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 Table of Contents  
Year : 2022  |  Volume : 11  |  Issue : 1  |  Page : 120-122

Ethambutol-induced bullous skin lesions in mycobacterium kansasii lung infection

1 Department of Pulmonary and Critical Care; Salem VA Medical Center, Salem, VA; Virginia Tech Carilion School of Medicine, Roanoke, Virginia, USA
2 Department of Pulmonary and Critical Care; Salem VA Medical Center, Salem, VA, USA
3 Department of Infectious Disease, Salem VA Medical Center, Salem, VA, USA
4 Salem VA Medical Center, Salem, VA; Virginia Tech Carilion School of Medicine, Roanoke, Virginia; Department of Infectious Disease, Salem VA Medical Center, Salem, VA, USA

Date of Submission06-Oct-2021
Date of Decision27-Oct-2021
Date of Acceptance29-Dec-2021
Date of Web Publication12-Mar-2022

Correspondence Address:
Venkateswara K Kollipara
1970, Roanoke Blvd, Department of Pulmonary, Salem Veterans Affairs Medical Center, Salem, VA 24153
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijmy.ijmy_204_21

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Mycobacterium kansasii is the second most common cause of nontuberculous mycobacterial (NTM) lung disease after Mycobacterium avium complex infection in the United States.[1] The first-line therapy for M. kansasii is a three-drug regimen including rifampin, isoniazid, and ethambutol. We present a case of a patient with pulmonary M. kansasii who developed bullous skin lesions while receiving this regimen and again after rechallenge with ethambutol. In patients with intolerance to one of the first-line antibiotics, a multidisciplinary team approach to starting second-line agents is needed. Ethambutol should be included in the differential diagnosis of drug-induced bullous skin lesions in treated patients with NTM, who develop new onset rash with blisters or ulceration.

Keywords: Direct immunofluorescent, drug-induced skin reactions, ethambutol, Mycobacterium kansasii, pemphigus vulgaris, suprabasilar bullous skin lesion

How to cite this article:
Kollipara VK, Horowitz M, Lantz J, Nagy-Agren S. Ethambutol-induced bullous skin lesions in mycobacterium kansasii lung infection. Int J Mycobacteriol 2022;11:120-2

How to cite this URL:
Kollipara VK, Horowitz M, Lantz J, Nagy-Agren S. Ethambutol-induced bullous skin lesions in mycobacterium kansasii lung infection. Int J Mycobacteriol [serial online] 2022 [cited 2022 May 21];11:120-2. Available from: https://www.ijmyco.org/text.asp?2022/11/1/120/339504

  Introduction Top

M. kansasii is an insidious acid-fast bacillus which has a similar presentation to Mycobacterium tuberculosis. Local water supplies are the major reservoir for the transmission in immunocompromised patients.[1] For susceptible isolates, a rifampin based 3-drug regimen including ethambutol and either isoniazid (INH) or macrolide is the cornerstone therapy.[1] A second-line regimen should be considered based on response, resistance patterns, and side effect profile of first-line medications through a multidisciplinary team approach.[2] Determining which agent is the inciting drug in the context of an adverse reaction during the treatment for mycobacterial disease is often difficult because of the multidrug regimens utilized, but discontinuation of therapy and reintroducing agents stepwise may help identify the causative agent. The development of blistering lesions may be life-threatening and mandate discontinuation of the offending drug. We present a case of ethambutol-induced bullous skin lesions in a patient with M. kansasii lung infection.

  Case Report Top

A 56-year-old HIV-negative male with a medical history of severe chronic obstructive pulmonary disease (COPD), pulmonary sarcoidosis, bronchiectasis, past tobacco use, and coronary artery disease presented with worsening dyspnea, fever, and fatigue. He was maintained on as needed low dose prednisone. Physical examination findings included tachypnea and diffuse expiratory wheeze. Chest computed tomography scan revealed right middle lobe infiltrate with interlobular thickening and pulmonary nodules. Sputum demonstrated 3+ acid-fast bacilli that were speciated as M. kansasii. INH, rifampin, and ethambutol were initiated, and then rifampin was switched to clarithromycin to avoid a potential drug interaction with ranolazine. Respiratory symptoms improved, and he was discharged in the stable condition.

The patient presented 6 weeks later with oral and truncal blisters, which started in the right upper buccal mucosa [Figure 1] and easily ruptured. Antimicrobials were held, and a punch biopsy of a truncal skin ulcer was obtained. Pathology revealed suprabasilar bulla with acantholysis (loss of intercellular cohesion between keratinocytes), and separation of epidermis from dermis, consistent with pemphigus [Figure 2]. Specimens sent for direct immunofluorescence (DIF) lacked epidermis to allow confirmation of pemphigus. HSV and VZV immunostains were negative. INH and ethambutol were considered the most likely inciting antimycobacterial agents by the dermatology consultant and were discontinued. He was started on prednisone 60 mg daily for 2 weeks with the resolution of dermal lesions. His antimycobacterial regimen was changed to rifampin, clarithromycin, and inhaled amikacin.
Figure 1: Right upper buccal mucosa lesion

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Figure 2: H and E stain (×10) of punch of the skin showed suprabasilar bulla with acantholysis and separation of the epidermis from dermis consistent with pemphigus

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He was readmitted 5 weeks later with worsening dyspnea, attributed to amikacin-induced bronchospasm, which was discontinued. He was rechallenged with ethambutol, as his previous drug reaction was considered relatively more likely due to INH. He again developed bullous skin rash of his oral cavity and trunk. Ethambutol was discontinued, and treatment adjusted to rifampin, azithromycin, and intravenous amikacin for 2 months. He was then continued on rifampin, azithromycin, and linezolid for 16 months, with negative serial sputum AFB cultures. There was no recurrence of mycobacterial infection or skin lesions off therapy for 18 months.

  Discussion Top

M. kansasii is typically susceptible to anti-tuberculous agents, with rifampin the cornerstone of therapy. In patients with rifampin-susceptible M. kansasii pulmonary disease, a regimen of rifampin, ethambutol, and either INH or macrolide is recommended for a duration of at least 12 months.[1] Adverse reactions, including drug-induced blistering, may interfere with treatment.

Pemphigus is a group of life-threatening blistering disorders characterized by acantholysis that results in the formation of intraepithelial blisters in the mucous membranes and skin. Acantholysis is induced by the binding of circulating autoantibodies to intercellular adhesion molecules. The differential for suprabasilar bullous lesions includes pemphigus vulgaris (PV), bullous pemphigoid, Pemphigus vegetans, Hailey Hailey, Grover's disease, and Darier's disease were unlikely clinically.

Drug-induced bullous pemphigoid has been reported with INH, rifampin, loop diuretics, spironolactone, angiotensin-converting enzyme inhibitors, penicillins, beta blockers, and antiepileptics,[3],[4] etanercept, and sulfasalazine.

Drug-induced biochemical and/or immunological reactions may contribute to the development of acantholysis in drug-induced pemphigus (DIP). These medications can be classified based on their chemical structure, as thiol drugs, phenol drugs, and nonthiol/phenol drugs. Most of the DIP is associated with thiol compounds in the drug, but many nonthiol drugs contain sulfur in their molecules. Such drugs have been termed “masked thiols,” as the sulfur may undergo change to active thiol groups.[5] Potential mechanisms for DIP include effects on enzymes that mediate keratinocyte aggregation, production of IgG autoantibody against desmoglein 1 and 3, and stimulation of neoantigen formation.

The types of pemphigus are distinguished by clinical features, associated autoantigens, and laboratory findings: IgG autoantibodies against desmoglein 3 are the characteristic of mucosal PV; autoantibodies against desmoglein 1 have been linked to pemphigus foliaceus; and autoantibodies to desmoglein 1 and desmoglein 3 have been linked to mucocutaneous PV.[6] The amino-terminal portions of desmogleins are epitopes for pathogenicity as evidenced by studies that demonstrate IgG directed against an amino-terminal recombinant fraction of desmoglein 3.[6] Skin biopsy in PV demonstrates suprabasilar bulla with acantholysis and separation of epidermis from dermis, and DIF shows intercellular deposits of IgG and C3 deposits. DIF and in direct immunofluorescence (DIF) studies aid in the diagnosis but can be negative in DIP. In a case series of 93 patients with pemphigus, the normal pattern on DIF was seen in 70% of DIP compared to 16% in idiopathic pemphigus.[7]

The development of blistering skin lesions in our patient treated for M. kansasii with a regimen including ethambutol, with recurrence following ethambutol rechallenge, strongly implicates ethambutol as the etiology. He responded to prednisone and discontinuation of ethambutol. In addition to bullous skin lesions,[8] additional skin reactions noted with ethambutol include lichenoid eruptions,[8] toxic epidermal necrolysis,[9] and hypersensitivity reactions[10] and ashy dermatosis-like pigmentation.[11] In patients treated with ethambutol, a new bullous skin eruption should raise concern for pemphigus or other serious adverse drug reaction, which mandates discontinuation, and if necessary, vigilant stepwise reintroduction of potentially responsible medications, as guided by a multidisciplinary team.


Jennifer Blankenship the librarian for assistance with literature.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Daley CL, Iaccarino JM, Lange C, Cambau E, Wallace RJ Jr., Andrejak C, et al. Treatment of nontuberculous mycobacterial pulmonary disease: An official ATS/ERS/ESCMID/IDSA clinical practice guideline. Eur Respir J 2020;56:2000535.  Back to cited text no. 1
Rajendran P, Padmapriyadarsini C, Mondal R. Nontuberculous mycobacterium: An emerging pathogen: Indian perspective. Int J Mycobacteriol 2021;10:217-27.  Back to cited text no. 2
[PUBMED]  [Full text]  
Lloyd-Lavery A, Chi CC, Wojnarowska F, Taghipour K. The associations between bullous pemphigoid and drug use: A UK case-control study. JAMA Dermatol 2013;149:58-62.  Back to cited text no. 3
Civatte J. Drug-induced pemphigus diseases. Dermatol Monatsschr 1989;175:1-7.  Back to cited text no. 4
Brenner S, Bialy-Golan A, Ruocco V. Drug-induced pemphigus. Clinics in Dermatology 1998;163:93-7. [doi: 10.1016/S0738-081X(98)00010-8].  Back to cited text no. 5
Bhol K, Natarajan K, Nagarwalla N, Mohimen A, Aoki V, Ahmed AR. Correlation of peptide specificity and IgG subclass with pathogenic and nonpathogenic autoantibodies in pemphigus vulgaris: A model for autoimmunity. Proc Natl Acad Sci U S A 1995;92:5239.  Back to cited text no. 6
Maruani A, Machet MC, Carlotti A, Giraudeau B, Vaillant L, Machet L. Immunostaining with antibodies to desmoglein provides the diagnosis of drug-induced pemphigus and allows prediction of outcome. Am J Clin Pathol 2008;130:369-74.  Back to cited text no. 7
Akrout I, Tangour E, Fenniche S, Hassene H, Feki L, Greb D, et al. Ethambutol induced bullous and lichenoid skin eruptions. Eur Res J 2011;38:p4412.  Back to cited text no. 8
Pegram PS Jr., Mountz JD, O'Bar PR. Ethambutol-induced toxic epidermal necrolysis. Arch Intern Med 1981;141:1677-8.  Back to cited text no. 9
Cernadas JR, Santos N, Pinto C, Mota PC, Castells M. Hypersensitivity reaction and tolerance induction to ethambutol. Case Rep Med 2013;2013:208797.  Back to cited text no. 10
Srivastava N, Solanki LS, Chand S, Garbyal RS, Singh S. Ashy dermatosis-like pigmentation due to ethambutol. Indian J Dermatol Venereol Leprol 2008;74:281-2.  Back to cited text no. 11
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