History
Known underlying diseases that contribute to nontuberculous mycobacteria (NTM) infections include chronic obstructive pulmonary disease, asthma, pulmonary emphysema, alpha-1 antitrypsin deficiency, cystic fibrosis (CF), non-CF bronchiectasis, primary ciliary dyskinesia, allergic bronchopulmonary aspergillosis, diabetes mellitus, leukemia, collagen diseases, systemic lupus erythematosus, [41, 42, 43] lung cancer, chronic kidney diseases, carcinomatous pleurisy, and previously treated tuberculosis.
Tumor necrosis factor (TNF)–alpha inhibitor therapy, as well as other immunosuppressive drugs such as azathioprine, mycophenolate mofetil, and cyclosporine, remain potential risk factors for atypical mycobacteria infections. [44]
Cases of cutaneous M chelonae infection, pulmonary M kansasii infection [45] occurring after liver transplantation, and disseminated M kansasii infection after renal transplantation [46] have been reported.
Drug abuse even in immunocompetent patients can present a risk factor for atypical mycobacteria infections. [47] Bilateral sporotrichoid lymphocutaneous dermatosis due to M fortuitum in a drug-abusing patient and cured by clarithromycin and ciprofloxacin has been noted. [47]
An outbreak of tattoo-associated NTM skin infections was recently reported in Florida. The investigators concluded that the open and unopened bottles of ink tested positive for mycobacteria and other contaminants. [48]
A case of breast infection with combined Prevotella melaninogenica and M fortuitum infections following nipple piercing has been reported. [49]
NTM infections after trauma, surgery, or cosmetic procedures should be considered especially if the infection is not responding to standard antibiotic regimens. [50] Surgery can provide a portal of entry for atypical mycobacteria. Procedures include cosmetic liposuction, [51] liposculpture, [51] breast augmentation mammoplasty, or median sternotomy.
Breast prostheses can be the site of atypical mycobacterial infections. [52] Cases of M fortuitum infection occurring after prosthetic breast reconstruction have been reported. [53] In 2017, three cases of NTM infection after silicone breast implant placement were reported. [54]
With an ever-increasing prevalence of cosmetic treatments, there also have been increasing rates of skin and soft-tissue infections (SSTIs) due to cosmetic procedures and other popular procedures such as acupuncture. In 2007, Sañudo et al [55] described NTB infection after mesotherapy in 15 patients. While in 2019, a case of M abscessus infection following home dermabrasion was reported. [56]
In 2007, Murdoch and McDonald [57] reported M avium-intracellulare cellulitis occurring with septic arthritis after joint injection. In 2014, Mycobacterium arupense was noted to cause large-joint osteoarticular infection. [58] Whenever a case of chronic granulomatous infection is encountered that does not respond to standard antituberculous treatment, with a history of open trauma, surgical intervention, or injection, a possible NTM infection should be considered and managed appropriately. [59]
Nosocomial disease has become increasingly important; pseudoepidemics associated with contaminated, automated endoscopic washing machines are the most recently described manifestation. M chelonae has been found in the colonic mucous membranes, the respiratory tracts, and as a contaminant in the tap water used for diluting concentrated chlorhexidine. The organism happened to be isolated with the mucous membranes that were picked up while using the washed fiberscope in the colons of six patients. These findings suggest that M fortuitum and M chelonae groups, in spite of the fact that they rarely cause infection, have a significant risk of infecting older patients (those >60 y) in general hospitals with various underlying diseases attributable to infections.
In 2014, atypical mycobacterial infections were noted in Louisiana in the exit sites of peritoneal dialysis catheters. [60]
Patients can report systemic and constitutional symptoms that include productive cough/purulent sputum, hemoptysis, weight loss, weakness, fever, and night sweats.
Injection abscesses due to M abscessus have been reported in a patient with diabetes. M chelonae wound infections after plastic surgery using contaminated gentian violet skin-marking solution [61] and infection with M abscessus associated with intramuscular injection of adrenal cortex extract have been reported. [62] M chelonae often occurs after puncture wounds and is a community-acquired disease. Infection can occur from scratches, road traffic accidents, and other trauma, such as from nails or wire.
In 2003, Sungkanuparph et al [63] reported a retrospective study of a series of patients infected with rapidly growing mycobacteria in Ramathibodi Hospital (Bangkok, Thailand) from January 1993 to June 1999. Eighteen patients had no underlying disease, and two were infected with HIV. Reported physical findings were lymphadenitis (7), skin and subcutaneous abscess (7), eye infection (4), pulmonary infection (1), and chronic otitis media (1). Sweet syndrome manifested in 4 of 7 patients with lymphadenitis. The organisms isolated included M chelonae/M abscessus group (17 cases) and M fortuitum group (3 cases). The atypical mycobacteria were susceptible to amikacin, netilmicin, and imipenem. The M fortuitum group was susceptible to more antibiotics than the M chelonae/M abscessus group. Histology findings demonstrated pathology that ranged from nonspecific to suppurative or caseous granulomas. Antimicrobial susceptibility defined the clinical response, which was good. A combination of two or more drugs provided effective therapy. Surgical resection was performed in apposite cases to reduce the load of the organism. Surgery was almost always used in cases with infections involving pan-resistant atypical mycobacteria.
Physical Examination
Humans encounter atypical mycobacterial species because of their ubiquity in the environment. Pathogenic mycobacterial species may breach the first-line barrier defenses of the innate immune system and modulate the activation of phagocytes to cause disease of the respiratory tract or the skin and soft tissues, sometimes resulting in disseminated infection. At one end of the spectrum, skin and soft-tissue infections (SSTIs) are almost always the result of iatrogenic or accidental inoculation of nontuberculous mycobacteria (NTM). Patients with NTM lung disease not uncommonly have a primary lung disorder or a systemic condition that predisposes them to these infections. At the other end of the spectrum, visceral and disseminated NTM disease invariably occurs in immunocompromised hosts.
Four clinical syndromes account for most infections with NTM: pulmonary disease, lymphadenitis, disseminated disease, and SSTIs.
Pulmonary disease
The most common form of localized NTM infection is chronic pulmonary disease in HIV-negative hosts. Diagnosis of NTM lung disease requires the integration of clinical, radiographic, and microbiological data, particularly as the symptoms, such as chronic cough, sputum, hemoptysis, fatigue, malaise, and weight loss, are often nonspecific and may also reflect underlying lung disease. Lung NTM infection remains a challenging diagnosis that requires extensive laboratory and imaging workup. M avium complex (MAC) followed by M kansasii and M abscessus are the most common responsible pathogens.
NTM lung disease has the following two major different radiographic manifestations [4] :
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Fibrocavitary form with cavitary lesions predominantly in the upper lobes, with radiographic findings similar to those of pulmonary tuberculosis
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Nodular bronchiectatic form that presents as multifocal bronchiectasis, clusters of small nodules, and branching linear structures that frequently involve the right-middle lobe and the lingular segment of the left upper lobe
Microbiological criteria include two positive sputum cultures, one positive bronchial wash or lavage sample, or other evidence of NTM, such as lung biopsy samples that are culture-positive for NTM and that have histological features consistent with the presence of mycobacteria.
Lymphadenitis
It typically affects immunocompetent children aged 1-5 years, with a female predominance. Isolated unilateral cervical adenitis is the most common form of presentation. It is important to differentiate it from tuberculous lymphadenitis, [64] as inappropriate management can lead to complications such as fistulas, sinus tracts, and scarring. The definitive diagnosis is established by recovery of the causative organism in tissue cultures. Approximately 80% of culture-proven NTM lymphadenitis is due to MAC. [65]
M scrofulaceum is the second most common cause of local lymphadenitis, [66] primarily in the submandibular and submaxillary regions. It usually has a benign, self-limited course with no systemic symptoms, although in some cases the involved lymph nodes may slowly enlarge and eventually result in ulceration and drainage with fistula formation.
Treatment of uncomplicated NTM lymphadenitis involves complete surgical resection of the involved lymph nodes. [36]
Visceral disseminated disease
It occurs almost exclusively in immunocompromised patients. Although a number of different species of NTM have been reported, the majority (90%) of these infections are caused by MAC. In HIV patients, MAC remains the most commonly implicated NTM. Disseminated disease in patients without HIV infection is seen in the setting of significant immunosuppression (eg, transplant recipients, long-term corticosteroid use, TNF-alpha inhibitor use, leukemia). Systemic dissemination of a primary cutaneous NTM can occur. In most cases, disseminated disease presents with disseminated cutaneous lesions. The rapidly growing mycobacteria species, as well as M kansasii and M haemophilum, are the most commonly isolated causative organisms.
Skin and soft-tissue disease
SSTIs caused by NTM typically present in the form of isolated or multiple nodules, commonly in a linear distribution following the local blood or lymphatic vessels.
SSTIs caused by NTM include two distinctive species-specific clinical entities: (1) fish-tank granuloma caused by M marinum and (2) Buruli ulcer caused by M ulcerans. However, most SSTIs caused by NTMs are nonspecific in their clinical presentations and may present as papules, plaques, abscesses, cellulitis, folliculitis, subcutaneous nodules with or without violaceus discolorations, sporotrichoid nodules, ulcerations, panniculitis, or draining sinus tracts.
M marinum
M marinum skin infections (also known as fish-tank granuloma or swimming-pool granuloma) are typically seen in immunocompetent persons with an extensive history of exposure to fresh, salt, or brackish water. Cutaneous infection requires a port of entry and the presence of breaks in skin barrier. [67] The clinical spectrum includes a solitary inflammatory papule or nodule that may later ulcerate and even spread in a sporotrichoid pattern (lymphangitic spread). [67] Because its optimal temperature for growth is around 30°C (86°F), cutaneous lesions most frequently occur in the upper or lower extremities and sometimes in the tip of the nose. It is not associated with marked regional lymphadenitis. Occasionally, deeper infections can be complicated by tenosynovitis, septic arthritis, or, rarely, osteomyelitis.
M ulcerans
M ulcerans, a toxin-producing NTM, is the causative organism of Buruli ulcer, considered a neglected tropical disease. [68] It is the third most common mycobacteriosis in immunocompetent hosts worldwide, after tuberculosis and leprosy. M ulcerans typically produces an exotoxin that is able to decrease inflammation, inhibit pain perception, and induce cell death. Children younger than 15 years are predominantly affected in western and central Africa.
Clinically, Buruli ulcer tends to affect predominantly the lower extremities and, to a lesser extent, the upper extremities and the face. The initial lesion presents as a single, small, firm, painless nodule that ulcerates and evolves into a painless ulcer over the course of 4-8 weeks. There is little to no regional lymphadenopathy or systemic manifestations. The ulcer itself is shallow, with an undermined edge and a base composed of necrotic fat. Ulcers can expand to 15 cm and more in diameter, and, if untreated, they may persist over many months and cause extensive scarring and deformity. Buruli ulcer may present in an atypical fashion, with manifestations of septic arthritis or osteomyelitis. [69]
M kansasii
Although M kansasii typically causes pulmonary disease that resembles tuberculosis, it has been recovered consistently from municipal water systems in endemic areas, including the United States. To date, it has not been recovered from soil or natural water supplies.
Cutaneous involvement usually presents in immunocompromised hosts and sometimes with concomitant pulmonary disease or disseminated disease. [70] It may present as nodules, pustules, verrucous lesions, erythematous plaques, ulcers, or abscesses. The lesions may be arranged in a sporotrichoid pattern. Deep lesions may also be associated with osteomyelitis and septic arthritis.
M. haemophilum
M haemophilum is a fastidious organism that requires iron and hemin to grow. It has structural similarities with M leprae. The cutaneous clinical spectrum includes a variety of skin lesions.
Most often, it presents with erythematous or violaceous papules, pustules, nodules, or plaques, some of which evolve into necrotic abscesses or deep-seated ulcerations. [71]
This organism preferentially grows at 30°C (86°F), explaining the predilection of lesions to locate on the extremities, particularly over joints. In immunosuppressed hosts, contiguous spread of the infection can be complicated with septic arthritis and osteomyelitis. In immunocompetent children, this infection usually presents as isolated cervical, submandibular, or inguinal lymphadenitis. [72]
M avium-intracellulare (MAC)
It is an opportunistic infection in patients with AIDS, occurring during the terminal stage and causing disseminated disease. Cutaneous infections are rarely reported in immunocompetent hosts. [73] It can present with primary cutaneous manifestations after trauma, surgery, or secondary to a disseminated infection. The clinical spectrum includes papulopustular, nodular lesions with a sporotrichoid pattern, which can progress to verrucous ulcers, inflammatory pseudotumors, sinus tracts, and abscesses. [74]
Rapidly growing mycobacteria
This group of NTM includes M chelonae, M abscessus, and M fortuitum, often referred together as the fortuitum complex. M abscessus was first identified in a patient with a knee infection and subcutaneous abscesses in 1950. [75] Posttraumatic infections, catheter-associated infections, postsurgical infections (breast implants, liposuction), and infections post cosmetic procedures (mesotherapy, fillers injections) can result in localized cutaneous infection. [76]
The clinical manifestations of cutaneous involvement include papules, violaceous nodules, abscesses, cellulitis, sinus tracts, subcutaneous nodules (pseudoerythema nodosum), and ulcerations. M chelonae and M abscessus usually present with multiple skin lesions, while M fortuitum tends to present as a single lesion. [77]
Less common forms of presentation
Gastrointestinal tract disease caused by MAC is well-described in the literature and can present as part of a disseminated illness. Findings can include hepatosplenomegaly, colonic ulcers, mesenteric involvement, and abscess formation. [78]
Musculoskeletal disease is not a common presentation for NTM, but all atypical mycobacteria have the potential to cause musculoskeletal infection and it is important to recognize this possibility if clinically plausible. [79]
Complications
Scarring and nerve damage can occur from long-standing untreated infections. Deep-seated infections, if left untreated, can progress to bone involvement with osteomyelitis as a consequence.
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Mycobacterium marinum is an atypical mycobacteria found in water with a wide range of temperatures and salinities
