily indicate true disease, especially when isolated from the respiratory tract, it is difficult to assess true prevalence of NTM disease. There have been several notable extrapulmonary infection outbreaks of M chelonae, including those after laser in-situ keratomileusis (LASIK) as well as from infected tattoo ink. ^{[19, 31]}  Interestingly, as a result of outbreaks of extrapulmonary NTM infections associated with medical devices, cosmetic procedures, and medical tourism, there has been an increase in the number of jurisdictions in the United States that consider extrapulmonary NTM infections to be reportable conditions. ^[32]

Mortality/Morbidity

Data on mortality attributable to M chelonae infection are very limited, but it appears to be more common when M chelonae is identified as a cause of NTM-PD than in localized or disseminated skin and soft tissue infections. ^[33]  A study examining RGM infections in patients with cancer found that of 59 patients with a definite/probable pulmonary RGM infection, 14 (24%) secondary to M chelonae, RGM infection contributed to death in 7 patients. ^[34]  For patients in this study having a bloodstream infection, the death of just 1 of 141 patients was felt to be attributable to RGM infection, in this case M chelonae. ^[34]  Finally, disseminated infection in this study was associated with a poor prognosis. Of 22 patients with disseminated infection for whom outcomes were reported, 15 (68%) died, with RGM infection either contributing or felt to be the primary cause of death in 7 of these patients. ^[34]  In patients presenting with severe or disseminated disease, their underlying disease process or immunosuppression that predisposed them to M chelonae infection often caused the mortality, rather than M chelonae itself. Much of the morbidity of M chelonae was due to the often toxic and prolonged courses of antimicrobial therapy necessary to treat these infections.

Prognosis is variable and depends upon the patient's clinical syndrome. In general, if the patient is able to tolerate appropriate antimicrobial therapy and any indicated surgical procedures, the prognosis is good.