mycobacterium avium-intracellulare pulmonary infection complicated by cutaneous leukocytoclastic...
TRANSCRIPT
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: [email protected]
P. J. Veldkamp
e-mail: [email protected]
V. Baca
Department of Medicine, Allegheny General Hospital,
Internal Medicine Residency Department, 7th Floor,
320 East North Avenue, Pittsburgh, PA 15212, USA
e-mail: [email protected]
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: [email protected]
A. A. Natalie
e-mail: [email protected]
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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