Report
Varicella-zoster virus (VZV) and alpha 1 antitrypsin: a fatal
outcome in a patient affected by endemic pemphigus
foliaceus
Ana Maria Abreu Velez1, MD, PhD, Bruce R. Smoller2, MD, Weiqing Gao3, MD,
Hans E. Grossniklaus3, MD, Zhe Jiao4, PhD, Luis F. Arias5, MD,
Samuel C. Dudley Jr6, MD, PhD, and Michael S. Howard1, MD
1
Georgia Dermatopathology Associates,
Atlanta, GA, USA, 2Department of
Pathology, University of Arkansas for
Medical Sciences, Little Rock, AR,
USA, 3Department of Ophthalmology,
Emory University Medical Center,
Atlanta, GA, USA, 4Department of
Cardiology, Emory University Medical
Center, Atlanta, GA, USA, 5Department
of Pathology, Faculty of Medicine,
University of Antioquia, Medellin,
Colombia, SA, and 6Section of
Cardiology, University of Illinois at
Chicago Medical, Chicago, IL USA
Correspondence
Dr Ana Maria Abreu Velez, MD, PhD
Georgia Dermatopathology Associates
1534 North Decatur Road
NE Suite 206
Atlanta
GA 30307
USA
E-mail: [email protected]
Funding sources: Georgia
Dermatopathology Associates (GDA;
Dr Howard) and the Embassy of Japan
in Colombia, Medellin, Colombia, SA
(Dr Abreu Velez).
Conflict of interest: none.
Abstract
Background Herpes virus infections are well known infectious complications of pemphigus
and bullous pemphigoid. We describe pathologic findings utilizing autopsy tissue from
several organs from a patient affected by a new variant of endemic pemphigus in El Bagre,
Colombia, South America.
Case report We describe a patient by a new variant of endemic pemphigus foliaceus from
El Bagre that was receiving high-dosage immunosuppressants when hospitalized and died
suddenly following contact with a second patient affected by chicken pox.
Materials and methods We performed studies utilizing hematoxylin and eosin, immunohistochemistry, and direct immunofluorescence techniques on tissues from several organs.
Results We detected the presence of varicella zoster virus, as well as strong positivity for
a-1 antitrypsin in the heart, kidneys, spleen, liver, skin, brain, lungs, pancreas, small and
large intestines, and skeletal muscle. In regard to structural damage in the kidney and
heart, we believe the observed damage is associated with the presence of autoantibodies
to these organs, since both of them are rich in plakins and El Bagre-EPF patients present
significant antibodies to plakin molecules.
Conclusion In patients with endemic pemphigus foliaceus, we recommend complete isolation of the patient when receiving high dosages of systemic immunosuppressive agents.
We further suggest the clinical possibility of a synergistic, fatal interaction between active
pemphigus foliaceus, varicella zoster virus, herpes simplex virus, immunosuppressive
agents, and a systemic activation of a-1 antitrypsin. Thus, we suggest adequate bed
spacing, barrier nursing, and preventative testing for a-1 antitrypsin activation are
warranted in these patients to address these complications.
Introduction
Multiple environmental factors have been implicated in
the pathogenesis and exacerbation of acantholytic skin
diseases, including drugs, diet, burns, x-rays, ultraviolet
radiation, neoplasms, and infections.1 Several reports
document clinical aggravation of pemphigus vulgaris
after exposure to herpes simplex virus (HSV), varicellazoster virus (VZV), Epstein-Barr virus, cytomegalovirus,
and human herpes virus-8 infections.1–9 Many patients
affected by a new variant of endemic pemphigus foliacª 2012 The International Society of Dermatology
eus (EPF) in El Bagre, Colombia (El Bagre-EPF), live in
isolated rural areas, limiting their exposure to selected
infectious agents.10–15 Many of these patients lack
vaccination against common childhood infections, such
as measles. We report a patient affected by El BagreEPF. Classically, due to limited therapeutic options in
El Bagre, patients affected by generalized El Bagre-EPF
are transferred to a reference hospital in Medellin,
45 minutes away by airplane.10–15 The patients are
typically thus hospitalized, and undergo therapeutic
baths in common tubs without special isolation or
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sterilization. In addition, patients with generalized bullous diseases receiving high dosages of immunosuppressants are often hospitalized in common rooms alongside
patients with multiple other diseases and without preventive laboratory testing before initiation of immunosuppressive therapy.
Report
We report a 38-year-old Mestizo male presenting with
generalized El Bagre-EPF who was hospitalized in Medellin after being referred from the endemic area in El Bagre.
The initial physical examination revealed an ocular ulcer,
clinically interpreted to be herpes virus infection (without
confirmatory testing). The patient lived in the endemic
area and displayed clinical and histopathological features
of EPF, as previously described.10–15 The patient also
demonstrated direct (DIF) and indirect immunofluorescence skin epidermal staining between keratinocytes, consistent with previously described EPF diagnostic criteria.
The patient’s serum contained antibodies to human total
IgG and IgG4 against skin epidermal keratinocyte cell
junctions.10–15 The patient’s serum also immunoprecipitated a Con-A affinity-purified bovine tryptic 45-kDa
fragment of desmoglein 1 (Dsg1), and his serum also
tested positive by: (1) immunoblotting for reactivity Dsg1
and plakin molecules; and (2) diagnostic ELISA testing,
as previously described.10–15 During the initial hospitalization, the patient denied systemic symptoms. No pretreatment infectious disease testing was obtained before
initiation of high-dosage immunosuppressant therapy. An
initial dose of 15 mg/d of prednisone was initiated,
increasing up to 120 mg/d, with the addition at that time
of azathioprine at 50 mg/d. During the course of the
hospitalization, the patient was receiving these dosages of
immunosuppressants without isolation from other
patients. During the course of the hospitalization, the
patient was also diagnosed with acquired molluscum contagiosum, in addition to furunculosis. The patient was
thus started on empiric treatment for furunculosis with
ciprofloxacin and topical bacitracin, without culture confirmation. The ‘‘ocular herpes’’ lesion was treated with
topical acyclovir. Several days after the initiation of the
immunosuppressive therapy, tests for tuberculosis and
stool ova and parasite tests were negative. The furunculosis
lesions were drained, and the lesions improved. The molluscum lesions were curettaged. Later, the patient was
diagnosed with cellulitis of the thigh; prostaphlin was initiated following culture of the lesions, which demonstrated
positivity for Staphylococcus aureus. During the course of
the hospitalization, a urinary tract infection was also
reported in the patient, again without culture confirmation.
The patient was subsequently diagnosed with diabetes
International Journal of Dermatology 2012, 51, 809–816
Abreu Velez et al.
mellitus secondary to the corticosteroid therapy, and insulin was initiated. Days after, the patient clinically displayed
signs of oral and esophageal candidiasis infection, and topical Nystatin was initiated, also empirically. Later, the
patient reported abdominal pain, and a renal computerized
axial tomography scan demonstrated urolithiasis and hydronephrosis of the left kidney. Serum renal studies at this
time showed increased creatinine and blood urea nitrogen.
The patient was hospitalized for a total period of four months and received high doses of systemic immunosuppressors throughout the hospitalization.
Near the end of this hospital course, the patient presented abruptly with numerous 2–4 mm vesicles and pustules with central crusting and small ulcerations over most
of his body (Figs. 1–3). Within 24 hours of the onset of
these lesions, an erythematous maculopapular eruption
developed on the upper trunk and face. The papules
rapidly evolved into clear vesicles, centered on an erythematous base. Systemic acyclovir at 0.3 mg/kg/d was administered. Within the next 24 hours, the vesicles became
cloudy and pruritus developed. A diagnosis of chicken pox/
varicella was made based upon the presence of a similar
outbreak throughout the ward. No confirmatory laboratory tests were performed. The patient died two days after
the onset of the initial vesiculopustular cutaneous eruption,
demonstrating clinical features of disseminated intravascular coagulation. Biopsies were taken of the maculopapular
skin lesions at autopsy and the collected tissue subsequently maintained in both buffered formalin and fresh
frozen in OCT for hematoxylin and eosin (H&E), DIF and
immunohistochemistry (IHC) studies.
Hematoxylin and eosin
Routine H&E staining was performed, and examination
of the skin tissue sections revealed epidermal keratinocytic cytological changes of nuclear multinucleation with
chromatin margination and cytoplasmic ballooning
degeneration (Fig. 2f). In addition, mild epidermal atrophy was seen, with a weak interface infiltrate of lymphocytes and histiocytes. Neutrophils and eosinophils were
rare. No vasculitis was observed, but large thrombi were
detected in several organ blood vessels. The heart and
kidney demonstrated significant structural damage
(Fig. 2c and e).
Direct and indirect immunofluorescence
Cryosections were prepared from skin and other organs,
as reported elsewhere.16,17 In order to co-localize selected
neural structures, we also used antibodies against protein
gene product 9.5 (PPG 9.5; Dako, Carpinteria, CA, USA).
Intercellular epidermal keratinocyte staining diagnostic of
EPF was weak, likely secondary due to the significant, pre
mortem immunosuppressant therapy. However, we were
ª 2012 The International Society of Dermatology
Abreu Velez et al.
Endemic pemphigus and chicken pox
Report
(c)
(a)
(b)
(d)
(e)
(f)
(g)
(h)
(i)
(j)
(k)
(l)
Figure 1 (a–i) IHC staining. (a) Positive staining with anti-VZV antibody inside epidermal keratinocytes and dermal macrophages (brown staining, red arrows; 200·). (b) Dermal lymphocytes with intracellular viral inclusions, displaying positive staining to VZV staining (brown staining, red arrows; 400·). These cells also demonstrated positive staining to CD3 and CD5
antibodies, indicative of T lymphocytes. (c) Similar positive VZV antibody staining, but located within a dermal lymphatic vessel (brown staining, blue arrow; 400·). The dermal lymphatic vessel identity was further confirmed by staining with D2-40
antibody (not shown). The red arrow highlights positive VZV antibody staining within a dermal macrophage, separately confirmed utilizing positive CD68 staining (not shown). (d) Strong anti-human alpha 1 antitrypsin antibody staining was noted
within pulmonary blood vessels (brown staining, red arrows; 200·). The blood vessel identity was confirmed with additional
positive staining to CD34 (not shown). (e and f) Further positive staining of dermal and pulmonary blood vessels with alpha 1
antitrypsin antibody (brown staining, red arrows). Anti-smooth muscle actin staining separately confirmed the vascular nature
of this structure (not shown). (g) Positive stain with alpha 1 antitrypsin antibody to large pulmonary blood vessels (brown
staining, red arrow; 400·). (h) Further positive staining with alpha 1 antitrypsin antibody near pulmonary blood vessels (brown
staining, red arrows). A blood vessel identity was confirmed by separate staining with CD34 (not shown; 400·). (i) Positive
staining of pulmonary lymphatics with alpha 1 antitrypsin and some cells around these vessels (red arrow). Lymphatic identity
is confirmed by staining with D2-40 (dark brown staining, blue arrow; 400·). (j and k) DIF: positive staining on structures
resembling viruses in the lung and spleen, respectively, utilizing FITC-conjugated anti-human IgG antibody on spleen (green/
yellow staining, white arrows; 1000·). (l) H&E-stained renal histopathology, demonstrating extensive tissue damage (400·)
ª 2012 The International Society of Dermatology
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(a)
(b)
(c)
(d)
(e)
(f)
(g)
(h)
(i)
(j)
(k)
(l)
Figure 2 (a) IHC-positive VZV antibody staining surrounding dermal blood vessels (brown staining, red arrows; 400·). (b)
Positive IHC staining with alpha 1 antitrypsin antibody to the renal glomerulus (brown staining, red arrow; 400·). (c) Positive
DIF staining of the identical renal glomerulus, utilizing FITC-conjugated anti-human complement/C3 (green staining, white
arrow; 200·). (d) Positive IHC staining for VZV antibody in splenic tissue (brown dots, red arrows; 1000·). (e) IHC-positive
staining of alpha 1 antitrypsin antibody in cardiac tissue (brown staining, blue arrows; 400·). (f) H&E histopathology, demonstrating ballooning degeneration of epidermal keratinocytes (black arrows; 200·). (g) Clinical EPF plaques on the chest of the
patient, observed early in the clinical course before regression of these lesions secondary to immunosuppressant therapy (blue
arrow). (h) Classic varicella maculopapular lesions on the face of the patient, observed late in the clinical course (blue arrow).
(i) H&E histological stain of post mortem autopsy skin biopsy, demonstrating massive dermal vascular thrombi consistent with
clinical disseminated intravascular coagulation (blue arrows; 200·). (j) DIF: positive VZV antibody staining (round, white
structures) within patient cardiac tissue utilizing FITC-conjugated IgG antibodies (red arrows; 400·). (k) IHC-positive VZV
antibody staining, displaying differential positivity (possibly due to viral migration) within dermal blood vessels (blue arrows)
and an eccrine gland duct (red arrow; 200·). (l) Positive, diffuse staining with alpha 1 antitrypsin antibody in the epidermal
stratum spinosum (brown staining, blue arrow), and at the BMZ (linear brown staining, red arrow; 200·). Notably, El BagreEPF displays immunological reactivity to both of these structures
International Journal of Dermatology 2012, 51, 809–816
ª 2012 The International Society of Dermatology
Abreu Velez et al.
Endemic pemphigus and chicken pox
(a)
(c)
Report
(b)
(d)
Figure 3 (a and c) DIF of deep subcutaneous tissue, demonstrating immunoreactivity against a partially autolytic PC utilizing
FITC-conjugated anti-human IgM, complement/C3 and fibrinogen (green staining, white arrows), colocalizing with antibodies
to Texas red conjugated anti-human PPG 9.5 (orange-red staining, blue arrows; 200·). The PC is partially opened, observed
best in (c; 200·). Please refer to ref. 23 for more information. (b) A corresponding H&E of the DIF pictures, displaying focal
dermal autolysis, as well as a lymphohistocytic infiltrate surrounding a PC (200·). (d) Positive staining of a PC, utilizing modified Bielschowsky silver staining (blue arrows; 400·)
able to appreciate EPF punctate immunoreactivity inside
several epidermal keratinocytes, as well against the epidermal basement membrane zone (BMZ) area. Additional
EPF reactivity was noted against sebaceous glands and
sweat glands, consistent with similar reactivity observed
in pre mortem skin biopsies. In addition, reactivity
against renal glomeruli and against heart cell junctions
was clearly observed in the post mortem biopsies, despite
the large dosages of immunosuppressants. In Figure 2c,
we show positive staining in the renal glomeruli utilizing
FITC-conjugated anti-human complement/C3 (green
staining, white arrow). Figure 2e (IHC) and j (DIF) show
heart tissue with positive staining of alpha-1 antitrypsin
antibody (brown staining, blue arrows; Fig. 2e), and in
Figure 2j, positive staining to VZV antibody (round,
white structures), both utilizing FITC-conjugated IgG
antibodies (red arrows). As noted above, observed autoreactivity against skin Pacinian corpuscles (PCs) and some
nerves was confirmed by co-localization with antibody to
PPG 9.5 and by modified silver (Bielschowsky) staining,
performed as previously described.16 Figure 3 shows
H&E staining and DIF demonstrating immunoreactivity
ª 2012 The International Society of Dermatology
against a partially autolytic PC utilizing FITC-conjugated
anti-human IgM, complement/C3, and fibrinogen. Figure 3b shows the corresponding H&E for the DIF images,
displaying focal dermal autolysis, as well as a lymphohistocytic infiltrate surrounding a PC. Finally, in Figure 3d
we demonstrate positive staining of a PC, utilizing modified Bielschowsky silver staining.
We demonstrate some of the most prominent H&E
and DIF patterns observed, as well as improvement of the
quality and power of DIF staining by the use of simultaneous multicolor fluorescence and counterstaining of cell
nuclei. The DIF results were classified as follows: (0, negative; +, weak positive; ++ and +++, positive; and ++++,
maximum positivity). We noted: (1) deposits of IgG in a
granular pattern at the skin epidermal BMZ; as well as
(2) at the BMZ of the sebaceous glands and within cytoplasms of selected sebocytes (+++); (3) deposits of IgM in
a granular pattern at the epidermal BMZ (+++); (4)
deposits of complement/C3 in a granular pattern at the
epidermal BMZ and the sebaceous gland BMZ (+++); and
(5) deposits of fibrinogen in a granular pattern at the epidermal BMZ (++). In addition, we found autoreactivity to
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multiple cell junctions within cardiac tissue, with FITCconjugated anti-human IgG, complement/C3, and fibrinogen antibodies. In the kidney, reactivity was also detected
with these antibodies and further with FITC-conjugated
anti-human IgA.
Immunohistochemistry studies
Immunohistochemistry studies were as previously documented.16,17 Testing for HSV-1 and -2 (Dako) was performed, with negative results. We utilized IHC stains for:
(1) blood vessel endothelium, including von Willebrand
factor, CD34, and CD31; (2) D2-40 for lymphatic endothelium; and (3) smooth muscle actin to confirm vascular
co-localization of positive alpha-1 antitrypsin staining.
Staining with polyclonal rabbit anti-human matrix metalloproteinase 9 was negative in all samples. Staining for
VZV was performed using IE62 (0361) antibodies (sc58211; Santa Cruz Biotechnology, Santa Cruz, CA, USA),
with positive staining observed in multiple organs
(Figs. 1–3). We also stained the VZV-positive cells with
CD3, CD4, CD5, and CD8, to co-localize infiltrating
lymphocytes to these cells. In addition, we found IHC
staining to antigen-presenting cells in the areas of VZV
infection, characterized by positive S-100, myeloid/histioid, and HAM-56 positivity in multiple organs. We found
strongly positive IHC staining for alpha-1 antitrypsin in
most organs (Figs. 1–3). In control, routine skin biopsies
from living patients affected by El Bagre-EPF, as well as
in unaffected, negative control biopsies from the endemic
area, alpha-1 antitrypsin IHC staining was negative (negative controls for the DIF and IHC staining were obtained
from cadaver donors at the same hospital, deceased secondary to cardiac arrest or traumatic injuries). The presence of strong staining for mast cell tryptase (MCT) and
immunoglobulin D (IgD) was seen around the vessels and
sweat and sebaceous glands. Finally, control tissues were
consistently negative when tested for HSV-1 and -2,
VZV, and anti-alpha-1 anti-trypsin utilizing IHC and
DIF.
Discussion
Varicella-zoster virus is an ubiquitous, neurotropic alpha
herpes virus that causes chickenpox (varicella), becomes
latent in dorsal root ganglia at all levels of the neuraxis,
and may clinically represent years following initial infection to produce shingles (zoster).18 Years ago when fogo
selvagem was more prevalent in Brazil, VZV superinfection was documented with occasional lethal outcomes.19,20 Both primary and recurrent VZV infections
may be fatal in immunosuppressed patients. In our
patient, we demonstrated the presence of VZV antibody
in multiple organ systems. The possibility of concurrent
International Journal of Dermatology 2012, 51, 809–816
Abreu Velez et al.
HIV infection was excluded in our patient by both polymerase chain reaction and ELISA testing. For many years,
herpes virus has been linked to pemphigus as a possible
etiopathogenetic factor or as a complication of the immunosuppressive treatment.2–5
Our study is the first report in the literature linking the
presence of VZV to a strong, disseminated presence of
alpha-1 antitrypsin antibodies in a patient affected by El
Bagre-EPF receiving large dosages of immunosuppressant
agents. Based on the clinical pre mortem findings and
autopsy, this patient was affected with disseminated intravascular coagulation, with the additional systemic presence of VZV and alpha-1 antitrypsin antibodies in
association with most blood and lymphatic vessels.
Selected previous studies document the presence of significant levels of alpha-1 antitrypsin in viral infections.21,22
The authors suggested that serine proteases are responsible for triggering inflammatory cascades, resulting in
increased titers of these proteins. Alpha-1 antitrypsin is a
small glycoprotein that readily diffuses throughout interstitial fluids. It functions as an inhibitor of serine proteases in general, but the critical targets are the proteases
released by stimulated neutrophils, specifically cathepsin
G and, more particularly, neutrophil leukocyte elastase.21,22 Alpha-1 antitrypsin is considered a suicidal protein, reflecting the patient’s ability to respond to stress by
increased synthesis, yielding a potential fourfold increase
in plasma concentration in an acute phase state. In our
case, we speculate that the patient’s body began producing this enzyme rapidly, to protect against deleterious
effects of the secondary VZV infection. The presence of
this protease inhibitor, and/or the presence of antibodies
against this inhibitor may represent contributory factors
in the outcome of our patient.
Kaposi’s varicelliform eruption represents widespread
cutaneous HSV infection in patients with pre-existing dermatoses, including fogo selvagem.8,19,20 Also, chicken
pox and other infections may occur in patients with EPF.
Occasionally, these infections may present as nosocomial
infections in hospital wards, especially if adequate bed
spacing and barrier nursing methods are not employed;
these infections may in turn result in a significant mortality increase in these patients.19,20
During initial exposure, HSV uses mucosal and epithelial cells, including epidermal keratinocytes, as its primary
portal of entry and spreads through the epithelium.16,23 It
has also been shown that the replication of HSV virus in
cultured cells is accompanied by the appearance of cell
receptors that have an affinity for the Fc region of IgG.16
The findings may help to explain observed associations
of HSV and/or VZV with areas of the skin containing
immunoglobulins deposited by EPF. In regard to the
structural damage in the kidney, heart, nerves,23 and
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Abreu Velez et al.
possibly other organs, we believe the damage is associated
with the presence of autoantibodies to these organs, as
many of them are rich in plakins, and patients with El
Bagre-EPF have significant antibodies to plakin molecules.23 The reasons for reactivity to MCT and IgD in
several biopsies, including sites other than the skin, also
remain unknown. However, some authors have also
reported strong responses to IgD with alpha-1 antitrypsin,
and with infections due to other microorganisms.24
In the referral hospital caring for our patient, the median hospitalization of patients affected by El Bagre-EPF
ranges from 6 to 12 months, which can make these
patients vulnerable to nosocomial diseases. We conclude
that vigilance to prevent infections with bacterial, fungal,
viral, and parasitic secondary infections is crucial, especially in long hospitalizations of these patients.25 Physicians need to recognize the risk of exposing these patients
to any viral, bacterial, mycoplasmic, parasitic, and/or
other superinfecting agent in the event of a positive test
for any infectious agent, especially those of the herpes
family (i.e. Tzanck smear or HSV serology). Finally, we
propose a specific, synergistic mechanism to account for
the increased alpha-1 antitrypsin found in our patient;
additionally, pertinent cases need to be documented.
However, we do strongly encourage physicians to perform autopsies on patients with fatal complications of
autoimmune bullous disease therapy and thus preserve
organ tissues for further studies.
Endemic pemphigus and chicken pox
5
6
7
8
9
10
11
12
Acknowledgment
For histopathological consultation, we thank Sherif R.
Zaki, MD, PHD, at the US Centers for Disease Control and
Prevention, National Center for Zoonotic, Vector Borne
& Enteric Diseases, Division of Viral and Rickettsial Diseases, Infectious Disease Pathology Branch.
13
14
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ª 2012 The International Society of Dermatology
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