900 kB Volume 08 No. 2 Dec 2007 Not yet electronically indexed

Q fever: the southern African perspective
ISSN 1448-4706
Official Journal of The Australasian College of Tropical Medicine
Volume 8 • No 2 December 2007
Official Journal of The Australasian College of
Tropical Medicine. The Annals of the ACTM will
be published twice a year.
Officers of The Australasian College of Tropical
Professor PA Leggat
Vice President
Emeritus Professor JM Goldsmid
Honorary Secretary
Dr V Efstathis, OAM, RFD
Honorary Treasurer
Associate Professor RG Hirst
President Elect
Dr T Inglis
Council Members
Dr K Daniell
Dr A Koehler
Professor WJ McBride
LTCOL P Nasveld
Mr D Porter
Associate Professor M Shaw
Dr D Tingay
Chair, Faculty of Travel Medicine
Dr M Klein
Chairs of Standing Committees
Dr Vlas Efstathis, OAM, RFD (Disaster Health)
Richard Bradbury (Medical Parasitology)
Dr K Winkel (Toxinology)
INVITED editorial:
Tropical medicine in surprising places
Dr T Inglis............................................................................................................................................... 29
INVITED review:
Q fever: the southern African perspective
Drs J Frean, L Blumberg and C Cutland................................................................................................... 32
The incidence of malignant melanoma detected in primary care and the value of
Dr S Kitchener........................................................................................................................................ 35
ACTM Secretariat, PO Box 123, Red Hill Qld 4059 Australia
Tel +61 (0)7 3872 2246 • Fax + 61 (0)7 3856 4727
Email: [email protected] • http://www.tropmed.org
Polly Ink Graphic Design • www.pollyinkgraphicdesign.com.au
Editorial Board
Emeritus Professor JM Goldsmid, PhD, FRCPath, Hon FRCPA, Hon
Email: [email protected]
Editor Bulletin
Professor PA Leggat, MD, PhD, DrPH, FAFPHM, FACTM, FFTM
Associate Professor A Menon, MBBS, MPH, MTM, FAFPHM,
Board Members and Review Panel
Dr I Bauer, PhD, FACTM
Emeritus Professor RSF Campbell, AM, PhD, DSc (h.c), DVMS
Associate Professor D Durrheim, MBChB, DTM&H, DCH, MPH&TM,
Associate Professor J Frean, MBBCH, M.Med (Path), DTM&H,
M.Sc (Med Parasit), FACTM
Dr M Humble, MA, BMBCh, FRCPath, MACTM
Professor J La Brooy, MD, FRACP, FACTM
Professor A Latif, MBChB, MFGP, DCH, Dip. Ven, FCP, MD, FACTM,
Dr A Mills, MA, MBBCh, BAO (Dublin), FRCPA, FACTM, FFPath,
RCPI, DCP, D Path (Eng)
Professor JH Pearn, AM, RFD, MD, PhD, FRACP, FRCP, FACTM,
Associate Professor DR Smith, BSc, BEd, MHSc, MPH, PhD,
Dr KD Winkel, BMBS, BMedSc, FACTM, PhD
© Copyright 2007 ACTM. Material published in the Annals of the
ACTM is covered by copyright and all rights are reserved, excluding
“fair use” as defined by the copyright law. Permission for use of
figures/tables etc. should be obtained from the authors and the
Editor of the Annals.
Morphologic and genetic pathways in the development of colorectal cancer
Drs F Konishi, H Noda, T Maeda and K Togashi........................................................................................ 38
HIV transmission through breast-feeding in sub-Saharan Africa: a review of the current
Ms KE McArthur...................................................................................................................................... 43
Leishmaniasis: a re-emerging problem for travellers
Professor PA Leggat................................................................................................................................ 49
The development of tropical occupational medicine in Australia: Anton Breinl, Weil’s Disease
and the AITM
Associate Professor DR Smith and Professor PA Leggat.......................................................................... 50
INSTRUCTIONS FOR AUTHORS..........................................................................................................iii
Cover Photo: The Australian Institute of Tropical Medicine in 1916 (photo courtesy of James Cook University)
Dr Tim Inglis, Division of Microbiology & Infectious Diseases, PathWest Laboratory Medicine WA
(Annals of the ACTM, 2007; 8,2:29-31)
Tropical medicine has gone through a series of changes since first coming into existence as a
recognisable discipline. Its practitioners have taken a pragmatic approach to important contributions
from scientific and paramedical disciplines, much to tropical medicine’s benefit. We can now take
pleasure in the insights parasitology, toxinology, travel medicine, military medicine and tropical
public health have given us. But the discipline continues to hold surprises, particularly when we
define tropical medicine according to the paradigm used when it supported the geopolitical priorities
of a European colonial empire. This article argues that as our discipline adapts to a 21st century
Australasian view of the world, it needs to develop a more inclusive professionalism. A personal
journey illustrates how a foundation in tropical medicine provided a starting point for a much richer
professional experience that has included to date public health microbiology, emerging infectious
disease outbreak response, biopreparedness, military and disaster medicine. The challenge in
taking such a comprehensive approach to where we draw the boundaries of our discipline, is to
identify the kind of professional leadership needed, the programmes we need to offer our members,
and the membership base we need to make it happen. We should not be too surprised if tropical
medicine slips in under the guise of other medical, paramedical or scientific disciplines. Perhaps
we should be a little quicker to identify shared territory that belongs to us too.
Dr T Inglis
Division of Microbiology & Infectious Diseases
PathWest Laboratory Medicine WA
Hospital Avenue
QEII Medical Centre
Locked Bag 2009
Nedlands WA Australia
Email [email protected]
Development of a discipline
Tropical medicine has its roots in the colonial ambitions of the major European powers of the 19th
century. Their expansion into the tropics depended in part on how effectively they contained or
controlled the unfamiliar diseases they encountered as they broke new ground. The military and
other arms of the colonial power, businesses that wanted to seize raw materials and local labour
or expand into new markets, and missionaries on the lookout for unreached peoples, all needed
pre-travel preparation for the challenging diseases that threatened the success of their overseas
operations. The most suitable locations for schools of tropical medicine were dictated by the main
ports of entry for quarantinable diseases brought in by ocean-going liners, cargo ships and naval
vessels. The pioneering work done in the field of infectious diseases by the alumni of the European
schools of tropical medicine and their partner institutions in far-flung colonies, shaped the field
of tropical medicine and defined its boundaries. Thus malaria and other parasitic diseases of the
tropics such as filariasis, leishmaniasis and Chagas’ disease were all included. But tuberculosis,
sexually transmitted diseases and many arbovirus infections were not. The menu was short,
manageable, specifically medical and mainly concerned with infectious diseases.
A century later, that short list seemed anachronistic to the highly motivated cohort of young
European doctors with whom I prepared for overseas service. An Imperial world view had long since
faded into obscurity and had been replaced by a desire to gain practical skills beyond the basic
medical training. Those skills included hands-on parasitology, entomology, health risk assessment
and tropical public health. My particular cohort went to work in parts of Africa and Asia, or found
short term positions with non-government relief agencies in some of the world’s hot spots. By
this time, the disease menu included newly emerging infectious diseases such as HIV/AIDS, reemerging diseases such as tuberculosis, nutritional diseases and a strong international and public
health component. Nobody made any apologies for the eccentricities of the colonial period. The
changing world order was there for all to see, and many of my classmates were highly tuned into
a changing political climate. Perhaps a down side of the international adjustment was a shake-out
of the European schools of tropical medicine, resulting in closures and
substantial curriculum changes to cater for expanding demands in newer
fields such as travel medicine.
Melioidosis microcosm
The bacterial infection known as melioidosis has become a personal
microcosm of tropical medicine. The disease was mentioned in passing
during my DTM&H course and only began to take on any immediate
significance after my move to Singapore where it was an endemic
issue. Local infectious disease physicians had a little fun at the expense
of visiting European and American specialists when they presented
cases of culture-confirmed melioidosis and waited for the disease to
score a mention in the visiting expert’s differential diagnosis. There
were occasions when eminent names failed to consider the possibility.
They were not alone. General physicians in Singapore were sometimes
perplexed by a laboratory mis-identification, leading to a potentially
missed diagnosis and important consequences for antibiotic choice1. Even
during a brief sojourn in the UK between Singapore and Western Australia,
I heard of a case of late onset melioidosis in a former Far East prisoner of
war (FEPoW) that had proved a difficult laboratory diagnosis. But the level
of challenge stepped up shortly after my arrival in Australia when a small
outbreak occurred in the West Kimberley2. The preliminary, hot outbreak
investigation was a hasty introduction to the realities of public health
microbiology in remote, rural Australia. It took just over a year to nail down
the likely cause of the outbreak and implicate a specific component of the
drinking water supply3. The abrupt end to the outbreak and subsequent
results appeared to confirm that we had identified an Australian version
of the Broad Street pump episode. We were advised that this was the
first time in half a century that deaths had been attributed to an infection
transmitted by drinking water in Australia. Since then, collaboration with
colleagues in Darwin and Townsville has mapped out aspects of the
environmental risk in northern Australia4, and work in northeast Brazil
has highlighted the emerging nature of this disease in other parts of the
tropics5 (Figures 1-3). Following the anthrax attacks in the USA in late
2001, we have become increasingly aware of the Biosecurity aspects of
the disease overseas, despite its local endemic status. The most recent
development has been recognition of the relationship between disease
Figure 1.
glassware in
Brazil. Tropical
often involves
making do
with unfamiliar
tools, or
while a long
way from
tertiary centre
support and
home comforts.
All these lab
supplies had to
be requested
and checked in
risk and climatic variables by our colleagues in Darwin6. In Western
Australia we have had to address the growth of the mining industry and
have recognised a potential occupational health and safety hazard for
mine site workers7.
Figure 2. Making light work of recruiting tropical public health
assistants. On the right is a member of the local public health
unit staff extension programme. To his left is a veterinary health
worker and on the right are two volunteers from a nearby
Figure 3. Distant end of the supply chain. We still haven’t got a
field lab set up there, in northeastern Brazil. These are remote,
tight-knit communities where the pace of life is slower than the
city and few cars are seen.
Expanding on the microcosm
Extrapolating from this mono-disease-centric view, we can pick up several
threads that lead to areas into which tropical medicine can comfortably
expand. Public health aspects of tropical medicine such as disease
surveillance, disease control and health impact assessment are likely
to have increasing relevance to the expanding mining and resources
industry in our tropical north. This is not only an adjunct to the remote
and rural medicine practiced by paramedical staff. It is also intrinsically
bound up in conventional tropical medicine. So too is occupational health
and safety, though its emphasis on risk identification, prevention and
mitigation may be unfamiliar to some specialist medical practitioners.
Other notable public health aspects are emerging infectious diseases
and biopreparedness – terms that have only come to the fore in the last
decade, and which impinge on many areas of infectious diseases. Another
area that lurks in the background of all these areas of health care is the
field of military and disaster medicine. This overlaps with Australasian
tropical medicine for obvious geographic reasons.
Our paramedical colleagues are highly visible in rural and remote practice,
often substituting for a medical practitioner when the doctor is an RFDS
flight away. Less visible and too often taken for granted are the scientists
who have contributed so much in recent years to the expanding horizons
of tropical medicine. Parasitology in particular is undergoing a quiet
revolution due to the impact of molecular and cell biology techniques,
leading to improved diagnostic tools, drug discovery and vaccine
development for neglected tropical diseases. This year, for instance, we
have seen our WA outbreak strain of Burkholderia pseudomallei (NCTC
13177) fully sequenced and made available via GenBank8. The scientific
capability for high throughput molecular analysis is now within our grasp,
but has yet to be integrated within tropical medicine at a practical and
operational level. True, these areas of biomedical activity are only a part
of the bigger picture, but these previously fringe areas provide us with
stepping stones to an expanded and more inclusive discipline.
21st century frame-shift
The challenge, then, is to re-examine those surprising places where we
encountered elements of tropical medicine and ask if they have something
to offer our discipline. We have already started on this path with travel
medicine, toxinology and parasitology. These areas need no debate,
though we can always ask how we can better service the professional
needs of their representatives. But other areas including tropical public
health, tropical environmental health, health threat assessment, emerging
infectious diseases, biopreparedness, disaster and military medicine have
yet to bed down comfortably within the framework of tropical medicine.
Individuals know how they bring these elements together in day-to-day
practice, but there is a significant difference between practitioner-specific
perspective and a shared view of the professional world. The bigger
challenge is surely one that we as a College can address together: how to
develop and maintain a cohesive programme for an increasingly diverse
and numerous membership, while building on our existing strengths in
professional standard setting, instruction, advocacy of College interests,
and conference organisation. These are all areas on which I invite your
comment as we review our programme and plan its development.
Inglis TJ, Chiang D, Lee GS, Chor-Kiang L. Potential misidentification of Burkholderia pseudomallei by API 20NE.
Pathology. 1998; 30: 62-64.
Inglis TJ, Garrow SC, Adams C, Henderson M, Mayo M. Dry-season outbreak of melioidosis in Western Australia.
Lancet. 1998 14; 352:1600.
Inglis TJ, Garrow SC, Henderson M, Clair A, Sampson J, O’Reilly L, Cameron B. Burkholderia pseudomallei traced
to water treatment plant in Australia. Emerg Infect Dis. 2000; 6: 56-59.
Inglis TJ, Foster NF, Gal D, Powell K, Mayo M, Norton R, Currie BJ. Preliminary report on the northern Australian
melioidosis environmental surveillance project. Epidemiol Infect. 2004;132: 813-820
Rolim D, Vilar DC, Sousa AQ, Miralles IS, de Oliveira DC, Harnett G, O’Reilly L, Howard K, Sampson I, Inglis TJ. Melioidosis, northeastern Brazil. Emerg Infect Dis. 2005; 11:1458-1460.
Currie BJ, Jacups SP. Intensity of rainfall and severity of melioidosis, Australia. Emerg Infect Dis. 2003; 9: 15381542.
Inglis, TJJ. Occupational health risk of melioidosis. Minerals & Energy Resources Institute of Western Australia,
project report, 2007 (unpublished).
Read,T.D., Lentz,S.M., Nolan,N.M. et al.. NZ_ABBQ01000001-NZ_ABBQ01001077. Burkholderia pseudomallei
NCTC 13177 WGS.
The Australasian College of Tropical Medicine looks forward to supporting the 6th World Melioidosis Congress in
Townsville in 2010.
Dr John Frean
Dr John Frean, MB BCh, MMed (Path), MSc (Med Parasitol), DTM&H, FFTM RCPS (Glasgow),
FACTM and Dr Lucille Blumberg, MB BCh, MMed (Microbiol), FFTM RCPS (Glasgow), DTM&H,
DOH, DCH, National Institute for Communicable Diseases and University of the Witwatersrand,
Johannesburg, South Africa
Dr Clare Cutland, BSc, MB BCh, DCH (SA), Respiratory and Meningeal Pathogens Research Unit,
University of the Witwatersrand and Medical Research Council, Johannesburg, South Africa
(Annals of the ACTM, 2007; 8,2:32-34)
Dr Lucille Blumberg
Dr Clare Cutland
Dr J Frean
National Institute for Communicable Diseases
P/Bag X4, Sandringham 2131, South Africa
Tel +27 11 555 0308
Fax +27 11 555 0446
Email [email protected]
Dr Lucille Blumberg
National Institute for Communicable Diseases
P/Bag X4, Sandringham 2131, South Africa
Tel +27 11 386 6337
Fax +27 11 555 6584
Email [email protected]
Dr Clare Cutland
Respiratory and Meningeal Pathogens Research
Unit, University of the Witwatersrand and Medical
Research Council, Johannesburg, South Africa
Tel +27 11 989 9891
Fax +27 11 989 9886
Email [email protected]
Q fever was first recognised during an outbreak of febrile illness in abattoir workers in Australia, but
is now known to be a zoonosis that is present in nearly all countries. Initially thought to be closely
related to the rickettsiae, Coxiella burnetii is now classified in a different order. It is characterised
by a highly environmentally-resistant extracellular form, and most infections are acquired by the
airborne route, particularly when handling parturient animals or slaughtered ruminants. The disease
has a widely variable presentation, with up to 60% of cases being clinically inapparent, and is
probably extensively underdiagnosed. Unlike rickettsial infections, Q fever may cause chronic
infection, and a post-Q fever chronic fatigue syndrome has been described. While newer macrolide
and quinolone antibiotics show activity against this pathogen, the treatment of choice for acute
infection is still tetracycline-group antibiotics. Chronic Q fever remains challenging to treat.
Q (for ‘query’) fever was first clinically characterised by Edward Derrick in 1935 during an outbreak
of febrile illness in abattoir workers in Brisbane.1 The agent, thought then to be a type of rickettsia,
was subsequently isolated in Australia and the United States, and named Coxiella burnetii in 1948. It is an unusual aerobic Gram-negative obligate intracellular bacterium and molecular taxonomy
now places it in the gamma-proteobacteria, order Legionellaceae, whereas the rickettsiae are
classified as alpha-proteobacteria, order Rickettsiales.2 C. burnetii is a zoonotic pathogen and
humans are generally accidental hosts. A history of domestic animal contact, as in the case report
below, is typical, but is not always elicited. Although the organism is widespread in the southern
African region, it is seldom identified as a cause of human disease.
Case report
The patient was a 33-year-old engineer who lived on a smallholding on the outskirts of Johannesburg.
On the property were dogs, cats, sheep, goats and guinea fowl. He had travelled in Zimbabwe and
the west coast of South Africa at three months and three weeks, respectively, before the onset of
illness. Falciparum malaria and tick bite fever had been diagnosed one week after his return from
Zimbabwe; he had been appropriately treated and recovered fully. On 14 March he vaccinated his
sheep against bluetongue virus disease. On 20 March he felt very tired; three days later he presented
with headache, rigors, lower abdominal pain and generalised myalgia. His condition deteriorated
rapidly and he was transferred to the intensive care unit with acute respiratory distress syndrome,
depressed mental state, and liver and coagulation dysfunction. He was jaundiced, but was not
anaemic clinically. His temperature was 39ºC, blood pressure was 100/60 mmHg, pulse rate was
110/minute, respiratory rate was 38/minute. He was bleeding from the nose, there was blood in
the nasogastric drainage tube, and there were some petechiae. There were no insect or tick bite
marks; the chest was clear on auscultation; no enlargement of liver or spleen was detected; no
meningism was present. There was tender inguinal lymphadenopathy. The chest x-ray showed
bilateral changes suggestive of acute respiratory distress syndrome (Figure 1). The haemoglobin
level was 12.9 g/dL; the white cell count was 1.7 x 109/L, 70% neutrophil polymorphonuclear
leukocytes; the platelet count was 57 x 109/L; urea and creatinine levels were normal; the plasma
bicarbonate concentration was 24 mmol/L. Liver function tests were as
follows: total and conjugated bilirubin, 107 and 72 µmol/L, respectively;
alkaline phosphatase, 99 U/L; gamma-glutamyl transferase, 118 U/L;
alanine aminotransferase, 1357 U/L; aspartate aminotransferase, 3120
U/L; lactate dehydrogenase, 5058 U/L. Coagulation studies showed a
partial thromboplastin time of 41.8 sec. (control 33 sec.) and prothrombin
ratio (INR) of 2.11. Blood, urine, and stool cultures were negative; blood
smears were negative for malaria, relapsing fever, and trypanosomiasis.
Antibody studies were negative for Legionella, Mycoplasma, Chlamydia,
typhoid, brucellosis, yersiniosis, rickettsiae, leptospirosis, cytomegalovirus
and Epstein-Barr virus, herpes simplex, hepatitis A, B, and C, arboviruses,
and viral haemorrhagic fevers (Crimean-Congo, Rift Valley, yellow fever,
and Hantaan viruses). Autoantibodies were not present. IgG antibodies
to Toxplasma gondii were present. Coxiella burnetii serology showed
presence of phase I (IgM titre 1/16, IgG 1/128) and phase II (IgM 1/256, IgG
1/128) antibodies, compatible with acute Q fever. The patient was treated
initially with piperacillin-tazobactam and imipenem; when the diagnosis
was established tetracycline was added, and finally ciprofloxacin was
used. Respiratory function deteriorated and fever persisted, followed
by clinical improvement and return of normal respiratory, liver, and
coagulation functions. The patient was discharged well 14 days after
admission. Q fever serology two months later showed only low IgG titres
(1/64) of phase I and phase II antibodies.
Figure 1. Chest radiograph (supine) showing bilateral,
predominantly perihilar and basal densities, with small nodules
and larger confluent areas of opacification.
The distribution of Q fever is worldwide, except for Antarctica and New
Zealand.3 Q fever is a tick-associated zoonosis, with an extremely wide
host range. The traditional reservoirs of human importance are domestic
stock: cattle, sheep, and goats; parturient domestic cats and dogs have
also been sources of outbreaks.3 Organisms localise to placenta and
mammary glands, and while infections in animals are usually silent,
they can cause outbreaks of abortion. Organisms are excreted via birth
products, milk, faeces, and urine. C. burnetii differs in several ways
from rickettsiae in being highly environmentally resistant, because of
a spore-like stage; it shows antigenic phase variation; it produces a
granulomatous, rather than vasculitic pathology; and it demonstrates a
potential for chronic infection. Most importantly, acquisition by humans
is predominantly by the airborne route, especially when exposed to or
handling animal birth products, or slaughtered animals. The organism is
highly infectious, and therefore poses an infection risk (not necessarily
disease risk) to persons occupationally or otherwise exposed to it, and
it has potential for use as a biological weapon (category B). However,
person-to-person spread is uncommon.3 Transmission via unpasteurised
milk4 or by crushing ticks has been described rarely; tick bites are thought
to be unimportant for human infections, but inhalation of tick faeces is a
likely mode of infection. Q fever has been described (without supporting
data, however) as the most prevalent ‘rickettsial’ infection in South Africa,5
although the adjective is now taxonomically obsolete, as mentioned above.
The seroprevalence in humans in South Africa is not known, although it
is likely to be lower than in the past because of rapid urbanisation. It is
difficult to get a general picture of the extent of transmission to humans
in southern Africa from the very few studies that have been published. A
small selective study in Namibia showed 10 of 211 subjects (4.7%) had
serological evidence of exposure.6 In Zimbabwe a 37% prevalence of
antibodies to C. burnetii was recorded in humans in 1993.7 In Zambia there
was an average seroprevalence of 8.2% (range, 3% to 11.8%) reported
in 1999.8 Seroprevalences ranging from 1% to 24% have been found
elsewhere in Africa.9 Regarding animal seroprevalence, in South African
cats and cattle rates were 2% and 8%, respectively; for Zimbabwe the
corresponding figures were 13% and 39%, and 10% and 15% in goats
and dogs, respectively.7,10
In contrast to the vasculitis caused by rickettsiae, the hallmark of C.
burnetii infection is granulomatous inflammation. The organism targets
macrophages and monocytes, and the two antigenic states of the
organism are intimately linked to cell entry, intracellular survival, and
ultimate elimination or persistence. Different sets of phagocyte membrane
receptors are involved in internalization of phase I and phase II forms.11 The Toll-like receptor 4 (TLR4) plays a central role in pathogen uptake,
cytokine response, and granuloma formation. Once internalised, C. burnetii
survives and replicates in acid vacuoles (pH 4.5); this contrasts with the
cytoplasmic location of rickettsiae. Phase I forms are less efficiently
phagocytosed; phase II mutants therefore proliferate more rapidly initially,
and the antibody response is primarily directed at phase II organisms in
acute infections. Although macrophages can kill phase II bacteria, phase
I stages initially avoid death by inhibiting the final phagosome maturation
step, but this function can be restored by gamma-interferon. Ultimately,
only phase I organisms may survive and persist. In chronic Q fever the
immune response is ineffective, despite high levels of antibodies to both
phases, and may cause harmful effects like leucocytoclastic vasculitis
and glomerulonephritis.11 Cytokine dysregulation, particularly of TNF, has
been implicated in the pathophysiology of chronic Q fever infection.12
Histologically, characteristic non-caseating ‘fibrin ring’ or ‘doughnut’
granulomas are found mainly in the liver, bone marrow and lungs. Other
pathological changes include small vessel vasculitis and fatty change in
the liver in some cases, and an interstitial pneumonitis with a mononuclear
inflammatory cell infiltrate in the alveolar septa, plus fibrinous exudates
in the alveolar air spaces.13
Clinical features
Life-threatening Q fever, as described in the case report above, is unusual.
The incubation period is normally around two to three weeks, but is dosedependent.3,14 Up to 60% of C. burnetii infections are asymptomatic. The
most common acute presentations are a self-limited influenza-like febrile
illness, pneumonia, or hepatitis; other clinical manifestations include
neurological involvement (encephalitis, meningoencephalitis, GuillainBarré syndrome, other neuropathies), and foetal loss in pregnancy.11 Q
fever is an important cause of community-acquired ‘atypical’ pneumonia. There are geographical differences in the relative frequency of pneumonia
and hepatitis presentations.3,11 The clinical presentation is variable;
cough is often absent; the illness is usually mild to moderately severe,
but sometimes progresses rapidly to an acute respiratory distress
syndrome and respiratory failure. Clinically and radiologically, Q fever
pneumonia is indistinguishable from other atypical pneumonias; multiple
rounded opacities on chest radiographs have been described, but this
is not a consistent feature.3 Q fever hepatitis presents in three ways: a
predominantly infectious hepatitis picture; an incidental finding during
acute Q fever; and a fever of unknown origin picture, proven by typical
histology of liver biopsy. A study in France estimated that the rate of
clinical Q fever was 13 times higher in HIV-positive patients than in the
general population.15 Skin involvement may take the form of punctiform
or maculopapular rashes or erythema nodosum.11 The recognised acute
clinical spectrum has expanded to include acalculous cholecystitis,
pancreatitis, thyroiditis, orchitis, rhabdomyolysis, endo-, myo- and
pericarditis, glomerulonephitis and haemolytic uraemic syndrome,
amongst others.14 Inapparent Q fever may be acquired concomitantly or
consecutively with other tickborne infections.16 Chronic Q fever classically
manifests as endocarditis, typically infecting previously damaged valves;
rarely, aneurysms or vascular grafts may be infected; untreated, Q fever
endocarditis is usually fatal. Osteomyelitis, hepatitis, prolonged fever,
and persistent infection in pregnancy are other uncommon chronic
presentations. An emerging third category of infection is long-term
sequelae after acute disease, particularly chronic fatigue syndrome17
and cardiovascular complications. About 10% of acutely ill British
and Australian patients developed fatigue of more than six months’
Q fever is a protean illness with a wide differential diagnosis,
encompassing causes of atypical pneumonia, hepatitis, encephalitis,
carditis, osteomyelitis, miscarriage, and fever of unknown origin. Rarely,
as in the case report above, Q fever may present as multi-organ failure
and resemble bacterial septicaemia. It is likely that many cases are
missed; a history of animal contact is important to elicit or exclude in
making a clinical assessment. Laboratory diagnosis rests on serological
tests (preferably the indirect micro-immunofluorescence assay) to show
rising titres (Figure 2).
Figure 2. Positive indirect micro-immunofluorescence assay for
Q fever antibodies, showing C. burnetii organisms as small, bright
green dots.
Antibodies (IgM and IgG) to phase II antigens dominate in acute infections;
high levels of IgG and IgA phase I antibodies, equalling or exceeding
phase II IgG antibody titres, indicate chronic disease.14 The Weil-Felix
test is negative in Q fever. PCR of serum is relative insensitive (a rapid
nested PCR had a sensitivity of 18%),18 in contrast to PCR on heart valve
tissue, where the technique performed well.19
The treatment of choice for acute Q fever is tetracycline, generally in the
form of doxycycline (100 mg twice daily for 14 days). Early treatment
seems to reduce the duration of the disease.20 Alternative agents used
include the 4-fluorinated quinolones and chloramphenicol. Erythromycin
has been shown to be less effective,21 but newer macrolides may
be useful. Cotrimoxazole is recommended for children and pregnant
women.14 Prolonged antimicrobial treatment for Q fever endocarditis is
required. Doxycycline, in combination with ciprofloxacin or rifampicin,
for at least two years, should be considered.21 The combination of
hydroxychloroquine (to alkalinize phagolysosomes) and doxycycline for
18 months has been effective.3,14 A whole-cell vaccine is licensed in
Australia and used in abattoir workers, and other vaccine formulations
are available elsewhere.
Derrick E. Q fever, a new fever entity: clinical features, diagnosis and laboratory investigation. Med J Aust 1937;
2: 281-299.
Raoult D, Fournier P-E, Eremeeva M, et al. Naming of rickettsiae and rickettsial diseases. Ann NY Acad Sci 2005;
1063: 1-12.
Marrie TJ, Raoult D. Q fever – a review and issues for the next century. Int J Antimicrob Agents 1997; 8: 145161.
Fishbein DB, Raoult D. A cluster of Coxiella burnetii infections associated with exposure to vaccinated goats and
their unpasteurized dairy products. Am J Trop Med Hyg. 1992 Jul;47(1):35-40.
Gear JHS, Wolstenholme B, Miller B, Sher R, Schneider J. Q fever in South Africa. In: Gear JHS, Ed. Medicine in a
Tropical Environment. Cape Town: AA Balkema, 1977: 471-478.
Wessels G, Hesseling PB, Cooper RC. Q fever, OX19, OX2 and leptospirosis antibodies in patients with onyalai and in
negroid, bushman, and white inhabitants of Kavango, Namibia. Trans Roy Soc Trop Med Hyg 1986; 80: 847-848.
Kelly PJ, Matthewman LA, Mason PR, Raoult D. Q fever in Zimbabwe. A review of the disease and the results of a
serosurvey of humans, cattle, goats and dogs. S Afr Med J 1993; 83: 21-25.
Okabayashi T, Hasebe F, Samui KL, et al. Short report: prevalence of antibodies against spotted fever, murine typhus,
and Q fever rickettsiae in humans living in Zambia. Am J Trop Med Hyg. 1999; 61: 70-2.
Tissot Dupont H, Broqui P, Faugere B, Raoult D. Prevalence of antibodies to Coxiella burnetii, Ricketsia conorii, and
Rickettsia typhi in seven African countries. Clin Infect Dis 1995; 21: 1126-1133.
Matthewman L, Kelly P, Hayter D, et al. Exposure of cats in southern Africa to Coxiella burnetii, the agent of Q fever.
Eur J Epidemiol 1997; 13: 477-479.
Raoult D, Marrie TJ, Mege JL. Natural history and pathophysiology of Q fever. Lancet Infect Dis 2005; 5: 219226.
Honstettre A, Imbert G, Ghigo E, et al. Dysregulation of cytokines in acute Q fever: role of interleukin-10 and tumor
necrosis factor in chronic evolution of Q fever. J Infect Dis 2003; 187: 956-962.
Isaäcson M, Hale MJ. Infections caused by rickettsiae and rickettsia-like organisms and bartonellosis. In: Doerr W,
Siefert G, eds. Tropical Pathology. Berlin: Springer-Verlag, 1995: 264-276.
Parker NR, Barralet JH, Bell AM. Q fever. Lancet 2006; 367: 679-688.
Raoult D, Levy PY, Dupont HT, et al. Q fever and HIV infection. AIDS 1993; 7: 81-86.
Rolain JM, Gouriet F, Brouqui P, et al. Concomitant or consecutive infection with Coxiella burnetii and tickborne
diseases. Clin Infect Dis 2005; 40: 82-88.
Ayres JG, Flint N, Smith EG, et al. Post-infection fatigue syndrome following Q fever. Q J Med 1998; 91: 105123.
Fournier P-E, Raoult D. Comparison of PCR and serology assays for early diagnosis of acute Q fever. J Clin Microbiol
2003; 41: 5094-5098.
Lepidi H, Houpikian P, Liang Z, Raoult D. Cardiac valves in patients with Q fever endocarditis: microbiological,
molecular, and histologic studies. J Infect Dis. 2003; 187: 1097-106.
de Alarcon A, Villanueva JL, Viciana P et al. Q fever: epidemiology, clinical features and prognosis. A study from
1983 to 1999 in the south of Spain. J Infect 2003; 47: 110-116.
Mandell GL, Bennett JE, Dolin R, (eds.) Principles and Practice of Infectious Diseases, 6th edition. Elsevier Churchill
Livingstone, Philadelphia. 2005: 2284-2301.
The incidence of malignant melanoma
detected in primary care and the value of
Dr Scott Kitchener, Toowoomba & Darling Downs Health Service, Toowoomba
(Annals of the ACTM, 2007; 8,2:35-37)
Thank you for the opportunity to present one of the Royal Society of Tropical Medicine and Hygiene
Centennial lectures at this conference. Being a Fellow of both the Royal Society and the Australasian
College of Tropical Medicine, this is a real honour.
Anton Breinl was the first director of the Australian Institute of Tropical Medicine where I attended
for tropical medicine training and doctoral studies, though Brienl had left by that stage. During his
time at the institute he was interested in the diseases of relevance in the area despite being told
that there were no diseases in the region which were not understood. I am sure Breinl would have
been most interested in the incidence of skin cancers among the white population of the region,
these being undoubtedly not well understood based on the European framework of knowledge
regarding skin cancer.
One of Breinl’s successors as Director of the Australian Institute of Tropical medicine was Sir
Raphael Cilento. Recently, I was fortunate enough to receive a copy of Cilento’s first edition text:
Tropical Diseases of Australasia, published in 1940. In the foreword, Cilento writes that... “no
bio-geographical area is so well situated for the study of those tropical diseases that exist within
it. In Queensland alone, for example, there are more than one million white people living normal
lives as working men and women between latitudes 10 and 28 degrees South...” Notably, even
though Cilento includes non-communicable disease in the text, he fails to include skin cancer as
such a disease, yet, the epidemiology of melanoma is one of the most strongly associated with
latitudinal variation particularly among lighter skinned people. It is therefore truly a disease worthy
of inclusion in tropical medicine.
Dr S Kitchener
Toowoomba & Darling Downs Health Service
Peachee Street
Toowoomba Qld 4350
Email [email protected]
Anton Breinl was Viennese. Austria, through it’s fair population and placement in southern Europe,
has quite an incidence of melanoma and plays a leading role in research into clinical means
of skin cancer detection, specifically, dermoscopy, which I would like to discuss further in this
Dermoscopy has been discussed in scientific literature for nearly a century. Early work using
surface microscopy established terminology and capabilities of the technique with particular focus
on pigmented lesions utilising colour variation for differentiation12. Use of oil immersion expanded
the capabilities of surface microscopy of the skin, though not as a stand-alone technique, rather
for assessment of pigmented skin lesions prior to surgical intervention3. However, later detailed
description of the image aspects began to be discussed specifically for the diagnosis of pigmented
skin lesions4. Dermoscopy was recognised and described as a tool for detection of earlier stage
melanoma5,6 and the first “methods” of image interpretation appeared7.
Much of the early research and development of dermoscopy into regular clinical use was based
upon the labours of dedicated dermatologists bringing the technique into being as a regular tool for
diagnosis of pigmented skin lesions with appropriate targeted training8,9,10. The natural development
of this technique has been towards enhancing detection of melanoma in primary care through
specific training programs for primary care physicians11.
Concurrent with utilisation of dermoscopy in primary care skin cancer
medicine has been the improvement of the images produced by
dermoscopes through hardware development with lesser dependence
upon oil-immersion to produce high resolution images. Augmenting
dermoscopy with digital imaging has permitted digital monitoring to go
beyond “spot” diagnosis to improve accuracy of detection by using paired
images taken over time12,13.
Nevertheless, clinical detection and diagnosis of melanoma is not
accurate. In a prospective study, dermatologists nominated excised
pigmented lesion correctly as melanoma in only 3.7% of cases (149/4036
lesions removed)14. More than half of these lesions were removed for
aesthetic, functional or (patient) reassurance reasons, however, even
among those considered suspicious a priori, only 11.8% (141/1199) were
correctly nominated. The most reliable criteria identified were overall
irregularity, the “ugly duckling” sign15, and evolution according to the
patient, though these only achieved modest positive predictive values
(0.107, 0.090, 0.074 respectively).
Unaided diagnosis of melanoma compares poorly with diagnosis assisted
by dermoscopy which has significantly higher discriminating power16. A
meta-analysis of 14 studies directly comparing unaided diagnosis with
dermoscopy found an improvement of 49% in diagnostic accuracy17.
However, without training, dermoscopy did not improve accuracy. This
meta-analysis included only one study of primary care physicians. In
this study of 74 primary care physicians, surface microscopy improved
diagnostic accuracy but only in that group provided with education in
the approach. In Australia, early diagnosis of melanoma translates into
improved patient outcomes as tumours of lesser thickness are identified18. Primary care physicians in Australia generally have a high standard of
provisional diagnosis of suspicious pigmented skin lesions19,20. Australian
General Practitioners interpreting dermoscopic images of pigmented
skin lesions provided to them diagnosed melanoma with 65% sensitivity
compared to their dermatologist colleagues reading the same set (of
images) achieving 81% sensitivity21. In another Australian study of mostly
Primary Care Physicians, assessment of a set of 40 macroscopic images
achieved only 61% sensitivity for melanoma detection22. Training these
physicians in dermoscopic algorithms improved sensitivity up to 85% for
reading the 40 corresponding dermoscopy images.
Increasingly complex algorithms for interpreting dermoscopic images
produce improved accuracy but lose simplicity23,24. More recent algorithms
have focused on the sensitivity of dermoscopy in the detection of
melanoma and these are most relevant for the primary care environment.
Overall, clinical examination and the 3-point checklist algorithm has
been found to be sensitive (96.3%) in the hands of minimally trained
While the high sensitivity of the 3-point checklist approach provides a
safety net for missing melanoma, it is at the expense of specificity (32.8%).
The more dedicated skin cancer medicine practitioner should achieve a
much higher specificity and lesser unnecessary excision/treatment rate
than this would suggest. This is certainly achievable through subsequent
use of other algorithms. In the initial assessment of 3-point checklist,
expert users achieved high specificity in diagnosis (94.2%) by following
initial screening with more complex algorithmsxxv.
Whereas the 3-point check list described above is effective in the
detection of melanoma, algorithms of dermoscopic features have been
developed for the diagnosis of pigmented skin lesions. Algorithms consist
of an analytic approach using particular dermoscopic features as criteria
for the morphologic diagnosis of these lesions. Many algorithms have
been developed in the past two decades. Key approaches are the ABCD
rule for dermoscopy and the 7-point checklist26, CASH Algorithm27, the
Menzies approach28 and Pattern Analysis29.
An Australian focused comparison of some of these methods as used by
non-experts found the Menzies method to have the highest diagnostic
accuracy (81%) and sensitivity (85%)22. It was preferred by most
participants, though they were mostly Australian participants which
probably compounded this finding since the Menzies method is Australian
in origin. Highest specificity (the objective of algorithms used additionally
to primary analysis) was found with Pattern Analysis 85.3%).
The challenge for every practitioner in skin cancer medicine is the earliest
diagnosis of melanoma to maximise the health outcomes for the patient.
Unfortunately, the earlier the melanoma, the less the features identifiable
using the algorithms discussed above.
Figure 1: The top image is a pigmented skin lesion found on
the back of a 32 year old man who came in to our practice for a
routine skin check. It looked unusual, however, not so much as to
warrant excision. However the bottom image was recorded only
months later – after which it was removed and found to be an
early stage melanoma.
The key to sequential monitoring of pigmented skin lesions is images
compared with sufficient time lapsing to allow identification of change,
but not so much time as to allow the melanoma to escape to a grade less
amenable to treatment. This is essentially moving from spot diagnosis
to using paired data which will always be more powerful. Some digital
dermoscopy units allow split screen imaging to facilitate the dermoscopist
visually comparing and others attempt to use computer generated
comparison (Figure 1).
Visual comparison of paired images began in the late 1990’s30,31. The
period of time suitable to elapse between images has been the focus of
quantitative research. Monitoring periods have reduced from 12 months
to three months32,33. Six months and less are commonly referred to as
“short term monitoring”. Short term monitoring has become the standard
for comparative or sequential dermoscopy34.
I would like to present some of our data graphed from the publication of
this research of comparative dermoscopy in primary care in Australia35.
Figure 2: Age distribution of patients screened and melanoma
Figure 2 represents the demographics of the first 7,081 patients screened
at a primary care clinic in the north west of Brisbane. All patients were
screened clinically including the use of dermoscopy with digital recording
of images for mild and moderately atypical pigmented skin lesions not
otherwise removed or biopsied. Overall 21 melanoma were diagnosed
from this sample representing a number needed to screen of 338 and
a rate of melanoma detected of three per 1,000. This is comparable to
specialist-based programs for melanoma detection in Australia36 and
North America37,38.
Of these 21 melanoma, seven were found on comparative dermoscopy.
This was particularly useful in early stage melanoma among which five of
the 14 level 1 melanoma were detected following review of comparative
Our conclusions were that melanoma is common in primary care in
Australia. Primary care physicians are well placed to detect melanoma
early and this is enhanced with the use of dermoscopy. Some training is
necessary to utilize a dermoscope efficiently in clinical examination and
this will improve the ability of the physician to detect melanoma. Further,
comparative dermoscopy has a role in detection of melanoma in primary
care, particularly early stage melanoma.
Goldman L, Younker, W. Studies in microscopy of the surface of the skin. J Invest Dermatol 1947; 9: 11-16.
Goldman L. Some investigative studies of pigmented nevi with cutaneous microscopy. J Invest Dermatol 1951;
16: 407-427.
Mackie, R. An aid to the perioperative assessment of pigmented lesions of the skin. Br J Dermatol 1971; 85:
Fritsch P, Pechlaner R. The pigmented network: a new tool for the diagnosis of pigmented skin lesions. J Invest
Dermatol 1980; 74: 458-459.
Steiner A, Pehamberger H, Wolff K. In vivo epiluminescent microscopy of pigmented skin lesions. II Diagnosis of
small pigmented skin lesions and early detection of malignant melanoma. J Am Acad Dermatol 1987; 17: 584591.
Pehamberger H, binder M, Steiner A. Wolff K. In vivo epiluminescent microscopy: Improvement in early diagnosis
of melanoma. J Invest Dermatol 1993; 100: S356-362.
Nachbar F, Stolz W, Merkle T, et al. The ABCD rule of dermatoscopy. J Am Acad Dermatol 1994; 30: 551-559.
Stanganelli & Buuchi, 1998; Binder etal, 1995; Binder etal, 1997. The natural development of this technique has
been towards enhancing detection of melanoma in primary care through specific training programs for primary
care physicians [Westerhoff etal, 2000.
Binder M, Schwarz M, Winkler A, et al. Epiluminescent microscopy: a useful tool for the diagnosis of pigmented
skin lesions for formally trained dermatologists. Arch Dermatol 1995; 131: 286-291.
Binder M, Puespoeck-Schwarz M, Steiner A, et al. Epiluminscent microscopy of small pigmented skin lesions:
short-term formal training improves the diagnostic performance of dermatologists. J Am Acad Dermatol 1997;
36: 197-202.
Westerhoff K, McCarthy WH, Menzies SW. Increase in the sensitivity for melanoma diagnosis by primary care
physicians using skin surface microscopy. Br J Dermatol 2000; 143: 1016-1020.
Menzies SW, Gutenev A, Avramidis M, Batrac A, McCarthy WH. Short-term digital surface microscopy monitoring
of atypical or changing melanocytic lesions. Arch Dermatol 2001; 137: 1583-1589.
Kittler H, Pehamberger H, Wolf K, Binder M. Diagnostic accuracy of dermoscopy. Lancet Oncol 2002; 3: 159165.
Gachon J, Beaulieu P, Sei JF, Gouvernet J, Claudel JP, Lemaitre M, Richard MA, Grob JJ. First prospective study of
the recognition process of melanoma in dermatological practice. Arch Dermatol 2005; 141: 434-438.
Grob JJ, Bonerandi JJ. The “ugly duckling” sign. Arch Dermatol 1998; 134: 103-104.
Bafounta ML, Beauchet A, Aegerter P, Saiag P. Is dermoscopy (epiluminescent microscopy) useful for the diagnosis
of melanoma? Arch Dermatol 2001; 137: 1343-1350.
Kittler H, Pehamberger H, Wolff K, Binder M. Diagnostic accuracy of dermoscopy. Lancet Oncol 2002; 3: 159165.
Marks R. Two decades of public health approach to skin cancer control in Australia: Why, how and where are we
now? Australas J Dermatol 1999; 40: 1-5.
Baade P, Del Mar C, Lowe J, Standton W, Balanda K. Clinical diagnosis and management of suspicious pigmented
skin lesions – a survey of GPs. Aust Fam Physician 2005; 34: 79-83.
Moffat CRM, Green AC, Whiteman DC. Diagnostic accuracy in skin cancer clinics: the Australian experience. Int J
Derm 2006; Online publication date: 20-Jan-2006.
Menzies SW, Bischof L, Talbot H, et al. The performance of SolarScan. Arch Dermatol 2005; 141: 1388-1396.
Dolianitis C, Kelly J, Wolfe R, Simpson P. Comparative performance of 4 dermoscopic algorithms by nonexperts
for the diagnosis of melanocytic lesions. Arch Dermatol 2005; 141: 1008-1014.
Soyer H, Smolle J, Hodl S, Pachernegg H, Kerl H. Surface microscopy. A new approach to the diagnosis of cutaneous
pigmented tumours. Am J Dermatopath 1989; 11: 1-10.
Argenziano G, Soyer HP, Chimenti S, et al. Dermoscopy of pigmented skin lesions: results of a consensus meeting
via the internet. J Am Acad Dermatol 2003; 48(5): 679-693.
Soyer HP, Argenziano G, Zalaudek I, et al. Three-point checklist of dermoscopy. A new screening method for early
detection of melanoma. Dermatology 2004; 208: 27-31.
Argenziano G, Fabbrocini G, Carli P, De Giorgi V, Sammarco E, Delfino M. Epiluminscent microscopy for the diagnosis
of doubtful melanocytic skin lesions. Comparison of the ABCD rule of dermatoscopy and a new 7-piint checklist
based on pattern analysis. Arch Dermatol 1998; 134: 1563-1570.
Henning JS, Dusza SW, Wang SQ, Marghoob AA, Rabinovitz HS, Polsky D, Kopf AW. The CASH algorithm for
dermoscopy. J Am Acad Dermatol 2007; 56: 45-52.
Menzies SW. A method for the diagnosis of primary cutaneous melanoma using surface microscopy. Dermatol Clin
2001; 19: 299-305.
Pehamberger H, Steiner A, Wolff K. In vivo epiluminescent microscopy of pigmented skin lesions. I. Pattern analysis
of pigmented skin lesions. J Am Acad Dermatol 1987; 17: 571-583.
Stolz W, Schiffner R, Pillet L, etal. Improvement of monitoring of melanocytic skin lesions with the use of a
computerized acquisition and surveillance unit with a skin surface microscopic television camera. J Am Acad
Dermatol 1996; 35: 202-207.
Braun RP, Lemonnier E, Guillod J, Skaria A, Salamon D, Saurat JH. Two types of pattern modification detected on
the follow-up of benign melanocytic skin lesions by digitalized epiluminescence microscopy. Melanoma Res 1998;
8: 431-437.
Kittler H, Pehamberger H, Wolff K, Binder M. Follow-up of melanocytic skin lesions with digital epiluminescence
microscopy, atypical nevi, and common nevi. J Am Acad Dermatol 2000; 43: 467-476.
Menzies SW, Gutenev A, Avramidis M, Batrac A, McCarthy WH. Short-term digitial surface microscopic monitoring
of atypical or changing melanocytic lesions. Arch Dermatol 2001; 137: 1583-1589.
Kittler H, Guitera P, Riedl E, Avramidis M, Teban L, Fiebiger M, Weger R, Dawid M, Menzies S. Identification of clinically
featureless incipient melanoma using sequential dermoscopy imaging. Arch Dermatol 2006; 142: 1113-1119.
Kitchener S, McMaster S, Nasveld P. Dermoscopy in primary care for detection of melanoma. Int J Derm 2007, in
Williams HA, Fritschi L, Reid A, Beauchamp C, Katris P. Who attends skin cancer screening in Western Australia?
Results from the Lions Cancer Institute skin cancer screening program. Aust NZ J Pub Hlth 2006; 30: 75-80.
Koh HK, Norton LA, Geller AC, Sun T, etal. Evaluation of the American Academy of Dermatology’s national skin
cancer early detection and screening program. J Am Acad Dermatol 1996; 34: 971-978.
Engelberg D, Gallagher RP, Rivers JK. Follow-up and evaluatin of skin cancer screening in British Columbia. J Am
Acad Dermatol 1999; 41: 37-42.
Understanding of melanoma should be an essential part of tropical
medicine practice, particularly in regions with larger populations of
susceptible fair skinned such as Australia. Ultimately, health outcomes
will improve with the earlier detection of melanoma in primary care
tropical medicine practice therefore, dermoscopy must be a basic skill
of the tropical medicine practitioner.
Morphologic and Genetic Pathways in the
Development of Colorectal Cancer
Fumio Konishi, Hiroshi Noda, Takafumi Maeda and Kazutomo Togashi, Department of Surgery,
Saitama Medical Center, Jichi Medical University
(Annals of the ACTM, 2007; 8,2:38-42)
Adenoma (polyp)-carcinoma sequence is a well established pathway in the evolution of colorectal
cancer. This was followed by the reports on flat cancer pathway which is considered to be an
alternative route in the development of colorectal cancer. Recently, in addition to the traditional
pathway of adenoma-carcinoma sequence, certain types of serrated (hyperplastic) lesions are
hypothetically considered as one of the precursors of right sided colon cancer. Although morphologic
and genetic pathways are in some way interrelated, the correlation between the morphological
changes and genetic changes are still unclear. In 1988 Vogelstein reported sequential genetic
changes involved in the adenoma-carcinoma sequence. In the 1990s, defects of mismatch repair
genes were reported as the genetic changes involved in HNPCC as well as some of the sporadic
colorectal cancer. According to our analysis and the reports by other investigators, the genetic and
morphological pathways of colorectal cancer can be categorized into several types. Firstly, the
pathways will be classified into MSS and MSI-H pathways. The former pathway includes FAP and a
large number of sporadic cancer cases that develops following the traditional adenoma-carcinoma
sequence. As MSI-H pathways, HNPCC and sporadic MSI-H cancer in the right colon are included.
As for the sporadic MSI-H cancer in the right colon, there might be two possible pathways. One
is non-serrated pathway and the other is serrated pathway. The genetic pathway of flat cancer is
still unclear, but it might follow the pathway of MSI-H sporadic colon cancer.
Morphologic and genetic pathways in the development of colorectal cancer were presented and
discussed. Flat neoplasia to carcinoma sequence is a distinct and clinically important morphological
pathway. The genetic pathways of MSI-H sporadic colon cancer are still controversial, and this is
the challenging field of research at the present time.
F Konishi, MD
Department of Surgery
Saitama Medical Center of Jichi Medical School
1-847 Amanumacho omiyaku Saitamashi
Saitamaken 330-8503 JAPAN
Tel 048-647-2111
Fax 048-648-5166
Email [email protected]
Morphologic pathways in the development of colorectal cancer have been investigated for a long
time, beginning with the theory of adenoma (polyp)-carcinoma sequence, and later on followed by
the recognition of the flat lesions in Japan as an important precursor of colorectal cancer. Recently,
in addition to the traditional pathway of adenoma-carcinoma sequence, certain types of serrated
(hyperplastic) lesions are hypothetically considered as one of the precursors of right sided colon
cancer. Although morphologic and genetic pathways are in some way interrelated, the correlation
between the morphologic changes and genetic changes are still unclear. For example, in HNPCC
although genetic changes are totally different from those of common sporadic colorectal cancer that
originates in adenoma, HNPCCs also develop through morphologic pathway of adenoma-carcinoma
sequence. In the first part of this article, the gross morphologic pathways will be presented with a
special emphasis of flat type lesions in comparison with the traditional adenoma (polyp)-carcinoma
sequence. In the second part, genetic pathways of colorectal cancer development will be discussed
with an emphasis on the status of microsatellite instability and related genetic changes, and also
in relation to the morphologic characteristics of precursor lesions.
1. Morphologic Pathways (Polypoid adenoma vs. Flat neoplasia)
(1) Polypoid adenoma as a precancerous lesion
The classification of colorectal polyps was firstly proposed by Morson in mid 1970s.1
Table 1: Classification of colorectal polyps by Morson BC,
modified by Konishi F.
Single or Isolated
Multiple Polyps
Polypoid, flat
Juvenile polyp
Peutz-Jeghers polyp
Benign lymphoid polyp
Familial Adenomatous
Polyposis (FAP)
Juvenile polyposis
Peutz-Jeghers syndrome
Benign lymphoid polyposis
Inflammatory polyposis
Hyperplastic polyp
were reported in many of the papers.5-8 In flat type carcinomas in early
stages the size of the lesion is usually smaller than 10mm, the surface
is entirely flat, and the thickness of the lesion is often thinner than that
of the normal mucosa.
For the detection of small flat carcinoma, it is important to pay attention
to a slight color change or slight rough areas during colonoscopic
observation of the mucosa.9 When such abnormalities are found, dye
spray using 0.2% indigo carmine solution should be done. Indigo carmine
dye spray is essential to have the visualization of small flat lesions of
the colon and rectum.10
Figure 1: A flat early stage cancer measuring 7mm. (Indigo
carmine dye spray).
Hyperplastic polyposis
In his classification, adenomas are considered to be neoplastic and to
have a malignant potential (adenoma-carcinoma sequence).2 An extreme
example of adenoma-carcinoma sequence is familial adenomatous
polyposis (FAP) in which cancer develops in nearly a 100% of patients
if prophylactic surgery is not carried out. In Morson’s classification,
other polyps such as hyperplastic polyps, juvenile polyps, P-J polyps
and inflammatory polyps were classified as non-neoplastic because
of the very low risk of developing carcinoma. However, at the time of
Morson’s classification, polyps in Juvenile polyposis and P-J syndrome
had already been recognized as possibly precancerous because of the
higher frequencies of cancer development in these polyposis syndromes,
though not at all as high as in FAP. In Morson’s classification, hyperplastic
polyp (metaplastic polyps) was considered to be non-neoplastic. However,
in recent years special types of hyperplastic polyps (serrated lesions)
are hypothetically considered to have a potential of developing cancer
particularly in the right side of the colon. The issue of hyperplastic polyp
as a precancerous lesion will be discussed later in this article.
There are two reports on the effect of endoscopic resection of adenomas
in reducing the incidence of colorectal carcinomas. In the study published
by Winawer et al.,3 1,418 patients who had polypectomy were followed
up for the average of 5.9 years. The results of their study showed a
significantly lower incidence of colorectal carcinoma among the patients
in comparison to the expected number of colorectal cancers in the general
population. Among the 1,418 patients studied, in 494 (35%) adenomas
were larger than 1cm, and 10% of the adenomas removed were those
with severe dysplasia. Murakami et al.4 analyzed patients with polyps
in a colonoscopoic series and followed up the patients with and without
polypectomy. They reported a lower observed versus expected ratio of
cancer occurrence in the polypectomy group versus non-polypectomy
group. However, 45% of the polyps removed in the polypectomy group
were larger than 1cm. According to the results of the two reports, it can
be speculated that endoscopic removal of larger adenomas would have
possibly contributed to the reduction of in the incidence of colorectal
cancer. However, we do not know if the endoscopic resection of smaller
polyps, less that 1cm, contributes to the reduction of colorectal cancer
(2) Importance of small flat lesion as a precursor of colorectal cancer
The macroscopic appearance of adenomas and carcinomas in early
stages is classified into two, i.e. polypoid type (usual type) and flat type.
Figure 1 shows a good example of flat type carcinoma in an early stage.
In Japan, flat type neoplastic lesions have been investigated in detail and
Muto et al5, the first describers of flat adenoma, did not state a clear
definition of flat adenoma, but they described that the characteristic
features of flat adenoma were a slight elevation with a reddish surface and
that the height of the lesion was less than twice the thickness surrounding
normal mucosa on histological sections. On the other hand, Kuramoto et
al proposed that the height of flat early cancer did not exceed 50% of the
longer diameter,11 but his proposal is not generally accepted. Wolber et
al advocated a strict definition composed of three points; 1. flat lesions
lack exophytic polypoid configuration, 2. histologically the dysplastic
mucosa is never greater than two times the thickness of the adjacent
non dysplastic mucosal segment, 3. flat lesions show radial extension of
the dysplastic epithelium in the superficial luminal portion of the mucosa
without vertical extension.12 So far their definition has been well accepted
by Japanese as well as Western investigators.13-15
Often, a flat lesion is totally occupied by a highly dysplastic epithelium
that are equivalent to carcinoma on histology. Such a lesion is usually
interpreted as “intramucosal carcinoma” in Japan, though the diagnosis
of such a lesion by Western histopaghologists is usually “adenoma
with severe dysplasia”. Our data showed that the flat type cancer
occupies approximately 20% of all the carcinomas in early stages. Also,
regarding the shape, malignancy rate (Tis + T1) of flat depressed type
was significantly higher than those of any other shapes (p<0.05).16
When malignancy rate was defined according to the Western criteria
(those with invasion in the submucosa), flat depressed type showed a
tendency of higher rate than any of other types, and significantly higher
rate than those of flat elevated type, sessile type and pedunculated type
Figure 2: Malignancy rate (percentage of TI stage cancer) in our
colonoscopy series (Konishi, F and Togashi, K).
Flat and depressed type shows the highest malignancy
rate among other types.
graded into three: microsatellite-high (MSI-H), microsatellite-low (MSIL) and microsatellite stable (MSS).23 In HNPCC, MSI is present in up to
85-90% of cases, whereas in sporadic cases, it is present in 15-20% of
cases. Jass reported that serrated polyps might be the precursor of MSI
positive colon cancer in the right side of the colon, and that there are
two different serrated pathways developing MSI-H or MSI-L/MSS colon
cancer.24-26 However, MSI-L/MSS pathway is not entirely clearly reported
in the previous studies. In the present discussion I will focus on genetic
pathways in the development of MSI-H colon cancer.
(2) Sporadic MSI-H cancer
Because the malignancy rate of small depressed lesions is higher while
the lesions are still small (5-10mm), the growth rate of small flat cancer
can be presumed to be faster than the growth speed of polypoid type
lesions. There are anecdotal cases in which the process of the fast
growth was observed.
There is another type of flat and slightly depressed lesion which is
usually larger than 1cm and shows different marginal appearance from
the typical small depressed lesion. This type of lesion is nicknamed as
“lateral spreading non-granular type” by Kudo.7 The malignancy rate of
such lesions is not as high as small flat and depressed lesions.
Flat neoplastic lesions are not only reported in Japan but in other countries
in the word including Western countries. Rembacken et al reported that
in the series of 1000 colonosocpies in UK, 117(36%) out of 321 detected
lesions were flat and 0.6% showed depressed appearance, and that 54%
(20/37) lesions containing severe dysplasia or Dukes’A cancer were flat
and depressed.17 In 2004, Hurlstone et al reported that in the series of
599 EMR cases, 40% were flat or depressed and 23% of the flat lesions
contained high-grade dysplasia of beyond, compared to 9.0% in sessile
Ten to fifteen percent of sporadic colorectal cancers (CRC) show
microsatellite instability (MSI). 27 The clinicopathological features of MSI
positive sporadic colon cancers are right sided location, old age, female
gender, mucinous or poorly differentiated histology and lymphocyte
infiltration (intra-tumor cell lymphocyte).28 MSI in most of such sporadic
tumors is caused by methylation of promotor region in hMLH1 gene.21,
The silencing of hMLH1 gene is considered to be related to the
carcinogenesis in MSI-H tumors in the right colon. Among the sporadic
CRCs with MSI, 80-90% shows MLH1 methylation. But 10-20% of tumors
do not show MLH1 methylation, and the reasons of MSI in such tumors
are unknown.
(3) Serrated pathway for MSI-H colon cancer
Precursor lesions for MSI-H colon cancer: Candidates of precursor
lesions of sporadic MSI positive colon cancers are not yet clear. It can
be adenoma, hyperplastic polyp, or flat carcinoma. Jass reported that
polyps with serration, such as large sessile hyperplastic polyps (sessile
serrated adenoma:SSA) or traditional serrated adaenoma, can be the
candidates of precursor lesions for sporadic MSI-positive colon cancer
in the right colon.24, 26
Figure 3: Sessile serrated adenoma measuring 15mm
(Indigo carmine dye spray). Pit pattern shows that of a
hyperplastic polyp.
2. Genetic pathways
(1) General overview
In 1988 Vogelstein reported his theory of sequential genetic changes
involved in the process of adenoma carcinoma sequence.18 The changes
in APC, KRAS, TP53 and DCC genes were reported to be involved in the
process of adenoma carcinoma sequence. Thereafter, changes in the
DNA mismatch repair genes were reported as a cause of carcinogenesis
in the colon and rectum. Germ line mutations of mismatch repair(MMR)
genes is the cause of HNPCC,19,20 and also, methylation of promoter
region in a MMR gene (hMLH1) is considered to be the cause of
functional loss in MMR gene in some of the sporadic colon cancer
cases.21, 22 Microsatellite instability (MSI) is a frequent phenomenon that
occurs when there are abnormalities in MMR genes. This is due to the
loss of function to repair the redundant sequences of nucleotides that
occurs during the DNA replication. MSI is detected as the changes in the
length of nucleotide sequence in micro-satellites that contains repeated
nucleotide sequences (mono-, di-, or tri-nucleotides). MSI is usually
Circumstantial evidences for serrated pathway in the development
of MSI-H colon cancer are similar location (right-sided), serrated
histology within MSI-H colon cancer, and increased frequency of sessile
hyperplastic polyps (SSA)29 inpatients with MSI-H cancer.30 Similar genetic
changes in MSI-H sporadic colon cancer and sessile serrated adenoma
(SSA)/traditional serrated adenoma were also reported, such as higher
percentage of hMLH1 methylation, low rate of KRAS mutation and high
rate of BRAF mutation.25, 31 Such genetic similarities are the reasons for
serrated pathway theory proposed by Jass.24
Table 2: KRAS BRAF mutation, hMLH1 methylation and MSI in
MSI-H colon cancer, SSA/SA and MSS sporadic colon cancer
Colon Cancer
Colon Cancer
the development of SCC with MSI-H status. In HNPCC patients, several
studies have shown that MSI and MMR protein loss are frequently present
even in minute adenomas. Adenomas in such patients are considered
more prone to malignant conversion than in sporadic adenomas. On the
other hand, in sporadic cases, we consider that the transition from MSInegative to MSI-positive status may occur, not at the stage of initiation
but during the progression from early-stage to advanced-stage SCCs. In
HNPCC, MSI may be an early event during carcinogenesis, but it may be
a late event in the development of sporadic colon cancer.
(5) Genetic changes of flat lesions
Considering the morphologic and genetic similarities, the theory of
serrated tumor to carcinoma sequence is understandable. However, there
is a missing link in the analysis. Early stage cancers in the right colon have
not been tested for MSI, hMLH1 methylation/expression, KRAS and BRAF mutation. There is only one report of MSI status in early stage colon cancer.
In 1996, Konishi M et al reported that the frequency of MSI in colorectal
cancers in advanced stages was 13.3%, which is a usual percentage.
However, the authors also stated that MIS in Tis tumors was only 4.2%.32
There was a significant discrepancy in the rate of MSI between colorectal
cancers in advanced stages and those in early stage.
(4) Alternative pathway for MSI-H sporadic colon cancer
In sporadic colorectal cancer cases, hMLH1 promotor methylation is
the main cause of MSI. However, we still do not know whether hMLH1
methylation is an early event or late event in the genesis of sporadic
MSI high colon cancer. In our laboratory we investigated the MLH-1
methylation status, immuno-staining of MLH-1 protein and MSI status in
early stage right sided colon cancer.33 The material we examined did not
show serrated changes on histology. We used formalin fixed and paraffin
embedded tissue. Therefore, in our study, methylation specific PCR was
set to test the methylation in a part of the entire promoter region with CpG
sites. Because of such a setting in PCR, both partially methylated cases
and fully methylated cases were detected as methylation positive in our
study.34 As a result, in the right side of the colon, among hMLH1 promoter
methylation positive cases (partial methylation + full methylation), MSI
was found in only one out of 17 (5.9%) in early stage cases (Tis and T1),
and four of nine (44.4%) in advance stage cases (T2,T3, T4).33 Therefore,
among right-sided tumors with hMLH1 promoter methylation, the
frequency of MSI-positive tumors in early stage cases was significantly
lower than that in advanced stage tumors. Provided early stage cancers
develop into more advanced stage cancers, our results suggested that the
frequency of full methylation and MSI-H status may increase in frequency
with tumor progression in right side. In a subset of right-sided sporadic
colorectal cancers (SCC), hMLH1 promoter methylation may occur at
an early stage, but we consider that, in the majority of such lesions
methylation is partial and is not sufficient to inhibit hMLH1 expression. With further tumor progression, methylation may become more extensive,
leading to inhibition of hMLH1 expression and MSI. We consider that the
pathway we presented might be an alternative to serrated pathway in
There is a possibility of de novo carcinogenesis in flat type cancer, because
often small flat cancers are totally occupied by cancerous glands with the
absence of residual adenomatous tissue. According to the Vogelstein’s
sequential genetic changes, KRAS gene mutation is considered to work
in the process of adenomas becoming more dysplastic. If the process of
adenoma-carcinoma sequence does not exist in flat type lesions, there
might be the loss of KRAS gene change. Therefore, we examined the
rate of KRAS point mutation in flat and polypoid type early cancer. The
percentage of KRAS mutation in flat cancer was significantly lower than
in polypoid type caner in early stages (Tis and T1).35 Similar data were
reported by other researchers,36-38and our recent data also showed a
lower percentage of KRAS mutation in flat cancer than in polypoid type
early stage cancer.39
Table 3: KRAS mutation rate in flat type cancer and polypoid
type cancer in early stages
Hasegawa et al. 1995
Yamagata et al. 1995
Kojima, Konishi 1997
Yamagata et al. 2000
Sakashita et al. 2000
Noda, Konishi 2004
Flat Type
Flat-elevated 18.2%
Flat-depressed 0%
Polypoid Type
Polypoid 47.2%
Among the reports on KRAS mutation rate in flat lesions, it is important
to notice that Sakashita et al. reported that none of the depressed lesions
they tested showed KRAS mutation.38 In 1998 we reported that the rate
of MSI in flat type early stage cancer was significantly higher in the
right side of the colon.40 However, unfortunately the data are not entirely
reproducible. Interesting results were reported in our more recent study
where we examined genetic changes in the RAS signaling pathways in
30 flat cancer and 43 polypoid cancers in early stages. Important result
in this study was that although the rate of BRAF mutation was low (3
cases in all the lesions tested), all of the cases with BRAF mutation were
all flat and depressed type lesions.33 Considering the fact that KRAS and
BRAF mutations are mutually exclusive, the Sakashita’s data presenting
that none of the flat and depressed type early stage cancer showed KRAS
mutation might be concordant with our results of BRAF mutation detected
exclusively in three depressed type early stage cancers.39 Considering the
results sated above, the genetic pathway of flat type cancer in the right
side might be similar to that of the serrated and non-serrated pathway
of the MSI-H cancer in the right side.
The genetic and morphological pathways of colorectal cancer can be
categorized into several types.
Figure 4: Genetic and morphologic pathways in the development
of colorectal cancer.
Firstly, the pathways will be classified into MSS and MSI-H pathways. The
former pathway includes FAP and a large number of sporadic cancer cases
that develops following the traditional adenoma-carcinoma sequence. As
MSI-H pathways, HNPCC and sporadic MSI-H cancer in the right colon
are included. As for the sporadic MSI-H cancer in the right colon, there
might be two possible pathways. One is non-serrated pathway and the
other is serrated pathway. We need to examine the genetic changes in
serrated tumors in our own materials to prove which one of these is the
major pathway. The genetic pathway of flat cancer is still unclear, but it
might follow the pathway of MSI-H sporadic colon cancer.
Morphological and genetic pathways in the development of colorectal
cancer were presented. Flat neoplasia to carcinoma sequence is a distinct
and clinically important morphological pathway. The genetic pathways
of MSI-H sporadic colon cancer are still controversial, and this is the
challenging field of research at the present time.
Morson B (ed). Differential diagnosis of polyps and polyposis.Morson and I.M.P. Darson ed. Gastrointestinal Pathology..
Chapter 37, Blackwell Scientific Publications. Oxford, London Edinburgh Melbourne. Second edition 1979.
Konishi F, Morson BC. Pathology of colorectal adenomas: a colonoscopic survey. J Clin Pathol 1982;35(8): 830841.
Winawer SJ, Zauber AG, O’Brien MJ, Ho MN, Gottlieb L, Sternberg SS, Waye JD, Bond J, Schapiro M, Stewart ET, et
al. Randomized comparison of surveillance intervals after colonoscopic removal of newly diagnosed adenomatous
polyps. The National Polyp Study Workgroup. N Engl J Med 1993;328(13): 901-906.
Murakami R, Tsukuma H, Kanamori S, Imanishi K, Otani T, Nakanishi K, Fujimoto I, Oshima A. Natural history of
colorectal polyps and the effect of polypectomy on occurrence of subsequent cancer. Int J Cancer 1990;46(2):
Muto T, Kamiya J, Sawada T, Konishi F, Sugihara K, Kubota Y, Adachi M, Agawa S, Saito Y, Morioka Y, et al. Small
“flat adenoma” of the large bowel with special reference to its clinicopathologic features. Diseases of the colon
and rectum 1985;28(11): 847-851.
Kudo S. Endoscopic mucosal resection of flat and depressed types of early colorectal cancer. Endoscopy 1993;25(7):
Kudo S, Kashida H, Tamura T. Early colorectal cancer: flat or depressed type. J Gastroenterol Hepatol 2000;15
Suppl: D66-70.
Kudo S, Kashida H, Tamura T, Kogure E, Imai Y, Yamano H, Hart AR. Colonoscopic diagnosis and management of
nonpolypoid early colorectal cancer. World journal of surgery 2000;24(9): 1081-1090.
Togashi K, Konishi F, Koinuma K, Ishitsuka T, Kojima M, Okada M, Nagai H. Flat and depressed lesions of the colon
and rectum: Pathogenesis and clinical management. Ann Acad Med Singapore 2003;32(2): 152-158.
Hurlstone DP, Cross SS, Adam I, Shorthouse AJ, Brown S, Sanders DS, Lobo AJ. Efficacy of high magnification
chromoscopic colonoscopy for the diagnosis of neoplasia in flat and depressed lesions of the colorectum: a
prospective analysis. Gut 2004;53(2): 284-290.
Kuramoto S, Oohara T. Flat early cancers of the large intestine. Cancer 1989;64(4): 950-955.
Wolber RA, Owen DA. Flat adenomas of the colon. Hum Pathol 1991;22(1): 70-74.
Rubio CA, Kumagai J, Kanamori T, Yanagisawa A, Nakamura K, Kato Y. Flat adenomas and flat adenocarcinomas
of the colorectal mucosa in Japanese and Swedish patients. Comparative histologic study. Diseases of the colon
and rectum 1995;38(10): 1075-1079.
Saitoh Y, Waxman I, West AB, Popnikolov NK, Gatalica Z, Watari J, Obara T, Kohgo Y, Pasricha PJ. Prevalence
and distinctive biologic features of flat colorectal adenomas in a North American population. Gastroenterology
2001;120(7): 1657-1665.
Tsuda S, Veress B, Toth E, Fork FT. Flat and depressed colorectal tumours in a southern Swedish population: a
prospective chromoendoscopic and histopathological study. Gut 2002;51(4): 550-555.
Konishi F. Runme Shaw Memorial Lecture 2002. Modern management of colorectal polyps: Are they all premalignant?
Ann Acad Med Singapore 2003;32(2): 263-268.
Rembacken BJ, Fujii T, Cairns A, Dixon MF, Yoshida S, Chalmers DM, Axon AT. Flat and depressed colonic neoplasms:
a prospective study of 1000 colonoscopies in the UK. Lancet 2000;355(9211): 1211-1214.
18. Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, Nakamura Y, White R, Smits AM, Bos JL.
Genetic alterations during colorectal-tumor development. N Engl J Med 1988;319(9): 525-532.
19. Fishel R, Lescoe MK, Rao MR, Copeland NG, Jenkins NA, Garber J, Kane M, Kolodner R. The human mutator gene
homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 1993;75(5): 1027-1038.
20. Hemminki A, Peltomaki P, Mecklin JP, Jarvinen H, Salovaara R, Nystrom-Lahti M, de la Chapelle A, Aaltonen LA.
Loss of the wild type MLH1 gene is a feature of hereditary nonpolyposis colorectal cancer. Nat Genet 1994;8(4):
21. Benachenhou N, Guiral S, Gorska-Flipot I, Michalski R, Labuda D, Sinnett D. Allelic losses and DNA methylation at
DNA mismatch repair loci in sporadic colorectal cancer. Carcinogenesis 1998;19(11): 1925-1929.
22. Cunningham JM, Christensen ER, Tester DJ, Kim CY, Roche PC, Burgart LJ, Thibodeau SN. Hypermethylation of the
hMLH1 promoter in colon cancer with microsatellite instability. Cancer research 1998;58(15): 3455-3460.
23. Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, Meltzer SJ, Rodriguez-Bigas MA,
Fodde R, Ranzani GN, Srivastava S. A National Cancer Institute Workshop on Microsatellite Instability for cancer
detection and familial predisposition: development of international criteria for the determination of microsatellite
instability in colorectal cancer. Cancer research 1998;58(22): 5248-5257.
24. Jass JR. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features.
Histopathology 2007;50(1): 113-130.
25. Kambara T, Simms LA, Whitehall VL, Spring KJ, Wynter CV, Walsh MD, Barker MA, Arnold S, McGivern A, Matsubara
N, Tanaka N, Higuchi T, Young J, Jass JR, Leggett BA. BRAF mutation is associated with DNA methylation in serrated
polyps and cancers of the colorectum. Gut 2004;53(8): 1137-1144.
26. Jass JR, Whitehall VL, Young J, Leggett BA. Emerging concepts in colorectal neoplasia. Gastroenterology 2002;123(3):
27. Senba S, Konishi F, Okamoto T, Kashiwagi H, Kanazawa K, Miyaki M, Konishi M, Tsukamoto T. Clinicopathologic and
genetic features of nonfamilial colorectal carcinomas with DNA replication errors. Cancer 1998;82(2): 279-285.
28. Takemoto N, Konishi F, Yamashita K, Kojima M, Furukawa T, Miyakura Y, Shitoh K, Nagai H. The correlation of
microsatellite instability and tumor-infiltrating lymphocytes in hereditary non-polyposis colorectal cancer (HNPCC)
and sporadic colorectal cancers: the significance of different types of lymphocyte infiltration. Jpn J Clin Oncol
2004;34(2): 90-98.
29. Torlakovic E, Skovlund E, Snover DC, Torlakovic G, Nesland JM. Morphologic reappraisal of serrated colorectal
polyps. Am J Surg Pathol 2003;27(1): 65-81.
30. Spring KJ, Zhao ZZ, Karamatic R, Walsh MD, Whitehall VL, Pike T, Simms LA, Young J, James M, Montgomery GW,
Appleyard M, Hewett D, Togashi K, Jass JR, Leggett BA. High prevalence of sessile serrated adenomas with BRAF mutations: a prospective study of patients undergoing colonoscopy. Gastroenterology 2006;131(5): 1400-1407.
31. O’Brien MJ, Yang S, Mack C, Xu H, Huang CS, Mulcahy E, Amorosino M, Farraye FA. Comparison of microsatellite
instability, CpG island methylation phenotype, BRAF and KRAS status in serrated polyps and traditional adenomas
indicates separate pathways to distinct colorectal carcinoma end points. Am J Surg Pathol 2006;30(12): 14911501.
32. Konishi M, Kikuchi-Yanoshita R, Tanaka K, Muraoka M, Onda A, Okumura Y, Kishi N, Iwama T, Mori T, Koike M, Ushio K,
Chiba M, Nomizu S, Konishi F, Utsunomiya J, Miyaki M. Molecular nature of colon tumors in hereditary nonpolyposis
colon cancer, familial polyposis, and sporadic colon cancer. Gastroenterology 1996;111(2): 307-317.
33. Noda H, Kato Y, Yoshikawa H, Arai M, Togashi K, Nagai H, Konishi F, Miki Y. Microsatellite instability caused by
hMLH1 promoter methylation increases with tumor progression in right-sided sporadic colorectal cancer. Oncology
2005;69(4): 354-362.
34. Miyakura Y, Sugano K, Konishi F, Ichikawa A, Maekawa M, Shitoh K, Igarashi S, Kotake K, Koyama Y, Nagai H.
Extensive methylation of hMLH1 promoter region predominates in proximal colon cancer with microsatellite
instability. Gastroenterology 2001;121(6): 1300-1309.
35. Kojima M, Konishi F, Tsukamoto T, Yamashita K, Kanazawa K. Ki-ras point mutation in different types of colorectal
carcinomas in early stages. Diseases of the colon and rectum 1997;40(2): 161-167.
36. Yamagata S, Muto T, Uchida Y, Masaki T, Higuchi Y, Sawada T, Hirooka T. Polypoid growth and K-ras codon 12
mutation in colorectal cancer. Cancer 1995;75(4): 953-957.
37. Hasegawa H, Ueda M, Watanabe M, Teramoto T, Mukai M, Kitajima M. K-ras gene mutations in early colorectal
cancer ... flat elevated vs polyp-forming cancer. Oncogene 1995;10(7): 1413-1416.
38. Sakashita M, Aoyama N, Maekawa S, Kuroda K, Shirasaka D, Ichihara T, Kuroda Y, Minami R, Maeda S, Kasuga M.
Flat-elevated and depressed, subtypes of flat early colorectal cancers, should be distinguished by their pathological
features. Int J Colorectal Dis 2000;15(5-6): 275-281.
39. Noda H, Kato Y, Yoshikawa H, Arai M, Togashi K, Nagai H, Konishi F, Miki Y. Frequent involvement of ras-signalling
pathways in both polypoid-type and flat-type early-stage colorectal cancers. J Exp Clin Cancer Res 2006;25(2):
40. Okamoto T, Konishi F, Kojima M, Senba S, Kanazawa K, Tsukamoto T. Significance of microsatellite instability in
different types of early-stage nonfamilial colorectal carcinomas. Diseases of the colon and rectum 1998;41(11):
HIV Transmission through breastfeeding in
sub-Saharan Africa: A REVIEW OF CURRENT
K McArthur, MPH Student School Public Health, James Cook University, Townsville Qld Australia
(Annals of the ACTM, 2007; 8,2:43-49)
There has been a substantial amount of research on Human Immunodeficiency Virus (HIV) in mother
to child transmission (MTCT) through breastfeeding. While breastfeeding is an important part of a
mother’s womanhood and has contributed significantly to childhood survival in this region, these
gains have been compromised by HIV/AIDS. Factored into this public health dilemma are the
feeding practices, traditional mores and the precarious environments in Africa. MTCT significantly
impacts on women and children in most areas sub-Saharan Africa; causing disease, death, and
orphan-hood. Antivirals (AVR) may only provide a brief opportunity to contain HIV. The increase in
global funding needs to be utilised appropriately to counteract the grim statistics. Reviewed in this
article is HIV epidemiology; the virology, susceptibility of the mother and infants to HIV through
breastfeeding. There are many challenges and research questions in MTCT yet to be answered. Effective programs have been developed, and exclusive breastfeeding (breast milk only with no
other liquid or solid foods given) for the first six months has evolved as a possible intervention for
HIV infected mothers who breastfeed.
In the mid 1980s, it was established that HIV was transmitted to infants through breastfeeding.
Vertical transmission of HIV/AIDS (Acquired Immunodeficiency Syndrome) in infants, can be acquired
by the transplacental, or intrapartum route, or through breastfeeding. In sub-Saharan Africa, within
a background of escalating poverty, HIV co-exists with a dependence on breastfeeding. Given the
grim statistics in the region and the level of inadequate access to healthcare, MTCT of HIV/AIDS
is a public health dilemma that continues to escalate.
K McArthur
MPH Student School Public Health
James Cook University
Townsville Qld Australia
Tel 07 4724 4527
Email [email protected]
There are many preventive MTCT strategies, and while these can reduce the prenatal risk, the
reduction of transmission in breastfeeding has been less successful. It appears that MTCT in HIV occurs throughout lactation; yet strangely, the majority of breastfed infants who have daily exposure
to HIV-1 remain uninfected. The viral load in breast milk is a major determinant of infection risk for
the infant. The mechanism of transmission and neonatal susceptibility is not yet clearly understood.
The impact of biologic and sociological complexities associated with MTCT in breastfeeding is
enormous. Recent studies show that variations in breastfeeding patterns are important factors
in safer breastfeeding, as is the health status of both infant and mother and the stages of HIV infection. A more holistic approach is needed together with an understanding of the determinants
associated for HIV infected mothers in resourced constrained countries.
The purpose of this paper is to review current research in the areas of epidemiology and virology
and to access other determinants such as traditional practices associated with MTCT of HIV in breastfeeding. Articles for this review were mainly sourced from Pub-med and the WHO
(World Health Organisation) site. The public health issue of whether the extent or the different
developments, overall increase or decrease the infectivity and maternal and child survival rate in
their AIDS situation is discussed. Considered also is the accessibility, acceptability and sustainability
of the strategies that can be monitored and evaluated is also considered.
Epidemiology and trends
Despite the inadequacy of some surveillance systems, global estimates at the end of 2004 were
that 39.5 million people were living with HIV/AIDS70. Sub-Saharan Africa is the worst affected as
7.4% of the overall population or 25.4 million70 people are affected. In
sub-Saharan Africa, new HIV infections (three million) are matched by
high levels of AIDS mortality 70. In sub-Saharan Africa, 57% of all people
living with HIV/AIDS are women and it has become a major cause of
death for women of childbearing age57.
The rates of infections vary considerable within the region total. South
Africa and other southern African countries (such as Botswana, Lesotho,
Namibia and Swaziland) (Figure 1) have the fastest growth rates of
HIV/AIDS in pregnant women70. In Swaziland, HIV prevalence among
pregnant women was 39% in 2002, up from 24% in 200070. Elsewhere
in the region, Malawi, Zambia, and Zimbabwe, HIV infections rates in
pregnant women have stabilized at lower levels70. Some of the East African
countries, namely Uganda and possibly Kenya, have a downward trend
in HIV prevalence70. In West Africa, there have been varying degrees of
scale and intensity of HIV infections, the highest being in Burkina Faso,
Côte d’Ivoire, and Nigeria70. Even when the epidemic is reversed, havoc
wrought by AIDS will shape the future generations70.
Figure 1: Median HIV prevalence in pregnant women attending
antenatal clinics in sub-Saharan Africa.
Consequently the number of orphans continues to grow in this region. There are now more than 12 million AIDS orphans in sub-Saharan Africa57.
Countries with high HIV (40 per 1000) for children under five years of age
are; Botswana (57.7), Zimbabwe (42.2), and Swaziland (40.6) 72. Vertical
transmission of HIV in sub-Saharan, Africa, is estimated at approximately
35%44. Breastfeeding is responsible for one third to one half of the total
vertical transmission rate, and the longer the duration of breastfeeding
the greater the risk of an infant contracting HIV/AIDS 42. Fifty percent
of infants, who contract HIV through vertical transmission, and in the
absence of specific antiretroviral therapy (ART), will die within their first
two years of life34. Ironically in this region, bottle-fed babies do not have
a higher survival rate than breastfed infants whose mothers are infected
with HIV-1 39. This is attributable to poverty and reflects the cyclical and
deadly interplay between these two factors 57.
Diagnosis of HIV in Africa is often dependant on clinical judgement and in
some cases is supported by antibody testing12. Estimation of the timing
of HIV transmission in infants is difficult with ELISA antibody tests, as
HIV maternal antibodies (IgG) are detectable up to 18 months after birth
in infants34. Selected antenatal health services in sub-Saharan Africa
have become focal points for both diagnosis and screening (sentinel) of
pregnant women, providing proxy estimates of the prevalence of HIV/AIDS
infections in the population 4.
Table 1: HIV diagnostic tests for infants.
Type of Test
HIV ELISA Antibody Test
For children after 15 months or older.
Saliva and Urine Testing
Measures ELISA antibody IgG in saliva/urine. This test
can be used by untrained personnel.
Polymerase Chain Reaction
Can be performed at birth. Breastfed children
require further tests at six weeks after cessation of
Filter Paper DNA PCR
Blood spots dried and stored on filter paper for
In the worse affected areas (South Africa, Zambia and Zimbabwe) young
women aged between 15-24 years are three to six times more likely
to be infected than men, and three quarters of the young people living
with AIDS are women70. In this region, married women have higher HIV infection levels (10%) than sexually active unmarried girls70.
Providing assistance to young people in Botswana
Providing young people with skills, information, tools, and services to protect
themselves against HIV/AIDS is critical in halting the spread in sub-Saharan
Africa. In this region many young girls have either never heard of AIDS, or
have major misconceptions about it75. Botswana has made significant strides
in this area. Schools have been engaged in the country’s AIDS response, by
initiating a national distance learning television program, targeting teachers
and students75.
HIV Viral Culture
Sensitivity and specificity similar to PCR, expensive,
results not available for two to four weeks.
P24 Antigen
Sensitivity is low especially in the first few weeks of
life but relativity inexpensive.
Used to detect intrauterine exposure of HIV.
In developed countries, three types of virologic tests are used for infants. This includes molecular technique, polymerase chain reaction (PCR),
which can be used to confirm diagnosis as early as 48 hours of age, but
it is expensive19. Viral culture and HIV antigen assay can also be used to
test plasma or serum for HIV viral proteins19.
HIV is an RNA virus, which is classified as a lentivirus68. Viruses HIV-1 and
HIV-2 are members of this genus88. Morphologically similar, HIV-2 has
the same method of transmission but it is significantly less transmissible
and virulent 88. HIV-1 is divided into several groups of virus known as M,
N, and O and within the M group, there are at least nine sub-types A-D,
F-H, J, and K22, 47. Three sub-types A, C and D have caused the largest
number of infections in sub-Saharan Africa22, 47.
After a cell has been infected, production of new virions occurs inside the
host cell, causing the cell to either die or form syncytial masses88. The HIV externally studded receptor bind to sites in a lock and key mechanism
docking onto the surface of host cells88. The transmembrane glycoprotein
molecule (CD4) is the principal surface receptor for HIV88. HIV exists as
a mixture of active and inactive viruses in different cells throughout the
body88. This chronic, unrelenting, and ultimately progressive infection is
divided into three distinct stages; primary infection, clinical latency, and
symptomatic diseases88.
Maternal factors that influence MTCT
The determinants associated with mothers contracting HIV and then
transmitting it through breastfeeding is both dependant on high HIV prevalence rates and inter-dependant on other factors. In sub-Saharan
Africa, women contract HIV mainly during unprotected sex with an
infected partner. However HIV has a low infectivity rate of 0.3%60 for this
method of transmission. Men are four times more efficient transmitters
of HIV/AIDS than women15 but women are biologically more vulnerable35.
In some countries within this region, women contract HIV infection from
contaminated blood transfusions. A woman’s age appears to have some
relationship with susceptibility to HIV (young women and those over 45
years, being more susceptible), as does contraceptive practice, and the
presence of systemic disease27.
High maternal viral load and immune-suppression increases the risk of HIV transmission23. Women with an HIV primary infection are twice as likely
to pass on the virus, and those with HIV related illness are three times
more likely to transmit the virus43. Research has established the presence
of HIV in breast milk and that breast disease increases transmission of
HIV23. Vitamin A deficiency is associated with elevated levels of HIV DNA
in breast milk59. Clinical trials however have failed to demonstrate that
vitamin A supplementation reduces MTCT of HIV9, 59. Breast pathologies
(cracked or bleeding nipples, breast thrush, breast abscesses, sub-clinical
and clinical mastitis) are common (30%) in breastfeeding women, and it
is thought that these conditions double the risk of MTCT of HIV19.
There is now epidemiological evidence of how other diseases increase
the infectiousness of and susceptibility to HIV transmission. Studies have
suggested that poor maternal health plays a major role in MTCT 18. Both
ulcerative and inflammatory Sexually Transmitted Infections (STIs) are cofactors in HIV transmission27. Treatment of STIs reduces HIV incidence by
40%27. Timely diagnosis and treatment are important pillars in preventing
HIV infection; however, only two countries in this region have treatment
coverage of more than 50% for STIs 56.
Tuberculosis (TB) has emerged as a synergistic twin of HIV/AIDS80. Latent
TB appears reactive in the presence of HIV; 31% of adult TB cases are
attributable to HIV in the region80. Outbreaks of multi-drug resistant TB are
associated with HIV infections79. Other co-factors in HIV transmission are
helminthiasis65 and malaria, which activate a chronic immune response
increasing the risk of HIV transmission 61,64.
Observational studies have shown a direct relationship between
malnutrition/nutritional status and vertical transmission of HIV. Some
studies suggest that breastfeeding creates a metabolic burden with HIV-1;
causing nutritional impairment that accelerates progression of HIV related
deaths,40 while other studies dispute this hypothosis35. Vitamin B, C, E,
have been shown to have some protective effects on MTCT of HIV in breast
milk 56. Early mortality in HIV/AIDS has been associated with low levels of
vitamin A, selenium, and zinc56. These low levels maybe markers rather
than causal factors for the advance stage of HIV/AIDS disease56.
In the 1990s, there were major advances in the development of
antiretroviral therapy (ART) that changed the natural history of the
progression of HIV. Research established and endorsed by the World Health
Organisation (WHO) recommended that a short course of Zidovudine
(AZT) be administered during the last four weeks of pregnancy50, 51 to
HIV infected women. This measure reduced the overall transmission by
more than half however; HIV transmission during the postnatal period
remained largely unaffected29. In most resource scarce settings, a single
dose of nevirapine (NVP) is given, one dose to the mother during delivery
and one to the infant within 72 hours of birth38. NVP has been shown to
be more effective (47%) in reducing transmission of HIV than AZT 38 and
reduces the risk of transmission of HIV associated with breastfeeding for
at least the first year of life49.
Of increasing concern however is the increase in drug resistance. Up to
40% of women and children develop NVP resistance30 in this region. WHO
recommends the ART drug combinations of d4T (stavudine) or AZT + 3TC
(Lamivudine) +NVP for pregnant women 20. Adding the drug Combivir (AZT
and 3TC) to a single-dose of ART has been found to significantly reduce
drug resistance if the combination is correctly timed 52.
Infant susceptibility
There is a need to not only protect infants but also to reduce susceptibility
to HIV infection. Providing micronutrient supplements to infants born to
infected mothers irrespective of the infants HIV status may be important
in reducing mortality and morbidity56. Studies have found that both
zinc and vitamin A supplementation in infants is beneficial in reducing
both transmission and progression of HIV, and significantly reducing
diarrhoea56. Progression of the disease in infants is much more rapid
than in adults34. Infectious complications for example Pneumocystis
jiroveci with HIV in infants are preventable by primary prophylaxis with
co-trimoxazole from six weeks of age until their first birthday69. Risk
factors such as prematurity, (less than 34 weeks of age) low birth weight,
teething lesions, breaches in the oral mucosal and thrush make infants
more susceptible to infective mothers who breastfeed 56.
There is growing evidence of the risks to infants of nosocomial
transmission of HIV. The traditional use of wet nurses is also thought to
be unsafe when HIV status is not known11. HIV-negative children may
also be inadvertently infected through the common use of expressed
breast milk from HIV-positive women11. In one milk room in South Africa,
where the milk was being pooled, nearly 25% of women who expressed
milk were HIV-positive11. It is recommended that in these situations
that breast milk must be pasteurised before use11. Lack of universal
infectious control measures in maternity, paediatric, and dental facilities
and with traditional healers is thought to be responsible for additional
HIV-positive cases11.
Breast milk factors
The mechanism of transmission of HIV through breast milk does not
appear to be completely understood. HIV has been identified in both
cell associated and cell free conponents of breast milk5. The risk of
transmission of HIV through breast milk occurs at any point during
lactation and the longer the duration the greater the risk35. The cumulative
probability of an infant becoming infected through breast milk is less at
4 weeks (1.6%) than at 18 months of age (9.3%)35.
Breast milk contains immunologic factors and the maintenance
of mammary epithelial integrity is thought to reduce the risk of
transmission31. Studies have indicated that colostrum protects the infant
from HIV but conversely; high concentrations of virus in colostrum could
put the infant at risk45. Studies that suggest colostrum may protect against
MTCT found greater concentrations of immune modulating factors such
as IgA, vitamin A and lactoferrin1, that appear to inhibit binding of HIV to
CD4 molecules10. Associated with these protective factors, mucins have
been found in infant’s saliva, which are thought to inactivate HIV-128. In a
study in Rwanda, it was found that the lack of the IgM antibody in breast
milk collected at 18 months postpartum was associated with a high risk
of transmission of HIV in infants of this age1.
Traditional practices associated with MTCT and breastfeeding
Traditional practices are intertwined with the determinants of MTCT.
Greater attention is needed in understanding these traditions; the control
they have, and how in some cases they can be strengthened when
beneficial. Collaboration between traditional and biomedical healthcare
systems is needed to find new and effective ways to fight and prevent
HIV/AIDS. The WHO advocates the inclusion of traditional healers in
national AIDS programs54. There is a high level of use of traditional health
care by this population (80%)54; in Uganda traditional and biomedical
healthcare personnel work together in a program to provide sustainable
prevention and care 63.
Key behaviours have the potential to influence the rates of transmission
of HIV. One study has suggested that more emphasis should be placed on
safe sex practices41. In high prevalence areas, 5% of mothers seroconvert
in the year following a delivery; and given that the primary infection of
HIV is the most virulent, this puts infants significantly at risk during the
breastfeeding period2. While taboos against postpartum sexual activity are
widespread in Africa, the duration of abstinence varies greatly within and
amongst different countries78. This can lead men to seek out extramarital
relations increasing a woman’s risk of infection once a couple resumes
sexual relations15. Male circumcision is found to be protective against
HIV (twofold)46, 83; however, female circumcision is thought to be a risk
factor37. The common use of vaginal desiccating agents has not been
conclusively demonstrated as a risk factor in transmission of HIV; however,
such a relationship is plausible36.
Intervention study in MTCT of HIV/AIDS in Zambia74
A study was carried out in a southern province of Zambia, in a area of high
rates from HIV/AIDS. Reasons for theses rates were; sexual cleansing of a
widow after her husbands death, women being forced into sexual exchange
because of poverty, inter-generational sex, the sexual freedom of young
people, the lack of prevention efforts, prostitution, migrant workers, and not
using condoms.
Results of this study suggest that to achieve successful preventive MTCT
intervention programs, they should simultaneously include care, support and
the reduction of stigma within the community. The practice of mixed feeding
was reduced before suggesting to HIV infected mothers not to breastfeed.
Feeding supplements were introduced however the cost of alternative feeding
is beyond the reach of most households in this location. Breastfeeding was
widely practised and cherished in this region, and a decision to not breastfeed
often resulted in women being labelled a prostitute.
There appears to be a link between the infant’s gender and the
transmission of HIV-1 in association with traditional breastfeeding
practices. Female infants are 40% less likely than males to become
infected through breastfeeding after four weeks of age43. While duration
of breastfeeding appears similar for both sexes it is thought that males
are being mixed fed at an earlier age putting them at higher risk43.
Further research is required to examine the possible traditional beliefs
and mores surrounding male preference and how the different practices
impact on infant feeding.
Exclusive breastfeeding
Recent research has suggested that exclusive breastfeeding is a possible
intervention for HIV infected mothers who breastfeed. African infants are
breastfed for an average of 21 months; however, exclusive breastfeeding
is not widely practiced9, 14. In the process of mix feeding, the virus may
enter the infant’s mucosa6 either through mucosal breaches or lesions7.
Mixed feeding is thought to make the infant’s gut more susceptible to
HIV transmission through a mechanical or inflammatory mechanism7.
The practice of mixed feeding contributes to the incidence of mastitis7.
The introduction of solids or animal milks before three months of age, to
breastfed infants born to HIV-positive mothers almost doubles the risks of
MTCT of HIV48. An important study from South Africa found that exclusive
breastfeeding might pose less of a risk of transmission of HIV-1 than mixed
feeding33. From this study, it was suggested that exclusive breastfeeding
facilitated maturation of the infant’s gut, maintained the mucosal barrier,
and enhanced an infant’s immune response9. Further studies are now
providing justification for shortening the period of exclusive breastfeeding
to six months followed by, a short weaning period of two weeks48. This
may prevent about one third of the transmissions35.
WHO recommends for HIV infected mothers when replacement feeding
is not feasible, acceptable, affordable, or sustainable that infants
should exclusively breastfeed for the first six months 24. The practice on
exclusive breastfeeding has been endorsed by WHO for women who are
HIV infected, HIV-negative or don’t know their HIV status86. There are
other variations of exclusive breast milk options such as wet nursing,
heat treatment of breastmilk and breastmilk banks 60. There is now
evidence that HIV infected infants can transmit HIV to their non-infected
breastfeeding mothers6o. Where infectious diseases and malnutrition are
primary causes of death during infancy, exclusive breastfeeding will be
the only alternative as many mothers will not be able to provide suitable
replacement foods.
Traditional Birth Attendants (TBAs) involvement in preventive MTCT
service delivery in rural locations in Tanzania73
In high HIV/AIDs burdened rural settings in Tanzania, almost 60% mothers
deliver out side health facilities. In two rural districts in Tanzania, TBAs
were trained to participate in preventive MTCT programs implemented by
the district health authorities, with technical assistance from Axios and
funding from the Elizabeth Glaser Paediatric AIDS Foundation. Antenatally
these programs provided HIV/AIDS education and voluntary counselling and
dispensed Nevirapine under “Directly Observed Therapy” to HIV-positive
mothers in their care. These mothers were also referred to health facilities
for post-natal fellow up, their infants received Nevirapine syrup; and reporting
back to health facilities on a monthly basis. This program found that TBAs can
be used effectively in program implementation and contribute significantly to
reaching women who deliver outside health facilities.
Reproductive healthcare
HIV interventions pose significant challenges in resource-scarce
countries that want to implementing prevention and treatment of MTCT.
In low-resource settings women generally attend antenatal care only
late in pregnancy, and HIV-positive women often have their infection
diagnosed shortly before childbirth67. In this region, the training of health
professionals varies, and skilled practitioners attend few deliverers67. In many sub-Saharan African countries health services were reduced
to repay national debt, but at the same time these countries are forced
to cope with the burden of HIV, and the loss of essential staff through
sickness and deaths related to AIDS71.
(such as heat-treatment of breast milk and wet nursing) are important71.
Other measures such as; availability of lactation counselling, provision of
immediate treatment for mastitis and other infections make breastfeeding
safer71. Studies have shown that education and counselling were found
to be the strongest predictors of exclusive breastfeeding48.
Prevention of MTCT of HIV has been made a global priority increasing
the focus on reproductive healthcare. The United Nations special session
on HIV in 2001 made a commitment to reduce the proportion of infected
infants by 50% by 201071. Except for Botswana, Nigeria and Uganda, ART
is not widely available in sub-Saharan Africa71. Partnerships formed across
a variety of sectors including the Global Fund to Fight AIDS Tuberculosis
and Malaria, the United States President’s Emergency Plan for AIDS Relief,
the World Bank, the Clinton Foundation, Medicines Sans Frontiers74 in the
WHO, “3 by 5” anti-retroviral strategy, to enable three million HIV infected
persons to receive ART53.
The barriers to the provision of breast milk substitutes are enormous13.
One study investigating pregnant women’s views on infant feeding options
for HIV-infected women, found that most women would choose cows
milk as an option8,17. Their decisions was based on; what health workers
recommended, that the milk would be distributed free of charge there was
clean water and structured antenatal care available8,17. In this same study,
concern was expressed for the social consequences of not breastfeeding8.
Future research into infant feeding options should include the broader
cultural context, economic barriers and the psychological stress that
HIV-infected women face when choosing infant feeding methods8.
There is a need not only to strengthen and integrate family planning and
STI services, but also to improve access and acceptability to prevention
and treatment services67,71. Strategies to reduce MTCT included the
prevention of unintended pregnancies among HIV infected women and
prevention of vertical transmission of HIV67. In the developed world,
MTCT can be almost preventable by; universal precautions, antiretroviral
prophylaxis, elective caesarean section (before the onset of rupture of
membranes) and refraining from breastfeeding67. Presently, elective
caesarean section cannot be recommended as a routine intervention for
HIV infected mothers in resource-scarce countries67.
Future developments
There has been an enormous amount of research on HIV by MTCT;
however, replicated studies are needed to verify recent findings along
with the wider complexities that need to be examined. Transmission of
HIV through breastfeeding during the first four weeks of an infant’s life
needs further investigation, as does the correlation between the risk of
transmission, and the presence of anti-infective substances in breast
milk6. Micronutrient status and food insecurity has created much interest
and studies continue into nutritional support for breastfeeding women
and their infants56. Micronutrient supplementation (Vitamin B, C, and E)
may be a cost effective prophylactic and a successful treatment modality
particularly with infants56.
Increasing voluntary counselling and testing in Zambia
A low rate of HIV serostatus disclosure, among women in antenatal settings, has
implications for prevention of MTCT of HIV77. In Zambia, expansion of voluntary
counselling (VCT) services has been through collaboration between government, NGOs
and the district health management teams76. VCT starts before having a HIV test, enabling
an informed choice about being teasted75. Expectant mothers who discover they are
HIV-positive through the use of VCT are more likely to seek measures to prevent the
transmission75. Counselling of HIV-positive and HIV-negative people helps to dispel
stigma and discrimination75. Knowledge of serostatus can be a motiving force for both
HIV-positive and HIV-negative people to practice safer sexual behavior75.
Keeping HIV infective mothers well is an important prevention in postnatal
MTCT. HIV testing and counselling of pregnant women should become
standard practice71. Providing mothers with care preserves the family unit,
supports disclosure, and adherence to difficult infant feeding choices and
ART regimens71. It has been suggested that rapid HIV testing of women in
labour, whose HIV status is unknown would be useful58. This could allow
the immediate provision of ART prophylaxis to HIV infected women and
their newborns58. However, a scaling up of treatment may impact on the
importance of preventive behaviours67. Preventive behaviours such as
safer sex/condom use must not be over looked as these measures are
the most effective in reducing HIV transmission71.
The process of decision making for HIV-positive mothers to either
exclusively breastfeed or artificially feed, generates a high degree of risk
when the mother only partially adheres to her chosen option13. These
women have to anticipate their condition for at least six months within
a context of cultural and psychosocial factors, material conditions and
resources of their health care system13. Providing support for HIV infected
mothers and their families with decisions on whether to breastfeed,
bottle-feed, cease breastfeeding early, and replacement strategies
ART may only provide a brief opportunity to contain HIV. Of concern
is the lack of general laboratory infrastructure in sub-Saharan Africa
needed to monitor drug toxicity and thus prevent multi-drug resistance
in the region21. The use of NVP for prevention of MTCT of HIV needs to
be restricted to effective combinations25. The long-term health effects of
drug exposure to ART are unknown and there are increasing reports of
hepatotoxicity73. With the promise of increased availability of ART therapy,
effective distribution along with cost sustainability is needed20. There are
important ongoing pharmacokinetic studies in not only the use of ART but
in combining therapies. A recent discovery from the Queensland Institute
of Medical Research in Australia identified a group of HIV drugs that also
protects against the malaria parasite66.
Many other difficulties and research questions must be overcome. The
use of preventable, efficacious HIV vaccines and microbicides has the
potential to significantly curb the HIV/AIDS pandemic. The search for
vaccines and microbicides faces many obstacles such as scientific
challenges and inadequate funding62. Vaccine development has been
focused on HIV viruses that are prevalent in the developed world76.
Studies in the use of vaccines have combined both active and passive
immune strategies, and integrate humoral and cellular immunity32. Many
candidate HIV vaccines have entered trials but are hindered by a lack of
knowledge about protective immunity62. Microbicides are currently being
investigated in clinical trials but no product is ready for endorsement62.
These compounds may offer protection to women who are both vulnerable
and are unable to negotiate safe sex61,71.
In 2001, the Declaration of Commitment a global consensus set out goals
to reverse this pandemic through a rapid up-scaling up of preventative
measures57. Despite improvements of global funding, (USD2.1 billion in
2001 increased to USD6.1 billion in 2004) coverage of prevention and
care services remains uneven71. No more than 1% of pregnant women
in heavily infected countries are offered services aimed at prevention of
MTCT70. Expansion of intervention strategies is needed especially to young
women who are disproportionelly at risk, and affected by HIV/AIDS71. The
acknowledgement of human rights principles is required to accelerate
this progress.
Issues such as poverty, ignorance and the intersection of the principal
determinant political will are important. This mature pandemic increases
the burden on women and children, reflecting multiple economic,
legal, and social inequities. Social norms can impose a dangerous
ignorance74; and more research is needed on how gender relations
impact on this epidemic. The affect of the survival strategy; exploitative
or transactional sex, greatly increases the vulnerability of acquiring HIV74.
Women need greater power and skills to help decide the terms of their
sexual relationships74. The “rights” of young girls need to be protected71.
Discrimination and stigmatisation are subtle but very real obstacles in the
battle with AIDS. The gap between awareness and action in the process
of compliance needs further investigation to achieve greater success in
risk reduction strategies. Coherent nationally lead responses are needed
along with multi-sectoral national AIDS strategies that translate into an
efficient and concerted action71.
A review of policies is needed and dissemination of this information
made readily available. Infectious control polices must be stringently
maintained and include traditional healers. The mother-baby friendly
policy encourages all mothers to breastfeed, which ideally is the most
beneficial for children. However, where the mother is HIV-positive and the
child is HIV-negative, increased flexibility of this policy is required.
The determinants of HIV infection on both the HIV infected mother who
breastfeeds and her infant are multi-factorial. Avoidance of the practice
of breastfeeding by HIV-positive mothers in sub-Saharan Africa is not
generally feasible for this population. There are great opportunities
for the developed nations to minimise vertical transmission of HIV and
maximise child survival, but they are not as available in the developing
nations. Access to prevention and treatment needs to be improved.
Greater collaboration is needed between formal health care system and
traditional healers. While variations of exclusive breastfeeding can reduce
the risk of MTCT, safe replacement feeding programs need to take into
consideration indicators such as poverty and social norms in individual
settings. Increase awareness is needed of the practices associated
with son preference in Africa. Despite the intrinsic merits of antivirals,
development of vaccines, microbicides and treatment of conditions that
are co-factors, are important for future prevention of MTCT.
Paradoxically, the problems and their causes are obvious of this pandemic
of HIV/AIDS in the sub-Saharan Africa but solving them is more difficult. It is hard to provide counselling on safe sex and milk substitutes if you
know the mother is starving and poverty is rife. With the prediction of
progressive acceleration of new HIV infections, the burden of HIV in
vertical transmission in disease, death, and orphan-hood is significant. The primary determinants of health including traditional practices and
the precarious individual environments in Africa must be factored into
risk reducing strategies to alleviate this cataclysmic suffering.
Van de Perre P (1997). Transmission of Human Immunodeficiency Virus Type 1 through Breastfeeding. Infect Dis;
179: S405 S407.
Mbizvo, M, J Kasule, K Mahomed and K Nathoo . (2001). HIV-1 Seroconversion Incidence Following Pregnancy and
Delivery among Women. Zimbabwe. Central African Journal of Medicine, 47: 115–118.
Dunn T, Newell L, Ades E, Peckham S (1992) Risk of Human Immunodeficiency Virus Type 1 Transmission through
Breastfeeding. Lancet 340:585 588.
Chin, J (1990) Public Health Surveillance of AIDS and HIV Infections. Bull World Health Org 68 (5): 529-36.
Van de Perre P. Simonon A, Hitimana DG, Dabis F, Msellati P, et al. (1993).Infective and Anti-Infective Properties of
Breastmilk from HIV-1-Infected Women. Lancet; 341:914–918.
Featherstone C. M (1997) Cells: Portals to the Mucosal Immune System. Lancet, .350:1230.
Rollins N et al. (2001) Feeding Mode, Intestinal Permeability and Neopterin Excretion: A Longitudinal Study in Infants
of HIV-Infected South African Women. J Acquire Immune Def Synd, 28: 132–139.
De Paoli1 M, Manongi & R, Klepp K (2004). Are Infant Feeding Options that are Recommended for Mothers With
HIV Acceptable, Feasible, Affordable, Sustainable, and Safe? Pregnant Women’s Perspectives. Pub H Nut, 7 611619(9).
Coutsoudis A, Pillay K, Spooner E, Kuhn L, Coovadia H (1999) Influence of Infant Feeding Patterns on Early Mother
to Child Transmission of HIV-1 In Durban, South Africa: A Prospective Cohort Study. Lancet; 354:471-476.
Newburg, S. Viscidi RP, Ruff A, Yolken R (1992) A Human Milk Factor Inhibits Binding of the Human Immunodeficiency
Virus to CD4 Receptor. Paediatr Res; 31: 22-28.
Nelson Mandela Foundation (2005) HIV Risk Exposure among Young Children. A Study of 2-9 Year Olds Served
By Public Health Facilities in the Free State, South Africa. Human Science Council. http://www.hsrcpress.ac.za/
Nicoll A & Killewo, J (1991) AIDS surveillance in Africa. BMJ, 303(6811):1151-2.
Desclaux A (2004). Preventing Transmission of HIV through Breastfeeding: A Review of Knowledge and Experience.
Ester Scientific Council. www.ester.fr/snk_rc/snk_rc.enfiles/Allaitement.pdf. Accessed on 17.07.05.
Smith M, Kuhn L (2000) Exclusive Breastfeeding: Does it have the Potential to Reduce Breastfeeding Transmission
of HIV-1. Nutr Rev.; 58 (11): 333-40.
UNAIDS (2000) Men and AIDS a Gender Approach. UNAIDS www.UNDP.org/gendr/resources/UNDP_Men_
Masculinities.pdf. Accessed on 17.07.05.
Bredberg- Raden U, Urassa E, Grankvist O, et al (1995) Early Diagnosis Of HIV-1 Infection In Infants In Dar-EsSalaam, Tanzania. Clin Diagn Virol; 4:163-173.
Leroy, V Sakarovitch, C Viho, R Ekouevi, Bequet, L et al (2007) Acceptability of Formula-Feeding to Prevent HIV
Postnatal Transmission, Abidjan, Cote d’Ivoire: ANRS 1201/1202 Ditrame Plus Study. Acquir Immune Defic Sydr
Jan 1:44(1):77-86.
Phiri W. Kasonka L, Collin S Makasa M, Sinkala et.al (2006) Factors Influncing Breast Milk HIV RNA Viral load among
Zambian Women. AIDS Jul:22 (7)607-14.
Sebire, K. McGavin, S. Land, T. Middleton and C Birch, (1998) Stability Of Human Immunodeficiency Virus RNA In
Blood Specimens As Measured By A Commercial PCR-Based Assay. J. Clin. Microbiol. 36:493-498.
WHO (2004) Scaling up Retroviral Therapy in Resource Limited Settings. Treatment guidelines for a public health
approach. www.who.int/medicines/organization/par/ed/expertnotes.shtml. Accessed on 17.07.05.
Wainberg M, Friedland G (1999) Public Health Implications of Antiviral Therapy and HIV Resistance. JAMA ;
Robertson D, Anderson J and Bradac J. (2000) HIV-1 nomenclature proposal. Science; 288 (5463): 55-56.
Semba R. Kumwenda N, Hoover D, Taha T, Thomas C. et al. (1999) Human Immunodeficiency Viral Load in Breast
Milk, Mastitis and Mother to Child Transmission of Human Immunodeficiency Virus Type –1. J Infect Dis. 199,180
WHO (2003) Global strategy for Infant and Young Child Feeding. Geneva, World Health Organization. www.who.
int/puyblications/2003/9241562218.pdf. Accessed on 17.07.05.
Clayden P (2004) Single-Dose Jeopardizes Long-Term Therapy. HIV Treatment. Bulletin, Vol 3-5.
Kuhn L, Abrams E, Matheson, P (1997) Timing of maternal-infant HIV transmission: associations between intrapartum factors and early polymeraze chain reaction results. AIDS. 11: 429-435.
Grosskurth H, Mosha F, & Todd J (1995) Impact of improved treatment of sexually transmitted diseases on HIV infection in rural Tanzania: randomized controlled trial. Lancet. 346:530-536.
McNeely T, Shugars D, Rosendahl M (1997) Inhabitation human immunodeficiency virus type 1 infectivity by
secretary leukocyte protease inhibitor occurs prior to viral reverse transcription. Blood; 90: 1141-9
Newell M (1998) Mechanisms and timing of mother-to-child transmission of HIV-1. AIDs.12:831-837.
Gordon M, Graham N, Bland R , Rollins N, DeOliveira T,et al (2004) Surveillance of resistance in KZN South Africa,
including mother-infant pairs six weeks after single dose nevirapine. XIII Intl Drug Resistance Workshop, Antiviral
Therapy; 9:S80.
Rousseau C, Nduati R, Richardson B, Steele M, John-Stewart G, et al (2003) Longitudinal analysis of human
immunodeficiency virus type 1 RNA in breast milk and of its relationship to infant infection and maternal disease.
Infect Dis, 187:741-747.
Safrit, J Ruprecht, R Ferrantelli, F Xue, W Kitabwalla (2004) Immuno-Prophylaxis to Prevent Mother to Child
Transmission of HIV-1.J Acquir Immune Defic Syndr 35: 169-77.
Bobat R, Moodly D, Coutsoudis A (1997) Breastfeeding by HIV-1 Infected women and out-come in their infants: a
cohort study from Durban, South Africa. AIDS; 11:1627-1633.
Spira R, Lepage P, Msellati P, Van de Perre P, Leroy V, Simonon A et al (1999) Natural History of HIV Type 1 Infection
in Children: A Five Year Prospective Study in Rwanda. Pediatriecs; 104:e56.
The Breastfeeding and International Transmission Study (BHITS) Group (2004) Late Postal Transmission of HIV-1
in Breastfed Children: An Individual Data Meta-Analysis. J Infect Dis; 189:2154-66.
Dallabetta G, Moiotti P, Chiphangwi J, et al (1995) Traditional Vaginal Agents Use and Association with HIV Infection
in Malawian Women. AIDS, 9: 2993-297.
Odoi A Brodly K & Elkans T (1997) Female Genital Mutilation in Rural Ghana, West Africa. Int J Gynecol Obstretrics,
1997; 56:179-180.
Jackson B, Musoke P, Fleming T, Guay L, Bagenda D,A et al. (2003) Intrapartum and Neonatal Single-Dose Nevirapine
Compared with Zidovudine for Prevention of Mother to Child Transmission of HIV-1 In Kampala, Uganda: 18 Month
Follow-Up of The HIVNET 012 Randomised Trial. Lancet. 362: 859-868.
Coutsoudis A, Pillay K, Spooner E, Coovadia, Pembrey L, and Newell M (2003) Morbidity in Children Born to HIV Infected Women in South Africa: does mode of feeding matter? Acta Paediatr Scandinavica, 2003.92(8):890895.
Nduati R, Richardson A, John G. D. Mbori-Ngacha D, A. Mwatha A, et al. (2001) Effect of Breastfeeding on Mortality
Among HIV-1 Infected Women: A Randomized Trial. Lancet; .357: 1651–1655
Travengwa V, Piwoz G Illiff, J, Moulton H Zunguza D et.al (2007) Adoption of Safer Infant Feeding and Postpartum
Sexual-practices and their Relationship to maternal HIV Status and the risk of acquiring HIV in Zimbabwe. Trop
Med INT Health. Jan:12(1):97-106
De Cock K, Fowler M, Mercier E, De Vincenzi I, Saba J, et al (2000) Prevention of Mother-To-Child HIV Transmission
in Resource-Poor Countries: Translating Research into Policy and Practice, JAMA. 283(9):1175-82
Read S, Newell L, Leroy V, Dabis F (2003).Late Postnatal Transmission of HIV in Breastfed Children: An Individual
Patient Data Meta-Analysis (The Breastfeeding and HIV International Transmission Study). Abstract 97, X Conference
on Retroviruses and Opportunistic Infections, Boston, USA, 10–14
WHO (2000) New Data on Prevention of MTCT of HIV and Their Policy Implications. http://www.who.int/reproductive_
health/publications/new_data_prevention_mtct_hiv/identified_needs.en.html Accessed on 17.07.05.
Ruff, A, Coberly J, Halsey A, Boulos R, Desormeaux J, et al, (1994) Prevalence of HIV-1 DNA and P24 Antigen in
Breast Milk. J Acquir Immune Defic Syndr, 7:68–72.
Weiss H, Quigley M, Hayes R. (2000) Male Circumcision and Risk of HIV Infection in Sub-Saharan Africa: A-Systematic
Review and Meta-Analysis. AIDS, 4: 2361-2370.
47. Simon F, Manclere P, Roques P, Loussert-Ajaka I, Michaela C.et al (1998) Identification of New Human
Immunodeficiency Virus Type 1 Distinct From Group M and Group O. Nat Med, 1032-1037.
48. Iliff P, Piwoz E, Tavengwa N, Zunguza C & Marinda E (2005) Early Exclusive Breastfeeding Reduces The Risk Of
Postnatal HIV-1 Transmission And Increases HIV-Free Survival. AIDS; 19(7):699-708.
49. Eshleman S, Becker-Pergola G, Deseyve M, Guay L; Mracna M. et al. (2001) Impact Of HIV-1 Subtype on Women
Receiving Single Dose Nevirapine Prophylaxis to Prevent HIV-1 Vertical Transmission (HIV Network for Prevention
Trials 012 Study). J Infect Dis.184: 914-917.
50. Wiktor, S. Ekpini, E, Karon, J. et al (1999) Short Course Oral Zidovudine for Prevention of Mother to Child Transmission
Of HIV-1 in Abidjan, Cote D` Ivoire: A Randomized Trial. Lancet, 1999.353:781-785.
51. Gray G. The Petra study (2000) Early and Late Efficacy of Three Short ZDV/3TC Combination Regimens to Prevent
Mother to Child Transmission of HIV-1. X111 International AIDS Conference: 2000, Durban, South Africa. 52. McIntyre J, Martison N, Gray G et al. (2004) Addition of Short Course Combivir (CBV) to Single Dose Viramune (Sdnvp)
for Prevention of Mother-To-Child Transmission of HIV-1 Can Significantly Decrease the Subsequent Development
of Maternal NNRTI-Resistant Virus. XV Intl AIDS Conference. Bangkok.
53. WHO (2004)”3 by 5” Progress Report, December. http://www.who.int/3by5/progressreport05/en/ Accessed on
54. UNAIDS (2000) Collaboration with Traditional Healers in HIV/AIDS Prevention and Care in sub-Saharan Africa - A
literature review. http://www.UNAIDS.Org/WAC/2001/background.html. Accessed on 17.07.05.
55. Filteau, M, Rice J, Ball S, J Chakraborty, R Stoltzfus, et al.(1999) Breast Milk Immune Factors in Bangladeshi Women
Supplemented Postpartum with Retinol or B-carotene. Am. J. Clin.Nutr, 69: 953-958.
56. Fawzi W (2000) Nutritional Factors and Vertical Transmission of HIV-1: Epidemiology and Potential Mechanisms. Annals New York Academy of Sciences; .918:99-114
57. AIDS (2004) Report on the Global AIDS Epidemic. 2004 http://www.unaids.org/bangkok2004/ Accessed on
58. Bulterys M, Jamieson D, O’Sullivan M, Cohen M, Maupin R et al.(2004) Mother-Infant Rapid Intervention At Delivery
(MIRIAD) Study Group. Rapid HIV-1 testing during labour: a multi-centre study. JAMA. ; 292(2):219-23.
59. Nduati R, John C, Richardson A. et al (1995) Human immunodeficiency virus type 1-infected cells in breast milk:
association with immunosuppression and vitamin A deficiency. J Infect Dis, 172: 1461-1468.
60. Rollins N, Meda N, Becquet R, Coutsoudis A, Humphrey J, et al. (2004) Preventing Postnatal Transmission of HIV1
through Breastfeeding: Modifying Infant Feeding Practices. J Acquir Immune Defic Syndr, 35(2): 188-195.
61. Palmer J, Validum L, Loeffke K, et al (2002) HIV Prevalence in a Gold Mining Camp in the Amazon Region, Guyana.
Emerg Infect Dis. (3): 330-1.
62. Alliance for Microbicide Development (2004) Microbicides in Development. Complete.Listing Alliance for Microbicide
Development web site. http://www.ipm-microbicides.org. Accessed on 17.07.05.
63. NADIC (2004) Traditional Healers and modern Practitioners together against Aids (THETA). Uganda Aids Commission.
http://www.thetauganda.org. Accessed on 17.07.05.
64. Brahmbhatt R (2004) The Effects of Placental Malaria on Mother to Child HIV Transmission in Rakai, Uganda AIDS,
65. Markus B & Fincham E (2000) Worms and Paediatric Human Immunodeficiency Virus Infection and Tuberculoses.
J Infect Dis. 181(5):1873.
66. Andrews K & Skinner- Adams T (2004) HIV Drugs Known as Protease Inhibitors also Protect Against Malaria. J
Infect Dis QIMR. Vol 190 p 1998–2000
67. WHO (2004) Prevention Research Linking Prevention to Access to Treatment. http://www.who.int/whr/2004/
chapter5/en/index1.html. Accessed on 17.07.05.
68. Kennedy J (2003) HIV in Pregnancy and Childbirth. BFM Pp1-7.
69. Coutsoudis A, Kubenden P, Spooner E, Coovadia H, Pembray L, Newell M (2005) Routinely Available Co-Trimoxazole
Prophylaxis and Occurrence of Respiratory and Diarrheal Morbidly Infants Born to HIV Infestive Mothers in South
Africa. SA Fr Med J. 95(5): 339-345.
70. UNAIDS, WHO (2004). AIDS Epidemic Update. www.unaids.org/wad2004/EPIupdate2004. Accessed on 17.07.05.
71. FHI UNAIDS (2004) Preventing Mother to Child Transmission of HIV a Strategic Frame Work. www.fhi.org/en/hivaids/
pub/strat/mtctstrategy.htm. Accessed on 17.07.05.
72. UNICEF WHO (2004) Call for Stronger Support for the Implementation of Joint United Nations HIV Infant Feeding
Framework. New York and Geneva, December 22. Bull World Health Organ.; 68(5):529-36.
73. Sanne I, Mommeja-marin H, Hinkle J, Bartlett J, et al (2005) Severe Hepatotoxicity Associated with Norapine use
in HIV-Infected Subjects. J Infect Disae; 191:825-829.
74. B Bond G, Ndubani P & Nyblade L (2000) Formative Research on Mother to Child Transmission of HIV/AIDS in
Zambia. International Centre for Research on Women (ICRW) www.uncicef.org/evaldatabase/index_14401.html.
Accessed 17.07.05.
75. UNAIDS (2003) Accelerating Action Against AIDS in Africa. http://pdf.usaid.gov/pdf_docs/PNACU032.pdf Accessed
76. Binswanger H (2000) Scaling Up HIV/AIDS Programs to National Coverage. Science; 288:2173-2176
77. Medley A, Garcia-Moreno C, McGill S & Maman S (2004) Rates, Barriers and Outcomes of HIV Serostatus Disclosure
among Women in Developing Countries: Implications for Prevention of Mother-To- Child Transmission Programmes.
Bull World.Health.Org; 82 (4): 299-307
78. Glynn J, Buvé A, Caraël M, Macauley I, Kahindo M, et al (2001) Is Long Postpartum Sexual Abstinence a Risk Factor
for HIV? AIDS: 2001.ol (8) 25 p 1059-1061.
79. Ritacco V, Di Lonardo M, Reniero A, et al. (1997) Nosocomial Spread Of Human Immunodeficiency Virus-Related
Multi-Drug-Resistant Tuberculosis in Buenos Aires. J Infect Dis. 176:637-642.
80. Cantwell M, Binkin N (1996) Tuberculosis in sub-Saharan Africa: A Regional Assessment of the Impact of The Human
Immunodeficiency Virus And National Tuberculosis Control Program Quality. Tuber Lung Dis.; 77:220-225.
81. Tess B, Granato C, Parry V, et al (1996) Salivary Testing for Human Immunodeficiency Virus Type 1 Infection In
Children Born To Infected Mothers In Sao Paulo, Brazil. Pediatr Infect Dis J, 15:787-790.
82. Panteleeff D, John G, Nduati R, et al. (1999) Rapid Method For Screening Dried Blood Samples On Filter Paper For
Human Immunodeficiency Virus Type 1 DNA. J Clin Microiol, 37:350-353.
83. Latif AS. HIV Infection and sexually transmitted infections in southern Africa. Annals of the ACTM 2002;3:4-13.
option. The following preventive measures may be useful and are mostly
directed at reducing contact with sandflies: stay in tight buildings, where
possible; spray out the accommodation area; permethrin impregnated
clothing to cover as much of the body as possible; diethyl methyltoluamide (or DEET) repellents; control of vermin and stray animals; and
fine mesh bed net soaked in permethrin. Sandflies are most active from
dusk to dawn.2
leishmaniasis: a re-emerging
problem for travellers
Professor Peter A Leggat, MD, PhD, DrPH, FAFPHM, FACTM, FFTM
(Annals of the ACTM, 2007; 8,2:49)
Leishmaniasis is caused by a protozoan parasite transmitted by the bite of
infected female phlebotomine sandflies. There are several different forms,
but the most common is cutaneous leishmaniasis (CL). CL is increasing
being reported in travellers as they venture into endemic areas,1 in about
90 countries.2 Adventure travellers, humanitarian aid workers, military
personnel and long term travellers amy be particularly at risk.2
CL presents with skin sores, usually one or more chronic skin lesions
where sandflies have fed. It has been coined the “Baghdad boil” reflecting
the areas of operation where it is currently being encountered, including
southwest and central Asia,3 although the leishmaniasis is widely
distributed in other locations around India, the Mediterranean basin,
central Africa and South America. Skin lesions usually develop within a
few weeks of being bitten and are unresponsive to antibiotics or steroids.
Lesions commence as a papule then often enlarge and then ulcerate. They
can be painless or painful, especially if secondarily infected. The peak
sandfly period is April to November, peaking in September/October.
Diagnosis of CL is normally through a biopsy or skin scraping. Treatment
is available, including sodium stibogluconate,2,4 but prevention is the best
Other forms of leishmaniasis include the potentially disfiguring
mucocutaneous or mucosal leishmaniasis and diffuse cutaneous
leishmaniasis, primarily found in tropical South America, as well as visceral
leishmaniasis (VL). Leishmaniases are regarded as a fairly heterogenous
collection of clinical diseases caused by many different species of
Leishmania, each with its own unique properties, including a fairly specific
geographical location.1 VL is the most serious form of leishmaniasis and
affects some of the body’s internal organs, most commonly the spleen,
liver and bone marrow. It usually takes several months to years develop
and may present with fever, weight loss hepatomegaly and significant
splenomegaly.2 VL is not common in travellers,2 but it has been reported
amongst soldiers deployed to Iraq and Afghanistan.5 Severe cases of VL
are typically fatal, if untreated.2
Leishmaniasis should be considered in those travelling to and returning
from endemic areas. Further information is available from the Centres
for Disease Control and Prevention.2
Magill AJ. Cutaneous Leishmaniasis in the returning traveler. Infect Dis Clin N Am 2005; 19: 241-266.
Centres for Disease Control and Prevention. Prevention of Specific Diseases (Ch 4): Leishmaniasis. In CDC Health
Information for International Travel 2008. URL: http://wwwn.cdc.gov/travel/yellowBookCh4-Leishmaniasis.aspx
(accessed 4 December 2007)
Anonymous. Update: Cutaneous leishmaniasis in U.S. military personnel-Southwest/Central Asia, 2002-2004.
MMWR 2004; 53(12): 264-265.
Minodier P, Parola P. Cutaneous leishmaniasis treatment. Travel Med Inf Dis 2007; 5: 150-158.
Myles O, Wortmann GW, Cummings JF, Barthel RV, Patel S, Crum-Cianflone NF, Negin NS, Weina PJ, Ockenhouse
CF, Joyce DJ, Magill AJ, Aronson NE, Gasser RA. Visceral leishmaniasis: clinical observations in 4 US army soldiers
deployed to Afghanistan or Iraq, 2002-2004. Arch Intern Med 2007; 167: 1899-1901.
Submitted Review:
The Development of Tropical Occupational
Medicine in Australia: Anton Breinl, Weil’s
Disease and the AITM
Associate Professor Derek R Smith, BSc, BEd, MHSc, MPH, PhD, DrMedSc, FACTM, FRIPH,
CPMSIA, CPE and Professor Peter A Leggat, MD, PhD, DrPH, FAFPHM, FACTM, FFTM ACTM,
(Annals of the ACTM, 2007; 8,2:50-52)
Associate Professor DR Smith
Professor PA Leggat
Associate Professor DR Smith, BSc, BEd, MHSc,
International Centre for Research Promotion and
Informatics, National Institute of Occupational
Safety and Health, Kawasaki, JAPAN; and
Anton Breinl Centre for Public Health
and Tropical Medicine
James Cook University
Townsville Qld Australia
Email [email protected]
Professor PA Leggat, MD, PhD, DrPH, FAFPHM,
Anton Breinl Centre for Public Health
and Tropical Medicine
James Cook University
Townsville Qld Australia
Email [email protected]
Practicing occupational medicine in the topics is well-known to incur numerous challenges, as
one deals with the health care of productive, working adults on a daily basis.1 Some of the earliest
tropical occupational medicine was practiced in ancient Egypt, where workers in regular contact
with water were known to suffer from a disease that is now believed to have been schistosomiasis.2
Many years after this, the colonization of early Australian society also brought with it numerous
hazards, as immigrants attempted to adapt predominately British culture and traditions to a new
and harsh environment.3 Aside from the inherent difficulties faced during convict life, additional
hardships arose from the fact that around 40% of the new country lay in the tropics, with much of
the remainder being essentially subtropical.4 Environmental conditions undoubtedly compounded
the misery felt by early convicts and their guards, leading to sunstroke, dehydration and other
tropical maladies, as a large proportion of all labor for the new settlement was originally performed
Although workplace ‘records’ for this period are scant, it can be assumed that numerous unofficial
‘hazard management’ and ‘harm reduction’ strategies were undoubtedly employed by early convicts
in order to simply stay alive. Not all were successful in doing so however. Diarrhea and dysentery
reportedly accounted for 15% of all mortalities in Port Arthur between 1830 and 1835, while at
Macquarie Harbor, around 14% were murdered by their colleagues.5 Partly as a response, one of
the earliest occupational and public health successes, and one which appears to have reduced
the crude mortality rate somewhat, was a reduction in dysentery in the early 19th century, due
to the adoption of basic hygiene measures.3 Some of the earliest occupational medicine research
was conducted in the early 20th century, with tuberculosis and lead poisoning outbreaks being
investigated among mine workers between 1907 and 1909,6 and pneumoconiosis between 1919
and 1921.7 The medical profession was similarly being expanded, and by 1925, there were eight
full-time and approximately 30 part-time occupational physicians in the country, working in a
range of industries.6
Slightly before this time in 1909, a young Viennese physician named Anton Breinl was offered
a position as foundation director of the Australian Institute of Tropical Medicine (AITM).8 Political
motivation to form the AITM had arisen by the turn of the century, as there remained lingering
doubts in colonial Australia as to whether tropical regions could be successfully colonized by what
was termed a ‘working white race’.4 Although much of Breinl’s work would be dedicated to finding
this out, he began in less than auspicious surroundings. Breinl arrived on 1 January 1910 to take
up his new post in a tin roofed, converted wardsman’s quarters beside the Townsville hospital.9
Eager from the start, Breinl began conducting important medical surveys in the Northern Territory
during 1911, and later in New Guinea between 1912 and 1913.8 Partly as a result of post-war
intolerances and partly due to conflicts with certain management figures, Breinl quietly resigned
in October 1920 and moved into general practice in Townsville,10 where he would remain until
just before his death in June 1944.11
Aside from these ongoing developments in tropical medicine, the 1900s in Australia was also a
seminal period in the evolution of occupational medicine, as increasing
community and scientific interest was being directed towards improving
the health of people at work.12 A pivotal moment for occupational medicine
in the tropics was an outbreak of Weil’s disease among Queensland cane
cutters between 1933 and 1934, when the incidence rate rose to 18%.13
The cause of these outbreaks, exposure to Leptospira from the urine of
rats and field mice inhabiting cane fields, would later be demonstrated
by laboratory and epidemiological research.14 Although clinical cases
had subsided by the end of the decade, Weil’s disease would become
the catalyst for ongoing political conflict between the government, the
Communist Party and the Australian Workers Union. It would also rekindle
an active political interest in tropical diseases of the north, which had
otherwise fallen into neglect by 1930, when the AITM was transferred
to the University of Sydney.10
1974.17 Over 300 years after the Italian physician Ramazzini first added
a simple, yet pivotal question to Hippocrates’ clinical interrogation (What
work do you do?),18 the discipline of occupational medicine is now
entrenched in contemporary Australian society, and continues to make
important progress in the quest for safer and healthier work practices.
Figure 2: The AITM in Townsville Shortly After Its Construction
Figure 1: Anton Breinl (1880-1944)
(Photo courtesy of James Cook University)
Australian postgraduate training in tropical medicine preceded
occupational medicine somewhat, with the first Diploma of Tropical
Medicine and Hygiene (DTM&H) students graduating in 1926, and the
qualification having been more or less continually offered since that
time.19 The discipline nevertheless hibernated somewhat after the 1930s,
until the late 1980s and early 1990s, when many academic training
programs in tropical health and tropical medicine were reestablished.20
Part of this renewed interest catalyzed the Australasian College of Tropical
Medicine, which was founded in Townsville, during 1991.21 Anton Breinl’s
seminal contribution to tropical medicine was finally honored in 2002
when the Department of Public Health and Tropical Medicine at James
Cook University in Townsville was renamed the Anton Breinl Centre. Until
that time the school had been located in the original AITM building, next
to the Townsville hospital.22
(Photo courtesy of James Cook University)
The AITM’s assimilation into a new School of Public Health and Tropical
Medicine was not entirely negative however, as this relocation would
later help link occupational health and tropical medicine in Australia, to
some extent. A similar situation also occurred in the northern hemisphere,
when the London School of Hygiene and Tropical Medicine was founded
in 1929, and where an occupational health unit was later created in
1956.15 Education and research would become important areas for the
British school,16 and this may have influenced the creation in 1952 of
an occupational medicine section in the New South Wales branch of the
British Medical Association.6 Either way, times were changing and the
Australian Society of Occupational Medicine was founded in 1969, with
New Zealand added to the title in 1972.7 Australian educational programs
for occupational medicine officially began at the University of Sydney in
In reflection, it can be surmised that the two seemingly disparate fields
of Australian occupational health and tropical medicine, have in fact,
been fairly closely linked from a historical perspective. Although he has
often been lauded as a pioneering figure in tropical medicine, Anton
Breinl’s contribution to tropical occupational medicine has been generally
overlooked, even though his original mandate was to establish if a ‘white
race’ could successfully live and work in the tropics,3,23 an issue also
described by Cilento.24 Unfortunately, Breinl never lived to see the postwar
evolution of both occupational and tropical medicine in Australia, having
died from renal failure during the second last year of World War Two.
As we enter the twentieth century, tropical medicine, is flourishing in
contemporary society, and the country now has an increasingly important
role to play in training and research for this field in the Asia-Pacific
region.25 Given its colorful and sometimes turbulent history, it remains to
be seen what the next 100 years of both disciplines will bring.
For readers with a particular interest in the historical development of these
fields, more detailed reviews on Australian occupational health, tropical
medicine and Anton Breinl have been published elsewhere by Smith et
al.,3,12,17,26 Leggat et al.19-22,25 and Douglas,4,8-10 respectively. An excellent
website listing publications from the original AITM has also been recently
created by Ben and Rick Speare, and is available at the following address:
Important Dates for Tropical Occupational Medicine in Australia
First Fleet arrives in Australia and establishes a penal colony in Sydney
Diarrhea and dysentery cause significant mortality among convicts at the
Port Arthur settlement
Lead poisoning is first investigated among mine workers in South
Anton Breinl is offered the position of director at the Australian Institute
of Tropical Medicine (AITM)
Breinl arrives to take up his new post in a wardsman’s quarters beside
the Townsville hospital
Breinl begins conducting medical surveys in the Northern Territory and
New Guinea
Breinl resigns from the AITM and moves into general practice in
Inaugural class of Diploma of Tropical Medicine and Hygiene (DTM&H)
students graduate
The London School of Hygiene and Tropical Medicine is founded in the
AITM is relocated to the School of Public Health and Tropical Medicine at
the University of Sydney
Outbreak of Weil’s disease among cane cutters in Queensland – incidence
rate reaches 18%
Death of Anton Breinl at the Royal Prince Alfred Hospital in Sydney, due
to renal failure
An occupational medicine section is formed in the NSW branch of the
British Medical Association
Australian Society of Occupational Medicine is founded
Educational programs for occupational medicine officially began at the
University of Sydney
Australasian College of Tropical Medicine (ACTM) is founded in
Department of Public Health and Tropical Medicine at JCU is renamed the
‘Anton Breinl Centre’
Hall S. Occupational medicine in the tropics. Trop Doct 1974; 4: 56-8.
Phoon WO. Recent developments in occupational health in tropical countries. Trop Dis Bull 1982; 79: 653-66.
Smith DR, Leggat PA. The historical development of occupational health in Australia. Part 1: 1788-1970. J UOEH
2004; 26: 431-41.
Douglas RA. Dr Anton Breinl and the Australian Institute of Tropical Medicine. Part 1. Med J Aust 1977; 1: 713-6.
Gandevia B. Occupation and disease in Australia since 1788. Part 1. Bulletin of the Post-Graduate Committee in
Medicine, University of Sydney 1971; 27: 157-97.
Ferguson DA. Eighty years of occupational medicine in Australia. Med J Aust 1994; 161: 35-40.
Ferguson D. Occupational medicine in Australia: The past, the present and the future. J Occup Health Saf (ANZ)
1988; 4: 481-8.
Douglas RA. 'Breinl, Anton (1880-1944), medical scientist and practitioner', In. Nairn B & Serle G (eds), Australian
Dictionary of Biography, Vol. 7, Melbourne University Press, Melbourne, 1979: 394-5.
Douglas RA. Dr Anton Breinl and the Australian Institute of Tropical Medicine. Part 2. Med J Aust 1977; 1: 74851.
Douglas RA. Dr Anton Breinl and the Australian Institute of Tropical Medicine. Part 3. Med J Aust 1977; 1: 78492.
Obituary. Anton Breinl. Aust J Sci 1944; 2: 28-9.
Smith DR, Leggat PA. The historical development of occupational health in Australia. Part 2: 1970-2000. J UOEH
2005; 27: 137-50.
Gillespie R. Epidemics and power: Weil's disease in North Queensland, 1929-39. Occas Pap Med Hist Aust 1990;
4: 59-65.
Fain S. ‘Medical Bacteriology’. In. Fenner F (ed). History of Microbiology in Australia. Canberra: Australian Society
for Microbiology, 1990: 235-263.
Schilling RS, McDonald JC. Occupational health at the London School of Hygiene & Tropical Medicine. Br J Ind
Med 1990; 47: 135-7.
Smith CE. The London School of Hygiene and Tropical Medicine. Trans R Soc Trop Med Hyg 1981; 75 (Suppl):
Smith DR, Yamagata Z. An overview of occupational health and safety in Australia. J UEOH 2002; 24: 19-25.
Davies TA. Evolution of concepts in industrial medicine. Br J Ind Med 1966; 23: 165-72.
Leggat PA, Heydon JL. Postgraduate training in tropical and travel medicine in Australasia. Travel Med Infect Dis
2003; 1: 77-9.
Leggat PA, Winkel KN. Professional organisation profile: The Australasian College of Tropical Medicine. Travel Med
Inf Dis 2005; 3: 39-41.
Leggat PA. A College of Tropical Medicine for Australasia. Med J Aust 1992; 157: 222-3.
Leggat PA. The Australasian College of Tropical Medicine: The first 15 years. Ann ACTM 2006; 7; 17-8.
Breinl A, Young WJ. Tropical Australia and it’s settlement. Med J Aust 1919; 1: 353-61.
Cilento RW. Observations of the white working population of tropical Queensland. Health 1926; Jan: 5-14.
Leggat PA. Australia's role in training and research in tropical medicine. Southeast Asian J Trop Med Public Health
1998; 29: 311-5.
Smith DR, Leggat PA. The historical development and future challenges for occupational health services in Australia.
Elsevier Science International Congress Series 2006; 1294: 69-70.
Instructions for Authors:
The format of the Annals of the ACTM will, in general, follow the guidelines “Uniform
requirements for manuscripts submitted to biomedical journals” and published by the
International Committee of Medical Journal Editors (http://www.icmje.org/index.html).
The Annals will appear twice a year and will consider for publication, papers on a wide range of
topics relating to tropical and travel medicine. All papers will be refereed prior to acceptance for
Papers will be included in one of the following categories:
a) Invited/submitted reviews (5,000–10,000 words).
b) Submitted research papers (up to 5,000 words).
c) Case reports (1,000–2,000 words).
d) Research reports (1,000–2,000 words).
Figures to be included: 1/4 page size = 250 words; 1/2 page size = 500 words etc. One page with
image – 900 words; two pages with image –1,800 words etc.
Manuscripts should be double spaced and a short summary should be included at the beginning
of the paper after the title and author details.
Title page with contributor names and addresses should be on a separate page.
Each table and figure should be on a separate page together with appropriate caption, explanatory
notes etc. Any acknowledgements should be included at the end of the paper before the
Where appropriate, authors must confirm in the paper that experimental procedures on humans
and animals conformed to accepted international ethical guidelines.
References should be numbered consecutively in order of appearance in the text. For details of
references, consult “Uniform requirements for manuscripts submitted to biomedical journals” at
In the first instance, papers submitted for consideration should be sent to:
The Editor – Emeritus Professor JM Goldsmid
Discipline of Pathology
University of Tasmania
GPO Box 252-29
Hobart Tas 7001
Email: [email protected]
Fax + 61 (0)3 6226 4833
Final copy text files should be sent to [email protected] as an attachment (Microsoft
Word) or provided on CD or Floppy. If photographs to be included need to be scanned, they can be
posted to: Attention: Jillian Custance, ACTM Secretariat, PO Box 123, Red Hill Qld 4059, Australia. These will be returned to the author if so requested.
Statements or opinions in papers published in the Annals of the ACTM are solely those of the
authors and not necessarily those of the Editorial Board or The Australasian College of Tropical
Medicine. The inclusion of commercial advertising material in the Annals of the ACTM does not
constitute a guarantee or endorsement of the product on the part of the Annals or the College. The
College disclaims any responsibility for any injury to persons or property resulting from published
material or products referred to in articles or advertisements.
On acceptance of an article for publication in the Annals, copyright of the article is automatically
transferred to the ACTM.
© Copyright 2007 The Australasian College of Tropical Medicine
Related flashcards
Viral diseases

35 Cards

Create flashcards