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Recurrent
Respiratory
Papillomatosis
Paolo Campisi
Editor
123
Recurrent Respiratory Papillomatosis
Paolo Campisi
Editor
Recurrent Respiratory
Papillomatosis
Editor
Paolo Campisi
Department of Otolaryngology - Head
and Neck Surgery
University of Toronto
Toronto, ON
Canada
ISBN 978-3-319-63822-5 ISBN 978-3-319-63823-2 (eBook)

https://doi.org/10.1007/978-3-319-63823-2
Library of Congress Control Number: 2017956567
© Springer International Publishing AG 2018

This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of
the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation,
broadcasting, reproduction on microfilms or in any other physical way, and transmission or information
storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology
now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
does not imply, even in the absence of a specific statement, that such names are exempt from the relevant
protective laws and regulations and therefore free for general use.
The publisher, the authors and the editors are safe to assume that the advice and information in this book
are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the
editors give a warranty, express or implied, with respect to the material contained herein or for any errors
or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims
in published maps and institutional affiliations.
Printed on acid-free paper
This Springer imprint is published by Springer Nature

The registered company is Springer International Publishing AG
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
This collaborative work is dedicated to the
children and adults that courageously live
with recurrent respiratory papillomatosis.
Together we will advocate for the prevention
of RRP and strive for the development of
novel, effective treatments.
Foreword
It is with great pleasure and honour that I write the foreword to this most impressive
book on RRP edited by a trusted friend and colleague, Dr. Paolo Campisi.
As a retired paediatric otolaryngologist/head and neck surgeon, I dealt first-hand
with many patients suffering from this disease. Throughout my education as a resi-
dent and during my career for more than 30 years, I witnessed the pain, suffering
and disruption of quality of life of child, parent and family alike. In my early years,
I sensed frustration amongst all the health-care providers, myself included, and
researchers with the lack of understanding and effective treatment options available
for these children. To put it bluntly, we were poorly equipped and lacking on all
fronts. With pure motivation to relieve pain and suffering, we all wanted to do better,
and so we did.
Course crude debulking techniques performed via direct laryngoscopy were
replaced with innovative microsurgical techniques, powered instrumentation and
laser technology with the intent of producing better voice outcomes.
A fresh understanding of the disease—including its epidemiology, proposed
aetiology and relationship to the human papilloma virus and cancer—brought new
interest to the table from many research groups, from both the adult and paediatric
research realm alike. This research translated into a variety of new treatment options
and trials from interferon to cidofovir. Initial response to these treatments incited
both optimism and controversy, making efficacy and safety a paramount consider-
ation. Vaccine technology not only offered another treatment option but also
weighed heavily in the prevention of the disease. A better understanding of the
epidemiology and transmission of disease allowed surgeons to better inform and
advise patients and families. Intervals between treatments were optimized and out-
comes could be better predicted. Parental guilt was replaced by knowledge and
optimism.
RRP is an example of how a single disease with both paediatric and adult impli-
cations can excite and promote collaboration from a variety of disciplines from the
social, clinical, research and public health worlds. The pressing need to find better
treatments and ultimately a cure for those suffering from RRP will continue to drive
this collaborative effort into the foreseeable future.
vii
viii Foreword
I congratulate Paolo and his dedicated team of contributing authors, truly experts
in their field, for bringing their knowledge together in what can arguably be
described as the best single-source reference ever published on RRP. Thank you all!
Toronto, Canada Vito Forte, MD, FRCSC

Contents
1 Fundamental Biology of Human Papillomaviruses.............................. 1

Meghan Lambie and Scott V. Bratman
2 The Epidemiology of Recurrent Respiratory Papillomatosis.............. 19
Paolo Campisi
3 Monitoring Public Health Impact of HPV Vaccination on RRP......... 33
Vidisha Singh, Elissa Meites, and Adam Klein
4 Advances in Vaccine Technology............................................................ 45
Julie Ahn, Simon R.A. Best, and David E. Tunkel
5 Human Papillomavirus Vaccination: Making Sense of the Public
Controversy.............................................................................................. 59
Talía Malagón and Eduardo L. Franco
6 Impact on Quality of Life........................................................................ 95
Neil K. Chadha
7 Contemporary Management of Recurrent Respiratory
Papillomatosis in Adults.......................................................................... 103
R. Jun Lin and Clark A. Rosen
8 Contemporary Management of Recurrent Respiratory
Papillomatosis in Children...................................................................... 115
Sarah N. Bowe and Christopher J. Hartnick
9 The Cidofovir Controversy..................................................................... 137
Griffin D. Santarelli and Craig S. Derkay
10 Malignant Transformation and Distal Airway Complications............ 153
Eleanor P. Kiell and Steven E. Sobol
ix
x Contents
11 Human Papillomavirus and Head and Neck Cancer............................ 167

Shao Hui Huang, Patrick Gullane, and Brian O’Sullivan
12 Advocacy for Recurrent Respiratory Papillomatosis........................... 183
Bill Stern and Susan Woo
Index.................................................................................................................. 193
Chapter 1
Fundamental Biology of Human
Papillomaviruses
Meghan Lambie and Scott V. Bratman
1.1 Introduction
Papillomaviruses are a family of non-enveloped double-stranded DNA viruses that

infect a number of different species including birds, cows, and humans. The human
papillomavirus (HPV) can be found globally, with very little impact of geographic
location on prevalence infection (De Villiers et al. 2004; Forman et al. 2012).
HPV causes abnormal cellular proliferation within infected tissues, which can be
broadly categorized as mucosal or cutaneous; HPV types that infect mucosal tissues
are the cause of many benign neoplastic conditions such as condylomata acuminata
(genital warts) and recurrent respiratory papillomatosis, and those types that infect
cutaneous tissues are the cause of common skin warts (verrucae). HPV gained
attention following the discovery that it is the causative agent in cervical cancer
(zur Hausen 1976, 1996). Since, it has also been shown to be involved in the genesis
of some head and neck cancers, as well as penile, vaginal, vulva, and anogenital
cancers (Forman et al. 2012).
Over 170 different HPV types have been sequenced to date (de Villiers 2013),
a number that has been rising steadily with the improvement of sequencing meth-
ods. It can be difficult to ascertain the precise portion of the population that is
infected at any given time, as in most cases the virus remains latent or shows no
symptoms. Up to 80% of sexually active women harbor a genital HPV infection at
any one time, and men are thought to be similarly afflicted (Antonsson et al. 2000;
Donne et al. 2010; Doorbar et al. 2015). One challenge of assessing the prevalence
M. Lambie
Medical Biophysics, Princess Margaret Cancer Centre, Toronto, ON, Canada, M5G 1L7
e-mail: meghan.lambie@mail.utoronto.ca
S.V. Bratman (*)
Radiation Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada, M5G 1L7
e-mail: scott.bratman@rmp.uhn.ca
© Springer International Publishing AG 2018 1

P. Campisi (ed.), Recurrent Respiratory Papillomatosis,
https://doi.org/10.1007/978-3-319-63823-2_1
2 M. Lambie and S.V. Bratman
of HPV has been that not all cells within an infected tissue contain HPV genomes,
requiring the sampling of a large area in order to confidently give a negative
diagnosis (Donne et al. 2010).
The contrast between the common prevalence of the virus and the relatively
small number of individuals who experience symptoms lends credence to the theory
that HPV is most often a commensal entity rather than a disease-causing pathogen
(Antonsson et al. 2000). Nonetheless, HPV infection can lead to numerous diseases
in humans. The profound impact of this class of pathogens on human health has
spurred the development of vaccines with the potential to significantly reduce the
incidence of HPV infections and HPV-associated diseases (Dochez et al. 2014).
Multiple vaccines are now approved for human use and are being incorporated into
population-based vaccination schemes.
Several factors will limit the immediate impact of vaccines on HPV prevention,
guaranteeing the continued prevalence of HPV-associated diseases for the foreseeable
future. First, the available vaccines provide protection against only a small subset—
albeit the most common—of the HPV types that cause human disease. Second, most
HPV-associated diseases have a long latency (years to decades) following initial
infection and colonization of tissues by the virus. Third, a negative social stigma
toward vaccines that prevent sexually transmitted diseases has reduced uptake of
HPV vaccines in some segments of society. Finally, the high cost of these proprietary
vaccines means that for now, wealthy developed countries derive the greatest benefit
(Moody and Laimins 2010; Dochez et al. 2014). Thus, the need for knowledge of the
management and treatment of HPV-associated diseases will remain for years to come.
1.2 Genetics and Types of HPV
HPV types carry differential risk of causing invasive malignancy (Donne et al.
2010; Doorbar et al. 2015). Types that are more likely to cause invasive malignancy
are referred to as high-risk types (Fernandes 2013). High-risk HPV types (the most
commonly studied being types 16 and 18) have been determined to be the causative
factor in 99% of cervical cancers (Walboomers et al. 1999). RRP is most commonly
caused by two low-risk HPV types—6 and 11—which are also associated with
benign warts and other hyper-proliferative lesions (Donne et al. 2010; Fernandes
2013). Invasive malignancy is very rare in low-risk types, affecting only a small
percentage of patients with cervical infections or RRP (Donne et al. 2010).
1.2.1 Genomic Organization of HPV
HPVs are small, non-enveloped viruses with a genome of approximately 8000 base
pairs, contained in a single closed double-stranded circular DNA episome (Fernandes
2013; Doorbar et al. 2015). Within the genome there are eight open reading frames
that are divided into three regions:
1 Fundamental Biology of Human Papillomaviruses 3
• The early region (E) includes six open reading frames encoding the E1, E2,
E4, E5, E6, and E7 proteins. E1 and E2 regulate expression of viral
transcripts. E4 controls viral release and viral genome replication. E5, E6,
and E7 contribute to host cell division, which can sometimes lead to neoplas-
tic transformation (Tsakogiannis et al. 2012; Fernandes 2013). Overall these
proteins are responsible for subsistence of the virus within infected human
cells.
• The late region (L) encodes two histone-like capsid proteins, L1 and L2, which
provide the structure to the HPV virus (Kajitani et al. 2012). The major protein
capsid of the virus is L1, with L2 joining pentamers of L1 to stabilize the
structure.
• The long control region (LCR) is a noncoding region that regulates the
transcription of viral genes, including oncogenes E6 and E7. It is an approxi-
mately 1 kb long binding site for both positive and negative transcriptional
regulators.
The specific genes and their functions have been summarized in Table 1.1. The
genome of HPV, despite containing few gene templates, displays complex gene
expression programs with several possible alternative splice sites. These are
controlled by both cellular and viral transcription factors, mainly within the LCR,
as well as by the methylation of viral genomic sequences by the host cell (Kajitani
et al. 2012).
Table 1.1 HPV gene functions at a glance

Viral Transformation and
gene Viral life cycle oncogenesis Immune modulation
E1 DNA helicase activity.
Regulates viral gene
transcription
E2 Regulates early gene Knockout due to integration of
promoter viral genome can cause
deregulation of E6/E7
expression
E4 Control of viral release and Involved in viral genome
genome replication amplification
E5 Stimulates mitogenic Involved in inhibition of Interferes with MHC
signals of growth factors, apoptosis as well as triggering class 1 complex
including EGFR differentiation presentation
E6 Viral oncogene. Inactivates Significant. Prevents cell cycle Inhibits cytokines
p53. Regulates many other arrest and apoptosis triggered including interferon
cellular components by E7 activities
E7 Viral oncogene. Inactivates Significant. Triggers reentry Inhibits cytokines
Rb. Regulates many other into the cell cycle and including interferon
cellular components continued cell division
L1 Major capsid protein HPV vaccine target
L2 Minor capsid protein
1.2.2 HPV Taxonomy
The L1 open reading frame is the most conserved region in the HPV genome and
has, therefore, been used to define papillomavirus types. Distinct HPV types are
characterized by greater than 10% dissimilarity to the closest known type within
the L1 open reading frame (De Villiers et al. 2004). A great deal of sequence
similarity also exists in the E1, E2, and L2 open reading frames, with somewhat
less conservation of the E4, E5, E6, and E7 open reading frames (De Villiers
et al. 2004).
HPV types are categorized by genus into five main groups: alpha, beta,
gamma, mu, and nu (Fig. 1.1). Members of the same genus harbor greater than
60% nucleotide sequence identity within the L1 open reading frame and greater
Human Papillomaviruses
Alpha Beta Gamma Mu Nu
Cutaneous Cutaneous Cutaneous Cutaneous
Mucosal Cutaneous
HPV 5,9
Non-melanoma
skin cancer
HPV 1, 63
High- Low- Non-melanoma skin
Risk Risk HPV 10, 3, 28 HPV 4, 48, 65 cancer (Type 1) HPV 41
Non-melanoma skin
cancer
HPV 6, 11
Recurrent Respiratory
Papillomatosis, Genital
warts
HPV 16, 18, 31, 33

Cervical carcinoma, head
and neck carcinoma
Fig. 1.1 Phylogeny of HPV types. HPV genuses are shown at the first division level. Most studied
HPV subtypes exist within the alpha or beta genus. HPV types can either be mucosal or cutaneous,
and mucosal subtypes are further subdivided into high and low risk based on potential for malig-
nant transformation. Representative HPV types are shown below each subcategory, along with
most common malignancies associated with those types
than 45% identity across the entire genome (De Villiers et al. 2004). Within each
genus of HPV types are groupings referred to as species or clade. To be within
the same species, HPV types must share between 60% and 70% of their nucleo-
tide sequence (De Villiers et al. 2004). As mentioned above, HPV types are at
least 10% dissimilar from one another, and additional subtypes may exist with
nucleotide sequence dissimilarity of 2–5% (noted, e.g., as HPV6c and HPV6d)
(Donne et al. 2010).
The division of HPV types by genetic similarity does not necessarily indicate
functional similarity. For example, HPV-6 and HPV-11, which are the major con-
tributing factors to RRP, share the same pathology as well as the same phylogenic
subtype. In contrast, HPV-2 and HPV-4 are unrelated genetically, but both result in
similar cutaneous papillomas (De Villiers et al. 2004).
In addition to the genetically determined phylogeny described above, HPV types
are characterized by their predilection for infecting mucosal or cutaneous squamous
epithelia. All HPV types infect stratified squamous epithelial tissues. Most of the
symptomatic diseases result from types that colonize mucosal squamous epithelia,
including high-risk HPV types that cause anogenital and oropharyngeal carcinomas
as well as low-risk HPV types responsible for condylomata acuminata and RRP
(Fernandes 2013). Alternatively, some HPV types such as HPV-2 and HPV-4 cause
cutaneous lesions that infect the keratinized skin surface and are thought to be a risk
factor for nonmelanoma skin cancer (Weissenborn et al. 2005). Most mucosal HPV
types are of the alpha genus, and most cutaneous types are of the beta genus,
although some overlap exists. In comparison to these types, relatively little is known
regarding HPV types in the gamma, mu, and nu genera, from which most infections
are asymptomatic (Tommasino 2014). These differences in disease states are pos-
sibly linked to variation in transmission and propagation of the virus, as well as
differences in immune recognition and clearance (Doorbar et al. 2015). These sig-
nificant divisions of HPV types, as well as the common malignancies seen with each
division, are highlighted in Fig. 1.1.
1.3 Virus Life Cycle
HPV infects stratified squamous epithelial tissues, and its life cycle is closely tied to
the biology of cellular differentiation within such tissues. The reasons for this par-
ticular tropism are not entirely known, although most evidence points toward tissue-
specific transcription factors as opposed to cell surface receptors as the primary
restrictive factor (Doorbar et al. 2015). Once the virus gains entry into epithelial
cells, it embarks upon a well-characterized life cycle that is non-lytic, which in part
explains its relative ubiquity and comparatively infrequent symptoms. Immune-
mediated clearance and the function of putative viral oncogenes are what differenti-
ate transient infections that go unnoticed from benign papillomas and metaplastic
lesions that can progress to invasive carcinomas.
1.3.1 Viral Entry
The HPV virus initially infects cells within the basal layer of the stratified squamous
epithelia at the site of infection (Moody and Laimins 2010; Groves and Coleman
2015). The infective viral particle resembles an icosahedral capsid, composed of the
late region proteins, L1 and L2 (Doorbar et al. 2012). These proteins are able to
interact with heparin sulfate proteoglycans, as well as possibly laminin or integrin
α6 to facilitate cell entry (Giroglou et al. 2001). Micro-wounds within the epithelia
allow viral entry and replication. As epithelial cells divide during wound healing,
viral episomes gain entry to the nucleus (Groves and Coleman 2015). Low-risk
HPV types are particularly dependent on the signaling produced by healing cells to
facilitate viral episome maintenance, gene expression, and persistence of infection
(Doorbar et al. 2012). Conversely, high-risk HPV subtypes, which can drive cell
proliferation, may engage in alternative mechanisms for cell entry and persistence
of infection (Doorbar et al. 2012; Doorbar et al. 2015).
The HPV DNA uncoats and sheds the capsid structure and utilizes cellular
machinery to enter the nucleus (Kajitani et al. 2012). Upon reaching the nucleus, the
virus exists in episomes (Groves and Coleman 2015).
1.3.2 Viral Maintenance and Genome Amplification
Upon nuclear entry, transcription of early genes is initiated. Most early genes
(excluding E4) induce cell proliferation, leading to an increase of cells in the area
that contain the viral genome (Fernandes 2013). At this time, there is very low
expression of viral proteins and genetic material, allowing the virus to evade
immune detection (Doorbar et al. 2015). The HPV genome does not encode
polymerases or most of the other machinery necessary for DNA replication and
relies solely on the host proteins for viral DNA synthesis. The lone exception is
the E1 protein, which functions similarly to human DNA helicase (Moody and
Laimins 2010; Satsuka et al. 2015).The viral E1 and E2 proteins bind at the ori-
gin of replication, which allows the recruitment of cellular polymerases and
other cellular proteins that are required for replication (Moody and Laimins
2010; Kajitani et al. 2012).
Many transient viral infections may affect epithelial cells that are subsequently
shed or cleared by the immune system. Persistent infection is thought to occur as a
result of colonization of stem cells in the basal compartment of the epithelium
(Doorbar et al. 2012). These cells by definition have the capacity for self-renewal
and can give rise to differentiating cells within the stratified squamous epithelium.
By infecting basal stem cells, HPV can persist in the long-lived stem cell compart-
ment and also be passed on to differentiating daughter cells.
As the basal cells give rise to differentiating progeny within the stratified squa-
mous epithelium, HPV episomes are maintained in both cell compartments. Viral
genome replication is coupled to cell division; ensuring sufficient genetic material
is passed on to the mother and daughter cells. Within differentiating daughter cells,
expression of E1, E2, E6, and E7 is maintained, and expression of E4 increases. The
E4 protein promotes a dramatic acceleration in viral genome replication (Fernandes
2013). Meanwhile, E6 and E7 act together to ensure that cells reenter S phase of the
cell cycle. The daughter cells travel upward in the stratified epithelium throughout
the amplification process, as shown in Fig. 1.2 (Fernandes 2013).
Virons are packaged

via late gene expres-
sion of capsid
proteins, and shed
with kerritinocytes
Viral late gene expres-

sion triggers viral
genome amplification
HPV early gene expres-

sion triggers cell
differentiation, and
infect cell numbers
grow while maintain-
ing a low copy number
of viral genomes per
cell
HPV infects cells in

the basal layer
Fig. 1.2 Visualization of viral life cycle and amplification. The HPV virus initially infects cells in
the basal layer, entering through micro-wounds. Wound healing promotes cell replication, and the
virus is able to further induce cell division, resulting in the growth of the number of infected cells
within the area. During this process, the viral genome is kept at a relatively low copy number to
help evade immune detection. As the infected cells differentiate and reach the upper layers of the
epithelia, viral gene replication is triggered and viral copy number significantly increases. Viral
late gene expression leads to the production of functional virions that are shed with the keratino-
cytes, where they can infect new hosts
Upon reaching the superficial layers of the epithelium, the activity of the late
promoter is stimulated (Doorbar 2005). This activation results in expression of viral
capsid proteins (late proteins L1 and L2) as well as an upregulation of viral genes
that are involved in DNA replication, without altering the activity of E6 and E7 that
are required for maintaining the proliferative action of the host cell (Doorbar 2005).
As a result, the viral genome copy number increases from 50–200 to several thou-
sand copies per cell (Fernandes 2013; Doorbar et al. 2015). At the terminal stages
of cell differentiation, E2 mediates the downregulation of E6 and E7, and the cell
exits the cell cycle upon terminal differentiation (Fernandes 2013).
1.3.2.1 Specific Activities of E6 and E7
The E6 and E7 proteins are expressed from a single mRNA transcript. Expression
of E6 and E7 is under the control of E2, which represses transcription upon binding
to the LCR (Bernard et al. 1989). The primary influence of E6 and E7 proteins on
the viral life cycle stems from inhibition of the G1/S cell cycle checkpoint. This
causes the transition into S phase in cells that would otherwise not be dividing
(Doorbar et al. 2012), which allows the viral genome to replicate, amplify, and
eventually be packaged and released. Thus, cell proliferation is a secondary effect
that results from the release of the G1/S checkpoint in infected cells.
The E6 and E7 proteins interact primarily with p53 and Rb, respectively. Key
downstream cellular processes affected by the E6 and E7 proteins are highlighted in
Fig. 1.3. The phenotypic differences seen between the high- and low-risk types
relate to the efficiency by which binding and inactivation occur. Key differences in
the actions of high- and low-risk protein effects are outlined below.
The E7 protein is structurally similar to the adenovirus E1A protein and shares
its 3-domain structure. It was this similarity that leads to the efficient determina-
tion that the retinoblastoma (Rb) tumor suppressor was the target of the E7 protein
(Dyson et al. 1989; Klingelhutz and Roman 2012). The second conserved domain
of E7 (as well as E1A) contains an LXCXE motif, which interacts directly with
Rb and its two related proteins, p107 and p130 (Oh et al. 2004). Rb is a critical
gene in regulating the cell cycle. Rb negatively regulates the E2F family proteins,
resulting in their inactivation during Go and G1 phases of the cell cycle. Under nor-
mal c onditions, the E2F transcription factors are the regulators of the G1 exit and
progression to S phase (McLaughlin-Drubin and Munger 2009). Upon activation
of E2F family proteins, transcription of cyclin A and E occurs, leading to expres-
sion of CDK2 and entry into S phase (Tommasino 2014) (Fig. 1.3). High-risk E7
protein binds to Rb with tenfold greater affinity (White et al. 1994). E7 binding to
Rb leads to its inhibition in low-risk HPV types and proteasomal degradation in
high-risk types (Klingelhutz and Roman 2012). E7 has also been shown to bind
directly to the CDK inhibitors, p21WAFI, CIPI, and p27KIPI, neutralizing their cell
cycle inhibitory effects (Moody and Laimins 2010; Tommasino 2014). Finally, the
E7 protein alters chromatin structure within host cells as a result of Rb inhibition.
Specifically, E7 counteracts Rb-dependent histone deacetylase (HDAC) regulation
Cell Proliferation,
immortality
TERT Via PDZ domain

Reduction of Viral
E6 growth rates
DLG Loss of viral
episomes
P300 Many cell division

E6AP CBP pathways
Cell Cycle
Via E3 Ubiquitin ligase
checkpoint Degradation
activation, cell p53 of p53
cycle arrest (High-Risk)
p21 WAFI
E7 CIPI
p27 KIPI Cell Cycle
Arrest
Rb CyclinA
HDAC E2F
CyclinE CDK2
Chromatin remodelling
(Rb dependent)
Cell Growth
G1 S
Fig. 1.3 Significant cell signaling pathways of HPV E6 and E7 proteins. E6 and E7 proteins
inhibit tumor suppressor proteins p53 and pRb, respectively. The E6 protein associated with the
E6-associated protein (E6AP) degrades p53 via an E3 ubiquitin ligase in high-risk HPV types. This
association is seen in low-risk types, but does not lead to the degradation of p53; instead a loss of
function is seen. The lack of p53 activity results in a loss of the G1/S cell cycle checkpoint arrest.
Via a PDZ domain, E6 is able to inhibit DLG and associated proteins, preventing the complex from
exerting its function: inhibiting viral growth rates and eliminating viral episomes. E6 can interact
with other proteins to enhance cell proliferation and prevent cell senescence. The E7 protein inhib-
its Rb, which under normal cellular conditions prevents the cell from reentering the cell cycle via
the G1 to S phase transition. With Rb activation, E2F is inhibited, preventing cyclin A/E and CDK2
activation. E7 has also been shown to inhibit other proteins that ultimately result in CDK2 deacti-
vation. Finally, E7 binds HDAC proteins, which contributes to unrestrained cell growth through
aberrant chromatin remodeling
of E2F-regulated genes. Moreover, Rb-independent interaction of E7 with HDAC

has been shown to promote cell growth (Brehm et al. 1999).
The deregulation of the cell cycle induced by E7 function causes levels of the
G1/S cell cycle checkpoint protein, p53, to increase which leads to cell cycle arrest
(Moody and Laimins 2010). Both high- and low-risk HPV E6 proteins inactivate
p53 function to relieve this cell cycle arrest, but only high-risk E6 is able to incite
the ubiquitination and degradation of the protein (Klingelhutz and Roman 2012).
Specifically, high-risk E6 proteins interact with E6-associated protein (E6AP),

forming a complex that binds to the DNA binding domain of p53 and leading to its
degradation via E3 ubiquitin ligase (Fig. 1.3) (Scheffner et al. 1993). While low-risk
E6 proteins can also form a complex with E6AP, they do not incite ubiquitination,
suggesting that alternate mechanisms of p53 inhibition are more relevant, and ubiq-
uitination targets of the E6 and E6AP complex are unclear (Brimer et al. 2007). The
E6 protein itself can also bind to p53 to inhibit function in both high- and low-risk
types (Lechner and Laimins 1994), and this is believed to be the main mechanism
by which low-risk HPV types inhibit p53 activity (Moody and Laimins 2010).
E6 can also inhibit the activities of p300 and CREB-binding protein (CBP),
which are transcriptional co-activators involved in many pathways relevant to cel-
lular differentiation and proliferation (Patel et al. 1999; Moody and Laimins 2010).
One of the downstream transcriptional targets of p300/CBP signaling is p53 itself.
E6 proteins from both high- and low-risk HPV types bind to p300/CBP; however
the inhibition by the low-risk HPV6 E6 was only 50% as efficient as that by the
high-risk HPV16 E6 (Patel et al. 1999).
An additional mechanism by which high-risk HPV E6 proteins promote cell
cycle continuation and progression is through inhibition and degradation of the
tumor suppressor, DLG. High-risk HPV E6 proteins harbor a PDZ binding motif
(PDM) located at the C terminus of the protein (Doorbar et al. 2015), which facili-
tates binding to the PDZ domain within DLG. This binding results in the degrada-
tion of DLG and an augmentation in cellular growth rate (Pim et al. 2000; Pim and
Banks 2010). Blocking the interaction between HPV16 E6 and DLG was shown to
reduce the cellular growth rate and lead to a loss of viral episomes (Brimer et al.
2007; Nicolaides et al. 2011). While low-risk HPV E6 proteins are also critical for
maintenance of viral episomes (Oh et al. 2004), unlike high-risk HPV E6 proteins,
they are apparently unable to induce the degradation of DLG (Brimer et al. 2007).
The E6 protein has also been shown to interact with telomerase-related enzymes,
leading to an increase in TERT transcription. This allows indefinite proliferation
and the maintenance of cellular immortality, although this is only seen in high-risk
HPV types (Klingelhutz and Roman 2012; Tommasino 2014). There are many addi-
tional known targets of the E6 protein; however their exact cellular functions are
unknown (Tommasino 2014).
1.3.3 Virus Synthesis and Release
When the basal daughter cell approaches the surface of the stratified epithelium, it
reaches terminal differentiation, and encapsulation of the viral genome is triggered
(Kajitani et al. 2012; Doorbar et al. 2015). Alternative RNA splicing facilitates the
turnover from early to late gene translation (Kajitani et al. 2012). The capsid pro-
teins, L1 and L2, are expressed and transported into the nucleus where capsid
assembly takes place. L2 is guided into the nucleus through its association with
host protein, DAXX. PML bodies attract high levels of L2 protein and act as a scaf-
fold to facilitate viral capsid assembly. L1 is then recruited to these sites. L1 is
sufficient for viral capsid assembly, but this process is more efficient in the pres-
ence of L2 (Doorbar 2005). On the surface layer, dying keratinocytes undergo a
change lose their mitochondrial oxidative phosphorylation capability, decreasing
the overall pH of the viral environment. As a result, disulfide bonds form between
L1 proteins, which stabilizes the capsid structure (Buck et al. 2005; Doorbar et al.
2015). Virus maturation occurs as keratinocytes become cornified cells that are
shed along with mature packaged virions (Bryan and Brown 2001). Encapsulated
virions are then released from the shedding cells into the environment, where they
can survive for greater than 1 week prior to reinfection into a new host (Roden
et al. 1997).
1.4 Pathogenesis of HPV
Most HPV infections are cleared within 6–12 months without lasting effects
(Tommasino 2014). However, HPV is the causative agent in a number of neoplastic
conditions that have a significant impact on human health. It is therefore important
to consider the many factors involved in the transition from viral colonization to a
disease state.
1.4.1 Role of HPV in RRP
Recurrent respiratory papillomatosis (RRP) is a rare disease affecting children. RRP

is characterized by periods of recurrent growth of lesions in the mucosal surfaces of
the upper airways. HPV is the causative agent and is found within 91–100% of
lesions (Draganov et al. 2006), with the variety arising from different sequencing
methods used to detect HPV. With modern methods, it can be assumed that all cases
of RRP are caused by HPV infection.
Interestingly, the copy number of the HPV genome seen in RRP, at around
102–107 copies per μg, is significantly higher than that seen in carcinomas of the
cervix, pharynx, and larynx (Donne et al. 2010). Additionally, dramatic changes in
copy number are seen throughout the course of the disease (Major et al. 2005).
Increased copy number of HPV DNA is considered to be associated with severity in
RRP (Major et al. 2008).
Despite the ubiquity of HPV exposure, RRP remains a rare disease entity. The
reasons for the discrepancy are not well understood, and no clear biomarkers
have been confirmed to predict RRP incidence in children. Immune status is
thought to be a major contributor to RRP, as those with immunodeficiency (e.g.,
organ transplant and AIDS patients) experience more severe disease course in
other HPV-associated diseases (Doorbar 2005; Stern et al. 2007). Likewise,

immune function likely influences RRP progression in children. A prospective
study of 20 children with RRP examined disease severity and course compared to
immunological factors measured at regular intervals of 6 months over the course
of the study (Stern et al. 2007). In this small study, the ratio of CD4 + T cells to
cytotoxic CD8 + T cells was reduced in RRP patients compared to matched nega-
tive controls (Stern et al. 2007). Other studies have found additional differences
between the immune function (both innate and adaptive immunity) of RRP
patients and controls (Bonagura et al. 2010; Lucs et al. 2015). Nonetheless, no
single host immune factor identified to date can fully explain the diagnosis or
severity of RRP.
1.4.2 Neoplastic Transformation by E6 and E7
The neoplastic transformation of HPV stems in large part from disruption of the
tumor suppressor proteins p53 and Rb by E6 and E7, respectively. Low-risk E6 and
E7 cause aberrant cell proliferation within stratified squamous epithelia leading to
warts, RRP, and other benign papillomatous conditions. The development of inva-
sive malignancy is uncommon in tissues infected with low-risk HPV types. In RRP,
for example, approximately 3–6% of cases (<1% in juvenile cases) develop into a
malignant carcinoma (Donne et al. 2010). High-risk E6 and E7 impart a massively
greater risk for progression toward invasive malignancy due to higher potency of
p53 and Rb inhibition.
The role of E6 and E7 proteins in neoplastic transformation can be illustrated by
the way they promote the hallmarks of cancer. First described by Hanahan and
Weinberg in 2000 (Hanahan 2000) and expanded in 2011 (Hanahan and Weinberg
2011), the hallmarks of cancer describe a rational framework for understanding
processes that lead to neoplastic transformation. The E6 and E7 proteins perturb
pathways involved in several of the hallmarks, including:
• Sustaining proliferative signaling
• Evading growth suppression
• Resisting cell death
• Enabling replicative immortality
• Activating invasion and metastasis
• Deregulating cellular energetics
E6 and E7 promote these hallmarks of cancer through additional mechanisms
other than p53 and Rb inhibition. For instance, high-risk E6 promotes evasion of
growth suppression through inhibition of cell-to-cell contact and loss of cell polar-
ity (Pim et al. 2000; Pim and Banks 2010), and high-risk E7 deregulates cellular
energetics (McLaughlin-Drubin and Munger 2009). Cellular metabolism in HPV-
infected cells is shifted away from mitochondrial respiration and oxygen consump-
tion toward anaerobic glycolysis, a change that is triggered in part by E7 expression
(McLaughlin-Drubin and Munger 2009).
1.4.3 Neoplastic Transformation by Additional Mechanisms
The expression of E6 and E7 is integral to neoplastic transformation of HPV-infected

tissues. Nonetheless, E6 and E7 are insufficient to induce invasive malignancy in the
absence of additional “second hit” mutations. Supporting this, high-risk E6 and E7
expression is able to cause immortalization of human keratinocytes in culture (Brehm
et al. 1999), but activation of additional oncogenes is necessary to induce tumors
when the cells are injected into mice (McLaughlin-Drubin and Munger 2009).
A number of processes contribute to accumulation of second hit mutations that
promote invasive malignancy. First, passive accumulation of random mutations is
far more likely to occur within replicating cells than in uninfected quiescent cells.
Second, innate antiviral APOBEC-mediated mutagenesis, which is meant to dam-
age foreign viral DNA, also can result in collateral damage within host oncogenes
and tumor suppressors (Rebhandl et al. 2015). Third, viral genome integration leads
to activation of oncogenes or inactivation of tumor suppressors through varied
mechanisms. Fourth, chromosomal instability resulting in aneuploidy and rear-
ranged chromosomes (Duensing and Münger 2002) is tolerated by HPV-infected
cells as a result of p53 inhibition (White et al. 1994). Thus, a multitude of processes
can lead to increased mutagenesis and heightened genomic instability, which ulti-
mately can disrupt normal cellular and tissue homeostasis.
Integration of the viral genome into the host DNA, while not essential, contrib-
utes to the development of invasive malignancy (Moody and Laimins 2010;
Tommasino 2014). As described above, host genes that are activated or disrupted by
viral integration can directly drive oncogenesis. Moreover, disruption of the E2
gene upon linearization of the viral genome results in higher expression of E6 and
E7. Virus integration into the host genome often occurs at the E2 locus, therefore
disrupting gene function (Donne et al. 2010). However, recent high-throughput
sequencing studies have revealed that viral integration in cervical cancer can occur
at other viral loci in addition to E2 (Hu et al. 2015), so this mechanism might not be
necessary for the development of invasive malignancy.
Despite the variety of mechanisms by which HPV can induce a neoplastic
change, as mentioned previously, very few HPV infections even with high-risk
types cause neoplasia. Persistence of the virus is the critical factor in neoplastic
transformation (Moody and Laimins 2010; Doorbar et al. 2012). Immune-mediated
clearance of acute infections eliminates the risk of transformation (Tommasino
2014). Individuals whose immune systems fail to clear the virus, however, are at
risk. With persistence, unrestrained cellular division can continue.
1.4.4 Evasion of Immune-Mediated Clearance
Evasion of the immune recognition and clearance is critical for HPV to infect and
persist within epithelial tissues. Several intrinsic characteristics of HPV allow it to
counter immune detection. First, the virus produces no cell death or viral lysis.
Second, the entire viral life cycle occurs within intact epithelial cells resulting in no
virus entering the bloodstream. Third, viral replication does not promote inflamma-
tion (Doorbar et al. 2015). In addition, there are a number of molecular mechanisms
by which HPV evades both adaptive and innate immunity.
1.4.4.1 Mechanisms of HPV Evasion of Adaptive Immunity
HPV actively blocks antigen presentation in infected keratinocytes. HPV-related

tumors experience a loss of major histocompatibility complex (MHC) I, which is
required for antigen recognition by T cells (Kanodia et al. 2007). E5, E6, and E7
each contribute to reduced MHC-I expression on the surface of infected cells
(Kanodia et al. 2007). Moreover, many viral peptides are similar in composition to
human peptides; thus, endogenous mechanisms for self-tolerance are co-opted by
the virus to minimize immune recognition (Kanodia et al. 2007).
1.4.4.2 Mechanisms of HPV Evasion of Innate Immunity
Under normal conditions, keratinocytes express pathogen recognition receptors

(PRRs), which recognize specific pathogen-associated molecular patterns (PAMPs)
(Stanley 2012; Zhou et al. 2013). Two classes of PRRs drive recognition of HPV by
keratinocytes: Toll-like receptors (TLR family) and nucleotide-binding domain—
leucine-rich repeat-containing PRRs (NLR family) (Stanley 2012).
TLR activation triggers an antiviral response through type I interferon (IFN)
signaling (Zhou et al. 2013). In HPV-infected cells, E7 blocks the antiviral effects
of type I IFN signaling (Stanley 2012). In addition, E6 inhibits transcription of type
I IFN mRNAs (Stanley 2012; Doorbar et al. 2015) as well as downstream JAK-
STAT activation by type I IFN (Stanley 2012; Doorbar et al. 2015).
The NLR response is routinely elicited by keratinocytes during cell injury and
stress. Downstream signaling following NLR binding triggers interleukin 1 (IL-1)
secretion (Stanley 2012). IL-1 secretion is critical for the activation of
antigen-presenting cells of the skin and mucosa. Both E6 and E7 dampen the IL-1
response seen upon NLR activation (Stanley 2012).
1.5 Summary
The HPV family displays striking diversity in nucleotide sequence, but there is
much in common in the manner by which distinct HPV types infect human tissues
and cause disease. Despite a small and relatively simple genomic makeup, perturba-
tions caused by HPV infection can activate many of the classic hallmarks of cancer.
Viral factors are able to co-opt normal homeostatic processes within infected cells
and squamous epithelial tissues to establish persistent infections, evade host immune
detection, and activate neoplastic pathways.
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Chapter 2
The Epidemiology of Recurrent Respiratory
Papillomatosis
Paolo Campisi
Abbreviations
APSU Australian Paediatric Surveillance Unit

CDC Centers for Disease Control and Prevention
HLA Human leukocyte antigen
HPV Human papillomavirus
ICD International Classification of Diseases
JoRRP Juvenile-onset recurrent respiratory papillomatosis
KIR Killer-cell immunoglobulin-like receptors
PPV Positive predictive value
RRP Recurrent respiratory papillomatosis
2.1 Epidemiology: A Global Perspective
For rare conditions such as juvenile-onset recurrent respiratory papillomatosis

(JoRRP), it is important to have a firm understanding of the epidemiology of the
disease. This is only possible by combining the collective experience of multi-
ple centers as individual institutional experience is typically limited.
Collaborative efforts are necessary to define the clinical and economic burden
the condition poses to the health-care system and guide public health initiatives
such as vaccination programs. For the patient, understanding the disease is
important for patient and family counseling, the development of novel primary
P. Campisi
Department of Otolaryngology—Head and Neck Surgery, Hospital for Sick Children,
University of Toronto, Toronto, ON, Canada, M5G 1X8
e-mail: paolo.campisi@sickkids.ca
© Springer International Publishing AG 2018 19

P. Campisi (ed.), Recurrent Respiratory Papillomatosis,
https://doi.org/10.1007/978-3-319-63823-2_2
20 P. Campisi
Norway
Incidence: 0.17
Canada
Incidence: 0.24
Prevalence: 1.11 Copenhagen, Denmark
Incidence: 0.6
Funen, Denmark
Incidence:0.48
Seattle
Incidence: 0.36 USA
Prevalence: 1.69 Incidence: 0.4– 4.3
Atlanta
Incidence: 1.11
Prevalence: 2.59
Australia
Prevalence: 0.8
Free State Province Lesotho
South Africa Incidence: 0.49
Incidence: 1.34 Prevalence: 1.04
Prevalence: 3.88
Fig. 2.1 Global reported rates of incidence and prevalence of JoRRP. Rates are per 100,000
children
and adjuvant treatment strategies, and early detection or mitigation of serious

complications such as lower airway dissemination of papillomas and malignant
transformation.
Several health-care jurisdictions have developed databases and registries at a
regional or national level with the common goal of understanding JoRRP. The
results of these efforts have been reported from health-care regions in North
America, Europe, Australia, and Africa (see Fig. 2.1).
2.1.1 Africa
Estimates of incidence and prevalence for JoRRP have been reported for the Free
State province of South Africa and Lesotho, a small country of 1.9 million people
geographically situated within South Africa (Seedat 2014). The Free State province
has a population of 2.75 million people, and all cases of JoRRP from the Free State
and Lesotho are managed at the same referral center. The retrospective study
reviewed all cases in patients under the age of 15 years presenting between January
2011 and December 2013. The estimates of incidence and prevalence were calcu-
lated based on midyear populations of children aged 0–14 years published by
Statistics South Africa and the Lesotho Bureau of Statistics.
During this 3-year period, 31 new cases of JoRRP were diagnosed in the Free
State province with an average incidence of 1.34 per 100,000 per year. Year over
year, the incidence fluctuated between 0.52 and 2.36 per 100,000 population per
year. The average prevalence was 3.88 per 100,000 per year (range, 3.10–4.73 per
100,000 population per year). The median age at diagnosis was 4.3 years, and the
male to female ratio was 1:1.21.
2 The Epidemiology of Recurrent Respiratory Papillomatosis 21
In comparison, 10 new cases of JoRRP were referred from Lesotho, indicating

an incidence of 0.49 per 100,000 and a prevalence of 1.04 per 100,000 population
per year. The median age at diagnosis was slightly lower at 3.8 years, and the male
to female ratio was 4:1. The variability in the statistical measures is expected in
jurisdictions with relatively small populations. Moreover, the measures of incidence
and prevalence are probably an underestimation due to more difficult access to med-
ical care for patients from remote communities and the high rate of poverty in the
Free State province and Lesotho. Although not specifically studied, the high preva-
lence of coinfection with HIV may account for the higher incidence and prevalence
rate reported for Africa compared to populations in Europe, Australia, and North
America.
Estimates of disease burden have also been reported for academic referral cen-
ters in cities in Ghana and Nigeria. In 2012, Baidoo and Kitcher retrospectively
reviewed the theater records at the ENT Unit of Korle Bu Teaching Hospital, Accra,
Ghana (Baidoo and Kitcher 2012). Over a 10-year period, 69 patients were treated
for RRP. The median age of the patients was 8.5 years (range 2–54 years). Forty-
eight (70%) of the patients were children 10 years of age or younger. The patients
were subjected to a high cumulative rate of tracheostomy of 14.5%. The authors
recognized the need to avoid tracheostomy to prevent the distal airway spread of
papillomas. However, limitations to accessing medical care in remote communities
rendered the need for tracheostomy unavoidable.
A similarly large proportion of pediatric patients were identified in two studies
from Nigeria. In Ibadan, Nigeria, 74.4% of RRP patients were children (Nwaorgu
et al. 2004). In Enugu, Nigeria, an 11-year review of 54 cases of RRP revealed that
51.8% of patients were children (Mgbor et al. 2005). Epidemiological data from
South Africa, Lesotho, Ghana, and Nigeria confirm that RRP has a significant pedi-
atric footprint.
2.1.2 Australia
Efforts to estimate the incidence and prevalence of JoRRP in Australia have been
spearheaded by Novakovic and Brotherton. In a recently published study, Novakovic
and colleagues reported the results of a retrospective review of pediatric RRP cases
presenting at three tertiary pediatric hospitals in New South Wales (Novakovic et al.
2016). Cases were identified from hospital records using ICD-10 codes and RRP-
related procedure codes. The local epidemiological results were subsequently
applied to national hospital separations data to estimate national disease
prevalence.
The retrospective review at the three pediatric hospitals in New South Wales
identified 30 cases of JoRRP with a median age of onset of 36 months. There was a
small female preponderance (57%). The use of ICD-10 codes to identify cases was
found to have a very high positive predictive value of 98.1%. Assuming the high
positive predictive value was consistent nationally, the local data was applied to
national hospital separations data. This exercise revealed a national (estimated)
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THE WELLS AT THE FOOT OF GEBAL ARANG.
See p. 18.
On these inland marches we carried water in tanks, and were

obliged to hoard it. We had to go back in the morning to the
allowance which had served us for washing purposes overnight. In
all this region, every condition of life, important and unimportant,
depends upon the rivers. At Gebel Arang we saw gazelles and the
antelopes called ariels for the first time. We also caught sight of a
large bustard, and my companion stalked it unsuccessfully. It is hard
work to carry a gun in a hot country where every bush, and even the
grass, grows thorns that “mean business,” and the man who fails is
usually weary as well as disappointed.
Next day, December 16, we travelled at the foot of the hills. It was
a pleasant journey, for there was verdure, and the tall mimosas
threw shade on the track. Besides the flocks of guinea-fowl to which
we were accustomed, we saw a hare—the first we had found in the
Soudan. Before midday we reached the wells of Fau. The drinking-
water here is of a fairly good quality, but not quite free from mud.
Guinea-fowl again supplied our dinner. They are slow to rise, but not
easy to shoot; for they run in the most nimble fashion among the
thick covert, and to come within range, the “guns” have to run too.
The sun is strong overhead, the thorns are strong all round, and the
exercise is smart work, even for a man in sound condition.
In the evening a messenger from the Intelligence Department
reached our camp. He brought us letters and papers, and I
ascertained that he, on a fast camel and without baggage, had
travelled in two and a half days a distance which we had covered in
six.
Our halting-place was between two ranges of the hills. The wind
blew hard during the night, and the current of it came racing down
the valley where we lay. Great clouds of dust were carried with it,
and the particles were driven thickly into every crevice and corner.
Crawley and I tried to form a shelter by piling up our square boxes
behind us, but this was of little avail. It was an excitement of a sort,
but not pleasant to a sleepy man.
We lay later than usual next morning, December 17, as we did not
intend to strike our camp till midday. My companions went to shoot
the poultry, and I remained in my tent and nearly shot myself without
expending a cartridge. Our plan for securing fizzing drinks was to put
a sparklet in a bottle of water and screw in the top. I was busy upon
this operation when the bottle which I was handling burst. As luck
would have it, I received no injury, though I was peppered with
fragments of glass. One particle entered the eye of my boy Achmet. I
extracted it and found that no serious damage had been done to the
organ. After this, we abandoned the use of sparklets, and fizzing
drinks were things of the “dear, dead past,” and the uncertain future.
We left the camp at midday, after six guinea-fowl had been
brought in, and struck into the waterless country between our
halting-place and Gedaref. The distance is seventy-two miles. We
were obliged to carry the drinking supply for the whole journey. Our
route lay along a good track that follows the line of the telegraph.
The soil in this region is soft, friable earth, perfectly adapted for
cotton cultivation. But the district is unhealthy in the rainy season,
when malaria prevails and the country is a reeking swamp of dead
and living vegetation. It was perfectly dry when we traversed it, and
we ran no risk of disease. The tangle of desiccated tall grass lay
upon the ground, as in so many tracts of this part of the Soudan, and
our road was bordered by mimosa shrubs. They grow thickly in
places, but were not high enough to give protection from the sun.
We halted for the night at five o’clock, and unpacked only our
beds and such things as were strictly necessary, for we were to start
at half-past four next morning.
I was very sleepy when I was roused at 3.30 a.m. on the 18th. We
had a cup of cocoa, and then left our camping-ground at the
appointed time by moonlight. The air was chilly even after the sun
rose at six o’clock, and the warmth of the day did not make itself felt
before eight. At half-past ten we halted for a déjeuner à la fourchette,
and rested for a couple of hours.
Darkness had fallen by the time we reached our camping-ground
at the place called Terras Wad-el-Fau. We had covered thirty-two
miles of our journey since the morning. At this spot we rejoiced to
find that an Egyptian soldier in charge of two fantasses (watertanks)
had been sent to meet us by the Inspector of Gedaref. Our camel-
men with the baggage were some distance behind us, and we
lighted a bonfire of mimosa wood to cheer them forward. They
overtook us at their leisure, and our dinner of stewed guinea-fowl
was not served till a quarter to ten.
We were out of bed by five o’clock next morning, December 19,
and hastened the preparations for the start. We had to cover thirty
miles in order to reach Gedaref in the evening. All this country—I
cannot call it desert, though the conditions are not dissimilar—is
comfortless for travellers, but our last day’s journey in it was the
worst. The heat was intense; so much so that “resting” at lunch-time
seemed less tolerable than movement on camel-back. To quench an
incessant thirst we had only the water stored in our tanks, which was
warm and far from colourless. Even the hint of shade given by the
mimosa scrub had now disappeared, and our eyes were wearied by
the monotonous stretches of land, in which nothing was seen but the
dried and matted grass. It had been fired in places, accidentally I
think; for though it is often kindled to clear the ground for crops, in
this region there was no trace of agriculture. The flames had a
ghostly, exhausted, unreal look in the burning sunshine. After a
march that seemed interminable we beheld, from rising ground,
three trees with verdure on them, and then we knew that we were
near the boundary of this distressing district. A two miles’ journey
brought us to the house of Mr. Flemming at Gedaref[11]—a square
building made of sun-dried mud. At our countryman’s dwelling a
warm welcome and cool drinks awaited us. Here we found
Bimbashis Gwynn and Liddell. That evening Mr. Flemming gave us
our Christmas dinner—and we reconciled ourselves to antedating it
—with true British plum-pudding in the menu.
MR. FLEMMING’S HOUSE AT GEDAREF.

See p. 22.
REST-HOUSE BETWEEN GOZ REGEB AND ADARAMA.
See p. 214.
From a Photograph by Mr. C. E. Dupuis.
CHAPTER III
I had slept in the open by choice and felt it a luxury to awake on the
following morning with no prospect of a fatiguing journey. At seven
o’clock on December 20 we met again at Mr. Flemming’s house, and
busied ourselves with amateur photography.
“You are the last white men I shall see until June next year,” said
our host, “so I want to keep your faces.”
After breakfast we proceeded to the selection of seventeen
“boys,” who were to go up with our donkeys from Gallabat to
Abyssinia. The character of the country beyond the frontier of the
Soudan renders transit by camel impossible. It struck me as an
interesting fact, not without a bearing upon the doctrine of Evolution,
that the change from a flat or undulating to a mountainous region is
here accompanied not only by a variation in the means of access, in
the climate, in the flora and fauna, but in the race of inhabitants and
the creed which they profess. In fact, the highlands of Abyssinia may
be said to constitute “an island on the land,” if one may borrow the
phrase which Darwin applied to the peaks of the Andes. And a
similar peculiarity in the survival of types can be observed here as
that to which the great biologist referred in the other connection.
Mansfield Parkyns pointed out that the Abyssinians were, in his
time, poor swordsmen, ridiculous in their practice of musketry and
frequently wanting in genuine courage.[12] Their country has
constantly been the scene of civil war and other dissensions. Indeed
the Jews among them, to whom I shall refer in another chapter, at
one time established a separate state in the “mountain fastnesses of
Semien and Belusa, where, under their own kings and queens called
Gideon and Judith, they maintained till the beginning of the
seventeenth century a chequered and independent existence.”[13]
In spite of these hindrances and deficiencies the Abyssinian
people, government and creed, have survived among heights
protected on one side by the sea and on the other by a tract of
country which is uninhabitable and impassable from May to
September, on account of the incessant torrential rains and the
floods which they cause. If these favouring conditions had not
existed, the Abyssinian nation would long ago have been “converted”
to Islamism or exterminated, and in the former case they would have
become assimilated by consanguinity to, if not merged in, the
surrounding Arab and negroid tribes. As it is, the Abyssinians form,
ethnologically, an entirely distinct race.
This digression has carried me a long way from the “donkey-boys”
at Gedaref. They were paraded to the number of a hundred for our
inspection—Dongolis, Abyssinians, Tokrooris, Dinkas, Hadendowas,
men from every clan in the district. An uglier-looking crowd I never
beheld, and, as I gazed at the sinister, villainous faces, I hoped
rather than believed that our choice of seventeen would not include
robbers or murderers. We adopted the plan of choosing one or two
men from each of the different races. Experience showed that the
policy was sound, for no tribal quarrel was raised during our journey
in Abyssinia. None of the groups was strong enough to commence a
feud with confidence.
The business of selection was completed after the haggling and
confusion inseparable from a bargain among Orientals, and I spent
most of the remainder of this and the following day in acquainting
myself with the features of life in Gedaref. As this place is a type of
the more important towns in the Soudan, in which Great Britain has a
permanent interest, I hope the reader will tolerate the transcription of
a few of my notes.
The inhabitants number about eight thousand, and live—to use
Mr. Dufton’s description—“in a number of scattered villages, the
principal called Hellet-es-Sook, or the market town.”[14] The
dwellings in this part of the Soudan and in Abyssinia are of the same
construction, and I cannot better convey a conception of their
simplicity and their appearance to those of my readers who have not
seen them than by quoting the following passage from Mr. Dufton’s
work:—“Some of the houses are built of sun-dried bricks and have
flat roofs, but most of them” (almost all in Western Abyssinia) “are
conical thatched huts. The latter are made in the following manner:—
In the first place a circle of about twenty feet diameter is described
on the ground and surrounded by strong posts, each a yard apart,
which are interlaced with thin pliable branches of trees, the whole
being covered outwardly with durrha stalks, tied together with the
long grass common on the banks of the river. A roof is formed in
skeleton on the ground. A number of beams, corresponding to that of
the posts, are made to converge at the top, and are held in this
position by concentric circles of plaited twigs; the whole being then
raised to its position on the house, where it is fastened and made
ready to receive the thatch of straw and grass. Not a nail or rivet of
any kind is used in the construction of these buildings, and they are
rendered totally impervious to the wet. Of course their disadvantage
in comparison with mud houses is their liability to catch fire, one or
two cases of which I have witnessed; but they are generally built at
sufficient distance not to endanger others, and a house of this
description is rebuilt in a day or two.”[15] Hence the scattered
appearance of the huts. They cover a distance some five miles in
length at Gedaref. These dwellings are called “tokhuls,” and I shall
have occasion to allude to them frequently under that name. In the
Soudan storks build their nests round the upper part of the roofs, and
are not molested.
In Mr. Dufton’s time an open-air market was held twice a week in
Gedaref. He thus describes it:—“One part is devoted to the sale of
camels, cattle, sheep, and goats; another to that of corn and durrha;
another milk and butter; another raw cotton, dates, etc. The butcher
slaughters his meat on the spot, whether ox, sheep, or camel. The
camel is killed somewhat differently from the rest; for it may well be
imagined that a camel with merely its throat cut might be a long while
in dying. They therefore adopt the mode of striking it with a long knife
at once to the heart, having previously taken care to tie his long legs
in a manner that he cannot move.”[16]
The commerce of the place has been resuscitated since the
British and Egyptian occupation. The market is now held daily. In
addition there are the usual bazaars of an Oriental town. Gedaref
has the advantage of possessing wells from which water of good
quality is drawn. The place suffered severely in the time of the
Dervishes. They raided the district as often as their supplies ran low,
ruined the cultivation, and destroyed the greater part of the
habitations.
The people seemed to be peaceable and contented under the
present administration, and I was struck by their politeness towards
Europeans. As we passed, they rose, if they were squatting on the
ground; those riding dismounted as a token of respect; those who
were at work discontinued it and stood still.
There are a certain number of shops in the town kept by Greeks.
The commerce of the Eastern Soudan is almost entirely in the hands
of Hellenes, who import goods by way of Suakim. The merchandise
is brought up the country by camel-train. The articles most in request
among the natives are cheap mirrors, tumblers, coloured silk
handkerchiefs and similar goods—in short, cheap finery and cheap
small commodities. I am not a commercial man, and do not speak
upon the point with certainty, but I think German houses meet this
demand. The Greek retailers also carry on a brisk trade in olives,
which are imported in barrels. Olives and bread are the staple of the
diet of many Soudanese, and they eat this simple food with relish.
We found that we could purchase sugar, taken from the familiar
sugar-loaf, soap, similar sundries and tinned provisions at Gedaref. I
was pleased to observe—for my own sake and that of British
enterprise—that the latter bore the trade-mark of Messrs. Crosse
and Blackwell.
My impression with regard to commercial opportunities in these
towns is that a northern-bred storekeeper could not compete with the
Greek retailer. I do not refer, in making this inference, especially to
the singular astuteness of the latter. But it is an important
consideration that these men are able to live almost on the same
scale as the natives, and their profits are due to the frugality of their
life.
We managed to start our baggage-train on the journey from
Gedaref to Gallabat by a quarter to eight on the morning of the 22nd
December. Then we breakfasted with Mr. Flemming, and mounted
our camels to take the road again at 9.15. We moved forward at a
trot, and I, now making trial of my fourth “steed,” found I had good
luck for the second time. But I do not think that any one could devote
to the camel the affection which is so readily given to a horse after a
brief acquaintance. The animal with the “sculptured sneer” does not
invite friendship. It grunts and grimaces when one mounts, and the
rider can be under no illusion as to its sentiment towards him.
We saw some ariel, and my companions gave chase and tried to
get within rifle-range. But the animals were shy and wary. The
hunters exhausted their supply of ammunition, but brought no game.
We lunched as usual in the scrappy shade of a mimosa bush, and
reached Shisana well shortly after four o’clock.
We had now left the “cotton soil” region, and entered an
undulating country, where our road lay over rocky or stony ground.
The character of the vegetation changed, and we began to pass
through glades of the great mimosa forest which extends from the
neighbourhood of Gedaref almost to Gallabat. Here the mimosas are
not bushes but trees, and it is from them that the gum-arabic is
collected which gives Gedaref its highly valuable trade and its
prosperity. Large quantities of the gum are exported by way of
Suakim, and there is a market for it at Cairo and other towns of
Lower Egypt. For instance, much crape is manufactured in Damietta,
where I have watched the process. Gum from Gedaref is used to
stiffen the texture, and serves the same purpose in the preparation
of various silken fabrics.
The industry might be largely developed. At present it is in the
hands of Greek traders. As the supply of coin in the Soudan is small,
the gum is used as a kind of currency by the natives, who barter it for
other goods. A small duty is levied by the Government on the
quantity exported, and no one seems appreciably the worse. I
present this detail of information to fiscal controversialists, and make
no demand upon their gratitude in doing so.
The gum-bearing mimosas are, on an average, I should say,
about twenty-five feet high. The boles are straight. Thorns grow
thickly on the branches. The white bark gives a characteristic and
almost haunting feature to the great forest. The gum exudes, chiefly,
at the junction of the branches with the trunk. Its appearance has
been excellently described by Sir Samuel Baker: “At this season the
gum was in perfection, and the finest quality was now before us in
beautiful amber-coloured masses upon the stems and branches,
varying from the size of a nutmeg to that of an orange. . . . This gum,
although as hard as ice on the exterior, was limpid in the centre,
resembling melted amber, and as clear as though refined by some
artificial process. . . . The beautiful balls of frosted yellow gum
recalled the idea of the precious jewels upon the trees in the garden
of the wonderful lamp of the ‘Arabian Nights.’ The gum was
exceedingly sweet and pleasant to the taste.”[17] The trees were in
flower when we saw them, and the blossoms scented the air sweetly.
The present method of collecting gum is primitive and
unsystematic. Natives go a two or three days’ journey from Gedaref
into the forest, when they are pressed by want of a commodity to sell
or exchange, and return with as much as they have gathered at
hazard.
GUM BEARING MIMOSA TREES.
See p. 30.
TRYING THE TEMPERATURE OF A PATIENT AT THE DOCTOR’S PARADE.
See p. 115.
Throughout the day’s march we had seen fires raging in the dried
grass, and we had frequently passed places where the charred
surface showed the effect of the flames. The custom of setting the
undergrowth alight would destroy the mimosa forest, but for the fact
that the fires burn low and travel quickly. The branches of the trees
do not spring from the lower expanse of the boles, and there is
consequently no combustion of the timber, except where a quantity
of old, sapless wood is ignited.
Trouble threatened us at Shisana well. Grain for the donkeys and
boys, that were to accompany us into Abyssinia, had been packed in
sacks at Gedaref. The friction caused by the camels’ movement had
frayed these open, and the grain was lying on the ground when we
arrived. At first we feared that we should be obliged to return to the
town and purchase new sacks; but luckily the camel-men were
bringing with them a stock of capacious and pliable baskets, made of
slit palm-leaves, which they had intended to sell at Gallabat. These
we commandeered, and so extricated ourselves from the difficulty.
Our journey next day was through entirely similar scenery, over
undulating, rocky ground. We saw some ariel, but again they were
too shy for us. Then we “declined upon” guinea-fowl, and bagged
two after a brisk, exciting run.
The heat was overpowering, and at lunch-time we had no rest.
Bees abound in this region, and get their honey from the flowers of
the mimosa trees. As the land is almost waterless in the dry season,
these insects suffer much from thirst. Even the moisture of
perspiration attracts them in their parched state, and, in addition,
there was the smell of water from our drinking-supply. The result was
that they swarmed upon us; in fact, they mobbed us. Every drinking
vessel was crowded with them. Our boys drank from calabashes;
when these were put upon the ground, bees clustered on the edges
and crawled towards the liquor. Impatient successors thronged upon
the first comers and pushed them into the water, so that in a few
minutes the surface was a mass of “struggle-for-lifers.” In spite of the
heat we had to keep moving; for when we settled, so did the bees—
all over us.
That night we pitched our camp in the mimosa forest, six miles
from the village and watering-place called Doka.
Next day—Christmas Eve—we started at seven, carrying our
guns, and had not walked a mile when we disturbed a flock of
guinea-fowl. Away they sped through the tangle of dry grass, and we
after them. We blazed away here and there, but the birds, hit or not,
were out of sight in an instant amidst that cover, and we missed in
this way many that we had not missed in the other. Our bag
consisted of four. When a bird dropped, the Soudanese “gillies,” who
were carrying our rifles in case big game should be seen, pounced
upon it and decapitated it. Otherwise it would not have been clean
meat for a Mohammedan. The land around Doka is hilly, and the
ground rises to a height of which Primrose Hill would be a good
example. We reached the village about nine o’clock.
Here we found, to our surprise, that the camel-men wanted to
water every beast in our convoy. We were but a few miles from
another watering-place, where the business could have been done in
the evening without wasting the hours of daylight in which we were
able to travel. We compromised by hurrying up the animals as soon
as we had filled our tanks, and when half a score had drunk, the well
ran dry.
We pushed on through the mimosa country. The temperature was
about 102°, and I found the heat extraordinarily oppressive. The
trees around us and overhead—they grow thickly in parts of the
forest—seemed to shut out every movement of air, such as had
always relieved us a little in the open tracts. Our extreme thirst
constantly tempted us. We had made it a rule not to draw upon our
ration of water till eleven in the morning, and abstinence till then was
Spartan discipline. If one began to drink, it was a sheer impossibility
to leave off, and the supply did not hold out. On calm reflection at a
distance, I doubt whether our normal breakfast of tinned sausages
and tea was wisely selected under the circumstances. But it could be
quickly prepared, and we seldom had time to be leisurely.
While we were traversing the forest, I neither saw nor heard any
bird except the guinea-fowl. The dried grass in which they wander
was the only undergrowth. Usually the place was as still as a tomb.
Of larger animals I saw none but antelopes, and not many of these.
We halted for lunch in a small ravine, and the bees did not find us
till we had nearly finished the meal. We “smoked” them with
cigarettes, cigars, and a bonfire, to no purpose. Then we shifted our
quarters, but they followed. All of us were stung, and we were not
quit of them till we mounted our camels and outdistanced the
swarms.
We camped for the night among the mimosas about seven miles
from the watering-place called Zeraf Zaid. I thought we had been
delivered from the plague of insects, but I deceived myself. Our
camp was stormed by hosts of small creatures—tiny beetles, flying
ants, and the like. They thronged and crawled on one’s candle, one’s
book, one’s face, and one’s hands, and I found it difficult to write my
diary. Some of them—I do not know whether they were prompted by
hunger or malignity—added insult to injury by biting us.
On the morning of Christmas Day we started with our guns in
advance of the convoy and bagged two brace of the usual poultry. I
had not hitherto found the country unhealthy, though the climate tries
one’s condition; but on this occasion I felt “out of sorts,” and was
glad—for a wonder—to mount my camel after the tramp in the
sunshine.
At 9.30 we reached the village of Zeraf Zaid. Here a clean hut
serves as a rest-house. We found the place pleasant and cool.
Within it were trestle-beds, of the kind commonly used in the Soudan
and called “angareebs.” Sir Samuel Baker has given a concise
description of them: “The angareebs, or native bedsteads, are simple
frameworks upon legs, covered with a network of raw hide worked in
a soft state, after which it hardens to the tightness of a drum when
thoroughly dry. No bed is more comfortable for a warm climate than
a native angareeb with a simple mat covering; it is beautifully elastic,
and is always cool, as free ventilation is permitted from below.”[18] I
concur in this favourable opinion of the native bed, and hope that its
value in cases of sickness or injury that are not serious may be
brought to the notice of the medical authorities of the army. It would
be easy to furnish tent-hospitals with this simple appliance in any
part of the Soudan.
We rested in contentment, and then lunched while the camels
were watered. Our convoy started at noon, and we two hours later.
We overtook the baggage at half-past three.
At Zeraf Zaid there is an outpost of “the Arab Battalion,” which
consists of Soudanese natives and Soudanese (i.e. naturalized)
Abyssinians,[19] Egyptian non-commissioned officers, and two
Englishmen, first and second in command, with the rank respectively
of colonel and major. The strength is about two hundred, and the
permanent head-quarters are at Kassala. The duty of the battalion is
to protect the frontier and suppress the slave raids which are
frequently attempted by Abyssinian subjects. I doubt whether the
latter part of the supervision duty is quite successfully performed
owing to the smallness of the corps, and it is well to bear in mind that
these raids may upon some occasion lead to serious political
complications affecting the attitude of the Anglo-Egyptian
Government towards the Negus Negesti.[20] He has but slight control
over his more powerful feudatories near the frontier; moreover, the
succession to the throne will assuredly be disputed upon the death
of the present ruler, and the whole country will then be plunged in
misrule and civil war. It is clear that a very serious state of affairs
may at any time be established in this region. Questions arising from
incursions made into territory where the British flag flies from districts
where no effective or responsible government exists may assume
the gravest importance.
The “Arab Battalion” is a sort of legacy to us from our
predecessors, and the men still wear the picturesque uniform chosen
for them in the days of the Italian occupation. It consists of a white
tunic extending to the knees, loose white trousers, sandals
surmounted by white gaiters, a broad green sash round the waist,
and a red tarboush with a green tassel. I cannot offer a valid opinion
upon the sufficiency of this body as a frontier guard in the event of
disturbances over a wide area, and I am not able to judge what
effect the racial sympathy of some members of it with Abyssinians
“over the border” would have in such a case.
Shortly after we had left Zeraf Zaid on the road to Gallabat we
saw a great bustard near at hand. One of my comrades tried to
shoot it for our Christmas dinner, but his luck failed him. However, I
had brought the materials of a plum pudding with me from Cairo, and
hoped that it would be a solace and a pleasant surprise for the other
two members of our mess. The cook obtained some eggs in the
village, and I gave him careful and emphatic directions and swore
him to secrecy. Ours is a phlegmatic race. The cook did his work
creditably, the pudding came to table, and was eaten without
comment. The poultry in these villages is of a stunted size, but the
flesh is tender and makes good eating. Pigeons are to be had in all
the hamlets.
Our camping-ground for the night was a pleasant spot, bare of
grass, and surrounded by high trees. In honour of the day, and in
expectation of entering Gallabat early on the following afternoon, I
discharged a professional man’s duty towards his toilet, and scraped
a week’s stubble from my face. In the wilderness even a doctor can
neglect appearances.
On Boxing Day we entered rising country with features different
from those seen in the mimosa forest.
The sides of the rocky hills have been seamed with ravines by the
rains. Nearly all the trees are still of the same order, but certain
species have broader leaves, and their appearance resembles that
of the timber found in the temperate zones. However, I saw no
specimen of the varieties common in England. I heard one songbird
in this district, the chaffinch. Water-wagtails abound.
As usual, we made an excursion ahead of the baggage with guns
and rifles. The game birds are sand-grouse and partridges, and we
shot a brace of the latter. Crawley brought down an ariel buck, which
was in good condition. This was our first venison. The shot caused
intense excitement in our convoy, and the guides and boys all made
a rush for the beast to cut its throat before it died of the bullet wound.
It had been hit in the neck.
We rested in a ravine called Otruk—a lovely wooded gorge in
which a small stream was flowing. A little further down the course the
water disappeared in the sand. Here, for the first time, I saw a troop
of baboons. No doubt they inhabit caves and clefts in the
surrounding rocks. Some were fully of human stature. Partridges and
guinea-fowl were numerous here, and beyond question the rivulet in
the khor attracts animals of every kind existing in the district. It was
the first running water we had seen since we left the Blue Nile. We
rested until two o’clock, and then rode on towards Gallabat.
When we were half an hour’s journey distant from the town, we
were met by Mr. Saville, the Inspector, who accompanied us to our
quarters.
CHAPTER IV
Politically, Gallabat is a place of much importance, as the principal

station on the frontier between Abyssinia and the Anglo-Egyptian
dominions. It is the terminus of the telegraph line whose course we
had followed along a part of our route, and I shall presently explain
why I think it would be difficult to carry the wire from this point into
Menelek’s country.
The town consists of two main thoroughfares and of the scattered
“tokhuls” which form the villages throughout Abyssinia and the
Eastern Soudan. It contains about eight hundred inhabitants.
Formerly, I have no doubt, there was a larger population, but this
place, like all other trading centres in the land, suffered severely in
the days of the Dervish ascendency. The “shops,” which abut upon
the main roads, are hovels in a row under a heavily thatched roof,
and are separated by rough and ragged partitions of cane thatch.
They are “business premises” only, and the proprietor and his family
dwell elsewhere. A considerable trade is carried on by Abyssinians
who come to Gallabat to sell coffee; sometimes they have a
leopard’s skin or other hunter’s trophy to barter in addition. They
exchange their goods chiefly for cotton, which is used in the making
of shamas and other garments worn in Abyssinia. Sir S. Baker
mentions a commerce in bees’-wax and hides, but I saw no evidence
of it in Gallabat, and I think it must have declined.
The traffic in coffee proceeds regularly during the dry season, but
ceases, of course, when the rains make the neighbouring Abyssinian
hill-country impassable. A square, in which there are booths, is set
apart for the use of the Abyssinian traders. In the middle of it are the
large scales in which the coffee is weighed, and I was much
interested to learn that not only the amount of the import duty
payable to the Egyptian Customs, but also the sum charged as
export duty by the Abyssinian Government, was here determined by
the weight of the bundles. The latter tax is retained at the time in the
hands of the Anglo-Egyptian officials, and is afterwards remitted by
them to Menelek’s Revenue Department. I need hardly add that this
is a recent arrangement, and it seems to show that British influence
in the Soudan has inspired confidence at Addis Abiba.
The town of Gallabat is five miles distant from the bed of the
Atbara. It is built on the slope above a small watercourse. This rivulet
and the adjacent supply of drinking water which the inhabitants use
are—in all but details—as they were in Sir Samuel Baker’s time. He
thus described them:—“We were horribly disgusted at the
appearance of the water. A trifling stream of about two inches in
depth trickled over a bed of sand, shaded by a grove of trees. The
putrefying bodies of about half a dozen monkeys, three or four
camels, and the remains of a number of horses, lay in and about the
margin of the water. Nevertheless, the natives had scraped small
holes in the sand as filters, and thus they were satisfied with this
poisonous fluid; in some of these holes the women were washing
their filthy clothes.”[21] There are three wells in the town from which
good water is obtained. The soldiers of the garrison use this supply,
and it is available for all who will take the trouble to draw from it. But
generally, the inhabitants, either because they are too indolent to pull
up buckets or from mere adherence to custom, prefer the “poisonous
fluid” procured in the traditional way.
Our quarters were in the dismantled Dervish fort, which lies on the
summit of the hill, above the town. The thick brick wall which
surrounded it is now ruinous. In the enclosure are barracks for a
detachment of the Arab Battalion, a small rest-house, and the
telegraph station.
We set our boys to pitch three tents for us, and before long I had
the indescribable delight of tubbing in my portable rubber bath.
After this we received, in the rest-house, the interpreter whom
Menelek had sent to await us. His name was Johannes. I learned
that he had been three weeks in Gallabat, so perhaps it had been
expected that we should travel more rapidly than we did. With him
were an assistant, by name Walda Mariam, officially attached to his
“mission,” and a servant.
Johannes was a tall, handsome man, with grizzled hair and beard.
In person he seemed cleanly, but his shama—the toga-like robe,
also known as “quarry,”[22] which is universally worn by Abyssinians
—was soiled. It is unfashionable, and even a breach of established
custom, for a man to appear in a clean shama except at rare
intervals. As all sorts and conditions of men in the country are
infested by vermin it may be imagined that an Abyssinian’s clothes
usually add nothing to the pleasure of his company.
Our interpreter had spent three years in Marseilles, and we found
that he and his followers conformed to the requirements of
civilization as regards dirt much more closely than the generality of
his countrymen. I do not know whether Parkyns’s description of the
use of butter as pomade still holds good in parts of Abyssinia;
probably not very widely, as Mr. Wylde tells us that “European hats
are getting very common, and are generally of the bowler,
wideawake, or Terai patterns,”[23] but in the western provinces,
where nearly all the people whom we met were peasants, we saw no
sign either of this innovation or that the dairy had been drawn upon
to smarten the coiffure. Nevertheless, greasiness of person was the
rule.
I may mention here that bodily cleanliness is not only unusual in
Abyssinia, but raises a doubt as to the genuineness of a man’s
religious profession. In this respect matters have not changed since
Parkyns’s time. “St. John’s is the only cleanly day in the calendar; for
in the evening the whole population, male and female, old and
young, go down to bathe. It is a fact, that, excepting on this
occasion, there are many of the number, who, beyond washing their
hands before and after meals, and their feet after a journey, never
trouble the water from one year’s end to another. My habit of
washing every day in the European fashion gave rise to much
scandal on my first arrival; and it was constantly inquired, ‘Is he a
Mussulman, that he thus washes, and so often?’”[24] The
Abyssinians are fond of shaking hands, and it is impossible to avoid
this civility without giving serious offence. Nearly all, owing to their
independence of soap, suffer from a complaint once associated—
wrongly, no doubt—with a highland region nearer home, and the
result was that none of the Europeans of our party escaped scabies.
Johannes possessed a felt sombrero, which he held in his hand
when we received him in the rest-house. Like most of his
countrymen, he wore a cartridge-belt around his middle. He also
carried a revolver in his belt. His “boy” held his rifle. Altogether the
interpreter was a picturesque but piratical figure, and it occurred to
me that a group of Abyssinian “villains” would be effective in a
melodrama.
The interpreter bowed to the earth each time we addressed him.
He had brought letters for us from Menelek and from Colonel
Harrington, the British Minister at Addis Abiba, which is now the
capital of the country. The king’s letter is a kind of superior passport,
which is generally granted to Europeans who enter his realm with his
consent. It is useful, but is not too obsequiously respected in all parts
of the land. Johannes had a fair knowledge of French—a matter of
importance to one of his calling, seeing that the Abyssinians and the
French are neighbours, and that an increasing amount of the
commerce and traffic of the country is likely to pass through Jibuti. A
railway has been commenced from that point, and a concession
obtained from Menelek for its extension into his dominions. Mr.
Herbert Vivian has recently pointed out the important developments
which may be brought about by the construction of the line.[25]
The Dervish fort at Gallabat is literally a “cockatrice den.” We
speared eight or nine fine specimens upon the walls, using our
knives, and among them was the largest black scorpion I had seen.
The rest-house swarmed with these disquieting arthrogastra, and
one of our servants was stung during the evening. Parkyns remarked
that, though he had several times endured the sting himself without
serious consequences, he had heard of many instances which had
ended fatally.[26] Our boy probably had in his mind a similar dismal
record, for he howled till midnight. I had very little sympathy with him,
especially as he prevented me from sleeping. He, like the other
servants, had been provided with boots but persisted in running
about the fort barefoot.
I was delighted by the change of scenery which commenced at
Gallabat after the long tracts of desert and mimosa forest. To the
eastward, the Abyssinian mountains were visible, and there is a
most stirring splendour in the sight of the distant peaks when one
beholds them in the pink, hot glow of sunset.
An escort of ten men had been appointed for us. All these were
Abyssinians by race, but “naturalized” Egyptians, serving in the Arab
Battalion, and they spoke Arabic in addition to their native tongue.
There was an odd significance in the fact that our journey to Lake
Tsana familiarized the inhabitants of the western provinces of
Menelek’s kingdom with an Italian uniform which had become British.
On December 27 we “lazed” and enjoyed our indolence. Our only
activity was to make trial of our patent donkey saddles. We had
seventy of these, and found them anything but serviceable. The
natives fasten the loads on the donkeys by long thongs of hide,
giving about six girths for each animal. Our saddles allowed but one
girth, and, as the consequence, the loads slipped round. On the 28th
my companions went to take measurements in the course of the
Atbara. I remained in Gallabat and superintended the conversion of
camel loads into donkey loads. This involved getting the right weight
of flour and corn—fifty pounds—into the sacks. It was troublesome
work done by trying people, and the supervision of it would have
taxed the patience of a saint.
On the 29th we were all busy with the baggage, sorting our
supplies. We took with us sufficient for six weeks. The remainder
was left in the zaptieh,[27] and we fully expected that the rats and the
white ants would clear it up for us before our return. Our cook had a
touch of malarial fever, and during the day I gave him thirty grains of
phenacetine and nine grains of quinine. These quantities were
effective.
We were to start on the following morning, and sat longer than
usual over dinner, and many yarns were told about Egyptian officials.
One—I hope it is not a stale story to my readers—ran as follows:—
An Egyptian battalion, under a native officer, had been sent to a
remote district. The commander had orders to telegraph to head-
quarters if anything unusual occurred. He sent off a message
announcing that one of his soldiers had died suddenly, and that he
awaited instructions. The reply was, “Bury the man, but make sure
he is dead first.” The native officer thereupon reported by telegram,
“Have buried soldier, and know he is dead, because I hit him on the
head with a fishplate.” It need hardly be said that the fishplate was
not of the kitchen but the railway kind.
On the following morning, December 30, we had further proof of
the defects of the saddles which had been provided as baggage-
gear for the donkeys. When, after much tedious work, we had
balanced the load on an animal, we started it on the road and turned
our attention to another. Five minutes later, the beast that had been
despatched was brought back with its load under its stomach. My
companions toiled on through the heat of the day; but I fear my
services became rather like those of the fly on the wheel, for the
malarial fever had got hold of me, and the commencement of a bout
with it nearly took me off the list of effectives.
We made a start at last, a little after eleven o’clock, with the
intention of travelling about eight miles, and crossed the stream
below Gallabat by a stony ford, over which water a few inches deep
was running. I was told that this rivulet is never quite dry, and I
observed that in the bed of it were the stagnant pools usually found
in the watercourses of this district. We had seen the last of the
camels at Gallabat, and my companions and I now rode mules. They
are the best mounts in the rough, steep, and almost trackless region
which forms the western border of Abyssinia. Horses would be
useless here for a journey, either to carry men or for purposes of
haulage; and I doubt if ponies could anywhere be found that would
be more than an encumbrance, at least for long and steady travelling
at a fair pace. I believe that the Abyssinians of the Highlands use
horses in their hunting expeditions and slave-raiding forays—at all
events they do in their campaigns in their own country—and I have
little doubt that the inhabitants of the lofty hill district adjoining the
border tract, who are of mixed race and bandits by immemorial
tradition, use any animals they can lay their hands on when they, like
Roderick Dhu and his men, “with strong hands redeem their share”
from travelling merchants or Soudanese villagers. But these are
“spurts” of work, rapid dashes made by unencumbered men, not
plodding regular marches, and, generally speaking, those who
cannot pass through this country on a mule or an ass must use their
own feet or not go at all.
When my companions and I had advanced about four miles, we
halted for lunch at a pleasant spot beside a brook. After the meal,
some guinea-fowl were seen, and one was bagged. No doubt many
more were hit and lost, as usual, among the high grass. We were in
the saddle again at three o’clock, and reached our camping-ground
an hour and a half later.
The fever had a grip of me by this time, and I rested in bed, and
soon felt the benefit of a dose of quinine. It enabled me to tackle my
dinner, and that is no small boon to a sick traveller.
Our boys had cut down trees and formed a zareba, within which
the donkeys were penned to prevent them from straying and give
them protection from hyenas.[28] I lay idly watching the camp-fires
and listening to the occasional outbreaks of scuffling and braying
among the donkeys, and presently fell asleep till dawn.
The country which we entered on that day is full of rounded hills.
Boulders crop out from the surface of them, and they are separated
by ravines with sandy beds. There is no regularity in the
configuration of these hills, and no uniformity in their size. When I
saw them they were covered either with dried grass or with mimosa
scrub.
The region which we had now reached is, as I have said,
impassable in the wet season, and Abyssinia is then impregnable as
far as its western boundary is concerned. The violence of the storms
and the rush of rain are such that it is doubtful whether even a line of
telegraph posts and wires could be carried through the district with a
likelihood that it would be in working order for any length of time
between May and September. The floods would probably be as
prohibitive to an underground system of wires as to one overhead,
and in both cases allowance would have to be made for the extreme
electrical disturbances which often occur at brief intervals during the
rainy season.
I have already referred to the raids that take place from the
Abyssinian side when the country can be traversed, and will only add
here that they are carried out frequently enough to maintain a supply
of slaves for all persons in the country whose prosperity raises them
above the degree of a peasant. For example, when we reached
Gallabat on the return journey we found that eighty-three Soudanese
had been carried off during an incursion which had been made since
we left the place. It is needless to insist on the difficulties that may
arise from raids of this kind undertaken by people who are, nominally
at least, subjects of the Negus.
I can testify that slaves are found everywhere in Western
Abyssinia, but among the female victims I never had the good
fortune to behold one of the class which impressed Sir Samuel
Baker so pleasantly at Gallabat. He wrote, “On my return to camp I
visited the establishments of the various slave merchants; these
were arranged under large tents formed of matting, and contained
many young girls of extreme beauty, ranging from nine to seventeen
years of age. These lovely captives, of a rich brown tint, with
delicately formed features and eyes like those of the gazelle, were
natives of the Galla, on the borders of Abyssinia, from which country
they are brought by the Abyssinian traders to be sold for the Turkish
harems. Although beautiful, these girls are useless for hard labour;
they quickly fade away and die unless kindly treated. They are the
Venuses of that country, and not only are their faces and figures
perfection, but they become extremely attached to those who show
them kindness. There is something peculiarly captivating in the
natural grace and softness of these young beauties, whose hearts
quickly respond to those warmer feelings of love that are seldom
known among the sterner and coarser tribes. They are exceedingly
proud and high-spirited, and are remarkably quick at learning. At
Khartoum, several of the Europeans of high standing have married
these charming ladies, who have invariably rewarded their husbands
by great affection and devotion. The price of one of these beauties of
nature at Gallabat was from twenty-five to forty dollars.”[29]
CHAPTER V
On the morning of December 31, the donkeys were laden and our
journey was begun by a quarter to eight. We were again hindered on
the march by the shifting of the donkeys’ loads.
Our track now lay among craggy mountains, in the rain-scoured
district, where there is no single human habitation. I saw neither wild
beast nor bird, and the country gave a strange impression of stillness
and lifelessness. The flora is quite distinct from that of the Soudan.
The trees are tall and spreading and of many different species. I
recognized the “Matabele apple,” and saw the hard, uneatable fruit
on the branches. The ground in many places was covered with
“bamboo grass,” too high for a mounted man to look over, and the
thick, overtopping growth seemed to shut out the air. As we
advanced during the afternoon we discovered that the grass had
been fired at several spots along our route—I do not know by whom,
or whether it was kindled accidentally or by design. The flames drove
out some partridges, and Dupuis and I thought that we saw a tasty
breakfast for the next morning. But when we moved forward with our
guns the birds, to our amazement, ran back into the burning cover.
The fire died out in the evening, and all was quiet at night.
There is much stony land in this district. The soil of the fertile
tracts is not of the friable kind which we had so often seen in the
Soudan: but there are many fissures in it, due, no doubt, to alternate
drenching and drying in the rainy season. Our road often lay along
steep and wide gorges, through which an enormous volume of water
descends to the Atbara at the time of the floods. My mule was very
steady on his legs and the motion was easy when he trotted on open
ground. He only showed the waywardness of his kind when I led
him. It was pleasant to think that some sort of understanding existed
between the rider and his mount after one had been accustomed for
weeks to the impassive eye of the camel.
On January 1, a couple of shabby fellows visited our camp in the
morning. We questioned them and found, from the answers which
Johannes translated, that they were the escort sent to accompany
Gwynn and were on the way to join him at Gallabat. He might
consider their company a sign that he was honoured, but scarcely a
sound protection against robbery. We struck our camp after this and
commenced the day’s journey, following the bed of a river. As usual,
there were dry tracts and well filled pools in its course. Later, we
climbed the bank and struck into the country beyond, continually
riding up hill and down dale. Again we saw an abundance of tall
grass and fine timber. The former was dry at this season, and had
been burned in many places. The country here abounds in big game,
but the height and thickness of the grass make it very difficult to sight
animals. We saw a koodoo, three gazelles, traces of elephants, and
spoor of other beasts, but none came within range.
We had covered fourteen miles by half-past eleven, and then
halted, considering that the donkeys had journeyed far enough. Our
progress depended on them, and we were careful not to overwork
them. Three were suffering from girth sores. We pitched our camp in
a ravine about a quarter of a mile distant from the bed of the Gundar
Wahar—which is the river Atbara with an Abyssinian name.
One of our escort was reported ill with fever, and I found that his
temperature was 104 degrees. But quinine had brought about a
decisive improvement by nightfall. I had another patient. My friend
Crawley had chafed his instep, and there was a bad sore on it. I had
recourse to a little doctor’s diplomacy to keep him still, and put on
such a large fomentation that he could not walk. Then Dupuis and I
took our guns and rifles and tramped in the jungle—for the mass of
thick, lofty grass deserved the name. My companion shot a brace of
partridges, and we saw some guinea-fowl, and much spoor of big
game. But nothing more got into our bag, and the excursion was
wearisome and disappointing.
On January 2 our road again lay through hilly, verdurous country.
While the donkeys climbed or descended the steep inclines their
loads slipped as before, and kept all hands busy. The boys were
continually shouting for help, and the burdens were replaced amid
yelling and cursing. These natives never worked without talking,
singing, or swearing, and they were specially fond of hearing their
own oaths. But, I think, very little ill-will went with the words, and in
spite of the endless imprecations uttered over the donkeys, they
treated the animals well.
During the morning I took my rifle, filled my pockets with ball
cartridges, and rode ahead of our party in the hope of trying a shot at
big game. But I found small parties of Habashes[30] at intervals along
the track throughout a distance of two miles in front of our convoy.
Clearly it would be useless to search for any large wild beast in the
proximity of these groups. I recognized the men as folk who had
attached themselves to our train. They made a practice of camping
where we pitched our tents, and had hitherto forestalled us in the
choice of ground, and settled under the most suitable trees. They
sought protection from the robbers who infest the district—the most
notorious at the time was a Soudanese Arab called Hakos. I was
glad that these wayfarers should enjoy a sense of security, but
resented having sport spoiled. So I addressed a remonstrance to
Johannes, who promised that all camp followers should keep in the
rear in future, and he was as good as his word.
That afternoon we pitched our tents on the banks of the Gundar
Wahar, which was here a stream trickling from pool to pool. We had
travelled about fourteen miles. My friend Dupuis fitted out his angling
tackle, and tried his fortune in some of the pools, using an ordinary
spoon-bait. He caught three fair-sized fish, belonging to the perch
family. I saw him land the biggest, which weighed six pounds, and
showed fight. It had to be played into the shallows, and was brought
ashore in smart style. Crawley, who was lame, limped to the edge of
the river and cast a line with dough on the hook. He fished patiently,
and his perseverance was rewarded with two little creatures of the
size of sticklebacks.
All the camping-grounds by the waterside in this district are called
warshas, and as there are few distinctive names for places in the
uninhabited tract, we called the spots where we halted warsha
number one, warsha number two, and so on.

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Recurrent Respiratory Papillomatosis

1st Edition Paolo Campisi (Eds.)

ERS Handbook of Respiratory Medicine Paolo Palange

Recurrent Sequences Key Results Applications and

Applied Respiratory Pathophysiology 1st Edition Louis-

Recurrent Pregnancy Loss: Causes, Controversies and

Respiratory Medicine and Science 1st Edition Mieczyslaw

Acute Respiratory Distress Syndrome 1st Edition Davide

Abstraction and Infinity 1st Edition Paolo Mancosu

Abstraction and Infinity 1st Edition Paolo Mancosu

ISBN 978-3-319-63822-5 ISBN 978-3-319-63823-2 (eBook)

Library of Congress Control Number: 2017956567

© Springer International Publishing AG 2018

Printed on acid-free paper

This Springer imprint is published by Springer Nature

Toronto, Canada Vito Forte, MD, FRCSC

1 Fundamental Biology of Human Papillomaviruses.............................. 1

11 Human Papillomavirus and Head and Neck Cancer............................ 167

Meghan Lambie and Scott V. Bratman

Papillomaviruses are a family of non-enveloped double-stranded DNA viruses that

© Springer International Publishing AG 2018 1

1.2 Genetics and Types of HPV

1.2.1 Genomic Organization of HPV

Table 1.1 HPV gene functions at a glance

1.2.2 HPV Taxonomy

Alpha Beta Gamma Mu Nu

Cutaneous Cutaneous Cutaneous Cutaneous

HPV 16, 18, 31, 33

1.3 Virus Life Cycle

1.3.1 Viral Entry

1.3.2 Viral Maintenance and Genome Amplification

Virons are packaged

Viral late gene expres-

HPV early gene expres-

HPV infects cells in

1.3.2.1 Specific Activities of E6 and E7

TERT Via PDZ domain

P300 Many cell division

of ­E2F-regulated genes. Moreover, Rb-independent interaction of E7 with HDAC

Specifically, high-risk E6 proteins interact with E6-associated protein (E6AP),

1.3.3 Virus Synthesis and Release

1.4 Pathogenesis of HPV

1.4.1 Role of HPV in RRP

Recurrent respiratory papillomatosis (RRP) is a rare disease affecting children. RRP

other HPV-­associated diseases (Doorbar 2005; Stern et al. 2007). Likewise,

1.4.2 Neoplastic Transformation by E6 and E7

1.4.3 Neoplastic Transformation by Additional Mechanisms

The expression of E6 and E7 is integral to neoplastic transformation of HPV-­infected

1.4.4 Evasion of Immune-Mediated Clearance

1.4.4.1 Mechanisms of HPV Evasion of Adaptive Immunity

HPV actively blocks antigen presentation in infected keratinocytes. HPV-related

1.4.4.2 Mechanisms of HPV Evasion of Innate Immunity

Under normal conditions, keratinocytes express pathogen recognition receptors

APSU Australian Paediatric Surveillance Unit

2.1 Epidemiology: A Global Perspective

For rare conditions such as juvenile-onset recurrent respiratory papillomatosis

© Springer International Publishing AG 2018 19

and adjuvant treatment strategies, and early detection or mitigation of serious

Toronto, Canada Vito Forte, MD, FRCSC

1 Fundamental Biology of Human Papillomaviruses.............................. 1

11 Human Papillomavirus and Head and Neck Cancer............................ 167

1.2 Genetics and Types of HPV

1.2.1 Genomic Organization of HPV

1.2.2 HPV Taxonomy

1.3 Virus Life Cycle

1.3.1 Viral Entry

1.3.2 Viral Maintenance and Genome Amplification

1.3.2.1 Specific Activities of E6 and E7

of E2F-regulated genes. Moreover, Rb-independent interaction of E7 with HDAC

1.3.3 Virus Synthesis and Release

1.4 Pathogenesis of HPV

1.4.1 Role of HPV in RRP

other HPV-associated diseases (Doorbar 2005; Stern et al. 2007). Likewise,

1.4.2 Neoplastic Transformation by E6 and E7

1.4.3 Neoplastic Transformation by Additional Mechanisms

The expression of E6 and E7 is integral to neoplastic transformation of HPV-infected

1.4.4 Evasion of Immune-Mediated Clearance

1.4.4.1 Mechanisms of HPV Evasion of Adaptive Immunity

1.4.4.2 Mechanisms of HPV Evasion of Innate Immunity

2.1 Epidemiology: A Global Perspective