Original Paper Received: September 28, 2013 Accepted after revision: March 15, 2014 Published online: May 22, 2014

Dermatology 2014;229:88–96 DOI: 10.1159/000362208

Relationship between Radiation Therapy and Bullous Pemphigoid Tegan Nguyen a Julia M. Kwan b A. Razzaque Ahmed a   

 

Center for Blistering Diseases, Boston, Mass., and b Department of Dermatology, Naval Health Clinic, Honolulu, Hawaii, USA  

 

Key Words Autoimmune disease · Bullous pemphigoid · Cancer · Treatment · Pathogenesis · Radiation therapy

Abstract Background: Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease. Objective: To review the literature on radiation therapy (RT)-associated BP. Methods: A review of the English language literature on patients who developed BP during and up to 10 years post RT was performed. Results: 29 patients were reported. 25 (86.2%) were women, 84% of whom had received RT for breast cancer. Three patients were male (10.3%). Gender was not mentioned in 1 (3.4%). 72% developed BP post RT; 28% developed BP while undergoing RT. BP was initially localized to irradiated sites in 25 patients and to non-irradiated sites in 2 patients. Two patients presented with generalized disease. Disease control was reported in 12 patients, partial remission in 7 and complete remission in 5. Conclusion: The clinical profile, response to therapy and clinical outcome may indicate that RT-associated BP may be a specific subset of BP with a relatively benign course. © 2014 S. Karger AG, Basel

© 2014 S. Karger AG, Basel 1018–8665/14/2292–0088$39.50/0 E-Mail [email protected] www.karger.com/drm

Introduction

Bullous pemphigoid (BP) is an autoimmune, subepidermal blistering disease characterized by the presence of autoantibodies to hemidesmosomal plaque protein BPAg1 [1] and transmembrane protein BPAg2 [2]. In the majority of patients, BP is a generalized cutaneous disease that manifests as tense bullae on the extremities, axilla and abdomen [3]. In some patients, BP may be localized [4]. In this study, we report the development of BP in patients who received radiation therapy (RT) for cancer treatment. The data provide the time interval between RT and the onset of BP. We provide a hypothetical model that may partly explain this association.

Materials and Methods An English language literature search was performed, using PubMed and Embase with the following key words: ‘bullous pemphigoid’, ‘radiation-induced bullous pemphigoid’, ‘radiation therapy’, ‘malignancy’, ‘autoimmunity’ and ‘immune suppression’. The following inclusion criteria were used in this study: (1) Patient had a histologically diagnosed malignancy and received

A. Razzaque Ahmed, MD, DSc Center for Blistering Diseases 697 Cambridge St. Suite 302 Boston, MA 02135 (USA) E-Mail arahmedmd @ msn.com

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a

 

Table 1. Data overview of cases studied Total RT (Gy)

Onset of symptoms

Tests

dose onset; time interval location during/after RT

characteristics

8

F

39

cervix (SCC)

radium 36 months post RT implant

generalized

blister on tongue; recurrent vesicle formation on arms and trunk

histo (+)

9

F

48

vulva (SCC)

n/m

46 Gy during RT

SoI; generalized in 4 days

I: bullae over erythematous base; G: involved oral mucosa

histo (+); DIF (+); IIF (+)

10

M

53

lung

n/m

2nd week of RT

generalized

erythematous, raised patches on trunk and limbs with bullae at the borders

histo (+)

11

F

55

breast

n/m

36 months post RT

SoI

pruritic plaques and blisters on lymphedematous left arm

histo (+); DIF (+)

12

F

57

breast (IDC)

55

0.75 months post RT; SoI recurred 10 months later

tense bullae over an erythematous base

histo (+); DIF (+); IIF (+)

13

F

58

breast

n/m

5 months post RT

SoI

tense bullae, erosions, Nikolsky’s sign (+)

histo (+); DIF (+); IIF (–)

14

F

58

breast (lobular)

n/m

2 months post RT

SoI

erythematous plaques on right breast and upper arm; tense bulla and vesicle; truncal pruritus

histo (+); DIF (+); IIF (+)

15

F

59

breast (IDC)

60

0.75 months post RT

SoI; generalized in weeks

pruritic vesicular eruption over erythematous base

histo (+); DIF (+); IIF (+)

16

F

60

breast (lobular)

52.4

2nd week of RT

SoI; later generalized

I: recurrent erythematous bullae on left breast; G: right side of neck, oral mucosa; right side of forehead

histo (+)

17

F

65

breast

45

5 months post RT

SoI

pruritic, bullous lesions at SoI

histo (+); DIF (+); IIF (–)

18

F

66

breast (IDC)

50

20 Gy during RT

SoI; generalized in 1 week

I: erythema with confluating plaques; blister; G: bullae

histo (+); IIF (+)

19

F

66

breast

66.4

1 month post RT

SoI

4- to 5-cm tense blisters; denuded and crusted lesions in right axillary region

histo (+); DIF (+); IIF (+)

20

M

75

inguinal lymph 20 nodes metastasis (SCC)

20 Gy during RT

SoI; generalized in 1 week

sharply defined erythema; tense blisters

histo (+); DIF (+); IIF (–)

21

F

75

breast (IDC)

50

6 months post RT

SoI; generalized in 2 weeks

pruritic, erythematous erosions with hemorrhagic crusts; tense blisters

histo (+); DIF (+)

17

F

76

breast

50

16 months post RT

SoI

pruritic, bullous lesions

histo (+); DIF (+); IIF (+)

22

M

77

esophagus (SCC)

80

20 Gy during RT

localized to outside field; generalized in 3 months

I: tense bullae in right inguinal region; erythematous papules on back and lower extremities; G: vesiculobullous lesions

histo (+); DIF (+); IIF (+)

23

F

78

vulva (SCC)

59.4

0.75 months post RT

SoI; generalized in 1 month

I: pruritic rash; edema; blister; G: weeping lesions on trunk and chest; pruritic bullae in both groins

histo (+)

24

F

78

breast (IDC)

50

36 months post RT

SoI; generalized in 7 months

I: erosions, hemorrhagic crusts on right breast; G: blisters on dorsal and ventral trunk and upper leg

histo (+); DIF (+); IIF (+)

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Ref. Sex Age Cancer

Table 1 (continued) Ref. Sex Age Cancer

Total RT (Gy)

Onset of symptoms

Tests

dose onset; time interval location during/after RT

characteristics

11

F

78

breast

50

48 months post RT

SoI

pruriginous, hemorrhagic erosions

histo (+); DIF (+); IIF (+)

25

F

78

breast

50

12 months post RT

SoI

eczematous plaques; bullous lesions; erosions

histo (+); DIF (+); IIF (+)

26

F

79

breast

40 e–

5 months post RT

SoI

bullous eruption over an erythematous base; erosions; scaling and crusting

histo (+); DIF (+); IIF (+)

27

F

80

breast (lobular)

60

40 Gy during RT

SoI

tense blisters; severe pruritus

clinical

28

F

81

breast (IDC)

40

1 month post RT

SoI

tense bullae over erythematous base; erosions

histo (+); DIF (+); IIF (+)

27

F

83

breast (IDC)

60

20 Gy during RT

SoI

pruritic, blistering dermatoses

clinical

29

F

86

cervix

29

0.5 months post RT

left thigh; later generalized

n/m

n/m

30

F

94

breast

60

4 months post RT

SoI; generalized in 2 weeks

I: bullous lesions with erosions at SoI; G: tense blisters and denuded lesions on left breast, abdomen and limbs

histo (+); DIF (+)

31

F

n/m breast

n/m

post RT

SoI

n/m

n/m

29

F

n/m breast

n/m

years post RT

SoI

n/m

n/m

29

n/m n/m NHL

n/m

84 months post RT

SoI

n/m

n/m

DIF = Direct immunofluorescence; e– = irradiation with electrons; F = female; G = generalized presentation; Gy = Gray radiation unit; histo = histological study; I = initial presentation; IDC = infiltrating/invasive ductal carcinoma; IIF = indirect immunofluorescence; M = male; NHL = non-Hodgkin’s lymphoma; n/m = not mentioned; SCC = squamous cell carcinoma; SoI = site of irradiation.

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Results

A total of 29 patients were described. Table 1 provides a summary of patients’ profiles, cancer types, lesion characteristics, histology and immunopathology [8–31]. Demographic Data Age ranged from 39 to 94 years (mean 69.3 years). There were 3 males (10.3%) and 25 females (86.2%). The gender of 1 patient (3.4%) was not mentioned. Cancer Types A predominance of solid organ tumors was noted (fig. 1). In particular, 21 out of 29 cases (72.4%) were females with breast cancer. Infiltrating ductal carcinoma was diagnosed in 7 (33.3%), lobular carcinoma in 3 Nguyen /Kwan /Ahmed  

 

 

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RT as part of cancer treatment prior to the development and onset of BP. (2) Studies show that the immunosuppressive effects of RT may be present for a decade after RT has been completed [5, 6]. Therefore, only patients who developed BP up to 10 years post RT were included in this study. (3) The diagnosis of BP was based on patients’ clinical profile and histology and confirmed by direct immunofluorescence and/or indirect immunofluorescence. The following information was obtained from the cases present in the literature: (1) Sex and age at onset of clinical BP. (2) Total dose of radiation received before the onset of BP. (3)Treatments and clinical outcomes were defined according to recommendations by a panel of international experts [7]: (a) Time to control clinical disease is time for cessation of new lesions and healing of old lesions. (b) Time to achieve partial clinical remission is the point at which there is absence of new lesions while the patient is receiving minimal/maintenance therapy. (c) Time to achieve complete clinical remission is the time when no lesions are present and the patient is off systemic therapy.

2

1 1 1

2

1

21

Lung Esophagus Inguinal metastasis Breast Cervix Vulva Non-Hodgkin’s lymphoma

Fig. 1. Cases of cancer treated with RT. The majority of patients who underwent RT had solid tumors. There were 21 cases of breast cancer, 2 cases of cervical and vulvar cancer each, and 1 case of lung, esophageal, metastatic squamous carcinoma to the inguinal lymph nodes, and non-Hodgkin’s lymphoma each.

28% During RT Post RT

72%

a

14 12 10 8

Time between RT and Development of BP The onset of clinical BP after radiation exposure varied among 29 patients (fig. 2a). 21 patients (72%) developed BP after RT was completed (fig.  2b). 12 (57%) patients developed BP within 6 months, 1 patient (5%) between 7 and 12 months, and 7 patients (33%) after 13 or more months, but less than 7 years. In 1 patient (5%), time of onset post RT was not mentioned. The mean was 15.8 months while the median was 5 months (range 2 weeks to 7 years). The mean total dose of radiation these patients received was 50.3 Gy (range 29–66.4 Gy). There were 8 patients who developed the disease during the course of RT (28%). The mean dose of RT at the time of BP onset was 27.7 Gy (range 20–46 Gy).

6

12

4

7

2 0

b

1 Within 6 months

Between 7 and 12 months

1 –13 months

Not specified

Fig. 2. a Onset of BP. The onset of clinical BP varied among the 29

patients. Eight patients (28%) developed BP during the course of RT. 21 patients (72%) developed BP after completing RT. b Temporal relationship of the onset of BP post RT. 12 out of 21 patients developed BP within 6 months post RT (57%). One patient (5%) developed BP 12 months later. Seven patients (33%) developed BP after 13 or more months, but not more than 7 years, after RT was completed. In 1 patient, the time of onset post RT was not mentioned.

male patient presented during the second week of RT for lung cancer [10]. One female patient presented 36 months post radium implant for cervical cancer [8].

Clinical Course The clinical course was variable. 27 out of 29 (93%) initially presented with localized BP. Lesions were restricted to the area of radiation in all but 2 of the 27 patients. In these 2 patients, the lesions were outside the area of radiation [22, 29]. BP remained localized in 16 out of 27 patients (59%). In 11 out of 27 patients (41%), disease progressed to a generalized distribution. Two patients initially presented with generalized disease (7%). One

Diagnostic Features Histology and immunopathology were not reported in 6 patients. Indirect immunofluorescence was performed in 16 patients and detectable levels of anti-basement membrane zone (anti-BMZ) antibodies were reported in 13 patients (table  1). 13 patients developed generalized disease. Five patients had demonstrable levels of circulating anti-BMZ antibodies, while in 8 patients, the titers were negative or not reported (table 1).

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(14.3%), and histology was not mentioned in 11 (52.4%). There were 2 cases of cervical and vulvar cancer each (13.8%). Among the 3 male patients, lung cancer, esophageal carcinoma and metastatic squamous carcinoma to the inguinal lymph nodes were present in 1 each (10.3%). One patient whose gender was not mentioned had unspecified type of non-Hodgkin’s lymphoma (3.4%).

Table 2. Correlation between treatments and reported outcomes Clinical outcomes1

Disease control Partial remission Complete remission Not mentioned

Topical CS only

Non-systemic CS combination therapy

Systemic CS only

Systemic CS combination therapy

patients

reference

patients

reference

patients

reference

patients

reference

3 2 1 1

12, 16, 26 17 (2) 27 10

1 3

18 13, 14, 20

5

8, 9, 11, 22, 30

2

11, 25

3 2 2

19, 21, 24 23, 28 15, 27

Total number of patients 12 7 5 1

1 Treatments were not mentioned in 4 patients. Disease control: the point at which new lesions or pruritic symptoms cease to form and established lesions begin to heal. Partial remission: absence of new lesions while the patient is receiving minimal therapy. Complete remission: absence of new and established lesions or pruritic symptoms for at least 2 months.

Clinical Outcomes Clinical outcome was not uniformly reported. Treatments were not reported in 4 patients. In one study, treatment with topical CS was reported but the clinical outcome was not mentioned [10]. Control of disease was reported in 12 patients, partial remission in 7, and complete remission in 5. One patient, whose initial presentation was treated with topical CS, had a relapse at 10 months follow-up. The disease recurred in similar distribution and was controlled with topical CS [12]. No recurrences were observed in patients treated with systemic therapy. The correlation between treatments and reported outcomes is presented in table 2.

Discussion

The occurrence of BP following RT for cancer is an uncommon but interesting phenomenon. 29 patients were identified using the inclusion criteria. Approximately 86% of the patients were women, 84% of whom had breast cancer. 93% initially presented with localized lesions. Follow-up demonstrated that 41% subsequently 92

Dermatology 2014;229:88–96 DOI: 10.1159/000362208

developed generalized disease while the disease remained localized until remission in 59%. In the majority of patients with idiopathic BP (non-RT-associated), the disease presents in a generalized distribution with lesions that are frequently vesiculobullous in morphology [32]. Bullous lesions are usually tense and may be filled with clear or hemorrhagic exudate [3, 32]. Lesions may arise on erythematous or normal-appearing skin [32] and usually in conjunction with urticarial plaques [3, 32]. Atypical variants such as localized disease and non-bullous presentations, including prurigo nodularis-like, eczematous, erythrodermic and dyshidrosiform-like pemphigoid, have been described in approximately 20% of patients [33, 34]. The relationship between onset of BP and time of radiation revealed that 72% developed BP after RT was completed. In the majority, this occurred within 6 months. In contrast, 28% developed BP while undergoing RT. Those in whom BP occurred during RT had received only half the dose of radiation compared to those who developed BP post RT. The clinical outcomes in the RT-associated BP patients were reported to be favorable. Since the guidelines and recommendations to define outcomes [7] were not available when these cases were reported, it appears that based on clinical descriptions, the majority of patients achieved clinical control. Favorable outcomes were reported in patients treated with non-systemic CS therapy, including topical CS, with only 1 case of relapse at 10 months follow-up. This would suggest that RT-associated BP is indolent in nature and that non-systemic CS treatments are effective in inducing disease control and possibly remission. However, variations in the manner in which patients reported disease development and progression, inconsistency in follow-ups, and overall small Nguyen /Kwan /Ahmed  

 

 

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Treatments Disease control was achieved through a variety of treatments, including topical and systemic corticosteroids (CS), oral antibiotics and immunosuppressive agents. Treatments were not mentioned in 4 patients (14%). Seven patients were treated with only topical CS (24%). Four patients received non-systemic CS combination therapy, which included niacinamide, topical CS and/or antibiotics (14%). Seven patients received systemic CS monotherapy (24%) while 7 patients received systemic CS combination therapy (24%).

Table 3. Comparisons of RT-associated BP and idiopathic BP

RT-associated BP

Idiopathic BP1

Age

mean: 69 years; range: 39 – 94 years

late 70s

Gender distribution

M:F 1:8

no predilection

Pre-clinical features

erythema, variable degree of pruritus

erythema, variable degree of pruritus

Clinical features

tense blisters, pruritus

tense blisters, pruritus

Distribution

93% localized; 7% generalized

majority generalized (flexural areas of limbs, trunk); 20% localized or atypical variants [33, 34]

Pathology

subepidermal bullae, predominantly polymorphonuclear leukocytes dermal infiltrates

subepidermal bullae, predominantly polymorphonuclear leukocytes dermal infiltrates

Immunopathology

deposition of immunoreactants at BMZ; anti-BMZ antibodies present

deposition of immunoreactants at BMZ; anti-BMZ antibodies present

Treatments

11 non-systemic CS therapy; 14 systemic CS therapy

topical/systemic CS, antibiotics, niacinamide, immunosuppressive agents, plasmapheresis, intravenous immunoglobulin, immunoadsorption, rituximab

Recurrences/relapses

1 year: 1 patient

1 year: 29% [50]

Mortality rate

none reported

20 – 40%

noted otherwise, information is derived from [3].

number of patients may contribute to sampling error and explain for the differences between RT-associated and idiopathic BP. Demonstrable differences between the two entities are presented in table 3. Radiation as a Triggering Factor Tumor cells and epidermal cells are sensitive to RT in the G2M phase of the cell cycle and are more likely to undergo cell death during the course of therapy [35]. Langerhans cells have been shown to be resistant to radiationinduced apoptosis [36]. Thus, irradiated Langerhans cells may be capable of processing BPAg1 and BPAg2 released from dying epidermal cells (fig. 3). Following antigen uptake, there is upregulation in the expression of MHC class I and II molecules [37]. A concomitant increase in the expression of costimulatory molecules such as CD40, CD80 and CD86, and chemokine receptors such as CCR7 and CXCR4 is also observed [37]. Langerhans cells would then present relevant BMZ protein peptides in association with MHC class II molecules to CD4+ T cells, which complex with B cells to produce specific autoantibodies

to BPAg1 and BPAg2. The binding of autoantibodies to BPAg1 and BPAg2 within the BMZ results in the activation of the complement system [32]. It has been observed that such binding results in the release of IL-6 and IL-8 from basal keratinocytes [38]. Studies have shown that IL-6 is capable of penetrating the BMZ [38]. IL-6 can also influence IgG subclass differentiation and thus enhance pathogenic autoantibody production [39]. Keratinocytederived IL-8 plays a role in the recruitment of neutrophils in both the passive animal model of BP and in vitro studies [40]. Neutrophil-derived metalloproteinase-9 (MMP9) and neutrophil elastase then cleave the extracellular domain of BP180 and other BMZ proteins, resulting in blister formation [32]. MMP-9 is also capable of inactivating the α1-proteinase inhibitor of neutrophil elastase [32] and thus promotes further dermal-epidermal separation. Investigators have proposed different theories to explain how RT might influence the development of BP. One theory suggests that patients may already have had circulating anti-BMZ autoantibodies before RT was initi-

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1 Unless

Epidermis

BP

Ionizing radiation L/&

Basal cells

C3b C5a Blister formation

Antigen uptake

'HUPDOHSLGHUPDO separation Cancer cells MHC class II molecule BP antigen

Maturation L/&

Neutrophil Neutrophil elastase MHC class II molecule

T cell activation

APC

Peptide

ଭଭ,/ ଭଭ,/ Production of autoantibodies to BPAg1 and BPAg2

003 Eosinophil

TCR

T cell

Activated B cell T cell activation

B cell

Fig. 3. Hypothetical pathogenetic mechanism of radiation-associated BP. BP antigens are released from epidermal cells and possibly from tumor cells and ingested by immature Langerhans cells (iLCs). They are processed and presented to MHC class II molecules. These mature antigen-presenting cells (APCs) present BP antigen(s) to the T cell receptor (TCR). Activated T cells then present it to B cells that selectively produce BP autoantibodies. The

binding of autoantibodies to BPAg1 and BPAg2 activates the complement system. Simultaneously, the binding of BP autoantibodies results in the secretion of IL-6 and IL-8 by basal keratinocytes, which attract polymorphonuclear neutrophils and eosinophils. Neutrophil-derived MMP-9 and neutrophil elastase cleave the extracellular domain of BPAg2 and facilitate the separation of the dermis from the epidermis.

ated [31]. Remy et al. [41] demonstrated that a single Xray dose of 7,000–8,000 rad increased the binding of autoantibodies to the BMZ two- to three-fold. Thus, RTinduced tissue damage may have an enhancing effect on the binding of anti-BMZ autoantibodies and disease initiation. Other investigators have described RT-associated BP, with the initial localization of the disease, as an example of ‘immunocompromised district’ [42]. They postulate that an area of radiation dermatitis, with coexisting lymph stasis and locally altered neuromediator signaling, may become immunodestabilized. The destabilization facilitates the local onset of opportunistic infections and immune disorders even in the environment of systemic immune suppression. This hypothesis has validity in providing a rationale for limited disease presentation. It may also explain disease development post RT, in which a rapid immune response is prevented by radiation-induced T cell suppression and chronic lymphedema [43].

In this study, it was observed that patients with breasts, lung, vulvar and esophageal cancers developed BP following RT. The hypothetical basis for the development of anti-BPAg1 and anti-BPAg2 autoantibodies in these patients may be due to the fact that these molecules share similar pathogenic epitopes, as present in the normal human tongue, esophagus, trachea, cornea and urinary bladder [44]. This hypothesis is based on a report that on indirect immunofluorescence analysis, binding of hightiter BP sera to these tissues was observed [44]. In this cohort of patients, BP associated with RT occurred predominantly in women with breast cancer. There is no well-described or accepted explanation for this association. Isolated pieces of evidence may provide a partial explanation for the development of antibodies to hemidesmosomal proteins. Hemidesmosomes are usually described in stratified epithelia, but recent studies show that breast epithelium, including luminal and myoepithelial cells that appose the basement membrane, ex-

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Release of BP antigens

Dermis

BMZ

Apoptosis HD

press hemidesmosomes [45]. Such hemidesmosomes may be lost by invasive breast cancer cells, but in vitro primary malignant breast cells appear to exhibit a mixture of hemidesmosome phenotypes [45]. It is tempting to speculate that breast epithelial cells, while undergoing RT-induced cellular apoptosis, release hemidesmosomes that may become immunogenic and produce anti-BPAg1 or anti-BPAg2 autoantibodies. Since irradiated skin is reported to have increased vascular permeability [35], these autoantibodies may produce BP initially localized to the site of radiation. Additionally, studies have conclusively demonstrated that the correlation between BP and cancer is simply coincidental and not necessarily causative [46, 47]. However, in these patients, the cancers were limited to the breast and BP occurred in the majority of cases at the sites of radiation. This therefore creates a subset of BP patients that have some differences from idiopathic BP. It is estimated that approximately 60% of cancer patients in North America receive RT at some point in their treatment plan [35]. Though the use of RT is high, the incidence of RT-associated BP is very low. There is no definitive explanation for this paradox. However, this may in some measures be due to the lack of reporting. A speculative explanation can be derived from immunogenetic studies. In pemphigoid patients, the presence of

HLA-DQB1*0301 has been identified as providing enhanced disease susceptibility [48]. The frequency of HLADQB1*0301 may be low in cancer patients, hence the low incidence of BP in RT-treated patients. The interesting and beneficial aspect of studying patients who developed BP in association with RT lies in the fact that it helps define a subset of BP patients. Information derived from the study of such a subset may be of value and assistance in better understanding the pathomechanisms of BP. Liu et al. [49] described a murine model for the development of BP. This model could be used to study the effects and influences of RT in BP and possibly specific mechanisms of immune restoration. Such studies have the potential to help advance our understanding of the interaction between RT and the skin in the development of BP.

Disclosure Statement The authors have no conflict of interest or competing interests to disclose. There are no funding sources. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, nor the U.S. Government.

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