CASE REPORT

Mycobacterium avium-intracellulare pulmonary infectioncomplicated by cutaneous leukocytoclastic vasculitis in a womanwith anorexia nervosa

T. L. Walsh • V. Baca • S. S. Stalling •

A. A. Natalie • P. J. Veldkamp

Received: 11 November 2013 / Accepted: 13 December 2013

� Springer-Verlag Berlin Heidelberg 2013

Abstract A 53-year-old Caucasian woman with a his-

tory of anorexia nervosa developed a bilateral lower

extremity rash comprised of palpable red to violaceous,

sub-centimeter papular lesions that increased in quantity

rapidly. She also noted a 2-month history of non-pro-

ductive cough. Imaging modalities revealed a thin-walled

cavitary lesion in the right lung apex and scattered

nodular opacities. Acid fast bacilli (AFB) were found in

sputum and subsequently identified by culture as Myco-

bacterium avium-intracellulare (MAI). Punch biopsies of

her skin lesions yielded a histological diagnosis of small-

to-medium vessel vasculitis. Stains and cultures for

organisms were negative. Her skin lesions resolved

quickly after the initiation of antimicrobial therapy for

MAI. Hypersensitivity vasculitis associated with an

atypical mycobacterial infection is unusual. The postu-

lated underlying mechanism is the deposit of immune

complexes and not the bacillus itself. While cutaneous

leukocytoclastic vasculitis (CLV) due to MAI is certainly

a rare entity, it should be entertained in patients with

vasculitic skin lesions and a concomitant pulmonary

disease.

Keywords Mycobacterium avium-intracellulare �Mycobacteria � Leukocytoclastic � Vasculitis

Abbreviations

AFB Acid fast bacilli

ANA Anti-nuclear antibody

ANCA Anti-neutrophil cytoplasmic antibody

BMI Body mass index

CLV Cutaneous leukocytoclastic vasculitis

cm Centimeter

CT Computed tomography

dL Deciliter

ELISA Enzyme-linked immunosorbent assay

gm Gram

HIV Human immunodeficiency virus

kg Kilogram

NTM Non-tubercular mycobacteria

MAI Mycobacterium avium-intracellulare

mg Milligram

mm Millimeter

mm3 Cubic millimeter

MPO Myeloperoxidase

pANCA Perinuclear anti-neutrophil cytoplasmic

antibody

TB Mycobacterium tuberculosis

T. L. Walsh (&) � P. J. Veldkamp

Division of Infectious Diseases, University of Pittsburgh

Medical Center, Falk Medical Building, Suite 3A,

3601 Fifth Avenue, Pittsburgh, PA 15213, USA

e-mail: walshtl@upmc.edu

P. J. Veldkamp

e-mail: pjv4@pitt.edu

V. Baca

Department of Medicine, Allegheny General Hospital,

Internal Medicine Residency Department, 7th Floor,

320 East North Avenue, Pittsburgh, PA 15212, USA

e-mail: vbaca02@gmail.com

S. S. Stalling � A. A. Natalie

Department of Dermatology, University of Pittsburgh

Medical Center, Presbyterian South Tower, Suite 3880,

200 Lothrop Street, Pittsburgh, PA 15213, USA

e-mail: stallingss@upmc.edu

A. A. Natalie

e-mail: natalieaa@upmc.edu

123

Infection

DOI 10.1007/s15010-013-0574-0

Background

Mycobacteria are capable of producing cutaneous abnor-

malities directly through skin infiltration or indirectly via

hypersensitivity reaction causing a vasculitis [1]. Non-

tubercular mycobacteria (NTM), including Mycobacterium

avium-intracellulare (MAI), are organisms that are found

ubiquitously in the environment [2]. They occasionally

cause skin disease [3–8] through direct inoculation, con-

tiguous spread, or hematogenous routes. Cutaneous leuk-

ocytoclastic vasculitis (CLV) involves the deposition of

circulating immune complexes in the small vessels [9].

Infections are implicated in \10 % of cases of CLV [10–

13]. While the association between CLV and Mycobacte-

rium tuberculosis (TB) infection is well known, atypical

mycobacteria are very rarely associated with CLV. Here,

we describe an unusual case of MAI infection leading to

this cutaneous hypersensitivity reaction.

Case presentation

A 53-year-old Caucasian woman with a history of anorexia

nervosa and iron deficiency anemia presented to her pri-

mary care physician for the evaluation of a non-pruritic

bilateral lower extremity rash. Her rash started 1 week

prior to presentation and was initially comprised of pal-

pable, red to violaceous, non-blanching sub-centimeter

lesions. The lesions began on her ankles and calves and

extended proximally to her anterior and posterior thighs

and groin. Within 3 days, the lesions increased in number

to 50 on each lower extremity. She had also noted a non-

productive cough for the previous 2 months that was

present only at night and was worse when laying down flat.

The cough was not associated with fever or chills. She had

no night sweats or hemoptysis. She had no chest pain,

abdominal pain, nausea, loose stool, or lymphadenopathy.

While she suffered from anorexia nervosa, her weight had

been unchanged for over a year.

Her home medications included ergocalciferol, ferrous

sulfate, fluvoxamine, clonazepam, a multivitamin, and

weekly alendronate. None of these medications were new,

and she reported not using any over-the-counter

medications.

She lived at home with her husband. She did not use

tobacco, alcohol, or illicit drugs. Her only international

travel was to Mexico nearly 10 years ago. Her only outdoor

hobby was cycling. She did not use a hot tub or sauna. She

had no family history of autoimmune or pulmonary

disease.

Upon physical examination, the patient appeared thin

and anxious. Her blood pressure was 90/60 mm Hg, pulse

66 beats per minute, temperature 35.9� Celsius, and res-

piration 12 breaths per minute. She weighed 36 kg and had

a body mass index (BMI) of 14.2 (normal range 18.5–25).

There were no oral ulcerations or lymphadenopathy. Pul-

monary examination revealed clear lungs without rhonchi.

She had 2–4-mm round, non-blanching, red to violaceous

purpuric macules and papules on her bilateral calves,

popliteal fossae, and inner thighs with spread proximally to

her groin, with areas of confluence along her posterior

thighs (Fig. 1). There were approximately 50 lesions on

each extremity without involvement of her soles, upper

extremities, abdomen, or torso. There were no signs of joint

effusions or arthritis. The examination was otherwise

normal.

The patient’s white blood cell count was 7,200 cells/

mm3 [reference range (ref.) 3,800–10,600] with 74 %

neutrophils, 13 % lymphocytes, 10 % monocytes, 2 %

eosinophils, and 1 % basophils. Albumin was 3.1 gm/dL

(ref. 3.4–5.0). Human immunodeficiency virus (HIV)

enzyme-linked immunosorbent assay (ELISA) screen was

negative. Urinalysis revealed no blood, protein, glucose,

ketones, or bacteria. Other routine laboratory test results,

including platelet count, hemoglobin, serum creatinine,

liver enzymes, erythrocyte sediment rate, and C-reactive

protein, were normal.

A chest radiograph revealed a thin-walled cavitary focus

in the right lung apex, measuring 3 cm in diameter (Fig. 2),

Fig. 1 Photograph demonstrating round, non-blanching, red to

violaceous purpuric macules and papules on the lower extremities

T. L. Walsh et al.

123

with surrounding parenchymal opacities. There were left

upper lobe nodular opacities with patchy consolidation also

present.

High-resolution computed tomography (CT) scan con-

firmed the consolidation involving the apical segment of

the right upper lobe associated with bronchiectasis and

multiple ‘‘tree-in-bud’’ centrilobular nodules in the right

upper lobe (Fig. 3). Areas of focal nodular consolidation in

both lower lobes consistent with inflammatory airway

nodules were present.

The patient underwent punch biopsy of a lesion from

each inner thigh for hematoxylin and eosin as well as direct

immunofluorescence staining. Pathology revealed fibrinoid

degeneration of small-to-medium blood vessel walls with

perivascular neutrophil-rich infiltrate and karyorrhexis.

Additionally, the inflammatory infiltrate had admixed

eosinophils (Fig. 4). Gram, acid fast bacilli (AFB), and

Fig. 2 Chest radiograph revealing a thin-walled cavitary focus in the

right lung apex (arrow)

Fig. 3 High-resolution computed tomography (CT) scan revealing an

area of consolidation involving the apical segment of the right upper

lobe (arrow) associated with bronchiectasis and multiple ‘‘tree-in-

bud’’ centrilobular nodules in the right upper lobe

Fig. 4 Punch biopsy with hematoxylin and eosin staining of a lower

extremity lesion visualized at 209 magnification depicting karyor-

rhexis (asterisk), fibrinoid degeneration of blood vessels (arrow), and

extravasated red blood cells with a neutrophilic-rich infiltrate

consistent with leukocytoclastic vasculitis

Fig. 5 Photograph demonstrating increase in the amount of lesions

with areas of coalescence into plaques on the posterior aspects of the

leg

Mycobacterium avium-intracellulare pulmonary infection

123

Grocott–Gomori’s methenamine silver stains were negative

for microorganisms. Immunofluorescence staining was

negative for complement C3, immunoglobulin G (IgG),

and immunoglobulin A (IgA) deposition. The findings

were consistent with a small-to-medium vessel leukocyto-

clastic vasculitis of the papillary dermal vessels, as well as

vessels deeper in the reticular dermis and panniculus.

Three consecutive sputum smears were positive for AFB

and grew on culture media on day 9. DNA probe for MAI

complex was positive, while it was negative for TB com-

plex. Histoplasma urinary antigen was negative. The total

helper CD4? T cell count was 272/mm3 (ref. 441–2,156),

representing 45 % (ref. 28–63) of the total T-cell popula-

tion. Anti-neutrophil cytoplasmic antibody (ANCA), anti-

nuclear antibody (ANA), and cryoglobulin screens were

unremarkable. Rheumatoid factor as well as complement

C3 and C4 levels were within normal limits. Hepatitis C

antibody and hepatitis B surface antigen were negative.

Within 72 h after her presentation, the amount of lesions

had increased dramatically to [100 on each lower

extremity and there were areas of coalescence on the

posterior aspects of her legs (Fig. 5).

Therapy was commenced with azithromycin 250 mg

daily, rifampin 300 mg daily, and ethambutol 600 mg

daily. Other than these antimicrobial agents, she was

placed on no other therapy for her leukocytoclastic vas-

culitis. Physical examination at her outpatient clinic visit

2 weeks after the initiation of antimicrobial therapy

revealed near complete resolution of her lower extremity

lesions. Her cough slowly improved as well. Within

6 weeks of the initiation of therapy, all of her lesions had

resolved. The plan was to obtain monthly sputum AFB

cultures and to continue her antimicrobial regimen for

12 months after the sterilization of her sputum cultures.

Discussion

There are two types of skin manifestations associated with

mycobacteriosis [1]: (1) direct lesions, where the bacillus is

present by (a) direct inoculation, (b) through contiguous

infection, or (c) via hematogenous dissemination, and (2)

hypersensitivity vasculitis, where the microorganism is not

present and where the proposed pathogenic mechanism is

the deposit of immune complexes in the walls of the small

vessels.

MAI is ubiquitous in the environment [2], but cutaneous

infections due to direct inoculation are unusual. When it does

occur, there are a variety of appearances, such as multiple

ulcers [3], abscesses [4], painless nodules, plaques resem-

bling those of leprosy [5], ecthyma-like lesions, prurigo

nodularis-like lesions [6], erythematous masses [7], and

rosacea-like lesions [8]. These reports predominantly occur

in immunosuppressed patients [8]. On rare occasions, cuta-

neous lesions may be present with disseminated disease or

the involvement of deeper structures; this, too, typically

occurs in immunocompromised hosts [9, 10].

According to the International Chapel Hill Consensus

Conference classification system, leukocytoclastic vascu-

litis is classified as a small-vessel vasculitis [11]. Histo-

logically, the characteristic lesion is an angiocentric

inflammatory process associated with neutrophil fragmen-

tation and fibrinoid necrosis. It occurs most frequently in

small blood vessels, and the pathophysiological mechanism

remains uncertain but is believed to involve the deposition

of immune complexes that activate the complement path-

ways, leading to the expression of adhesion molecules and

the production of chemotactic factors and vasoactive sub-

stances that cause the accumulation of polymorphonuclear

cells and release of lysosomal enzymes, which leads to

vessel wall injury [12]. Thus, it is characterized as a

hypersensitivity vasculitis, typically limited to cutaneous

involvement (80 % of cases).

CLV can be idiopathic or secondary to infection, med-

ications, collagen vascular diseases, or neoplasm. Infec-

tions and medications each cause approximately 10 % of

cutaneous vasculitis lesions. Over 60 % of cases of CLV

are idiopathic [12–15]. Various infectious agents are

associated with vasculitis. CLV with mycobacterial infec-

tions other than TB is very rare. In cases of CLV, myco-

bacteria are not found in the vessel wall, which

differentiates it from cutaneous mycobacterial infections,

in which microorganisms are seen in the biopsy samples

[12–15]. There have been reports of rifampicin-dependent

antibody and then immune complex formation as another

possible mechanism for CLV in patients with mycobacte-

rial infections who developed CLV after the initiation of

therapy with rifampicin. In cases of mycobacterium-related

vasculitis, the skin lesions improve with the initiation of

the treatment regimen targeted against the underlying

mycobacterial infection, without the need for specific anti-

inflammatory therapy, as demonstrated in the case pre-

sented here [13–15].

Most cases reports of CLV associated with mycobacte-

rial infections are due to TB. To our knowledge, there have

been only two previous reports of vasculitic skin lesions

associated with MAI [16, 17]. In 2004, Yano reported a

case of a 57-year-old woman with a history of pulmonary

MAI infection that had been treated with various anti-

mycobacterial agents for 11 years prior to the development

of bloody sputum, high-grade fever, palpable pruritic

lesions on the bilateral lower extremities, and microscopic

hematuria [16]. She was diagnosed with Henoch–Schon-

lein purpura associated with pulmonary MAI. In this case,

the purpura did not resolve until prednisolone was added to

the regimen.

T. L. Walsh et al.

123

In 2005, Chaiamnuay and Heck reported a 75-year-old

woman with intermittent chronic non-productive cough,

migratory polyarthritis, and microscopic hematuria [17].

She was found to have a cavitary lesion in the right upper

lung field and was diagnosed with MAI infection after right

thoracoscopic wedge resection. Two months after the dis-

continuation of MAI treatment for 18 months, she devel-

oped hemoptysis, migratory polyarthritis, worsening renal

function, microscopic hematuria, and purpuric skin lesions.

Perinuclear anti-neutrophil cytoplasmic antibodies (pAN-

CA) and myeloperoxidase (MPO) levels were elevated.

Skin biopsy revealed necrotizing vasculitis of the small and

medium arteries with eosinophils. It was felt that alveolar

hemorrhage secondary to alveolar pANCA vasculitis

associated with MAI infection was the most likely cause of

the hemoptysis.

Our patient’s only known risk factor for mycobacterial

infection prior to her presentation was her history of

anorexia nervosa. Usually, infection caused by NTM

occurs in those patients with serious underlying pul-

monary disease or who have debilitating comorbidities.

She was subsequently found to have changes consistent

with bronchiectasis on CT imaging [18]. It has been

suggested that patients with bronchiectasis, as with other

chronic lung diseases, are predisposed to infection with

these organisms. However, many NTM cases have not

been associated with any underlying diseases. In some

cases, it is difficult to determine whether the lung dis-

eases are the cause or the result of NTM. Anorexia

nervosa may predispose to unusual infections with

organisms of low pathogenicity. It is suspected that the

dietary indiscretion of anorexia nervosa patients may

cause sufficient cell-mediated immunodeficiency to

change colonization by low-virulence mycobacterium to

actual infection and invasive disease [19]. Therefore, our

patient had two underlying conditions, malnutrition and

underlying structural lung disease, which may have

placed her at increased risk of the development of MAI

infection.

In summary, while CLV due to MAI is certainly a rare

entity, it should be entertained in patients with vasculitic

skin lesions and a concomitant pulmonary disease. Infec-

tious disease, dermatology, and rheumatology practitioners

should be aware of this unusual association.

Conflict of interest On behalf of all authors, the corresponding

author states that there is no conflict of interest.

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